WEEK 8 - parasites, viruses, poverty and cancer

Question 1

Burkitt(s) lymphoma

Answer 1

highly aggressive lymphoma
- tumour can double in size every 18-24hrs

composed of momomorphic medium-sized B-cells

Question 2

Burkitt(s) lymphoma
cell of origin

Answer 2

a germinal B cell
- express membrane IgM
- B cell markers e.g. CD19, CD20, CD22
- negative for CD5, CD23 and TdT
(allow us to diagnose)

Question 3

Burkitt(s) lymphoma
cancerous form of normal counterpart

Answer 3

Geminal centres in lymph nodes and spleen responds to the antigen and b cells proliferate really rapidly in response to antigen stimulation

Body is allowing the B lymphocytes in our lymph node to proliferate and then those which are producing antibody that is active against the antigen
- Those cells get selected to contribute to the immune reaction
The b cells that are not specific don’t get selected and die by apoptosis

Represent a cancerous form of their normal counterpart

Question 4

Burkitt(s) lymphoma
constant feature

Answer 4

translocation involving c-Myc is a constant feature

Question 5

Burkitt(s) lymphoma
translocation involving c-Myc
what do tumours show:

Answer 5

tumours show clonal rearrangements of Ig heavy or light chain genes
somatic mutations of the Ig genes are found
- supports germinal centre origin
—>(deliberate machinery to induce mutations into DNA)

Question 6

Burkitt(s) lymphoma
translocation involving c-Myc
inherited antibody sequences

Answer 6

Mixture of antibody sequences inherited from mum and dad

Question 7

Burkitt(s) lymphoma
translocation involving c-Myc
germinal cell origin?

Answer 7

The fact that these somatic mutations are present in these genes tells us that the origin of this tumour is a germinal centre cell (and not a b cell)

Question 8

Burkitt(s) lymphoma
translocation involving c-Myc
all cases have:

Answer 8

all cases have a translocation of c-Myc at band q24 from chromosme 8 to either:

• Ig heave chain region on chromosome 14 q32 [t(8;14)]
• Ig kappa light chain locus on chromosome 2p12 -t(2;8)]
• Ig lambda light chain locus on chromosome 22q11 [t(8;22)]

This is not making a fusion gene
It is translation of c-Myc near to these other loci

Question 9

Burkitt(s) lymphoma
translocation involving c-Myc
Myc becomes constitutively under the influence of

Answer 9

Ig gene promotors
- drives cells through repetitive cycles

C-Myc is a powerful gene that regulates processes like apoptosis, cell division and proliferation
Because so potent in normal cells it is regulated very tightly –> protein has short half life
- So unless cells actively making c-Myc levels fall very quickly

Question 10

Burkitt(s) lymphoma
translocation involving c-Myc
is this a fusion gene?

Answer 10

NO

Question 11

Epidemiology of Burkitt lymphoma

Answer 11

three clinical variants are recognised

sporadic
endemic
immunodeficiency related

each have differences in clinical presentation, morphology and biology

Question 12

sporadic Burkitts lymphoma overview

Answer 12

seen throughout the world
mostly in children and young adults
incidence is low (very rare)
- 1-2% of all lymphomas
- however remains 30-50% of childhood lymphomas (Although rare over represented in children)

median age in adults ~50 years in UK
males to female ratio 2-3 to 1

Question 13

sporadic Burkitts lymphoma:
what

Answer 13

breakpoint on chromosome 14 involved Ig switch region

indicates a tumour of later B-cell developement

Question 14

sporadic Burkitts lymphoma:
location in body

Answer 14

the majority present with abdominal masses
- ileo-coecal region common

ovaries, kidneys and breasts also frequently involved

breast involvement is often bilateral and extensive
- has been associated with:
–> onset of puberty
–> pregnancy
–> lactation

Something hormonal about this disease

Question 15

immunodeficiency associated burkitt’s lymphoma:
overview

Answer 15

primarily seen in association with HIV infection

often forms first manifestations of AIDs

is less common in other immunodeficiencies

lymph node involvement and bone marrow involvement more common

Question 16

endemic burkitts lymphoma:
overview

Answer 16

occurs in equatorial africa and papua new guinea

fifty times the incidence of sporadic BL in other areas of the world

most common malignancy of childhood in these regions

incidence peaks between the ages of 4 and 7

male to female ratio of 2 to 1

breakpoint on chromosome 14 involves heave chain joining region (early B-cell)

Question 17

endemic burkitts lymphoma:
location in body

Answer 17

the jaws and other facial bones are the site of presentation in ~50% of cases

other sites include:
distal ileum
coecum and/or omentum
ovaries
kidneys
breast
- these are becoming more common than the facial bone presentation
–> Seems to be a switch occurring that we are yet to understand

Question 18

endemic burkitts lymphoma:
why has extensive study not benefited patients

Answer 18

Immoral
Very little of western science has found its way back to africa to actually help the children

Question 19

endemic Burkitts lymphoma:
distribution coincident with

Answer 19

malarial belt

Representation of information that Dennis Burkitt started collecting

Question 20

endemic Burkitts lymphoma:
malaria

Answer 20

remains a huge problem in africa

leading cause of death in children under 5 years of age in Malawi
68% of infants living alongside lake malawi are infected with plasmodium falcparum by the age of 10 months
children under the age of 5 years suffer an average of 9 clinical episodes per year
many remain chronically parasitaemic year round
- This drives immunosuppression
(so perhaps commonality with the HIV related disease)

Question 21

endemic Burkitts lymphoma:
bed nets as cancer preventative medicine?

Answer 21

use of bed nets reduces mortality from malaria among children

use of insecticide treated nets is one of the main objectives for the Roll Back malaria campaign in Malawi and other malaria-endemic countries

finding raise the possibility that nets may have the potential to decrease the risk of BL in African children

In Malawi widespread distributed of nets began in 2002
- no decline in frequency of BL to be reported (But as mentioned there is a shift in how the disease is presenting)
- may reflect lower uptake in rural areas

Question 22

endemic Burkitts lymphoma:
virus

Answer 22

association with epstein barr virus

Question 23

endemic Burkitts lymphoma:
Epstein Barr Virus:
what

Answer 23

DNA herpesvirus

infections common, cause of glandular fever

not usually tumourogenic

Question 24

endemic Burkitts lymphoma association with Epstein Barr Virus:

Answer 24

is associated with endemic BL and nasopharyngeal carcinoma

in endemic BL the EBV genome can be detected in the majorty of the tumour cells (in >90%, if not all, cases)

Question 25

epstein barr virus and sporadic BL

Answer 25

positivity frequency is <30% of cases

Question 26

epstein barr virus and immunodeficiency BL

Answer 26

EBV detected in 25-40% of cases

Question 27

endemic Burkitts lymphoma association with other viruses

Answer 27

Most have EBV but others are associated with other viruses as well

CMV: cytomegalovirus
KSHV: Kaposi’s sarcoma-associated herpesvirus
HTLV1: human T-cell leukemia type 1

Question 28

endemic Burkitts lymphoma:
real association

Answer 28

previous evidence for an association between BL and malaria had been largely ecological

case contol study provides more direct evidence of an association between malaria antibodies in the child and risk of BL

comparable data has been obtained from a study in uganda

cases were more likely than controls to be HIV positive

amongst the HIV negative cases were 13 times more likely than controls to have raised levels of EBV and malaria antibodies

Question 29

endemic Burkitts lymphoma:
real association evidence

Answer 29

Highest rate of burkitt’s lymphoma when patients have antibodies to both EBV and malaria

So evidence that both of these infection are leading towards the development of the disease in some way

Question 30

endemic Burkitts lymphoma:
example of malawi

Answer 30

facilities on ward and in the hosptial are very basic
there are only 4 nurses 1 on duty at a time and no full time doctors
children’s families provide much of the care, even in hospital
the unit struggles to obtain supplies of the vital chemo drugs that they are using so effectively on BL

nevertheless, the team has devised a simple but effective treatment protocol for treating BL
- just 4 weeks of treatment can cure about 50% of children (how receive and follow the treatment)

Question 31

endemic Burkitts lymphoma example of Malawi:
treatment schedule

Answer 31

28 day treatment schedule with cyclophosphamide and intrathecal methotrexate

Got as far as they can go with the chemotherapy
E.g. have to use low grade chemo because don’t have facilities to deal with infection and low immune response that happens with chemo

Question 32

endemic Burkitts lymphoma example of Malawi:
treatment results

Answer 32

88% achieved complete clinical remission by day 28

Achieving the same as us

Inexpensive treatment on a global scale

Question 33

endemic Burkitts lymphoma example of Malawi:
treatment conclusion

Answer 33

conclusion:
this short, inexpensive treatment schedule (<50 US$) cured almost 50% of epidemic BL patients in a setting of very limited resources

Question 34

Drugs and Burkitt lymphoma (trial):

Answer 34

medroxyprogesterone acetate (MPA)
- a contraceptive pill

Bezafibrate
- lipid lowering drug

drugs that are:
- avaliable
- familiar in the clinical setting
- associated with limited toxicities

Question 35

Drugs and Burkitt lymphoma (trial):
what do the drugs do

Answer 35

medroxyprogesterone acetate (MPA) and Bezafibrate

fibrates and medroxyprogesterone acetate indice apoptosis of primary BL cells and cell lines: potential for applying old drugs to new disease

Question 36

Drugs and Burkitt lymphoma (trial):
Aim and methods

Answer 36

Clinical trial in Malawi based on clinical data:
over 5 years from feb 2007 95 children with relapsed or resistant epidemic BL were recruited to assess three doses of BaP for toxicity and anti-eVL activity

at first diagnosis these children had recieved the treatment described above
- BaP was administered daily from study entry to end of all therapy
- in 61 patients BaP was given alone for a week before starting CPM 60mg/kg orally plus vincristine 1.5mg/m^2 on days 8,18 and 28
- in 34 patients BaP and chemotherapy were started concurrently

The kids that do relapse dismal outlook
When testing always patients who are out of options get tested first

Question 37

Drugs and Burkitt lymphoma (trial):
results suggest

Answer 37

This data suggests that the drug combination has promise in these relapse refractory kids

Question 38

prof drugs trial

Answer 38

rituximab as adjunctive therapy in treatment of BL
- Rituximab really expenisve
So proposed that use chemo then a single dose of rutuximab and see If it does the trick

does not stand up to statistical analysis

however if used where it was useful had an incredibly positive outcome
- better overall survival than without