Oncology Flashcards
1
Q
Cancer mutations: germline vs somatic mutations
A
Germline = mutations at conception
- Inherited from parents as mutation present in parent’s germ cells OR
- De novo - acquired during mieosis, conception or very early embryonic development
- Cancer predisposition come from germline mutations
Somatic = mutations acquired after conception in a subset of cells
2
Q
Solid tumours that can invade bone marrow
A
Paediatric small round blue cell tumours can invade marrow to cause bone marrow failure
- Ewings sarcoma
- Anaplastic hepatoblastoma (not foetal or embryonal subtypes)
- Medulloblastoma
- Neuroblastoma
- Alveolar rhabdomyosarcoma
- Retinoblastoma
- Wilm’s tumour
3
Q
Genetics associated with Wilm’s tumour
A
Hereditable disorders (germline/hereditary genetic mutations):
- WAGR syndrome: WT1 deletion (11p13)
- Denys-Drash syndrome: WT1 missense mutation (11p13)
- Beckwith Wiedeman syndrome: 11p15 (imprinting defect)
- Familial forms: FWT1 (17q12-q21) and FWT2 (19q13)
- Worse prognostic indicator: loss of heterozygosity at 1p and 16q
4
Q
Treatment of Wilm’s tumour
A
Stage 1: nephrectomy only if tumour wt <550g and <2yo
Stage 1 or 2: nephrectomy with chemotherapy - vincristine and dactinomycin for 18 weeks
Stage 3 or 4: nephrectomy with chemotherapy - vinc, dact, doxorubicin for 24wks, radiation to abdopelvis/lungs if mets
Stage 5: aggressive chemotherapy, partial nephrectomy or bilat nephrectomy, 1-2yrs of bridging dialysis with consideration of transplant if in remission
If anaplastic histology: intensive CTX and radiation - V and doxo, cyclophosphamide, ifosfamide, etoposide and carboplatin
5
Q
Risk factors for osteosarcoma
A
- Cancer predisposition: Li Fraumeni syndrome (TP53 germline mutation), hereditary retinoblastoma
- Previous radiation therapy
- Benign conditions: paget dz, enochondromatosis, fibrous dysplasia, hereditary exostoses
6
Q
Major differences between osteosarcoma and Ewing sarcoma
A
OS:
- Primary = bone only
- Metaphyseal distribution of long bones e.g. prox humerus, knee
- Pathological #
- XR: mixed lytic/blastic appearance, sclerotic, sunburst appearance
- Tx: no radiation
ES:
- Primary = bone AND/OR soft tissue
- Diaphyseal distribution including flat bones (e.g. pelvis, ribs)
- Systemically unwell, fevers, anorexia, anaemia
- Metastasis: lung, bone, MARROW (therefore, work up includes bone marrow aspirate)
- XR: lytic lesions, onion skinning (local periosteal rxn)
- Tx: radiation
7
Q
Genetics in Ewing sarcoma
A
t(11:22) is 90% diagnostic - ESWR1:FLI1
Remainder can have t(21:22)
ESWR1 = 22q11
8
Q
Genetics in rhabdomyosarcoma
A
Alveolar:
- Worse prognosis, if metastatic disease - incurable –> palliative chemotherapy
- t(1:13) or t(2:13) = PAX-FKHR
9
Q
Clinical manifestations of rhabdomyosarcoma
A
Most common sites of involvement:
- Head and neck esp orbit (favourable), parameningeal sites (unfavourable) such as nasopharynx
- Orbit: proptosis, ophthalmoplegia - Genitourinary tract: pelvic mass or urinary retention
- Bladder or prostate involvement is unfavourable; female genitalia or paratesticular are favourable - Extremity (unfavourable) and truncal tumours
10
Q
Risk stratification for rhabdomyosarcoma
A
- Histology: alveolar vs embryonal
- Initially given a stage, then assigned a “surgical” group
Stage depends on: site (favourable vs unfavourable), size, local invasiveness (T1 - confined, T2 - extension/fixative to surrounds), LN involvement, metastases
Group is assigned after resection: - Group 1: complete resection; Group 2: microscopic residual disease; Group 3: gross residual disease; Group 4: distant mets
Good prognosis (80-90%): stage 1 pre-op and group I/II/III post-op, embryonal histology
11
Q
Genetics in rhabdoid kidney or brain tumour (ATRT)
A
Loss INI1 = SMARCB1 - germline mutation 35%
Poor prognosis
12
Q
Li Fraumeni Syndrome
A
TP53 germline mutation
- Germline loss of TP53, autosomal dominant predisposition to solid tumours and leukaemia
- Screening exam, bloods, whole body MRI, USS etc required
13
Q
Genetics in neuroblastoma
A
Bad prognostic indicators:
- MYCN amplification (>8-200 copies)
- 11q aberrations or LOH 1p
Others: ALK mutation, PHOX2 (if breathing problem)
14
Q
Risk stratification in neuroblastoma
A
Risk is based on combination of both:
- Clinical features
- Worse: >18mths (embryonal cancers easier to treat in younger pts), large unresectable tumours, metastatic disease - Histological features
- Worse: MYCN amplification, 11q deletion
15
Q
High risk neuroblastoma
A
- Highly malignant and aggressive
- ~70% survival (long term survival 25-35%)
- MYCN amplification: intensive chemotherapy for 13-18mths regardless of local vs metastatic dz
- Tx: intense high dose CTX, autologous stem cell rescue, surgery, radiation, MIGB radioactive isotope, immune therapy with Ch 14.18, retinoic acid for differentiation therapy
16
Q
Intermiediate risk neuroblastoma
A
- Local (in older pts) or metastatic (<18mth of age)
- 95% survival
- 2-8 cycles of moderate intensity chemotherapy and surgery
- No transplant, no immune therapy, rarely require radiation
17
Q
Low risk neuroblastoma
A
- Localised disease in young pts
- 97-99% survival
- Small tumours in infants usually resolve spontaneously
- Larger ones are cured with resection, do not require chemotherapy
18
Q
Neuroblastoma 4S disease
A
a. k.a. MS = Metastatic Special - can remit spontaneously or kill rapidly
- Age <12mths
- Adrenal mass and metastases limited to liver, skin nodules (multiple subcut blueberry nodules) and bone marrow (<10%; does not involve cortex)
- 2 possible outcomes: spontaneous resolution (highest rate of any cancer) OR can rapidly grow –> expanding liver, respiratory embarrassment, subsequent death
- Tx: usually supportive cares, but if massive liver involvement - small dose cyclophos +/- hepatic radiation
- Survival >90%; 81% if treatment required
19
Q
Klinefelters is associated with which malignancy?
A
Increased risk of mediastinal germ cell tumours and breast cancer
20
Q
HSCT for solid tumours
A
Only autologous stem cell transplant is used in solid tumours as there is no graft vs disease (only relevant in leukemia and lymphoma), therefore risks associated with allogeneic HSCT are not worth it.
Autologous stem cell rescue is considered for HR-neuroblastoma, metastatic or large volume Ewing sarcoma and/or refractory Wilms tumour
21
Q
Beckwith Wiedemann Syndrome
- Common cancers
- Surveillance
A
5-10% get cancer
- Wilms tumour
- Hepatoblastoma
- Adrenocortical carcinoma
- Neuroblastoma
- Rhabdomyosarcoma
- AFP 3mthly for 4yrs
- Abdo USS 3mthly until 8yrs of age
22
Q
Li Fraumeni Syndrome
- Common cancers
- Surveillance
A
TP3 mutations
- Osteosarcoma age <30yrs - 3-10%
- Rhabdomyosarcoma in age <5yrs
- ALL hypodiploid
- Hepatoblastoma
- Medulloblastoma
Child has increased risk of second cancer
Surveillance for relations:
- Genetic testing for parents and siblings +/- whole body MRIs
23
Q
PTEN Syndrome
- Common cancers
- Surveillance
A
PTEN Harmatoma Tumour Syndrome
- Macrocephaly, autism/ID, skin lesions, lipomas, AVMs
- Thyroid, breast and endometrial cancer
- Colon cancer
- Melanoma
- RCC
Surveillance:
- Thyroid Ca - start at 10-12yrs
- Breast and colon - start at 25yo
24
Q
Rhaboid tumour syndrome
- Common cancers
A
Mutations in SMARCB1/INI1 gene
Atypical teratoid/rhabdoid tumours
- ATRT in CNS
- Malignant rhaboid tumours - renal and extra-renal
- Incomplete penetrance, most tumours occur <5yo
- 35% have germline mutation
No standard surveillance guidelines
25
Risk factors for hepatoblastoma
```
Prematurity/LBW (<1000g)
Beckwith Wiedemann Syndrome
FAP
Li Fraumeni Syndrome
Trisomy 18
Neurofibromatosis type 1
Ataxia-telangiectasia
Fanconi anaemia
Tuberous sclerosis
```
26
RB1 gene
Chromosome 13q14
Tumour suppressor gene: controls cell cycle by restricting cell's ability to progress from G1 to S phase
Germline RB1 mutations can lead to development of other malignancies e.g. osteosarcoma, soft tissue sarcoma, breast cancers
27
RB1 gene
Chromosome 13q14
Tumour suppressor gene: controls cell cycle by restricting cell's ability to progress from G1 to S phase
Germline RB1 mutations can lead to development of other malignancies e.g. osteosarcoma, soft tissue sarcoma, breast cancers
28
Role of corticosteroids in CNS tumours
Pre-operative steroids are given to reduce both intracranial pressure and tumour oedema
Tapered slowly post-operatively
29
Chemotherapy agents that cross the blood brain barrier
Lomustine (nitrosurea; alkylating agent)
Vincristine (vinca alkyloid; antimicrotubules)
Cisplatin (platinum; alkylating agent)
Cyclophosphamide (nitrogen mustard; alkylating agent)
Etoposide (topoisomerase II inhibitor)
30
ATRT
Highly malignant grade IV tumour that can be found most commonly in brain, spine or abdomen
Disseminated disease in 20%
INFANTS (<3yo)
Genetics: Biallelic inactivation of SMARCB1, INI1 loss (chrom 22q11.2)
Imaging: tumours are large, rapidly growing, cystic areas and calcifications
Poor prognosis: GTR associated with longer median survival of 12.5mths
31
T cell CD markers
CD1a, CD2, CD3, CD4, CD5, CD7, CD8
32
B cell CD markers
CD10, CD19, CD20, CD22, CD 79a
33
Myeloid cell CD markers
CD15, CD33, myeloperoxidase
34
Characteristics of a malignant lymphoblast
1. Immature
2. T or B cell differentiation
3. Abnormal intensity of CD marker expression
4. Abnormal expression of non-lymphoid cell markers
35
Immature cell CD markers (indicative of blasts on flow cytometry)
CD34, CD117, HLA-DR, TdT
36
Low risk B-ALL
1. Age: 1-10yrs
2. WBC: <50
3. Favourable cytogenetics: hyperploidy, ETV6-RUNX1 translocation
4. MRD at D8 (PB) <0.01%
MRD at D29 (BM) <0.01% - rapid response to treatment
5. No CNS2 or CNS3, no testicular involvement
- 5yr EFS >95%
37
Standard risk B-ALL
1. Age: 1-10yrs
2. WBC: <50
3. Neither favourable or unfavourable genetics
4. MRD at D8 (PB) <0.01%
MRD at D29 (BM) <0.01% - rapid response to treatment
5. No CNS3 or testicular leukemia
OR
1. Favourable genetics
2. MRD at D8 (PB) >0.01% or CNS 2 status
MRD at D29 (BM) <0.01% - rapid response to treatment
3. No CNS3 or testicular leukemia
- 5yr EFS 90-95%
38
High risk B-ALL
1. Age: >10yo
2. WBC: >50
3. Unfavourable cytogenetics: hypoploidy, Ph+, MLL rearrangements, iAMP21
4. MRD >0.01% at day 28-36 of induction
5. CNS positive leukemia
6. Testicular positive leukemia
- -> Those with HR features at start of induction with poor response to Tx (positive MRD at end of induction) are recategorised to very high risk
- 5yr EFS 88-90%
39
Very high risk B-ALL
1. Age: <1yo or >13yo
2. Unfavourable cytogenetics: extreme hyperploidy, MLL rearrangements, iAMP21
3. Failure to achieve remission at end of induction therapy (MRD >0.01%)
- 5yr EFS <80%
40
Predictors of outcome in relapsed ALL
1. Timing of relapse - later the better
2. Site of relapse - extramedullary, marrow, testes, CNS, mixed --> EM alone is better
3. T vs Pre-B - Pre-B is better
4. Response to relapse therapy (MRD)
5. Availability of stem cell donor
Depending on risk assignment, treatment will be CTX alone vs CTX and HSCT
41
Prognosis of relapsed ALL
1. Late relapse (>18mths off Tx) isolated extramedullary disease - 70% survival with CTX alone (if early achievement of MRD negative status)
2. Early relapse (<18mths since Dx, <6mths off Tx) - 50% with transplant
3. Very early (<18mths since Dx) - 20-30% with transplant
4. T-cell ALL - very poor 10-30%
42
What has changed the outcome of Ph+ ALL?
Addition of tyrosine kinase inhibitor (imatinib) with intensive chemotherapy regime has significantly improved outcomes
7yr EFS ~70%
43
Unfavourable cytogenetics for AML
- Monosomy 7
- Complex karyotype (3 or more aberrations, at least 1 structural aberration w/o favourable genetics or MLL)
- MLL rearrangements - t(9;11) w/ other aberrations or MLL other than t(9;11) or t(11;19)
- Monosomy 5 or del(5q)
- FLT3-ITD (chrom 13q12.2) - relapse risk proportional to allelic ratio (>0.4)
44
What type of AML is ATRA and arsenic used for?
APML
- Cellular arrest at promyelocytic stage
- PML-RARa oncoprotein blocks transcription of genes that allow differentiation of PM cells, promotes enhancement of self renewal. RARa = retinoic acid receptor alpha and PML is a nuclear regulatory protein that controls differentiation
- 30% present in DIC which can be fatal - therefore, important Dx to make
- Induction therapy with ATRA and arsenic can cure disease
- Very good prognosis if pt survives induction
45
Prognosis of AML
Reasonable - depends on risk group
| Overall survival 60-70%
46
Favourable cytogenetics for AML
- t(8;21)(22q:22q) = AML1-ETO
- t(15;17)(q22:q21) = PML-RARa
- NPM1 mutation
- CEBPA
- Inversion of chromosome 16
47
t(12;21)
ETV6-RUNX1
| - Favourable, ALL
48
t(4;11)
MLL rearragement
- Others include t(9;11), t(11;19)
- Unfavourable, ALL
49
t(9;22)
BCR-ABL = Philadelphia chromosome
- Novel tyrosine kinase
- Unfavourable, ALL
50
t(15;17)(q22;q21)
PML-RARa
- Oncoprotein in APML
- Favourable (if survive induction)
51
t(8;21)(22q;22q)
AML1-ETO
| - Favourable AML
52
Syndromes associated with an increased risk of ALL
```
Down syndrome
Ataxia-telangiectasia
Bloom syndrome
Fanconi anaemia
Neurofibromatosis
```
53
Malignancies at higher risk of tumour lysis syndrome
AML with hyperleukocytosis
Burkitt lymphoma
T-cell ALL
54
Chemotherapy used for ALL treatment
1. Induction: corticosteroids, vincristine, asparaginase, weekly daunorubicin (higher risk)
2. Consolidation: Cytarabine, anthracyclines, methotrexate, cyclophosphamide, etoposide
3. Maintenance: 6-mercaptopurine and weekly methotrexate. Intermittent pulses of vincristine and glucocorticoids
4. CNS prevention: intrathecal methotrexate (single agent) or IT MTX, Ara-C, hydrocortisone (triple therapy)
55
Chemotherapy used for AML treatment
Cytarabine backbone +/- anthracyclines, etoposide
| APML: ATRA and arsenic
56
Definition of "complete remission" in ALL
On morphological assessment, <5% lymphoblast population in bone marrow with haematological count recovery
However, now there is conflict re: definition of complete remission, as MRD is the strongest predictor of outcomes and have more robust measuring techniques compared to morphology and can overcome its limitations. No definite cut-offs available as there is discordance between values for remission by MRD and morphology.
From UKALL 2003 study: pts with morphological remission (<5% with count recovery), but high MRD had an inferior outcome.
57
Syndromes/conditions associated with a higher risk of Non-Hodgkin Lymphoma
Ataxia-telangiectasia
Wiskott-Aldrich syndrome
HIV
Other immunosuppression disease
58
Cytogenetics for Burkitt's lymphoma (NHL)
Burkitt's lymphoma:
- t(8;14) translocation (90%) or t(2;8), t(8;22) (10%)
- 13q deletion or complex karyotype = poor prognosis
Immunophenotype: positive for CD19, CD20, CD22
59
Cytogenetics for T cell lymphoblastic lymphoma (NHL)
Same as T-ALL
Breakpoints at 14q11.2 involving T cell receptor
t(5;14)
60
Cytogenetics for anaplastic large cell lymphoma
t(2;5)
| Immunophenotype: CD30
61
Cytogenetics for diffuse large B-cell lymphoma
t(8;14), complex or aneuploid karyotype
| Immunophenotype: positive for CD19, CD20, CD22
62
Non-Hodgkin Lymphoma presentation
- Burkitt's: arises from mature B cells in Peyer's patches in GIT (MC: ileocaecal junction) --> abdominal pain, N/V, abdominal mass; jaw involvement common in Africa. Tumour lysis at presentation very common
- LBL: biologically indistinguishable cells from ALL, 80% T cell origin --> mediastinal mass with resp distress, nontender cervical/supraclavicular/axillary LNs, liver/spleen/kidney involvement. B cell origin - skin, bone
- Large cell lymphomas: cells with large nuclei, mainfest anywhere e.g. GIT (like BL), mediastinal mass (like LBL) or unusual sites e.g. skin, bone, lung. CNS and BM spread rare
63
EBV and NHL
EBV DNA is present in tumour cells of 95% of endemic cases of Burkitt's in Africa, much less in developed countries
64
Epratuzumab
Anti-CD22 antibody
| - CD22 expressed in B cells across wide range of maturity
65
Blinatumomab
BiTE molecule = bispecific T cell engager
Specifically constructed with anti-CD19 Ab and anti-CD3 Ab --> binds CD19 positive B cells at one end and T cells at the other to cause T cell mediated lysis of leukemic B cells
Very promising results in early phase studies - 33% remission induction as monotherapy in multiply relapsing/refractory pts with B-ALL
66
Blinatumomab (BiTE molecule) side effects
Common: nausea, diarrhoea, hypokalemia
Serious:
- Cytokine release syndrome: widespread immune activation (like HLH) with fever, hypotension, capillary leak
--> Steroids given as first line therapy
--> Anti-IL6 therapy also effective (tocilizumab)
--> Severity of reaction is proportional to leukemic burden; used during consolidation therapy
- Neurotoxicity
67
CART Therapy
| Chimeric antigen receptor T cells
- Autologous T cells are genetically encoded to recognise tumour cell Ag (CD19) in host. It is infused back into pt to mediate cytotoxic T cell effects on tumour cells
- Indications: B-ALL (CD19+)
- Benefits: autologous cells --> minimal rejection, persists in circulation, capable of penetrating CSF
- Outcomes: remission in 5070% of relapsed/refractory B-ALLs (highly effective)
- Toxicity: cytokine release syndrome, ongoing depletion of B cell compartments (requiring Ig replacement)
68
Causes of primary HLH
- Famililal HLH: autosomal recessive monogenic mutations; cytotoxic defect due to mutations in perforin, MUNC, XIAP, SAP, lytic granule secretion etc
- -> Broadly, degranulation defects and signalling defects in NK cells and cytotoxic T cells
- -> Leads to lack of target cell kill --> uncontrolled, persistent activation of lymphocytes that dump cytokines --> loss of feedback inhibition on macrophages --> excessive activation of macrophages and cytokine storm
69
Genes implicated in primary HLH
PRF1, UNC13D, STX11, STXBP2
70
Causes of secondary HLH
- Primary immune deficiency disorders
- -> Griscelli syndrome (RAB27A)
- -> Chediak-Higashi syndrome (LYST)
- -> Hermansky-Pudlak 2 (Ap3B1) - oculocutaneous albinism, platelet abN
- -> X-linked lymphoproliferative disease (SH2D1A, XIAP)
- Rheumatological disorders
- -> JIA, Kawasaki disease, SLE
- Infections
- Malignancy
71
Infective agents causing HLH
1. Viral: EBV!!!, CMV, parvovirus, HSV (esp neonates), VZV, parechovirus, measles, HHV-6, HHV-8, H1N1 influenza, Dengue, HIV
2. Bacteria: Brucellosis, Mycobacterium tuberculosis
3. Fungal: histoplasma capsulatum
4. Parasitic infections: malaria, leishmania
72
HLH Diagnosis
If 1 or 2 are fullfilled:
1. Molecular diagnosis consistent with HLH OR
2. Diagnostic criteria for HLH are fulfilled - 5 out of 8 of...
1. Fever
2. Splenomegaly
3. Cytopenias affecting 2 or more lineages in peripheral blood
- Commonly, transfusion dependent anaemia and thrombocytopenia
4. Hypertriglyceridemia and/or hypofibrinogenemia
(fasting triG >3mmol/L, fibrinogen <1.5g/L)
5. Haemophagocytosis seen on BM, spleen or LN Bx
6. Low or absent NK cell activity
7. Ferritin >500
8. Soluble CD25 (sIL2 receptor) >2400
73
Common features of HLH
Relevant FHx: consanguinity
Features:
- Hepatosplenomegaly (95%), fever (93%), LAD, neurological Sx, rash
- Ferritin >10000 - 96% specific and 90% sensitive
- Evolving cytopenias - transfusion dependent Hb, Plt
- Multi-organ involvement (liver, kidneys, CNS)
- High triglycerides, low fibrinogen (liver consumption)
- Rising CRP, low ESR (due to reduced fibrinogen)
74
Management of HLH
1. Blood product replacement
- Induction of amenorrhea recommended in girls
2. Identify and treat the trigger e.g. infection, Dx malignancy
3. Chemotherapy +/- rescue HSCT if persistent, recurring or primary HLH
- Etoposide, cyclosporine A, corticosteroids
- IT MTX if CNS involvement
- Alternate regime: steroids and anti-thymocyte globulin (ATG)
- When planning induction therapy, HLA tissue typing needs to be sent in order to allow rescue HSCT if needed
75
Prognosis of HLH
Survival has dramatically improved with treatment protocols, but still poor
- Overall survival at 3yrs = 55% (51% in familial)
- 3yr probability of survival at 3yrs post-HSCT = 62%
76
High resolution typing in HSCT has caused reductions in what?
Reduced rates of GVHD
Reduced transplant-related mortality
*High resolution typing: development of oligonucleotide probes to specific HLA subtypes = allows allelic identification
77
What stimulates excess haematopoietic stem cells to be produced by the body?
1. Physiologically in umbilical cord blood
2. During bone marrow regeneration after myeloablative/myelosuppressive chemotherapy
3. Following G-CSF stimulation
78
HSC Harvesting: Cord blood
| - Engraftment risk
```
Advantages:
- Risk free collection
- Less requirement for HLA matching
- Low incidence of GVHD
- Rapid availability
Disadvantages:
- Low dose available
- Slow engraftment
- No possibility of donor lymphocyte infusion
```
79
HSC Harvesting: Bone marrow
| - Donor risk, GVHD risk
Advantages: Best option
- Moderately brisk engraftment
- Moderate risk of GVHD
- DLI available
Disadvantages:
- Increased risk associated with collection
- Contains all marrow cells including RBCs
80
HSC Harvesting: Peripheral blood
| - GVHD risk
```
Advantages:
- Rapid engraftment
- Low risk during collection
- Only CD34+ stem cells collected
- Availability of DLI
Disadvantages:
- Increased rates of GVHD esp chronic GVHD
- Not a practical procedure on small pt
```
81
Preference for allogeneic stem cell source
1. Matched sibling donor - marrow
- Matched sibling donor - PBSC
2. Matched unrelated donor - marrow
3. Matched unrelated donor - cord
4. Mismatched family donor (haploidentical) - marrow
5. Matched unrelated donor - PBSC
6. Mismatched unrelated donor - cord > BM > PBSC
82
When is cord blood more advantageous for HSCT?
Metabolic syndromes
| - "More enzymes" in cord cells
83
What do you need to consider for non-malignant indications of HSCT?
1. Non-malignant transplants are at greater risk of graft failure --> cord blood may increase risk (slow engraftment, low dose)
- Cancer pts: more exposure to CTX, marrow "more tired",
2. Non-malignant conditions do not benefit from graft vs leukemic effect (GVHD) --> consider transplant to minimise risk i.e. not PBSC
84
Hepatic Sinusoidal Occlusion Syndrome
- Complication after myeloablative stem cell transplant
- CTX-mediated sinusoidal endothlelial damage --> sinusoidal occlusion, hepatocyte necrosis and hepatic fibrosis --> ultimately, reversal of portal flow
- Onset within 30 days of HSCT
- Classic triad of weight gain, painful hepatomegaly and jaundice
- Other features: consumptive thrombocytopenia
85
Management of Hepatic SOS
1. Fluid restriction
2. Electrolyte replacement
3. Defibrotide therapy
- Single stranded polydoxyribonucleotide
- Antithrombotic, anti-ischaemic, anti-inflammatory activity without compromising antitumour effects of cytotoxic therapy
4. Prophylaxis for SOS: ursodeoxycholic acid
86
Risk factors for acute GVHD (7)
1. HLA disparity
2. Donor and recipient gender disparity
3. Alloimmunisation of donor (e.g. multip woman)
4. Increasing age of host
5. Graft type (PBSC highest risk > BM > cord)
6. Conditioning regimen
7. CMV status
87
Risk factors for chronic GVHD (5)
1. Higher degree of HLA disparity
2. Previous acute GVHD
3. Older age of donor or recipient
4. Total body irradiation containing regimen
5. CMV seropositivity
88
Post-transplant lymphoproliferative disease
- Uncontrolled EBV-infected lymphoblast proliferation occurring following solid organ or stem cell transplantation
- B cell > T or NK cells
- Spectrum of disease: mild glandular-like fever illness to lymphoma (diffuse large B cell lymphoma)
89
Risk factors for post-transplant lymphoproliferative disease
- Paediatric > adult pts
- T cell depleted graft from partially matched/unmatched HLA donor
- EBV neg recipient receives EBV+ organ
- Heavily immunosuppressed
- Associated CMV co-infection
- Amount of lymphoid tissue transplanted - lung/liver/heart > renal
90
Name 2 viruses that are not known to be oncogenic
HHV6
| CMV
91
Tumour lysis syndrome
Metabolic derangements due to rapid, spontaneous or treatment-induced death/breakdown of tumour cells
- LDH >600 - higher chance of developing TLS
- Occurs 3 days pre- and 7 days-post commencement of treatment
Derangements and effects:
- Cell lysis: hyperkalemia --> arrhythmias
- DNA breakdown: high uric acid and phosphate --> renal failure
- High Phos binds Ca: hypocalcemia --> dysrhythmia, tetany, renal failure
- Cytokine release: multi-organ failure and haemodynamic instability
92
RF for developing tumour lysis syndrome
1. High tumour burden
- Burkitt lymphoma
- Acute leukemias with high WBC or massive hepatosplenomegaly
- Massive mediastinal masses (T cell ALL/lymphomas)
- Large solid tumours e.g. neuroblastomas
2. Sensitivity of cancer to therapy --> increases risk after starting CTX
3. Intensity of therapy
4. Pre-existing renal impairment
93
Contraindication for rasburicase (urate oxidase)
G6PD
94
Causes of spinal cord compression (oncological emergency)
```
Neuroblastoma
Primary spinal tumour
Ewing sarcoma
Osteosarcoma
Soft tissue sarcoma (e.g. rhabdo)
Lymphoma/leukemias i.e. chloromas
Metastatic CNS tumour - drop metastases, leptomeningeal spread
```
95
Anaphylaxis is most commonly associated with...
Asparaginase (L-asp, erwinia, PEG-asp)
Etoposide and tenoposide
Carboplatin in 40% of pts on low grade glioma protocol
ATG
96
Extravasation injury is most commonly associated with...
Vincristine/vinblastine
Carmustine
Dactinomycin
Anthracyclines
97
Central line associated infections
Coagulase negative staphyloccocus - unlikely to cause shock
Alpha haemolytic streptococcus (streptococcus viridans or strep mitis)
Staphylococcus aureus
98
Mucositis is most commonly associated with...
```
Methotrexate (esp high dose!!!)
Bleomycin
Dauno/doxorubicin/Idarubicin
Thioguanine
Thiotepa
Vinblastine
Mercaptopurine
5-fluorouracil
```
99
Management of mucositis
Prevention:
1. Hyperhydration
2. Folinic acid rescue (leucovorin)
3. Oral cares
4. Optimise nutrition
5. Antifungals: local/oral/IV
6. Delay chemotherapy if necessary
Treatment:
1. Analgesia (often require PCA)
2. Mouthwashes
3. IV antifungal therapy, IV antiviral therapy if HSV suspected
4. ?Keratinocyte growth factor stimulant
100
Anti-emetics in chemotherapy
```
Ondansetron: 5HT receptor antagonist
Dexamethasone: corticosteroid
Aprepitant: NK1 antagonist
Cyclizine (vestibular centre effects): antihistamine
Metoclopramide/domperidone: dopaminergic
Chlorpromazine: phenothiazine
Hyoscine bromide: anticholinergic agent
Lorazepam: BZD
```
101
Alopecia is most commonly associated with...
Anthracyclines
Nitrogen mustards
Bleomycin
Dactinomycin
102
Anthracycline-related cardiotoxicity
- >250-300mg/m2 cumulative dose
- Hypertension is predictive of congestive heart failure
- Early intervention with ACEi may modify onset (adult trials)
- Dezrazoxane - conflicting evidence, decrease acute cardiotoxicity in older children, given prior to anthracyclines
- -> ?Increased rate of second cancers
- -> ?Chemotherapy effectiveness
- -> ?Borderline increase in typhilitis (--> sepsis?)
103
Methotrexate
Antimetabolite that acts via purine metabolism pathway (S phase)
Cotrimoxazole and penicillin drugs interfere with urinary extretion of MTX
Significant third spacing - pts with pleural effusion, ascites, pericardial effusions will not excrete medication
SE: mucositis, LFT derangement, myelosuppression, CNS toxicity (intrathecal)
104
Cytarabine
Antimetabolite (pyramidine analogue)
SE: conjunctivitis (with high doses), neurotoxicity, peripheral neuropathy, cerebellar ataxia, seizures
- Low dose: fevers 12hr post-dose
105
Synergistic ototoxicity
```
Platinum compounds (cisplatin > carboplatin)
Aminoglycosides
CNS radiation (posterior fossa)
```
106
Neurological side effects: leucoencephalopathy
HD methotrexate
Radiation therapy
Intrathecal chemotherapy
MRI: white matter changes
107
High frequency hearing loss and platinum drugs
- Need for hearing aids 30%
- No recovery of hearing
- Increasing risk with cumulative doses
- Considerable individual susceptibility - SNPs and some candidate genes identified, if >3 variants, >90% chance of deafness
- -> TMPT variants, UGT1A1, GSMTM3 etc
- Otoprotection with sodium thiosulphate - studies in progress
108
Pulmonary fibrosis and chemotherapy
Bleomycin
Lomustine
Busulphan
Lung irradiation
109
Cardiotoxicity and chemotherapy
- Radiation: pericardial effusion or constrictive pericarditis, premature coronary artery disease
- Anthracycline and high dose cyclophos: dilated cardiomyopathy, can be complicated by ventricular arrhythmias
- -> Risk of cardiomyopathy is related to cumulative dose used
110
Secondary malignancies
1. Radiation exposure - AML and sarcomas
2. Etoposide exposure - AML and sarcomas
3. Platinum exposure - leukemia
4. Hodkin's lymphoma - breast cancer with mantle field radiation
5. Genetic predispositions - Li Fraumeni, RB, fanconi anaemia, Gorlin syndrome etc.
6. Cyclophosphamide
111
Male infertility
- Can collect sperm for storage after >Tanner stage 3 spermache
- Collection needs to be PRIOR to initiation of CTX or >3mths off therapy (sperm have no DNA repair mechs)
- Storage funded in NZ
112
Ovarian insufficiency
Elevated LH, FSH and low oestradiol
113
Infertility
High risk:
1. Any alkylating agents with total body/pelvic irradiation
2. Total cyclophosphamide >7.5g/m2
3. Protocols containing procarbazine - lymphoma protocols
114
Neuropsychological impairment after CNS radiation therapy
- Reduced IQ - serial loss of points if CSI <7yo; both age and dose-dependent
- Perceptual motor deficits
- Memory impairment
- Academic underachievement
- Increased need for special education at school
- Employment problems in adulthood
- Most significantly affected in younger children (<7yo), deficits worsen over time
115
Tumour markers in germ cell tumours
- Teratoma: AFP neg (<10% in immature), BHCG neg
- Germinoma: AFP neg, BHGC <10%
- Embryonal carcinoma: AFP 70%, BHCG 30%
- Yolk sac (endodermal sinus) tumour: AFP 100%, BHCG neg
- Choriocarcinoma: AFP neg, BHCG 100%
- Gonadoblastoma: oestrogen; dysgenetic gonads - 46XY or 46XY/XO karyotype, 80% have female phenotype
- Sex cord tumours:
- -> Leydig cell tumours: androgens, Sertoli cell tumours: E
116
Dexrazoxane
Cardioprotectant which can be used with anthracyclines
117
Cerebral sinovenous thrombosis can be caused by...
L-asparaginase
