WEEK 5 FLASHCARDS

mechanisms of bacterial carcinogenesis

• chronic inflammation - leading to tissue damage

• ROS production , leading to DNA damage

• Genotoxins- eg cytolethal distending toxin, lead to mutations

• altered signalling eg in AKT, MAPK pathways.

which bacterium is linked to gastric cancer

Helicobacter pylori

what parasite is associated with Burkitt lymphoma

plasmodium falciparum- via EBV= epstein-Barr virus infection.

how do parasites cause cancer

Chronic inflammation, which activates signalling pathways like p53

ROS and DNA damage

Tissue injury and immune evasion.

tissue injury and wound healing leading to proliferation

how does malaria contribute to EBV driven Burkitt lymphoma?

Infected RBCs bind EBV infected B cells

increased AID expression, leading to DNA breaks and chromosomal translocations.

This genomic instability can lead to the production of malignant B cells.

Mechanisms of viral carcinogenesis

• Hijacking cell signalling and DNA damage response (DDR)

• inhibition of tumour suppressors like p53

• Inflammation leading to ROS and mutations

• genome integration- viral DNA integration, leading to oncogene activation

• epigenetic changes

Hallmarks induced by viruses

• avoid apoptosis

• promoting proliferation

• enable immune evasion

• induce angiogenesis

• promote genomic instability.

examples of viruses that can cause cancer

• HBV, HCV - liver cancer

• Epstein barr virus - lymphoma

• HPV - cervical cancer

what is oncolytic virotherapy

use of viruses to infect and kill tumour cells to enhance immune response.

how do anaerobic bacteria target tumours

grow in hypoxic tumours

engineered to deliver therapeutic agents

can bypass challenges faced by chemotherapy.

what immune checkpoint target is commonly overexpressed in tumours and targeted by bacterial therapy

CD47 . This blockade boosts phagocytosis and antigen presentation

which vaccines prevent cancer

• HPV

• HEP B

prevention strategies for cancer

• vaccination

• Abx for bacterial infections like h.pylori

• safe sex

• hygiene

• regular screening and self checking

why is chemotherapy often combination therapy

to target various stages of the cell cycle

phases of the cell cycle

G1- post mitotic - protein/ RNA synthesis occurs.

S- DNA synthesis

G2- pre mitotic phase- additional RNA synthesis

M- mitosis

what stage of the cell cycle does vincristine target

• M phase

what stage of the cell cycle does methotrexate act on

S phase ( DNA synthesis)

examples of side effects with chemotherapy

nausea

hair loss

immunosuppression

examples of targeted therapies

TKIs

antibody conjugates

immunotherapies

bispecific mabs

examples of immunotherapy

Bispecific T cell engagers- bring together t cells and cancer cells to enhance immune response

mAbs

immune checkpoint inhibitors - block immune evasion of cancer cells.

aim of personalised medicine approach

improve efficacy with fewer side effects.

symptoms of acute leukaemia

tiredness, fever, vulnerability to infection , weight loss , bruising.

risk factors for acute leukaemia

• age

• sex (male)

• family hx

• smoking

• comorbidities

• prev can treatment

• genetic disorders

diagnostic tests for acute leukaemias

• FBC

• Bone marrow biopsy

• general health and infections screening

• tissue typing

what is AML

Acute myeloid leukaemia - deformity in myeloid branch of the formations of blood cells.

How is AML treatment classified

intensive or non intensive treatment approaches based on the patient's health and disease characteristics.

what are the key molecular targets in AML

CD33 - targeted by antibody drug conjugates

FLT3 - Frequently mutated in AML and is associated with poor prognosis.

IDH1

the role FLT3 in AML

• cell surface protein involved in survival and proliferation

• mutation of this leads to poor prognosis.

• targeted with FLT3 inhibitors and chemotherapy.

when is a bone marrow transplant considered

adverse genetic profiles

what is APL

Acute promyelocytic leukaemia

rare subtype of AML

Involves chromosomal translocation

Risk of medical emergency bc of bleeding risk

Better progniosis if treated early.

risk of untreated APL

disseminated intravascular coagulation

treatment of APL

• tretinoin

• arsenic trioxide

• sometimes with chemo

What is ALL

Acute lymphoblastic leukaemia

cancer of lymphoid branch of blood cell formation

who is most commonly affected by ALL

children

types of ALL

B cell

T cell

what is used as CNS prophylaxis in ALL

intrathecal chemo

what genetic testing is needed before 6MP

• TPMT

• NUDT15

to determine the risk of toxicity to mercaptopurine.

when is CD-20 targeted therapy used in ALL

only b cell ALL

what is used in the treatment of Philadelphia chromosome positive ALL

TKIs

why are FLT3, IDH1 , TPMT AND NUDT15 TESTED IN LEUKAEMIA

• FLT3/ IDH1- identify targetable mutations in AML

• TPMT/ NUDT15- assess metabolism of 6MP and toxicity risk in ALL.

what novel therapies are used for relapsed ALL

• ADCs targeting CD22

• Bispecific t cell engagers- CD3 on t cell and CD19 on B cancer cells

• CAR-T therapy targeting CD19

what are the 2 main types of chronic leukaemia

• CML

• CLL

what is CML

myeloproliferative neoplasm with uncontrolled proliferation of myeloid cells

Usually slow growing

phases of CML

chronic phase

accelerated phase

blast crisis

what molecular abnormality is commonly seen in CML

• BCR-ABL fusion gene due to Philadelphia chromosome

what does BCR-ABL fusion protein do

• TK activity

• activates cell signalling pathways leading to uncontrolled myeloid cell growth.

• PI3K/AKT and RAS/MEK

first line treatment of CML

• Tyrosine kinase inhibitors (TKIs) such as imatinib, targeting BCR-ABL

what are second generation TKIs

more potent but higher side effect risk.

Nilotinib, ponatinib.

how is treatment response monitored in CML

measuring BCR-ABL transcript levels

What is CLL

Malignancy resulting from dysregulated B cell receptor signalling , leading to B cell proliferation.

subtypes of CLL

Based on IGHV status

Unmutated- worse prognosis

mutated - better

what genetic mutations predict poor prognosis in CLL

TP53 mutations

17p deletions

Sx of CLL

• Fatigue

• infections

• breathlessness

• night sweats

• bruising

First line therapies for CLL

• Targeted therapies

• Ibrutinib - TKIs

• Venetoclax- BCL-2 inhibitor

• can be used in combination.

• Anti CD20 mabs

How do BTK inhibs work

• inhibit B cell receptor signalling and promote apoptosis in malignant B cells.

side effects of BTK inhibitors

• HTN, bleeding , A fib

how do venetoclax work

BCL-2 inhibitor and restores apoptosis in malignant B cells.

risk of TLS and neutropenia

when is chemo immunotherapy used in CLL

young, fit patients with mutated IGHV

factors influencing treatment choice in CLL

• IGHV mutation status

• TP53 mutation

• 17p deletion

• age

• comorbidity

• renal function

• cardiac function

• pt preference

what is multiple myeloma

cancer of plasma cells at the end of lymphoid part of blood cell formation

Usually incurable but treatable

clinical features of multiple myeloma

bone/ back pain

fatigue

weight loss

recurring infection

breathlessness

how are immunoglobulins classified

• heavy (IgG, IgA, IgE) or light chain (kappa, lambda)

Significance of free light chains in multiple myeloma

• elevated or abnormal Kappa: lambda ratio = plasma cell dyscrasia indicates disease progression and response to treatment.

what is MGUS

monoclonal gammopathy of undetermined significance- asymptomatic and non cancerous , but increases the risk of myeloma.

what is paraproteinaemia

overproduction of monoclonal, dysfunctional immunoglobulin (paraprotein) which is detected by electrophoresis.

diagnostic tests for multiple myeloma

• FBC

• renal function

• calcium

• serum immunuglobulin

• free light chains

• electrophoresis

• bone marroe biopsy

• imaging - PET, MRI, CT

diagnostic criteria for symptomatic myeloma

> or = 10% plasma cells in marrow

AND ONE OF

• hypercalcaemia

• renal impairment

• anaemia

• lytic bone leasions

high risk biomarkers for multiple myeloma

• 60% plasma cells in bone marrow

• FLC ratio >/= 100

clinical features of multiple myeloma

• bone/ back pain

• fatigue

• recurrent infection

• fractures

• inc calcium , kidney dysfunction , anaemia

targeted treatments for multiple myeloma

immunomodulatory drugs- teratogenic, risk of thrombosis so need anticoagulation

mAbs - cell mediated cytotox , ADCs to deliver cytotoxin to myeloma cells

proteasome inhibs- inhibit protein degradation and lead to cell death.

Bispecific t cell engagers that link t cells to myeloma cells

what other drug is used in nearly all regimens for multiple myeloma

dexamethasone

factors influencing relapse treatment of multiple myeloma

• sensitivity to prior treatment

• age

• fragility

• cytogenetic risk

• pt preferece

• QoL

Always MDT decision.

what is lymphoma

cancer of lymphatic system, due to mutated lymphocytes.

how do lymphomas present

painless lump / swelling in lymph nodes

sometimes systemic symptoms

B symptoms- fever, night sweats, weight loss

types of lymphoma

• Hodgkin lymphoma

• Non Hodgkin lymphoma

subtypes of non -hodgkin lymphoma

B cell or T cell origin

High grade non Hodgkin lymphoma

• DLBCL - diffuse large B cell lymphoma = most common

• burkitt lymphoma

• lymphoblastic lymphoma

• anaplastic large cell lymphoma

low grade non hodgkin lymohoma

folicular lymphoma

marginal zone lymohoma

mantle cell lymphoma

waldenstrom’s macroglobulunaemia

small lymphocytic lymphoma

diagnostic investigations for lymphoma

examination of nodal areas

assess for B sx

performance status

imaging

FBC, biochem, viral

lymph node biopsy

CSF exam if present with neurological signs

lymphoma staging

1- 1 node group

2- >= 2 node groups on same side of diaphragm

3- nodes on both sides of diaphrag,

4- involves other organs

prognosis if diffuse large b cell lymphoma

curable if caught early

prognosis dependent on IPI score, age, comorbidity , treatment response

what is the standard treatment of DLBCL

R-CHOP

Rituxumab

cyclophosphamide

doxorubicin

vincristine

prednisolone

6 × 21d cycles

supportive treatment given alongside RCHOP

• allopurinol- prevent TLS

• omeprazole

• ondansetron

• aciclovir

• fluconazole

• filgrastim - for neutrophil recovery

• Intrathec methotrexate for CNS prophylaxis.

Rituximab MOA

targets CD20 on B cells - causes immune destruction via complement mediated lysis.

Treatment of Hodgkin lymphoma

• ABVD

• A- doxorubicin

• B- bleomycin

• V- vinblastine

• D- dacarbizine

ABVD cycle length and monitoring

28 day cycles.

After 2 cycles, PET scan to guide further therapy

usually 6 cycles.

what does CAR-T mean

chimeric antigen receptor T cell therapy

to genetically engineer patients own T cells to target specific cancer antigens

how is eligibility for CAR-T therapy determined

• National MDT meeting

first step in CAR-T therapy

collecting patients T cells

how are the T cells reprogrammed for CAR-T therapy

• CAR- coding viral DNA inserted to express receptor targeting cancer antigens.

what happens before re-infusing CAR-T cells

chemotherapy regimen goven to prepare body for CAR-T therapy.

when does CAR-T cell count peak post infusuion

• 10-12 days

what is bridging chemotherapy in CAR-T cell therapy

chemo given during 3-4 week manufacturing period to control disease

most common complication of CAR -T therapy

cytokine release syndrome

what triggers cytokine release syndrome

• huge cytokine release when CAR-T cells kill tumour cells

how is cytokine release syndrome treated

Tocilizumab - anti IL-6 mAb

what must be readily available before starting CAR-T therapy

Tocilizumab , in case cytokine release syndrome occurs.

what is immune effector cell associated neurotoxicity syndrome (ICANS)

neurotoxicity of CAR-T therapy with confusuino, seizures and neurological sx

how is ICANS treated

high dose C.steroids

potential toxicities of CAR-T

• CRS

• ICANS

• TLS

• Cytopenias

• B-cell aplasia

• infections