Week 2 - Cancer Flashcards
1
Q
What is meant by metastasis?
A
Tumours spreading to different sites.
2
Q
What is malignant tumour?
A
A tumour that will spread.
3
Q
Define a carcinoma.
A
A malignant tumour derived from epithelial cells.
4
Q
Define a sarcoma.
A
Malignant tumour derived from mesenchymal cells.
5
Q
Define a melanoma.
A
Malignant tumour derived from neural crest cells.
6
Q
Define leukaemia.
A
Malignant tumour derived from circulating white blood cells.
7
Q
Define a lymphoma.
A
Malignant tumour derived from the lymphatic system.
8
Q
What is the most common classification of malignant tumours?
A
Caricnoma
9
Q
What is the function of the basement membrane?
A
It delineates epithelial or endothelial tissues.
10
Q
What is the basement membrane secreted by?
A
The cells that lie next to it:
Basal keratinocytes or endothelial cells.
11
Q
Which collagen type is specific to basement membrane?
A
Type IV collagen
12
Q
What is meant by a carcinoma in situ?
A
The cells are histologically malignant but still trapped in the basement membrane.
13
Q
After which size will a tumour need its own blood supply?
A
> 1mm
14
Q
What is meant by intravasation?
A
The process of getting into the circulation .
15
Q
What is meant by extravasation?
A
The process of getting out of circulation.
16
Q
Which 4 steps in the metastatic cascade are common to invasion and metastasis?
A
Reduced cell-cell adhesion
Altered cell-substratum adhesion
Increased motility
Increased proteolytic ability.
17
Q
Which steps in the metastatic cascade only involve metastasis?
A
Angiogenic ability
Ability to intravasate and extravaste.
Ability to proliferate (locally and in ectopic sites).
18
Q
What type of junction is found between cells?
A
Adherans junctions.
19
Q
What does beta cadherin bind to?
A
Alpha cadherin
20
Q
What is meant by homotypic adhesion?
A
The ligand and receptor are the same molecule.
21
Q
Give an example of homotypic adhesion.
A
E cadherin in adjacent cells.
22
Q
What are E-cadherins bound to within the cell?
A
Catenins
23
Q
Where is E cadherin expressed?
A
On the cell surface of all epithelial cells.
24
Q
What is the structure of catenins on the inside of the cell?
A
B-catenin binds on one side to E-cadherin and on the other side to a-catenin. A-catenin binds on its other side to the actin-myosin cytoskeleton
25
What is required in the extra cellular space for E-cadherin adhesion?
Calcium
26
What does loss of E-cadherin lead to?
Epithelial mesenchyme transition
27
What is the correlation between E-cadherin expression and tumour grade?
Negative correlation.
28
In which ways might a tumour disregulate E-cadherin function?
Exon-skipping
Promotor turned off
Mutation in regulators of expression
29
What is meant by exon-skipping?
E-cadherin is mutated and loses two exons which code for the calcium binding domain. If calcium cannot bind, the E-cadherin molecule doesn't work.
30
Name 3 mutations in transcription factors that regulate E-cadherin.
Snail
Slug
Twist
31
Which proteins are important in cell adhesion to the substratum?
Integrins
32
What do integrins bind to?
ECM molecules
33
What is the structure of integrins?
Heterodimeric: alpha and beta chain.
34
Give an example of a molecule an integrin might bind to.
a5b1 - fibronectin receptor.
35
Which specific integrin seems to promot invasion?
Vitronectin receptor (integrin avB3).
36
What are the possible mechanisms by which integrins can promote metastasis?
Decrease adhesion to basement membrane surrounding epithelium.
Increase migration through stroma.
Increase adhesion to basement membrane or endothelial cells of blood vesse's binding site for proteolytic enzymes.
37
What can induce epithelial cells to dissociate?
HGF/Scatter factor.
38
What is HGF?
A mitogen (growth factor), a motogen (motility factor) and a morphogen.
39
What produces HGF?
Stromal cells in the tumour microenvironment.
40
What happens when HGF binds to c-met?
Increased tyrosine phosphorylation of B-catenin in tumour epithelial cells, which leads to disrupted E-cadherin mediated adhesion.
41
Give some example of a tumour-stroma interaction.
```
c-met/HGF
Chemokine receptor/chemokine
Protease receptor/protease
Integrin aB2/MMP-2
TGF/Stromelysin
VEGF/VEGFR
```
42
Which cells are in the tumour microenvironment?
```
Cancer-associated fibroblasts
Immune cells that have infiltrated the tumour
Myofibroblasts
Tumour-associated vasculature
Pericytes
```
43
What do cells in the tumour microenviornment secrete/
Growth factors
Chemokines
Enzymes
44
Give two classes of proteases that could be involved in metastasis.
Serine proteases
| Matrix metalloproteinases.
45
Give an example of a serine protease.
Urokinase plasminogen activator.
46
Where are membrane type - matrix metalloproteinases found?
Embedded in the membrane.
47
What are matrix metalloproteinases produced by?
White blood cells.
48
What does a tumour cell express when it is hypoxic?
HIF - hypoxia inducible factor.
49
What is the effect of expression of HIF?
Upregulation of VEGF.
50
What does VEGF bind to?
Nearby endothelial cells.
51
What is the effect of VEGF binding to endothelial cells?
Induces them to multiply and form tubes towards the tumour. New blood vessels are leaky - fibronogen and other plasma proteins leak out. Pro-coagulants will convert fibrinogen to fibrin. The fibrin clot is a good surface for endothelial cells to migrate on.
52
What is the rolling and sticking model of extravasation?
WBCs slow down by weak adhesion and adhere more firmly to vessel walls. That's a precursor to them moving into the surrounding tissue.
53
What is selectin important for?
Rolling and sticking
54
Where is selectin expresssed?
WBC surface
55
What was the experiement used to look at the role of selectin in mice?
A transgenic mouse has been created that only expressed L-selectin in the pancreas (rat insulin promotor has been stuck onto 5' end of L-selectin). The same lab generated a line of mice with the rat insulin promotor controlling T-antigen (a molecule that make human cells grow out of control). When they crossed both lines of mice the progeny had metastatic disease - 2 step process.
56
What are the principal sites of metastasis for breast cancer?
Bone
Lungs
Liver
Brain
57
What are the principal sites of metastasis for lung adenocarcinoma?
Brain
Bones
Adrenal gland
Liver
58
What are the principal sites of metastasis for skin melanoma?
Lungs
Brain
Skin
Liver
59
What are the principal sites of metastasis for colorectal cancer?
Liver
| Lungs
60
What are the principal sites of metastasis for pancreatic cancer?
Liver
| Lungs
61
What are the principal sites of metastasis for prostate cancer?
Bones
62
What are the principal sites of metastasis for sarcoma?
Lungs
63
What are the principal sites of metastasis for uveal melanoma?
Liver
64
What is the seed and soil theory?
Tumour cell is the seed but needs an appropriate microenvironment to grow.
65
What is the argument against seed and soil theory?
Lack of contralateral breast and kidney tumours.
66
What is the mechanical hypothesis?
It's all about blood supply.
67
What are the arguments against the mechanical hypothesis?
Dudoenal tumour fails to seed liver metastasis.
68
What are the general theories as to why tumours grow in different distance sites?
Selectins
Selective response to growth factors.
Selective migration to chemokines expressed in different tumours.
Factors released by tumour cells precondition certain distant organs to be receptive when the tumour gets there.
Balance of local angiogenic factors versus systemic anti-angiogenic facotrs.
69
What is the first thing that identifies cancer cells as foreign?
Down regulated MHC class 1 receptors.
70
How does the body respond to cells with downregulated MHC class 1 receptors?
NK, NKT look for damaged cells and attack. Either directly or by releasing interferon gamma which triggers a response around the tumour.
71
What will interferon gamma activate?
Local macrophages and dendritic cells which will start to kill tumour cells.
72
What do dendritic cells initiate?
The adaptive immune response.
73
How does the adaptive immune system respond to cancer cells?
T cells directed against the tumours.
B cells attack.
Plasma cells start producing antibodies
74
How do tumour cells avoid the immune system?
Genetic heterogeneity means there are new versions of the same cells constantly being produced.
75
What are the three E's of immunoediting?
Elimination
Equilibrium
Escape
76
What is meant by elimination in reference to immunoediting?
Default mechanism - in most cases the immune system removes the cancer before it ever becomes established.
77
What is meant by equilibrium in reference to immunoediting?
A state in which the immune system has no eliminated the cancer, but the cancer is not growing further. This phase can last for years or decades, until a person is immunosuppressed at which point the immune system loses the ability to suppress the cancer cells.
78
What is meant by escape in reference to immunoediting?
Tumour cells generate new variants of themselves all the time until they produce a type of cell that is able to avoid, evade or suppress the immune system. This is called an escape clone and is where a tumour arises from.
79
What are the four different approaches to immunotherapy?
Vaccination strategies.
Non-specific therapies.
Antibody therapies.
Cell-based therapies.
80
What was William Coley's non-specific therapy?
William Coley found if you injected a mixture of killed bacteria into a tumour it caused a non-specific inflammatory reaction and sometimes killed the tumour.
81
Give an example of a current non-specific therapy.
Imiquimod (Toll-like receptor antagonist.)
| IL2
82
What is the problem with non-specific therapies?
The immune response is very different in different patients.
83
What is IL2?
A T cell growth factor.
84
What is the problem with IL2?
You have to be a specialised IL2 physician to administer it because its therapeutic window is so narrow. It is therefore a very expensive therapy to use.
85
How have newer IL2 therapies been used to treat leukaemias?
Used to kill target cells by tagging a toxin onto the end of it and adminster it. For cases when cancers are driven predominantly by T-reg cells.
86
What do T reg cells do?
Suppress the immune system.
87
Name some common monoclonal antibodies.
Rituximab
Ofatumomab
Alemtuzumab
Trastuzumab
88
What do rituximab and ofatumomab target?
CD20
89
What does alemtuzumab target?
CD52
90
What does Trastuzumab target?
Her-2/neu
91
What does Cetuximab target?
EGFR
92
What does bevaciumab target?
VEGF
93
What does olaratumab target?
PDGFR
94
Which type of malignancy does rituximab target?
B cell lymphomas
95
What is Cd28?
It activates T cells and causes them to attack.
96
What is CTLA-4?
It stops T cells from attacking after an infection has been resolved.
97
What happens in CTLA-4 in cancer?
It's upregulated by tumour cells.
98
What does ipilimumab do?
Blocks CTLA-4. Stops T cells from being turned off.
99
What is a side effect of ipilimumab in 15-20% of cases?
Ulcerative colitis
100
What is used to balance off-target effects in ipilimumab?
Steroids
101
What does PD1 do?
It is expressed on T cells for programmed cell death.
102
What does PDL1 do?
It's a ligand for PD1 that is expressed on every cell, that lets T cells know that there is nothing wrong with the cell.
103
What does nivolumab do?
Blocks PD-1 blockade.
104
How are tumour-infiltrating T cells used in cell therapies for cancer?
Extracted from the tumour, expanded up and fed back into the patient again.
105
List some cell therapies for cancer.
```
Haematopoietic stem cells
Tumour-infiltrating T cells.
Dendritic cell vaccines
NK cells
Gamma-delta T cells
Virus-specific T cells
Genetically engineered T cells.
```
106
What does plerixafor block?
CXCR4
107
What is plerixafor used for?
Emptying out your bone marrow for a bone marrow transplant.
108
What are the problems with allogenic stem cells transplant?
Difficult to get patient stable again. Problem with graft vs host disease.
109
What is the problem wtih autologous stem cell transplants?
May not remove all of the bad stem cells, end up with the cancer again.
110
Which is the only dendritic cell therapy currently licensed?
Provenge
111
How does provenge work?
Take out monocytes, turn them into dendritic cells, feed them with a combination fusion therapy with the fusion antigen and GM-CSF growth factor and put them back into the patient to drive a new immune response.
112
What causes post transplantation lymphoproliferative disease?
EBV
113
Which cells does EBV stay dormant in?
B cells
114
What percentage of transplants leads to EBV?
1-10% of transplants.
115
How does the SNBTS cell bank work?
Reduces EBV viral load.
| Take white cells from the patient, isolate out the T cells and give them to the patient.
116
What is the CAR-T cell mechanism?
Two binding portions of an antibody with a linking hinge that crosses a transmembrane and an intralcellular signalling motif from a T cell receptor.
117
What does CAR stand for?
Chimeric antigen receptor.
118
How are CAR-T cells made for therapy?
Take blood donation from the patient and take the T cells out, transfect the T cells with a virus molecule which contains the receptor construct. Grow up the T cells, precondition patient (kill off T cells in patient so there's room for the new ones).
119
What are the problems with CAR-T cell therapy?
There are very few tumour specific antigens.
| CAR-T cells are only created for one specific target and tumour cells are heterogeneic.
120
What is the 5 year survival rate of chronic myeloid leukaemia?
60%
121
Name a translocation that can be found in chronic myeloid leukaemia.
9:22
| bcr-abl
122
What is abl?
A tyrosine kinase. It binds ATP and converts it to ADP + phosphate. This releases energy. uses the energy to stick the phosphate group onto the protein (tyrosine).
123
What is the function of VHL?
It binds to HIF and tags it for destruction.
124
What is broken in kidney cancer?
VHL
125
Name some angiogenesis inhibitors.
Sunitinib
Pazopanib
Axitinib
126
Describe castration therapy in men.
GnRH agonists - if you overdrive production you turn it off, e.g.
goserelin triptorelin
Leuprorelin
GnRH antagonists: Degarelix
Oestrogens
127
What is a side effect of docetaxel?
Bone marrow suppression
128
What are the advantages of newer targeted treatments?
More selective for cancer cells, less selective for normal cells - less side effects.
129
What is docetaxel?
An old fashioned chemotherapy drug.
130
What are the barriers to targeted therapy?
Few drugs which restore aberrant tumour suppressor genes.
| Drug resistance.
131
What is meant by personalised medicine?
Targeting specific groups of patients using targeted therapies.
132
What can critzotinib be used to treat?
Some types of lung cancers.
133
What are prognostic markers?
Inform about outcome regardless of treatment.
May help choose which patients to treat, but not how to treat them.
Examples include CTCs in breast cancer.
134
What are predictive markers?
Predict which patients will benefit from specific treatments.
Help choose which drug to use.
The basis of 'precision medicine'
135
Give a couple of examples of predictive markers.
EGFR mutations in lung cancer.
| Raf mutations in melanoma.
136
How many mutations do most cancers need to occur?
5 mutations
137
What are the problems with precision medicine?
To understand the current tumour, we need to perform biopsies.
138
What is enzalutamide?
An androgen receptor antagonist.
139
How does enzalutamide work?
It blocks the androgen binding at the receptor.
It inhibits translocation to nucleus.
It inhibits binding of androgen to DNA.
140
What is an androgen receptor?
A steroid hormone receptor that sits in the cytoplasm of the nucleus. The hormone diffuses through the membrane, binds with the androgen receptor, is translocated to the nucleus and binds DNA to cause cell division.
141
What is psychiatry?
Medical speciality concerned with diagnosis, treatment and prevention of mental health disorders.
142
What is the definition of psychosis?
Altered relationship with reality.
143
What is the definition of a delusion?
Fixed false belief held despite evidence to contrary, outwith sociocultural norms.
144
What is the definition of a hallucination?
Sensory held in the absence of external stimuli.
145
What is an illusion?
A misperception of real external stimuli.
146
What is meant by mood?
Subjective feeling of sustained emotion.
147
What is meant by affect?
Objective immediate conveyance of emotion.
148
What is depression?
Pathological decreased mood with decreased functioning.
149
Define bipolar disorder.
>2 episodes of mood disturbance, at least one of why is hypomania or mania and episodes of depression.
150
What is the evidence in support of the monoamine hypothesis of depression?
Metabolites of 5HT decreased in CSF.
Antidepressants work.
Neurochemical blockers induce depression.
151
What is the evidence against the monoamine hypothesis of depression?
Antidepressants don't work immediately.
| Antidepressants don't always work.
152
What is the psychological aetiology of depression?
Personality traits - anxious, obsessive.
Personality disorders
Coping skills
Adverse life events.
153
What is the social aetiology of depression.
Poor social support
Socioeconomic disadvantage
Northernization
154
What is the point prevalence of depression?
4-7%
155
What is the lifetime incidence of depression?
20%
156
What are the mean number of depressive episodes somebody who has experienced depression is likely to experience in their lifetime?
5
157
What are the core clinical features of depression?
Low mood +/- anhedonia +/- fatigue every day >2 weeks.
158
What are the associated biological symptoms of depression?
```
Diurnal variation
Insomnia
Decreased appetite
Decreased weight
Decreased libido
Constipation
Amenorrhoea
```
159
What are the associated cognitive symptoms of depression?
```
Decreased concnetration
Slow/negative thinking
Guilt
Loss of self esteem
Hopeless
Suicidality
```
160
Which cognitive distortions can be associated with depression?
```
Minimizing
Magnifying
Arbitrary inference
Selective abstraction Personalization
Overgeneralization Catastrophizing
```
161
Which psychotic symptoms can be associated with depression?
```
Mood congruent (nihilistic) delusions such as:
Guilt
Poverty
Hypochondriasis
Persecutory
```
162
What is Cotard's syndrome?
Belief that self or part of the self is dead.
163
How can hallucinations in depression be distinguished from other mental health disorders?
Auditory hallucinations in depression tend to be 2nd person rather than 3rd person.
164
How is the severity of depression measured?
Mild – >2 core + >2 associated, function ok
Mod – >2 core + >4 associated, function ↓
Sev – >2 core + >6 associated, function ↓↓
+/- psychosis
165
What is the mortality rate in depression?
8x that of the normal population
166
What is dysthymia?
↓mood, chronic >2yrs but not enough depression
167
What is cyclothymia?
alternating ↓mood (mild), ↑ mood (mild)
168
What is atypical depression?
Decreased mood with reversed associated symptoms.
169
What is seasonal affective disorder?
Depression that only occurs in winter due to lack of UV light.
170
What is adjustment reaction?
Adaptation to stressor
Can include low mood
Onset <1 month from stress
Duration <6 months max
171
What are the 5 stages of grief?
```
Denial
Anger
Bargaining
Depression
Acceptance
```
172
What is is the assessment for depression?
```
Clinical history
Risk assessment
Mental state exam
Physical exam
Baseline bloods
```
173
How is moderate depression treated?
Antidepressants
174
How is severe depression treated?
Antidepressants
Antipsychotics
ECT
175
Name two SSRIs.
Citalopram
Fluoxetine
Escitalopram
176
Name a tricyclic antidepressant.
Amitriptyline
177
Name a monoamine oxidase inhibitor.
Isocarboxid
178
What do SSRIs block?
5HT reuptake
179
How long does it take for SSRIs to have an effect?
4-5 weeks
180
What are the possible side effects of SSRIs?
```
Nausea
Vomiting
Weight gain
Dizziness
Discontinuation syndrome
Anxiety
Suicidality
Mania
Cardiac effects
```
181
What is the response rate of SSRIs?
33%
182
How do tricyclic antidepressants work?
Block 5HT and NA reuptake
183
What are the side effects of tricyclic antidepressants?
Anti-adrenergic (decreased BP)
Anti-cholinergic
ECG changes (arrhythmia, QTc prolongation)
184
How do monoamine oxidase inhibitors work?
Block MAO-A
Block MAO-B
Breaks down 5HT, NA, DA in CNS
185
What are the side effects of MAOIs?
Cheese reaction
186
How is electrotherapy given?
Controlled seizure under anaesthetic
187
How effective is ECT?
More effective than drugs.
188
What are the risks/side effects with ECT?
```
Anaesthetic risks
Memory loss (rare)
```
189
What is the psychological treatment for depression?
CBT
Psychotherapy
Family therapy
190
Which 7 sections are there to a mental state examination?
```
Appearance and behaviour
Speech
Mood and affect
Thought form and content
Perception
Cognition
Insight
```
191
How is appearance assessed in a mental state examination?
```
Describe how the person looks:
Ethnicity, build, hair colour, clothing
Biological vs. chronological age
Are they well kempt?
Is there evidence of self-neglect?
Do they appear physically unwell or
intoxicated?
Any distinguishing features
```
192
How is behaviour assessed in a mental state examination?
```
Describe how the person acts:
Level of motor activity (e.g. agitation or motor
retardation)
Eye contact
Rapport and engagement with interview
Body language & posture
Any unusual or socially inappropriate
behaviour
```
193
How is speech assessed in a mental state examination?
```
Describe how the person talks:
Rate & quantity of speech
Rhythm
Volume
Tone
Spontaneity
```
194
How is mood assessed during a mental state examination?
Subjective: how the person tells you they feel
in their own words
Objective: your impression of the person’s
mood during the interview
Euthymic (normal) Elevated/elated
Low/depressed
Anxious
195
How is affect assessed during a mental state examination?
Reactive – appropriate reaction to the
situation or topic being discussed
Flattened – limited emotional reaction
Blunted – no observed emotional reactions
(specifically associated with psychosis)
Labile – excessive emotional fluctuations
196
How is thought form assessed during a mental state exam?
The pattern of the person’s thoughts
Are there logical connections between the things they are saying?
Include specific quotes if possible.
197
How is thought content assessed during a mental state exam?
What the person is saying.
| Any topics discussed more than others.
198
Define a delusion.
```
A fixed, false belief that is out of
keeping with the person’s religious and
cultural background (e.g. psychosis).
```
199
What is a persecutory delusion?
Perceived threat from others.
200
What is a grandiose delusion?
Considerable overestimate of abilities or possession of special powers.
201
What is a nihilistic delusion?
Belief that they are dead or do not exist.
202
What is a delusion of reference?
Belief that external events/objects are directly related to them (e.g. TV programme).
203
What is thought interference?
Insertion, withdrawal or broadcast of thoughts.
204
What is an over-valued idea?
A false belief, not totally fixed but causing a great disability (e.g. anorexia, hypochondriasis)
205
What is an obsession?
recurrent, intrusive, distressing
ideas, impulses or images that the patient
recognises as their own (e.g. OCD).
206
How is risk assessed?
Any thoughts of harm to self or others,
including the degree of planning and intent.
Always include in mental state exam.
Always document, even if negative.
207
What are auditory halucinations often associated with?
Psychosis
208
What are visual, olfactory, gustatory or tactile hallucinations often associated with?
More often organic states, e.g. drug induced, brain tumour.
209
How is cognition assessed in a mental state exam?
Alertness: do they seem fully awake
Orientation: to time, place & person
Attention/concentration: are they able to
maintain focus during the interview, are they
easily distracted
Memory: tell them 3 objects, ask them to
repeat until they are correct, continue with
history then ask again after a few minutes.
210
How is insight assessed in a mental state exam?
Do they believe their experience is unusual?
Is it part of an illness? A mental illness?
Do they require treatment?
What type of treatment?
Do they need to be admitted to hospital?
211
What are the hallmarks of cancer?
* Self-sufficiency in growth signals
* Insensitivity to anti-growth signals
* Evading apoptosis
* Limitless replicative potential
* Sustained angiogenesis
* Tissue invasion and metastasis
