43. Neoplasia: The Molecular & Cellular Basis of Tumour Growth Flashcards
(494 cards)
1
Q
With regards to cell growth, what is contact inhibition?
A
- Regulatory mechanism that functions to keep cells growing into a layer one cell thick
- monolayer
- If a cell has plenty of available substrate space, it replicates rapidly and moves freely
- This process continues until the cells occupy the entire substratum.
2
Q
What happens during the three stages of interphase?
A
-
G1
- cell is metabolically active and continuously grows
-
S
- DNA replication, protein synthesis and replication of organelles
-
G2
- during which cell growth continues and the cell synthesizes various proteins in preparation for division
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M
- During which the duplicated chromosomes (known as the sister chromatids) separate into two daughter nuclei, and the cell divides into two daughter cells, each with a full copy of DNA
3
Q
What are centrosomes and what do they consist of?
A
Centrosomes are organelles near the nucleus of a cell, which contain centrioles (mother and daughter), and from which spindle fibres develop in cell division
4
Q
What happens to the centrosomes during G1 and S?
A
- The mother and daughter centrioles separate in G1
- Then the mother produces another daughter and the daughter produces another mother, resulting in the formation of 2 centrosomes (the duplication takes place during S phase)
5
Q
What are the points around the centrosome from which microtubules arise?
A
Nucleating sites
NOTE: nucleation is the assembly of microtubules
6
Q
Describe the condensation of chromatin that takes place duringprophase.
A
- The double helices wrap around histones to form beads-on-a-string
- This is then further compacted to form 30 nm fibres It is then compacted to form a chromosome scaffold and then further wrapped until you get a chromosome (1400 nm)
7
Q
What is a kinetochore?
A
Protein complexes that are attached to each sister chromatid – they are important in detecting the attachment of microtubules
8
Q
Describe the arrangement of centrosomes at the end of prophase.
A
They are on opposite sides of the nucleus
9
Q
What is formed when microtubule arrays from the two centrosomes meet in the middle?
A
Polar microtubules
10
Q
What happens to the sister chromatids as soon as they are captured by microtubule arrays from both centrosomes?
A
They slide towards the middle of the cell
11
Q
What are the three main types of half-spindle?
A
- Kinetochore microtubule – attached to kinetochores Polar microtubule – attached to a microtubule array from the other centrosome Astral microtubule – microtubule originating from a centrosome that does not connect to a kinetochore
12
Q
What keeps the sister chromatids stuck together?
A
Cohesin (protein complex)
13
Q
What happens in anaphase A?
A
Cohesin is broken down and the microtubules get shorter so the chromatids start moving towards their respective poles
14
Q
What happens in anaphase B?
A
Daughter chromatids continue to migrate towards the poles The centrosomes migrate apart
15
Q
Describe what happens in telophase.
A
Daughter chromatids arrive at the pole and the nuclear envelope reassembles Assembly of a contractile ring of actin and myosin filaments where the cells are going to split The contractile ring squeezes the cell so it divides into two daughter cells NOTE: cleavage furrow = where the cell is going to be cleaved
16
Q
What is the midbody?
A
The point where the actin-myosin contractile ring is formed
17
Q
Describe how the spindle assembly checkpoint works.
A
The kinetochore has proteins that emit a signal when the kinetochore is NOT attached to microtubules When a microtubule attaches to the kinetochore, it stops emitting the signal At the end of metaphase, you want all the kinetochores to stop sending signals before you can proceed to anaphase
18
Q
Name two proteins that allow the kinetochores to detect spindle attachment.
A
CENP-E BUB-protein kinase (this dissociates from the kinetochores when the chromatids are properly attached to the spindle – then they go on to signal progression to anaphase)
19
Q
What can cause aneuploidy?
A
Mitotic checkpoint defect Mis-attachment of the spindles (so chromatids end up at different poles to the ones that they should be at) Aberrant mitosis (production of an abnormal number of centrosomes leads to abnormal division of the chromatids, and abnormal cytokinesis)
20
Q
Name four different types of spindle attachment.
A
Amphitelic – normal spindle attachment Syntelic – both kinetochores of the sister chromatids are attached to spindles from one centrosome Merotelic – one kinetochore of one of the sister chromatids is attached to spindles from both centrosomes Monotelic – one kinetochore of one of the sister chromatids is attached to a spindle, the other is unattached
21
Q
Broadly speaking, explain how cell cycle checkpoints can be a target for anti-cancer therapy.
A
By targeting the cell cycle checkpoints, the cancer cells can be arrested in mitosis Cells are very vulnerable when they are in mitosis and are more easily killed
22
Q
Give an example of anti-cancer drugs that target cell cycle checkpoints.
A
Taxanes and Vinca alkaloids These alter microtubule dynamics and produce unattached kinetochores, which leads to long-term microtubule arrest
23
Q
What can happen to cells that are held up at a checkpoint?
A
They can undergo DNA repair and then proceed through the cell cycle If the damage is irreparable, they can undergo apoptosis
24
Q
Where are the main checkpoints within the cell cycle?
A
During G1 Just before mitosis to check for DNA damage Metaphase-anaphase checkpoint (spindle assembly checkpoint)
25
State some different types of DNA damage caused by carcinogens.
Base dimers and chemical cross-links Base hydroxylations Abasic sites Single strand breaks Double strand breaks DNA adducts
26
What are abasic sites?
During the repair process, the entire DNA base has been removed so the sugar backbone is maintained but we have removed the base from the mutagenic molecule During replication, this missing base can cause problems
27
What are the implications of single strand breaks?
These are common and useful Topoisomerase causes single strand breaks and it is involved in relaxing and unwinding the DNA before replication
28
What are the implications of double strand breaks?
These are NOT GOOD The two strands have a tendency to drift apart when a double strand break occurs There are repair mechanisms for dealing with this, but sometimes the DNA repair can go wrong and introduce DNA damage
29
What is the usual type of damage that is caused by chemicals?
DNA adducts
30
Why is DNA the target for many carcinogens?
Chemical carcinogens are usually metabolically activated and converted into electrophiles (they want electrons) DNA is very electron rich
31
What are the consequences of bulky DNA adducts?
The electrophiles bind and form a covalent bond The binding of these adducts causes problems, particularly during replication because it interferes with the ability of DNA polymerase to recognise the base (because of the bulky adduct)
32
What are the six types of Phase II reaction?
Glucuronidation Acetylation Sulphation Methylation Amino acid conjugation Glutathione conjugation
33
What are polycyclic aromatic hydrocarbons?
They are environmental pollutants formed from the combustion of fossil fuels and tobacco
34
Describe the two-step oxidation of benzo[a]pyrene.
B[a]P is a substrate for CYP450, which converts it to B[a]P-7,8-oxide (this is an electrophile) The body has a defence mechanism – epoxide hydrolase converts the oxide to a dihydrodiol (B[a]P-7,8-dihydrodiol) This is inactive However, this dihydrodiol is also a substrate for CYP450, which converts it to another oxide (B[a]P-7,8-dihydrodiol-9,10-oxide) This even more reactive than the previous oxide – it goes on to form DNA adducts
35
State two past components of dyestuff that are potent bladder carcinogens.
Benzidine and 2-naphthylamine
36
Explain the mechanism by which 2-naphthylamine is a bladder carcinogen.
2-naphthylamine is converted by CYP450 to a hydroxylamine derivative, which is reactive In the liver, this is glucuronidated (thus inactivating it) The inactive metabolite is excreted by the liver and then it goes to the bladder where it mixes with the urine The ACIDITY of the urine causes hydrolysis of the glucuronides – this releases the hydroxylamine derivative, which forms a nitrenium ion This is electrophilic so it leads to the formation of DNA adducts
37
What does UV radiation lead to the formation of?
Pyrimidine (thymine) dimers – adjacent pyrimidines can covalently link
38
What does ionising radiation generate?
Free radicals
39
Name 2 oxygen free radicals.
Superoxide radical (O2.) Hydroxyl radical (HO.)
40
What are the consequences of oxygen free radical attack on DNA?
Single and Double strand breaks Apurinic and apyrimidic sites Base modifications: Ring-opened guanine and adenine Thymine and cytosine glycols 8-hydroxyadenine and 8-hydroxyguanine
41
What are the p53 mediated responses to mild and severe physiological stress?
Mild – repair the damage and restore the normal function of the cell Severe – apoptosis
42
What are the main types of DNA repair?
Direct reversal of DNA damage Base excision repair Nucleotide excision repair During- and post-replication repair
43
Give two examples of direct reversal of DNA damage.
Photolyase looks for cyclobutane-pyrimidine dimers and cuts them Methyltransferases and alkyltransferases remove alkyl groups from the bases
44
What comes under during and post replication repair?
Mismatch repair Recombinational repair
45
Which base is most electron-rich and hence most capable of attracting electrophiles?
Guanine
46
Describe the process of base excision repair.
DNA glycosylase hydrolyses between the base and the sugar Then AP endonuclease splits the DNA strand so there is a gap in the backbone DNA polymerase then fills in the missing base (using the complementary strand as template) DNA ligase then seals the DNA
47
Describe the process of nucleotide excision repair.
Endonuclease makes two cuts in the DNA on either side of the site of damage (this demarcates a patch of DNA) Helicase then removes this patch, leaving the double strand with a patch missing DNA polymerase replaces the missing bases DNA ligase joins the DNA up
48
Describe the possible fates of carcinogen-DNA damage.
Low level of damage --\> effective repair --\> return to being a normal cell Severe damage --\> apoptosis Carcinogen causing altered DNA --\> incorrect repair/altered primary sequence --\> DNA replication and cell division (fixed mutation) --\> transcription and translation giving aberrant proteins + carcinogenesis if critical targets are mutated
49
Describe the process of testing whether a chemical can cause carcinogenesis.
Look at structure of compound Test in vitro on bacteria Test in vitro on mammalian cells Test in vivo on mammals
50
Describe the bacterial (Ames) test for mutagenicity of chemicals.
This test usually uses Salmonella typhimurium The bacterium is genetically engineered so that it can’t produce histidine, so it can only survive and grow on a culture medium that has exogenous histidine The compound to be tested is, firstly, incubated with rat liver enzymes containing CYP450 enzymes to metabolise the chemical into an active form that can be carcinogenic The bacteria are mixed with the active chemical and then placed on a culture medium with NO histidine Any colonies that survive will have become mutated by the chemical so that it regains the ability to produce its own histidine and hence cangrow in the absence of histidine Any bacteria that hasn’t been mutated will die on the dish The greater the DNA damaging capability of the chemical, the more colonies will grow in the absence of histidine
51
Describe the use of in vitro micronucleus assays.
This is trying to measure the ability of a chemical to break up DNA into fragments We need the cell to go through one replication cycle and then stop it when it’s at the binucleus stage – this is when you check for the presence of micronuclei
52
What is used to block cytokinesis and hold the cell in the binucleate stage in the micronucleus assay?
Cytochalasin-B
53
What are the two types of chromosomal damage that can be detected by this assay?
Clastogenicity – chromosomal breakage Aneuploidy – chromosomal loss/change in the number of chromosomes
54
Explain the reasoning behind the use of bone marrow micronucleus assays to test the mutagenicity of a chemical.
Bone marrow is pluripotent The animals are treated with the chemical and their bone marrow cells and peripheral erythrocytes are examined for the presence of micronuclei Erythrocytes normally remove the nucleus during development, but it CANNOT remove small fragments of DNA e.g. a micronucleus So the presence of micronuclei in erythrocytes indicates DNA damage
55
What are the six hallmarks of cancer?
Disregard of signals to stop proliferating Disregard of signals to differentiate Capacity for sustained proliferation Evasion of apoptosis Ability to invade Ability to promote angiogenesis
56
What is gene amplification?
Production of multiple gene copies
57
What are chimeric genes?
Genes that are formed by combinations of portions of one or more coding sequence to produce new genes (e.g. the swapping of tips of chromosomes)
58
When can the formation of chimeric genes be a problem?
If one of the pieces of translocated DNA is a promoter, it could lead to upregulation of the other gene portion (this occurs in Burkitt’s lymphoma) If the fusion gene codes for an abnormal protein that promotes cancer
59
What is the Philadelphia Chromosome?
Chromosome produced by the translocation of the ABL gene on chromosome 9 to the BCR gene on chromosome 22 The BCR-ABL fusion gene encodes a protein that promotes the development of cancer
60
State some important oncogenes in human cancers.
SRC – tyrosine kinase Myc – transcription factor JUN – transcription factor Ha-Ras – membrane bound GTPase Ki-Ras – membrane bound GTPase
61
What is an example of an inherited cancer?
Retinoblastoma – malignant cancer of the developing retinal cells
62
What mutation causes retinoblastoma?
RB1 gene 13q14
63
What are the functional classes of tumour suppressor genes?
Regulate cell proliferation Maintain cellular integrity Regulate cell growth Regulate the cell cycle Nuclear transcription factors DNA repair proteins Cell adhesion molecules Cell death regulators
64
State some important tumour suppressor genes in human cancers
P53 – cell cycle regulator BRCA1 – cell cycle regulator PTEN – tyrosine and lipid phosphatase APC – cell signalling
65
In what form is p53 inactive?
When it is bound to MDM2
66
What is p53 important for?
It is important for regulation of p53 target genes (involved in DNA repair, growth arrest, senescence etc.) and protein-protein interactions (e.g. apoptosis)
67
What is odd about p53 considering it is a tumour suppressor gene?
It acts in a DOMINANT manner –mutation of a single copy is sufficient to achieve dysregulation of activity
68
What deletion causes loss of the APC gene?
5q21
69
What is APC involved in?
Cell adhesion Cell signalling
70
What is the risk of people with this mutation developing colon cancer?
90%
71
What signalling pathway is APC involved in?
WNT signalling
72
What is the main role of APC that prevents uncontrolled growth?
It breaks down beta-catenin so that it doesn’t bind to LEF1 and promote uncontrolled proliferation
73
Describe the step-by-step development of colorectal cancer.
APC mutations --\> hyperproliferative epithelium DNA hypomethylation + K-ras mutation will make the polyps --\> adenomas P53 mutation will result in the development of carcinoma
74
What transcription factor is stimulated by growth factor signalling and is vital to starting the cell cycle?
c-Myc
75
Describe what happens to tyrosine kinase receptors when growthfactors bind to them.
Tyrosine kinase receptors are usually present on membranes as inactive monomers Most growth factors are dimers, so when they bind they bring tyrosine kinase receptors close together This allows the tyrosine kinase receptors to cross-phosphorylate each other (using the gamma phosphate from ATP to phosphorylate tyrosine residues in proteins) The phosphorylated domains on the tyrosine kinase receptors act as docking sites for adaptor proteins
76
Give an example of an anti-cancer drug that targets tyrosine kinase receptors.
Herceptin – inhibits the Her2 tyrosine kinase receptor (important in many tumours e.g. breast)
77
Name an important adaptor protein.
Grb2
78
Describe the structure of this protein.
It is modular It has an SH2 domain, which binds to the docking sites (phosphorylated tyrosine residues on the tyrosine kinase receptors) It has two SH3 domains, which bind to proline-rich regions of proteins
79
Describe how receptor protein tyrosine kinases can signal to Ras.
Grb2 is bound to an exchange factor called Sos When the tyrosine kinase receptors become active and the dockingsites become available, Grb2 binds to the docking site and it is also attached to Sos This brings Sos close enough to the cell membrane and Ras, to allow it to exchange the GDP on Ras for GTP GTP bound Ras is active
80
What must the Ras protein be bound to for it to work?
It must be bound to the plasma membrane NOTE: interference with the membrane binding of Ras can make a good anti-cancer drug
81
How is Ras turned off?
Ras has intrinsic GTP hydrolysis capability This GTPase activity is stimulated by GTPase-activating proteins (GAPs)
82
Broadly speaking, how might Ras signalling be different in cancer?
Ras could be permanently switched on (in the GTP bound form), thus it constantly signals cell division
83
Describe two mutations that lead to an increase in the amount of active Ras.
V21Ras – glycine is replaced by valine, which means that a simple hydrogen side chain is replaced by a hydrophobic sidechain. This hydrophobic side chain doesn’t allow GAPs to bind to Ras, thus preventing inactivation of Ras. L61Ras – glutamine is replaced by leucine (in position 61), which means that an amine side chain is replaced by a hydrophobic side chain. This inhibits the GTPase activity of Ras so Ras remains in the active, GTP bound form.
84
What cascade does Ras activate?
ERK cascade (Extracellular signal-regulated kinase cascade)
85
What is the family that this cascade belongs to called?
MAPK cascade (Mitogen-activated protein kinase cascade)
86
What are the three kinases involved in the ERK cascade?
Raf MEK ERK
87
What does the last kinase in the cascade phosphorylate?
It phosphorylates gene regulatory proteins (transcription factors), which go on to regulate the expression of genes involved in the cell cycle They also phosphorylate other proteins and change their activity
88
What important gene is turned on by the kinase cascade?
c-Myc
89
What type of kinase are cyclin-dependent kinases (Cdks)?
Serine-threonine kinases
90
What conditions do Cdks require to become activated?
Binding to cyclin Phosphorylation (activating phosphorylation and removal of inhibitory phosphorylation) (+ degradation of Cdk inhibitors)
91
What does the mitosis-promoting factor (MPF) consist of?
Cdk1 + cyclin B
92
What are the requirements, in terms of phosphorylation, for MPF to become active?
Activating phosphorylation by CAK (Cdk activating kinase) Removal of the inhibitory phosphorylation (that was placed by Wee1)by Cdc25
93
What activates MPF at the end of interphase?
Removal of the inhibitory phosphorylation by Cdc25
94
Describe the positive feedback loop that is formed by MPF activation.
Removal of the inhibitory phosphorylation by Cdc25 produces active MPF, which then phosphorylates Cdc25 and increases its activity meaning that more MPF can be activated
95
How does MPF put mitosis on hold before progressing to the next stage?
At the end of metaphase, it phosphorylates a number of key proteins and inhibits their action (thus putting mitosis on hold) until it is signalled to proceed. Then the cyclin B is degraded, Cdk is inactivated and the substrates become dephosphorylated and hence become active.
96
Which Cdk/cyclin is required for G1/S phase?
Cdk2-cyclin E
97
Which Cdk/cyclin is required for S phase?
Cdk2-cyclin A
98
How can the same Cdk be used for two different stages?
Cyclin binding alters the substrate specificity of Cdk Also, different substrates are available at different stages of the cell cycle
99
What is one of the most important transcription targets of c-Myc?
Cyclin D
100
What is the first Cdk/cyclin complex that is formed when a cell goes from G0 to G1?
Cdk4/6-cyclin D
101
This Cdk/cyclin complex then stimulates the expression of the next cyclin in the cell cycle. What properties does this system give to the cell cycle?
This gives the cell cycle direction and timing (because the Cdk-cyclin complexes must reach a certain concentration before they can triggerthe next stage of the cycle)
102
Give an example of a phosphorylation target of MPF that allows the cell cycle to progress.
Phosphorylation of nuclear lamins allows breakdown of the nuclear envelope
103
What is start kinase and what is one of its most important targets?
Start kinase = Cdk2-cyclin E Retinoblastoma
104
Describe the role of retinoblastoma in the quiescent G0 state.
Retinoblastoma is unphosphorylated and binds to and sequesters a group of transcription factors called E2F
105
What effect does Cdk4/6-cyclin D have on retinoblastoma?
It multiply phosphorylates retinoblastoma – as it becomes phosphorylated it loses its affinity for E2F and releases E2F This means that the E2F transcription factors can regulate gene expression and promote progression of the cell cycle
106
What is one of the main targets of E2F?
Cyclin E (the next cyclin in the cell cycle)
107
What type of gene is retinoblastoma?
Tumour suppressor gene (it acts a break on the cell cycle)
108
State some important genes that are regulated by E2F.
Proto-oncogenes – c-Myc, n-Myc Cell cycle – E2F-1,2,3, pRb, cyclin A, cyclin E, CDK4, CDK2 DNA synthesis – thymidine kinase, thymidine synthetase, dihydrofolate reductase, DNA polymerase
109
The initial release of E2F allows transcription of cyclin E leading to the formation of Cdk2-cyclin E. What effect does this complex have on retinoblastoma?
Cdk2-cyclin E further phosphorylates retinoblastoma so more E2F is released and the concentration of E2F increases
110
What is the significance of the increasing concentration of E2F?
This means that E2F can now bind to targets with a lower affinity (e.g. cyclin A gene promoter isn’t activated until the E2F concentration is high enough)
111
What are the two families of Cdk inhibitors?
NK4 CIP/KIP
112
During which phase do each of the families act and how do they inhibit Cdk?
INK4 – G1 phase – it displaces cyclin D from the Cdk4/6-cyclin D complex CIP/KIP – S phase – it binds to the Cdk/cyclin complexes and inhibits them NOTE: these inhibitors need to be degraded at various stages for the cell cycle to progress
113
State some common and important oncogenes.
EGFR/HER2 – mutationally activated or over-expressed in many breast cancers Ras – mutationally activated in many cancers Cyclin D1 – overexpressed in 50% of breast cancers B-Raf – mutationally activated in melanomas c-Myc – overexpressed in many tumours
114
State some important tumour suppressor genes.
Rb – inactivated in many cancers p27KIP1–under-expression correlates with poor prognosis in many malignancies
115
Define Metaplasia.
A reversible change in which one adult cell type (usually epithelial) is replaced by another adult cell type
116
Give two examples of metaplasia, one pathological and one physiological.
Barrett’s Oesophagus – gastro-oesophageal reflux can change the stratified squamous epithelium of the distal oesophagus to simple columnar Cervix during pregnancy – the cervix opens up and the columnar epithelium of the endocervical canal is exposed to the acidic uterine fluids making it squamous
117
What are the two types of metaplasia that can take place in Barrett’s Oesophagus?
Gastric metaplasia – stratified squamous to simple columnar Intestinal metaplasia – goblet cells begin to appear
118
State some features of cancer that are seen in dysplasia.
Large nuclei (and hyperchromatic) Increased mitoses Abnormal mitoses Increased nucleo-cytoplasmic ratio Loss of architectural orientation Loss of uniformity of individual cells
119
What is the difference between low and high-grade dysplasia?
They both show changes of dysplasia but the changes are more severe in high-grade dysplasia High-grade has a high risk of progression to cancer
120
What are the main features of benign tumours that separate them from malignant tumours?
They do not metastasise They do not invade They also are usually encapsulated (except for fibroids in the uterus), slow growing and have normal mitoses
121
Under what conditions can benign tumours be dangerous?
If they are in a dangerous location If they secrete something dangerous If they get infected If they bleed If they rupture If they become twisted
122
What are the features of malignant tumours?
Invade surrounding tissues Spread to distant sites They also have no capsule, can be well or poorly differentiated, rapidly growing and have abnormal mitoses
123
Define metastasis.
A discontinuous growing colony of tumour cells, at some distance from the primary cancer
124
What are the two different types of benign epithelial tumour?
Papilloma – of the surface epithelium Adenoma – of glandular epithelium
125
Define carcinoma.
Malignant tumour derived from the epithelium
126
What are the different types of carcinoma?
Basal cell carcinoma Squamous cell carcinoma Transitional cell carcinoma (transitional epithelium is found in the bladder) Adenocarcinoma
127
State some different types of benign soft tissue tumour.
Osteoma –bone Lipoma - fat Leiomyoma – smooth muscle
128
Define sarcoma.
Malignant tumour derived from connective tissue (mesenchymal) cells
129
What are the names given to malignant tumours of striated muscle, smooth muscle and the nerve sheath?
Striated muscle – rhabdomyosarcoma Smooth muscle – leiomyosarcoma Nerve sheath – Malignant peripheral nerve sheath tumour
130
Define leukaemia.
Malignant tumour of bone marrow derived cells, which circulate in the blood
131
Define lymphoma.
Malignant tumour of lymphocytes (usually) in lymph nodes
132
Define teratoma.
A tumour derived from germ cells, which has the potential to develop into tumours of all three germ layers
133
What is an important difference between teratomas in men compared to women?
Gonadal teratomas in men are almost always malignant Gonadal teratomas in women are almost always benign
134
Define hamartoma.
Localised overgrowth of cells and tissue native to the organ In other words, the cells and tissues present are appropriate for that particular location but their structural organisation is inappropriate
135
Which group of the population is hamartoma common in?
It is common in children and the hamartoma usually stops growing when the children stop growing
136
What is the difference between grading and staging?
Grading – how well differentiated the cancer is Staging – how far the cancer has spread Staging \> Grading
137
What is meant by the ‘degree of differentiation’?
How much the tumour cells resemble the cells from which they are derived
138
What are the grading systems for breast and prostate cancer?
Breast –Nottingham scoring system Prostate – Gleason classification
139
What is the term given to tumours that show little or no differentiation?
Anaplastic
140
What are the five most common cancers worldwide?
Lung Breast Bowel Prostate Stomach
141
What are the four main anti-cancer modalities?
Radiotherapy Chemotherapy Surgery Immunotherapy
142
List the different types of cytotoxic chemotherapy.
Alkylating agents Pseudoalkylating agents Antimetabolites Anthracyclines Vinca alkaloids and taxanes Topoisomerase inhibitors
143
What are the main types of targeted therapy for cancer?
Monoclonal antibodies Small molecule inhibitors
144
hat is the term used to describe chemotherapy that is given: a. Following surgery b. Before surgery
Adjuvant Neoadjuvant
145
How do alkylating agents work?
They add an alkyl group to the guanine residues in DNA This causes cross-linking of the DNA strands and prevents DNA from uncoiling at replication This then triggers apoptosis (via a DNA checkpoint pathway) It encourages mis-pairing
146
Name four alkylating agents.
Chlorambucil Cyclophosphamide Dacarbazine Temozolomide
147
How do pseudoalkylating agents work?
They have the same mechanism as alkylating agents but use platinum instead of alkyl groups
148
Name three pseudoalkylating agents.
Carboplatin Cisplatin Oxaliplatin
149
What are some side effects of alkylating and pseudoalkylating agents?
Alopecia (except carboplatin) Nephrotoxicity Neurotoxicity Ototoxicity (platins) Nausea, Vomiting, Diarrhoea, Immunosuppression, Tiredness
150
How do anti-metabolites work?
They masquerade as purine or pyrimidines leading to inhibition of DNA replication and transcription They can also be folate antagonists (dihydrofolate reductase inhibitors) This blocks DNA replication and transcription
151
Give six examples of anti-metabolites.
Methotrexate Capecitabine Gemcitabine 5-fluorouracil 6-mercaptopurine Fludarabine
152
State some side effects of anti-metabolites.
Alopecia (not 5-fluorouracil or capecitabine) Bone marrow suppression Increased risk of neutropenic sepsis Nausea, Vomiting, Mucositis, Diarrhoea, Fatigue Palmar-plantar erythrodysesthesia (PPE)
153
How do anthracyclines work?
They intercalate into DNA or RNA sequences and inhibit transcription and replication It also blocks DNA repair They create DNA damaging and cell membrane damaging oxygen free radicals
154
Give two examples of anthracyclines.
Doxorubicin Epirubicin
155
State some side effects of anthracyclines.
Cardiac toxicity (probably due to the free radicals) Alopecia Neutropenia Nausea, Vomiting, Fatigue Red urine (doxorubicin –‘the red devil’)
156
How do vinca alkaloids and taxanes work?
Vinca alkaloids inhibit assembly of microtubules Taxanes inhibit disassembly of microtubules This forces the cells into mitotic arrest
157
State some side effects of these drugs.
Nerve damage (peripheral neuropathy and autonomic neuropathy) Hair loss Nausea, Vomiting Bone marrow suppression Arthralgia (severe joint pain without swelling or signs of arthritis) Allergy
158
How do topoisomerase inhibitors work?
Topoisomerase is responsible for the unwinding of DNA and they induce temporary single and double strand breaks in the phosphodiester backbone Topoisomerase inhibitors alter the binding of topoisomerase to DNA and allow permanent breaks in the DNA
159
Give three examples of topoisomerase inhibitors.
Topotecan Irinotecan Etoposide
160
State some side effects of topoisomerase inhibitors.
Irinotecan = acute cholinergic type syndrome (diarrhoea, abdominal cramps, diaphoresis – so they are given atropine) Hair loss Nausea, Vomiting, Fatigue Bone marrow suppression
161
What are the six hallmarks of cancer?
SPINAP Self-sufficient Pro-invasive and metastatic Insensitive to anti-growth signals Non-senescent Anti-apoptotic Pro-angiogenic
162
What are the four hallmarks of cancer that have recently been added?
DIE U Dysregulated metabolism Inflammation Evades the immune system Unstable DNA
163
Give three examples of receptors that are over-expressed in cancer.
EGFR – over-expressed in many breast and colorectal cancers HER2 – breast PDGFR – glioma (brain)
164
Give an example of a ligand that is over-expressed in some cancers.
VEGF – prostate, kidney and breast cancer
165
Give two examples of constitutive (ligand independent) receptor activation in cancer.
EGFR – lung cancer FGFR – head and neck cancers, myeloma
166
What do each of the following suffixes mean in relation to monoclonal antibodies: a. -momab b. -ximab c. -zumab d. -mumab
a.–momab Derived from mouse antibodies b.–ximab Chimeric antibody c.–zumab Humanised antibody d.–mumab Fully human antibody
167
Describe the structure of humanised monoclonal antibodies.
Murine regions are interspersed within the with the light and heavy chains of the Fab portion
168
Describe the structure of chimeric monoclonal antibodies.
The murine component of the variable region of the Fab section is maintained integrally
169
What effect can monoclonal antibodies have on receptors and their activation?
They target the extracellular component of receptors and can prevent receptor dimerization, neutralise the ligand and cause internalisation of the receptor NOTE: they also activate Fc-receptor-dependent phagocytosis or cytolysis induced complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity (ADCC)
170
Give two examples of monoclonal antibodies used in oncology.
Bevacizumab (avastin) – binds and neutralises VEGF Cetuximab – targets EGFR
171
How do small molecule inhibitors work?
They bind to the kinase domain of tyrosine kinase receptors within the cytoplasm and block autophosphorylation and downstream signalling
172
What was the first targeted treatment for cancer and how did it work?
Glivec (imatinib) – it is a small molecule inhibitor that targets the ATP binding region within the kinase domain of BCR-ABL1 This inhibits the kinase activity of ABL1
173
Give four examples of small molecule inhibitors that inhibit receptors.
Erlotinib (EGFR) Gefitinib (EGFR) Lapatinib (EGFR/HER2) Sorafenib (VEGFR)
174
Give three examples of small molecule inhibitors that inhibit intracellular kinases.
Sorafenib (Raf kinase) – this is in addition to its anti-VEGFR effects Dasatinib (Src kinase) Torcinibs (mTOR inhibitors)
175
State some advantages and disadvantages of monoclonal antibodies.
Advantages: High target specificity Cause ADCC, complement-mediated cytotoxicity and apoptosis induction Can be radiolabelled Long half-life Good for haematological malignancies Disadvantages: Large and complex structure Less useful against bulky tumours Only useful against targets with extracellular domains Not useful for constitutively activated tumours Cause immunogenicity and allergy IV administration Expensive
176
State some advantages and disadvantages of small molecule inhibitors.
Advantages: Can target tyrosine kinases without an extracellular domain or which are constitutively activated Pleiotropic targets (useful in heterogenic tumours/cross-talk) Oral administration Good tissue penetration Cheap Disadvantages: Shorter half-life, more frequent administration Pleiotropic targets (more unexpected toxicity)
177
State some resistance mechanisms to targeted therapies.
Mutations in ATP binding domain Intrinsic resistance Intragenic mutations Upregulation of downstream signalling pathways
178
Explain how anti-sense oligonucleotides work.
These are short single-stranded DNA-like molecules They bind to the complementary sequence on mRNA and hinder its translation It then recruits RNase H to cleave the target mRNA Mechanism: anti-sense oligonucleotides
179
Name a successful B-Raf inhibitor.
Vemurafenib NOTE: side effects include arthralgia, skin rash and photosensitivity
180
Explain how the PD-1 receptor-PDL1 ligand system works.
PD-1 receptor is on the cell membrane When the ligand (PDL-1) binds to the PD-1 receptor, the body’s T cells can no longer recognise tumours as foreign So blocking the PD-1 receptor will stimulate the immune system
181
Name a drug that inhibiting PD-1.
Nivolumab (anti-PD1 antibody)
182
What type of carcinoma are most colon cancers?
Adenocarcinoma
183
What is the rate of turnover of cells in the colon?
2-5 million cells per minute
184
What is a polyp?
Any projection from a mucosal surface into a hollow viscus
185
What is an adenoma?
Benign neoplasm of the mucosal epithelial cells
186
What are the different types of colonic polyp?
Metaplastic/hyperplastic Adenoma
187
State some characteristics of hyperplastic polyps.
These are VERY COMMON 90% of all colonic polyps They have NO malignant potential 15% have K-ras mutations
188
What are the different types of colonic adenoma?
Tubular Tubulovillous Villous NOTE: the more villous it is the worse it is
189
What are the different shapes of colonic adenomas?
Pedunculated – looks like a tree Sessile – looks like a hedge
190
What is the difference between tubular and villous adenomas?
Tubular– COLUMNAR cells with nuclear enlargement, elongation, multi-layering and loss of polarity + increased proliferative activity + reduced differentiation Villous– MUCINOUS cells with nuclear enlargement, elongation, multi-layering and loss of polarity. May be exophytic.
191
What is the most famous condition that causes an increasednumber of colonic polyps?
Familial Adenomatous Polyposis
192
What gene mutation is FAP caused by?
5q21
193
What are the two genetic pathways in colorectal cancer?
Adenoma-carcinoma sequence = presence of adenomas will increase the risk of colorectal cancer Microsatellite instability
194
What are microsatellites?
Repeat sequences of DNA that are prone to misalignment Some microsatellites are found in coding sequences of genes which inhibit growth or are involved in apoptosis
195
State two genetic diseases that predispose to colorectal cancer.
Familial adenomatous polyposis – inactivation of the APC tumour suppressor gene HNPCC – microsatellite instability (affects mismatch repair genes)
196
State some dietary factors that can increase the risk of colorectal cancer.
High fat Low fibre High red meat Refined carbohydrates
197
State two dietary deficiencies that can increase the risk ofcolorectal cancer.
Folates– important for nucleotide synthesis and DNA methylation MTHFR– deficiency leads to disruption of DNA synthesis and DNA instability (this leads to mutation). It also causes decreased methionine synthesis leading to genomic hypomethylation and focal hypermethylation – this can have gene activating and silencing effects
198
What is the clinical presentation of colorectal cancer?
Change in bowel habit PR bleeding Unexplained iron deficiency anaemia
199
Describe the distribution of colorectal cancer.
RECTOSIGMOID –55% Caecum/Ascending –22% Transverse –11% Descending –6%
200
Describe the Dukes classification of colorectal cancers.
Dukes A Growth is limited to the wall (muscularis propria) Nodes negative Dukes B Growth beyond the muscularis propria Nodes negative Dukes C1 Nodes positive Apical nodes negative Dukes C2 Apical nodes positive
201
State some clinical features that affect the prognosis of colorectal cancer.
Bowel obstruction (diminished prognosis) Age \< 30 (diminished prognosis) Distant metastases (diminished prognosis)
202
State some pathological features that affect the prognosis of colorectal cancer.
Depth of bowel wall penetration Number of regional lymph nodes involved Venous invasion Lymphatic invasion
203
What are the criteria for a screening programme?
Condition should be important with respect to the seriousness and/or frequency The natural history of the disease must be known in order to: Identify where screening can take place To enable the effects of any intervention to be assessed
204
What are the characteristics of a screening test?
Simple and acceptable to the patient Sensitive and selective Cost effective Screening population should have equal access to the screening procedure
205
What does the NHS colorectal cancer screening look for?
Faecal occult blood (FOB) If positive and 55-60 years = sigmoidoscopy If positive and over 60 years = full colonoscopy
206
What are the five layers of the epidermis?
Stratum corneum Stracum lucidum Stratum granulosum Stratum spinosum Stratum basale
207
What are the main cell types in the epidermis?
Keratinocytes Melanocyts Langerhans Cells Merkel Cells
208
State the types of skin cancer that come under each of the following types: a. Keratinocyte derived b. Melanocyte derived c. Vasculature derived d. Lymphocyte derived
a. Keratinocyte derived Basal Cell Carcinoma Squamous Cell Carcinoma b. Melanocyte derived Malignant Melanoma c. Vasculature derived Kaposi Sarcoma – endothelium of lymphatics Angiosarcoma – endothelium of blood vessels d. Lymphocyte derived Mycosis fungoides
209
State two examples of genetic syndromes that massively increase the risk of getting skin cancer.
Gorlin’s Syndrome – regular BCCs Xeroderma Pigmentosum – increased risk of BCC, SCC and malignant melanoma
210
Give two examples of viruses that can lead to skin cancer?
HHV8 HIV
211
What is the difference between the depth reached by UVB radiation and UVA radiation?
UVB – reaches sea level UVA – reaches dead sea leve
212
How does UVB cause mutations in DNA?
Induces the formation of photoproducts Particularly affects pyrimidines – causing cross-linking Formation of cyclobutane pyrimidine dimers and 6-4 pyrimidine pyrimidone photoproducts
213
How are these mutations usually corrected?
Nucleotide excision repair
214
How can UVA promote skin carcinogenesis?
Forms cyclobutane pyrimidine dimers (but less effectively than UVB) Also generates free radicals that can damage DNA
215
Name a condition that is caused by a defect in nucleotide excision repair.
Xeroderma pigementosum
216
What are the features of this condition?
Increased risk of BCCs, SCCs and melanoma Photosensitivity and dry skin
217
What happens to keratinocytes in sunburn?
The UV damage leads to keratinocyte apoptosis The apoptotic cells in UV overexposed skin are called sun burn cells
218
Describe the immunomodulatory effects of UV light.
UVA and UVB affect the expression of genes involved in skin immunity It depletes Langerhans cells in the epidermis This reduces skin immunocompetence and immunosurveillance
219
What are the consequences of UV therapy for psoriasis?
Increased risk of skin cancer UV can act on keratinocytes and cause DNA damage If the Langerhans cells have been depleted then they will be unable to knock out the damaged cells so they could persist and become cancerous
220
Which system is used to categorise people based on their skin type and sensitivity to UV?
Fitzpatrick Phenotypes
221
Where are melanocytes found within the epidermis?
In the basal layer
222
What happens to melanin once it is produced by the melanocytes?
It is packaged into melanosomes and it passes along the processes of the melanocytes and is taken up by the keratinocytes The keratinocytes put the melanosomes around their nuclei, which protects the nuclei from DNA damage
223
What are the two types of melanin?
Eumelanin – black/brown Phaeomelanin – yellowish or reddish-brown
224
What is melanin formed from?
Tyrosine
225
What gene regulates the relative amounts of melanin produced?
MC1R
226
What is Lentigo Maligna?
Proliferation of malignant melanocytes within the epidermis There is no risk of metastasis This is also called melanoma in situ
227
What is it the name given to a large area of lentigo maligna that has a smaller area within it that has become invasive?
Lentigo maligna melanoma
228
What is a superficial spreading malignant melanoma?
Lateral proliferation of malignant melanocytes They invade the basement membrane so there is a risk of metastasis
229
What is the ABCDE for the diagnosis of superficial spreading malignant melanoma?
Asymmetry Border irregularity Colour variation Diameter (\>0.7 mm and increasing) Erythema
230
What is it called when a pale area appears in the middle of a melanoma?
Area of regression – this is associated with higher risk of metastasis
231
What is it called when you get a vertical proliferation of malignant melanocytes?
Nodular malignant melanoma
232
Describe the pattern of growth when a nodular melanoma arises from a superficial spreading malignant melanoma.
Downward proliferation of malignant melanocytes that is following previous horizontal growth
233
What is the type of melanoma that occurs on the palms and soles?
Acral lentiginous melanoma
234
What type of melanoma produced no melanin?
Amelanotic melanoma
235
What is the prognosis of melanoma based on?
Breslow thickness – thickness from the top of the tumour to the bottom
236
What is a keratoacanthoma?
It is either a benign lesion or a benign version of an SCC It grows rapidly but then disappears There is no risk of metastasis
237
What can squamous cell carcinomas (SCCs) be caused by?
UV exposure HPV Immunosuppression (main cancer in organ transplant patients)
238
How can you tell whether an SCC is well differentiated?
If the lesion has a keratin horn then it shows that the keratinocytes can still produce keratin and so they are well differentiated
239
What is a basal cell carcinoma (BCC)?
Malignant tumour arising from keratinocytes in the basal layer of theepidermis
240
Describe the appearance of BCCs
They are pearly, have a rolled edge and often have arborising telangiectasia
241
Name a cutaneous T cell lymphoma.
Mycosis fungoides
242
Which viruses are associated with Kaposi sarcoma?
HHV8 HIV
243
Name a disease that predisposes to SCCs and HPV induced warts (that can become incredibly keratotic).
Epidermodysplasia Veruciformis
244
What is special about the breast as an organ?
It is the only organ that develops after birth
245
Where do the vast majority of breast cancers originate?
In the luminal epithelium of the breast (\> 90%)
246
Describe the two layers of epithelial cells in the mammary gland.
Luminal epithelium Myoepithelium
247
What is found between the tubules?
Fatty stromal cells
248
What is special about the myoepithelial cells?
They have a contractile phenotype
249
Where are oestrogen receptors expressed in the breast?
They are ONLY expressed by luminal cells But not all luminal cells express oestrogen receptors (only about 10-15%
250
Describe the response to oestrogen in a normal breast.
The response to oestrogen is to stimulate growth The cell that express oestrogen receptors do NOT grow in response to oestrogen They act as a beacon and produce growth factors the stimulate the growth of nearby cells
251
How is this response different in breast cancer?
The cells displaying oestrogen receptors directly respond to oestrogen as a growth factor and stimulate their own growth
252
What is the difference between lobular and medullary carcinoma?
Lobular – the tumour has some resemblance of the architecture of the gland (there are tubules of some form) Medullary – the tumour cells don’t look anything like the epithelial cells from the mammary gland
253
What specific type of breast cancer accounts for almost 80% of breast cancers?
Infiltrating ductal carcinoma
254
What percentage of breast cancers is ER positive?
80%
255
State some risk factors for breast cancer.
Early age of onset of menstruation Late age to menopause Age to first full-time pregnancy Some contraceptive pills Some HRT
256
Where is the oestrogen receptor normally located?
It is a cytosolic receptor It is found in the cytosol bound to a heatshock protein
257
What happens when oestrogen binds to ER?
The oestrogen binds to ER and then two ERs dimerise and translocate to the nucleus (with oestrogen bound) The dimer then binds to response elements in the DNA sequence and regulates transcription
258
What are the most important target genes for the ER transcription factor?
Progesterone receptor Cyclin D1 c-myc TGF-alpha
259
Why does high dose therapy with synthetic oestrogens cause breast tumour regression in post-menopausal women with breast cancer?
High-dose therapy overstimulates the hormonal system leading to downregulation of ER so the cells are no longer responsive to oestrogen
260
How does the presence of ER affect prognosis
GOOD prognosis in women Worse prognosis in male breast cancer
261
What are three methods of reducing oestrogen action in the breast?
Ovarian suppression Blocking oestrogen production by enzymatic inhibition Inhibiting oestrogen responses
262
At what point during the menstrual cycle is oestrogen at its highest?
End of the follicular phase
263
How do post-menopausal women make oestrogen?
Aromatisation of androgens
264
What are two methods of ovarian ablation?
Surgical oophorectomy Ovarian irradiation
265
What are the problems associated with these methods?
They are irreversible
266
Describe a reversible and reliable medical ovarian ablation technique.
LHRH agonists bind to LHRH receptors in the pituitary leading to receptor downregulation and suppression of LH release and inhibitionof ovarian function, including oestrogen production
267
Give an example of a LHRH agonist.
Goserelin Buserelin Triptorelin Leuprolife
268
Name an important ER receptor blocker.
Tamoxifen
269
What is a SERM?
Selective oestrogen receptor modulator
270
Why is tamoxifen considered a SERM?
It is anti-oestrogenic in the breast It is oestrogenic in bone and cardiovascular system
271
Name a drug that is a pure anti-oestrogen, showing no oestrogen like activity at all.
Faslodex
272
What is raloxifene?
A SERM – it is oestrogenic in bone and anti-oestrogenic in the breast and uterus
273
What are the problems associated with tamoxifen?
Increased incidence of endometrial cancer (oestrogenic in the uterus) Increased risk of stroke, DVT, cataracts
274
Which adrenal hormones are aromatised in post-menopausal women?
Androstenedione (and testosterone, to a lesser extent)
275
What type of oestrogen is produced in aromatisation?
Oestrone
276
What does the aromatase complex consist of?
CYP450 heme containing protein NADPH CYP450 reductase
277
What are the two types of aromatase inhibitor?
Suicide inhibitors Competitive inhibitors
278
How do suicide inhibitors work?
They initially compete with the natural substrate for the active site The enzyme then specifically acts on the inhibitor to yield reactivealkylating species, which form covalent bonds at or near the active site of the enzyme Through this mechanism the enzyme is irreversibly inactivated
279
Give an example of a suicide inhibitor.
Exemestane
280
Give an example of a competitive aromatase inhibitor.
Anastrozole
281
What can progestin therapy be used for?
Metastatic breast cancer
282
What is the main progestin used for metastatic breast cancer?
Megestrol acetate
283
What is a big problem with endocrine therapy?
Resistance develops
284
Women in which age range are targeted for breast cancer screening? How often are they asked to go for screening?
50-64 yrs (this is being extended to 70 yrs) Every 3 years
285
What proportion of breast tumours are first spotted by the women themselves?
\> 90%
286
How can breast cancer be linked to the following symptoms: severe vertigo, unintelligible speech, truncal and appendicular ataxia?
Paraneoplastic cerebellar degeneration
287
Explain how breast cancer can lead to the degeneration of the cerebellum.
The antigen that the immune response is directed against is normally expressed in neural tissue It is only expressed in breast tissue when there is a tumour The abnormal expression of this antigen in the breast was noticed and an immune response was mounted, which then also reacted with the normal antigens in the neural tissue --\> destruction of purkinje cells in the cerebellum
288
Describe the cancer-immunity cycle.
Antigens are released from cancer cells and captured by APCs, which then migrate to local draining lymph nodes If the environment is sufficiently inflammatory and there is enoughcostimulation then you will get activation of the T cell response Once the T cells are activated they go back to the tumour – the processed antigens are then recognised by the T cells, which then kill the cancer cells NOTE: this cycle is pretty similar to viral infections
289
Describe the effect of the PD-1 – PDL-1 signalling on the T cell response.
When a T cell has been exposed to an antigen several times, it starts to express PD-1 receptors Tumour cells the upregulate expression of the PDL-1 ligand, which can bind to the PD-1 receptor and downregulate the T cell response Blockade of the PD1-PDL1 interaction could help stimulate the T cell response
290
What is the main difference between tumours and viral infections with regards to the immune response?
Viral infections trigger a lot of inflammation, which causes upregulation of costimulatory molecules so an immune response can take place Tumours do not cause very much inflammation, especially early on so they are more likely to be missed by the immune system
291
What are the requirements for activation of an adaptive anti-cancer immune response?
Local inflammation in the tumour Expression and recognition of tumour antigens
292
What are the main problems with the immune surveillance of cancer?
It takes a tumour a while to cause inflammation Antigenic differences between normal and tumour cells can be very subtle
293
Which MHC class presents endogenous peptides?
MHC Class I
294
Give two examples of opportunistic malignancies.
EBV positive lymphoma (post-transplant immunosuppression) HHV8 positive Kaposi sarcoma (occurs in HIV)
295
Give a few examples of viral infections that can cause cancer inimmunocompetent individuals.
HTLV1 associated leukaemia/lymphoma HepB virus- and HepC virus-associated hepatocellular carcinoma HPV positive genital tumours
296
Which oncoproteins of HPV are responsible for the induction andmaintenance of cervical cancer?
E6 E7
297
What proteins do the vaccines for HPV use?
Structural proteins are used to generate virus particles
298
Give an example of an HPV vaccine.
Gardasil
299
What are the two different times at which vaccines can be given?
Preventative vaccination (before the disease) Therapeutic vaccination (try to control the disease once it has occurred)
300
What are tumour-associated antigens?
They are generally derived from normal cellular proteins to which the immune system is not tolerant and become immunogenic when expressed by the tumour This is abnormal expression of a normal protein
301
Give examples of tumour-associated antigens.
Cancer-testis antigens – silent in normal adult tissues except male germ cells MAGE – melanoma-associated antigens – identified in melanoma, also expressed in other tumours
302
When is p53 considered a tumour-associated antigen and when isit considered a tumour specific antigen?
Tumour-associated antigen – when it is over-expressed Tumour specific antigen – when it becomes mutated
303
Describe the problem with tolerance in cancer immunotherapy.
T cells that react strongly with self are deleted (central tolerance) so most people have tolerance against tumour-associated antigens
304
What are the two major obstacles for the targeting of tumour-associated antigens in immunotherapy of cancer?
Autoimmune responses against normal tissues Immunological tolerance
305
What are three possible approaches to tumour immunotherapy?
Cancer vaccination – immunisation to stimulate natural anti-cancer responses Genetic modification of T cells to express a receptor capable of recognising the tumour – these are then inserted back into the patient so that the T cells can kill the tumour cells Blockade of molecules that inhibit T cell responses
306
What is the most common cancer in the 15-24 age group?
Cancers of the blood
307
What is the literal meaning of leukaemia?
White blood
308
Where does the problem exist in leukaemia?
In the bone marrow (not all patients have abnormal cells in the blood)
309
What does leukaemia result from?
A series of mutations in a single lymphoid or myeloid stem cell
310
What are the consequences to the progeny of the mutated cell?
These mutations lead to progeny of that cell to show abnormalities in proliferation, differentiation or cell survival leading to steady expansion of the leukaemic clone
311
Which cells can be affected in leukaemia?
Pluripotent haematopoietic stem cell Myeloid stem cell Lymphoid stem cell Pre B lymphocyte Pro T lymphocyte
312
What are the equivalent terms for ‘benign’ and ‘malignant’ in terms of leukaemia?
Leukaemias that behave relatively benignly are CHRONIC Leukaemias that behave in a malignant manner are ACUTE– the disease is very aggressive
313
What are the four main types of leukaemia?
Acute lymphoblastic leukaemia Acute myeloid leukaemia Chronic lymphocytic leukaemia Chronic myeloid leukaemia
314
Explain the significance of the terms acute lymphoblastic leukaemia and chronic lymphocytic leukaemia.
In ALL the cells are immature – they are lymphoblasts IN CLL the cells are mature lymphocytes
315
What are the important leukaemogenic mutations that have been recognised?
Mutation in a known proto-oncogene Creation of a novel gene e.g. chimeric or fusion gene Dysregulation of a gene when translocation brings it under the influence of a promoter or enhancer of another gene
316
State some inherited or other constitutional abnormalities that can contribute to leukaemogenesis.
Down syndrome Chromosomal fragility syndromes Defects in DNA repair Inherited defects in tumour suppressor genes
317
What are some identifiable causes of leukaemogenic mutations?
Irradiation Anti-cancer drug Cigarette smoking Chemicals e.g. benzene
318
What type of cell is seen in abundance in acute myeloid leukaemia?
Immature myeloid cells – the cells continue to proliferate but they no longer mature so there is a build up of immature cells (myeloblasts) in the bone marrow, which spread to the blood
319
Explain how acute leukaemia leads to bone marrow failure.
The leukaemic cells crowd out the normal cells in the bone marrow leading to a decrease in the production of other end cells e.g. neutrophils, monocytes, platelets
320
What do the responsible mutations normally affect in AML?
Transcription factors – the transcription of multiple genes is affected Often the product of an oncogene prevents the normal function of theprotein encoded by its normal homologue This leads to changes in cell kinetics and cell functions
321
What do the responsible mutations normally affect in CML?
A gene encoding a protein in the signalling pathway between a cell surface receptor and the nucleus The protein encoded may be a membrane receptor or a cytoplasmic protein
322
Describe the nature of the leukaemic cells in CML.
These are mature lymphocytes – their cell kinetics and function are not as seriously affected as they are in AML but the cells do become independent of external signals, there are alterations in the interaction with stroma and there is reduced apoptosis so that cells survive longer and the leukaemic clone expands progressively
323
How is the production of end cells affected in AML and CML?
AML – decrease in the production of end cells CML – increase in the production of end cells
324
What are the metabolic effects of leukaemic cell proliferation?
Hyperuricaemia Renal failure Weight loss Low grade fever Sweating
325
Which type of leukaemia increases the risk of intraventricular haemorrhage and why?
Acute promyelocytic leukaemia (APML) – this is associated with DIC so the platelet count and fibrinogen are low leading to increased risk of fatal haemorrhage
326
How can leukaemia cause proliferation of the gums?
Infiltration of leukaemic cells and monocytes can lead to inflammation of the gums There will be small haemorrhages due to thrombocytopenia
327
What does epidemiology suggest that B lineage acute lymphoblastic leukaemia may result from?
It may result from delayed exposure to a common pathogen
328
What are some factors that relate to risk of leukaemia?
Family size, new towns, socio-economic class, early social interactions
329
What can leukaemias in infants and young children result from?
Irradiation in utero In utero exposure to certain chemicals
330
What are the clinical features of acute lymphoblastic leukaemia?
Bone pain Hepatomegaly Splenomegaly Lymphadenopathy Thymic enlargement Testicular enlargement These all result from the accumulation of abnormal cells
331
What are some clinical features of acute lymphoblastic leukaemia that result from the crowding out of normal cells
Caused by anaemia – fatigue, lethargy, pallor, breathlessness Caused by neutropenia – fever and other features of infection Caused by thrombocytopenia – bruising, petechiae, bleeding
332
What investigations are performed in acute lymphoblastic leukaemia?
Blood count and film Check of liver function and renal function and uric acid Bone marrow aspirate Cytogenetic/molecular analysis Chest X-ray
333
What are the uses of cytogenetic and molecular genetic analysis in ALL?
It is useful for managing the individual patient because it gives us information about prognosis It permits the discovery of leukaemogenic mechanisms
334
What are the implications of hyperdiploidy in in the cytogenetic analysis of ALL?
Good prognosis
335
What features of the cytogenetic analysis are associated with a poor prognosis?
Chromosomal translocations resulting in the formation of a bad fusion gene
336
What translocation causes ALL? State the fusion gene.
Translocation between chromosome 12 and chromosome 21 Fusion gene: ETV6-RUNX1 on chromosome 12
337
What technique is used to detect the fusion genes in ALL?
Fluorescence in situ hybridisation (FISH)
338
What are the treatment options for ALL?
Supportive: red cells, platelets, antibiotics Systemic chemotherapy Intrathecal chemotherapy
339
What are the changes that occur in the cells that occur during tumour progression?
Genetic alterations lead to hyperproliferation, disassembly of cell-cell contacts, loss of polarity, increased motility and cleavage of ECM proteins
340
What are the different types of tumour cell migration?
Single cell migration (ameboid) Mesenchymal single cells Mesenchymal chains Clusters/cohorts Multicellular strands/sheets
341
What physiological phenomena does tumour migration mimic?
Morphogenesis e.g. angiogenesis
342
What did a comparison of the expression profile of invasive cells vs primary tumours show to be upregulated in invasive cells?
Cytoskeleton regulation Motility machinery
343
What makes normal migrating cells stop moving?
Contact inhibition of locomotion
344
How are tumour cells different in this aspect?
They lose contact inhibition of locomotion so they can multilayer
345
What is another term for ECM proteins?
Substratum
346
What are filopodia?
Finger-like protrusions that are rich in actin filaments They sense the local environment
347
What are lamellipodia?
Sheet-like protrusions that are rich in actin filaments
348
What are the four main stages of cell movement?
Extension Adhesion Translocation De-adhesion
349
What are the attachments between the cell and the surface that it is moving along called?
Focal adhesions
350
What are the monomers of actin filaments?
G-actin
351
Describe the polarity of acting filaments.
They have a plus end and a minus end The monomers preferentially get added on at the plus end
352
What protein complex is important in initiating polymerisation?
Arp2/3 This forms a trimer with actin and is good at initiating polymerisation
353
What is the limiting step in actin dynamics?
Formation of Arp2/3-actin trimers to initiate polymerisation
354
State two proteins that bind to free G-actin and describe how they affect elongation.
Promote elongation – profilin (these deliver the G-actin to the growing filament) Sequesters G-actin –beta4 thymosin ADF, cofilin
355
Name some + end capping proteins.
CapZ Gelsolin Fragmin/severin
356
Name some – end capping proteins.
Tropomodulin Arp2/3
357
Name some severing proteins.
Gelsolin ADF Framin/severin Cofilin
358
What are the features of the actin filaments in severed populations?
Actin filaments can grow and shrink more rapidly
359
What can happen to single filaments of actin to improve their structural integrity?
They can be bundled or cross-linked
360
Name some proteins involved in these processes.
Alpha-actinin Fimbrin Filamin Spectrin Villin Vinculin
361
Which protein allows branching of the actin filaments?
Arp2/3
362
At what angle do they branch?
70 degree
363
Summarise the actions of Arp2/3.
They initiate nucleation They cap filaments They cause branching
364
Describe what causes the gel-sol transition.
The actin filaments can be severed to make the cell more fluid
365
Describe the actin processes that take place during the protusion of lamellipodia.
There is polymerisation, disassembly, branching and capping There is net filament assembly at the leading edge
366
Describe the actin processes that take place during the formation of filopodia.
Actin polymerisation Bundling and cross-linking (NO branching) As soon as the finger wants to retract it will collapse at the base
367
State four signalling mechanisms that regulate the actin cytoskeleton.
Ion flux changes Phosphoinositide signalling Kinases/phosphatases Small GTPases
368
What are the three most important small GTPases in terms of the actin cytoskeleton and what does activation of each cause?
Cdc42 – filopodia Rac – lamellipodia Rho – stress fibres NOTE: these are all part of the Rho family
369
Explain how Rac causes actin polymerisation/organisation.
Rac binds to and activates WAVE WAVE then activates Arp2/3, which is important in actin organisation
370
Explain how Cdc42 causes actin polymerisation/organisation.
Cdc42 binds to WASP WASP also activates Arp2/3
371
Which small GTPases are involved in lamellipodia protrusion?
Rac
372
Which small GTPases are involved in focal adhesion assembly?
Rac and Rho
373
Which small GTPases are involved in contraction?
Rho (stress fibres are important for contraction)
374
What are the changes that occur in the cells that occur during tumour progression?
Genetic alterations lead to hyperproliferation, disassembly of cell-cell contacts, loss of polarity, increased motility and cleavage of ECM proteins
375
What are the different types of tumour cell migration?
Single cell migration (ameboid) Mesenchymal single cells Mesenchymal chains Clusters/cohorts Multicellular strands/sheets
376
What physiological phenomena does tumour migration mimic?
Morphogenesis e.g. angiogenesis
377
What did a comparison of the expression profile of invasive cells vs primary tumours show to be upregulated in invasive cells?
Cytoskeleton regulation Motility machinery
378
What makes normal migrating cells stop moving?
Contact inhibition of locomotion
379
How are tumour cells different in this aspect?
They lose contact inhibition of locomotion so they can multilayer
380
What is another term for ECM proteins?
Substratum
381
What are filopodia?
Finger-like protrusions that are rich in actin filaments They sense the local environment
382
What are lamellipodia?
Sheet-like protrusions that are rich in actin filaments
383
What are the four main stages of cell movement?
Extension Adhesion Translocation De-adhesion
384
What are the attachments between the cell and the surface that it is moving along called?
Focal adhesions
385
What are the monomers of actin filaments?
G-actin
386
Describe the polarity of acting filaments.
They have a plus end and a minus end The monomers preferentially get added on at the plus end
387
What protein complex is important in initiating polymerisation?
Arp2/3 This forms a trimer with actin and is good at initiating polymerisation
388
What is the limiting step in actin dynamics?
Formation of Arp2/3-actin trimers to initiate polymerisation
389
State two proteins that bind to free G-actin and describe how they affect elongation.
Promote elongation – profilin (these deliver the G-actin to the growing filament) Sequesters G-actin beta–4 thymosin ADF, cofilin
390
Name some + end capping proteins.
CapZ Gelsolin Fragmin/severin
391
Name some – end capping proteins.
Tropomodulin Arp2/3
392
Name some severing proteins.
Gelsolin ADF Framin/severin Cofilin
393
What are the features of the actin filaments in severed populations?
Actin filaments can grow and shrink more rapidly
394
What can happen to single filaments of actin to improve their structural integrity?
They can be bundled or cross-linked
395
Name some proteins involved in these processes.
Alpha-actinin Fimbrin Filamin Spectrin Villin Vinculin
396
Which protein allows branching of the actin filaments?
Arp2/3
397
At what angle do they branch?
70 degrees
398
Summarise the actions of Arp2/3.
They initiate nucleation They cap filaments They cause branching
399
Describe what causes the gel-sol transition.
The actin filaments can be severed to make the cell more fluid
400
Describe the actin processes that take place during the protusion of lamellipodia.
There is polymerisation, disassembly, branching and capping There is net filament assembly at the leading edge
401
Describe the actin processes that take place during the formation of filopodia.
Actin polymerisation Bundling and cross-linking (NO branching) As soon as the finger wants to retract it will collapse at the base
402
State four signalling mechanisms that regulate the actin cytoskeleton.
Ion flux changes Phosphoinositide signalling Kinases/phosphatases Small GTPases
403
What are the three most important small GTPases in terms of the actin cytoskeleton and what does activation of each cause?
Cdc42 – filopodia Rac – lamellipodia Rho – stress fibres NOTE: these are all part of the Rho family
404
Explain how Rac causes actin polymerisation/organisation.
Rac binds to and activates WAVE WAVE then activates Arp2/3, which is important in actin organisation
405
Explain how Cdc42 causes actin polymerisation/organisation.
Cdc42 binds to WASP WASP also activates Arp2/3
406
Which small GTPases are involved in lamellipodia protrusion?
Rac
407
Which small GTPases are involved in focal adhesion assembly?
Rac and Rho
408
Which small GTPases are involved in contraction?
Rho (stress fibres are important for contraction)
409
Broadly speaking, what are the two causes of abnormal haemostasis?
Lack of a specific factor Defective function of a specific factor
410
What can cause thrombocytopenia?
Failure of production – bone marrow failure e.g. leukaemia, B12 deficiency
411
State one very common cause of thrombocytopenia.
Autoimmune thrombocytopenia
412
What is a distinctive clinical feature of thrombocytopenia?
Petechiae
413
State three hereditary platelet defects.
Glanzmann’s Thrombasthenia – absence of GlpIIb/IIIa (prevents platelet aggregation) Bernard Soulier Syndrome – absence of GlpIb (prevents binding to von Willebrand factor) Storage Pool Disease – storage granules are not able to release adequately
414
Broadly speaking, state three causes of thrombocytopenia.
Failure of platelet production by the megakaryocytes Shortened half-life of platelets Increased pooling of platelets in an enlarged spleen (hypersplenism)
415
State a broad acquired cause of impaired platelet function.
Drugs e.g. NSAIDs, clopidogrel
416
What are the two roles of von Willebrand factor in haemostasis?
Binding to collagen and trapping platelets Stabilising factor 8 (if VWF is low, factor 8 may be low)
417
Von Willebrand Disease is usually hereditary. What are the threetypes of von Willebrand disease? State their pattern of inheritance.
Type 1 – deficiency of VWF but it functions normally (autosomal dominant) Type 2 – VWF does not function normally (autosomal dominant) Type 3 – VWF not made at all (autosomal recessive)
418
State two inherited vessel wall conditions that cause defects in primary haemostasis.
Hereditary haemorrhagic telangiectasia Ehlers-Danlos Syndrome
419
State some acquired causes of vessel wall conditions that cause defects in primary haemostasis.
Scurvy Steroid therapy Ageing (senile purpura) Vasculitis
420
Describe the pattern of bleeding in defects of primary haemostasis.
The primary platelet plug isn’t strong enough to stop the bleeding Bleeding is immediate Prolonged from cuts Epistaxes Gum bleeding Menorrhagia Easy bruising Prolonged bleeding after trauma and surgery
421
How are the clotting factors affected in severe von Willebrand disease?
Reduced factor 8 (because VWF stabilizes factor 8) This causes haemophilia type bleeding patterns
422
What tests can be done for disorders of primary haemostasis?
Platelet count Bleeding time Assays for VWF Clinical observation
423
What is haemophilia caused by? What is its pattern of inheritance?
Lack of Factor 8 (A) or Factor 9 (B) This leads to impaired thrombin generation In haemophilia you get failure to generate fibrin to stabilize the platelet plug It is X-linked recessive
424
Describe the difference in outcome for deficiencies of factors 2, 8 & 9, 11 and 12.
2 – lethal 8 & 9 (haemophilia) – severe but compatible with life 11 – bleeding after trauma but not spontaneously 12 – no excess bleeding
425
State some acquired causes of deficiency of coagulation factors.
Liver disease Dilution Anti-coagulant drugs (e.g. warfarin)
426
State some disorders of coagulation that are due to increased consumption.
Disseminated intravascular coagulation (DIC) Autoimmune thrombocytopenia
427
What happens in Disseminated Intravascular Coagulation (DIC)?
Generalised activation of coagulation It is associated with sepsis, inflammation and tissue necrosis It consumes and depletes coagulation factors Platelets are consumed
428
Describe the pattern of bleeding in coagulation disorders.
Superficial cuts DO NOT bleed (because primary haemostasis is fine) Bruising is common Spontaneous bleeding is DEEP, into muscles and joints Bleeding after trauma may be delayed and prolonged Frequently restarts after stopping
429
What is the hallmark of haemophilia?
Haemarthrosis
430
What simple medical procedure must you avoid doing to patients with haemophilia?
Intramuscular injection – it can cause deep bleeding patterns
431
State some tests that are used for coagulation disorders.
Screening Tests – APTT, PT & Platelet Count Factor Assays Tests for inhibitors
432
Describe the APTT and PT results for a patient with haemophilia.
Prolongs APTT but normal PT This is because the defect lies in the intrinsic pathway (factor 8 or 9)
433
State some bleeding disorders that are not detected by routine clotting tests.
Mild factor deficiencies Von Willebrand Disease Factor 8 Deficiency (cross-linking) Platelet disorders Excessive fibrinolysis Vessel wall disorders Metabolic disorders (e.g. uraemia) NOTE: urea interferes with platelet function
434
State a hereditary disorder of fibrinolysis.
Antiplasmin deficiency
435
State two acquired disorders of fibrinolysis.
Drugs such as tissue plasminogen activator Disseminated intravascular coagulation (DIC) – because everything has been used up
436
What is the treatment that is considered for a patient whoseabnormal haemostasis is caused by immune destruction of platelets?
Immunosuppression (e.g. prednisolone)
437
What clotting factors are found in cryoprecipitate?
Fibrinogen Factor VIII Factor XIII Von Willebrand Factor
438
Factor concentrates are available for all factors except which one?
Factor V
439
Describe the use of Desmopressin (DDAVP) in von Willebrand disease.
Desmopressin makes the endothelial cells release their stored VWF This is good for people with mild von Willebrand disease (as it releases endogenous stored of VWF)
440
State two other drugs that are used as haemostatic treatments.
Tranexemic acid (inhibits fibrinolysis) Fibrin glue
441
What is neoplasm?
Abnormal mass of tissue growth Growth continues after stimulus is removed
442
What do we call the cancer cells?
Parenchyma
443
What is stroma?
Tissue around the cancer cels that consists of connective tissue, blood vessels, macrophages
444
How to tell if a toy our is benign or malignant by name?
Benign tumours end in -Oma Except sarcoma and carcinoma
445
Difference between malignant and benign tumours
Malignant = undifferentiated cells Grow faster Infiltrate basal Latina Metastasise
446
4 ways of metastasis
Lymphatic Haematogenous Body cavity Contiguous = touching
447
3 ways of inheriting cancer
Autosomal dominant = familial adenomatous polyposis Defective DNA repair = Xeroderma pigmentosum Familial cancer syndrome = unknown cause but runs in family e.e multiple endocrine neoplasia
448
Non hereditary cancers
Risk factor e.g. liver cirrhosis and HCC Inflammation and cytokines can cause cancer
449
What is carcinogenesis?
Acquiring malignancy in over a period of time due to multiple mutation
450
Carcinogens
Chemicals= may need to be processed elder they are carcinogenic Viruses e.g. HPV cervical cancer Radiation UV
451
4 regulatory genes and examples of cancers caused by loss of regulation in each
Oncogene = burkitts lymphoma mYC Tumour suppressor genes = BRCA 1/2 DNA repair genes = genomic instability syndrome Apoptosis = bcl2 unregulated in lymphomas
452
Diagnosis and testing
Biopsy Fine needle aspiration Scans PCR / FISH
453
Difference between grading and staging?
Grading = histological , based on differentiation Staging = size, spread to lymph nodes, metastasis = for patient STAGING IS MORE USEFUL!!
454
How common are primary malignant brain tumors?
- 2% of all cancers in US adults - over 120 types of brain tumors - incidence higher in men than women - peaks b/t 65-79 years - more in children and older adults - 2nd leading cause of death in children behind leukemia
455
RFs of primary malignant brain tumors?
- genetic mutation - neurofibromatosis (assoc of tumors all over body) - exposure to high dose ionizing radiation: radiation therapy atomic bomb survivors CT scans, dental xrays -studies show slight increase in these groups: lab researchers, healthcare professionals electric workers prior head trauma
456
Classification of CNS neoplasms?
- based on cellular origin and histologic appearance: grade 1-IV: I: benign (still dangerous) II: malignant III: malignant tissue that has cells that are actively growing IV: malignant tisue has cells that look most abnormal and tend to grow quickly
457
Tumor classification?
- neuroglial (glioma): astrocytoma oligodendroglioma ependymoma -meningioma -schwannoma: acoustic neuroma
458
What is glial tissue? How common are gliomas?
- is supportive tissue of the brain - derived from astrocytes, oligodendrocytes, or ependymal cells - encompasses 30% of all primary brain tumors and 80% of malignant brain tumors
459
Astrocytic tumors?
- glioblastomas - astrocytomas - together these make up 76% of gliomas
460
Grading of astrocytic tumors?
- grade I: benign (excision is curative) almost always dx in childhood - grade II: slow growing and invade surrounding tissue - grade III: rare and require aggressive tx due to tentacle like growth are hard to resect - grade IV: called glioblastoma, aggressive fast growing cancer
461
Glioblastoma -location, tx, and survival?
- generally located within cerebral hemispheres of brain - usually HIGHLY malignant - most common malignant brain tumor - 60-75% of all astrocytomas - very difficult to remove due to finger like tentacles - survival is about 2 years - tx: surgery, radiation and chemo (debulk tumor - cause less sxs, if inoperable - chemo/rad)
462
What are oligodenrogliomas? Grade? Growth?
- 2% of primary brain tumors - can be grade II-III (malignant) - most common in frontal or temporal lobes - can have areas of hemorrhage - generally slow growing and present for years before dx
463
Most common presenting sxs of oligodendrogliomas? Tx?
- most common: seizure - if frontal lobe tumors - may cause: weakness on one side of body, personality changes, behavior changes, difficulty with short term memory (TBI sxs) Tx: surgery radiation chemo
464
Prognosis of oligodendrogliomas?
- better prognosis compared to astrocytic tumors - from time of dx to median time of surviva; 4-10 years
465
Ependymoma occurrence?
- ependymal cells line ventricles and center of spinal cord - relatively rare in adults (2-3% of brain tumors) - more common in children - bimodal distribution peaks at age 5-6 and 20-30 years
466
Most common in kids? spinal cord or intracranial? sxs assoc with this?
- intracranial more common - poor prognosis - sxs are from IICP: hydrocephalus HA N/V ataxia strabismus irritability altered mental status
467
Most common ependymoma tumor in adults? sxs?
- spinal cord - better prognosis - may cause cord compression sxs: paralysis, weakness, herniated disc sxs, won't present with seizures or other UMNL sxs,
468
What is a meningioma? How common is this?
- derived from meningothelial cells that arise from coverings of brain and spinal cord - 20-30% of primary brain tumors - most common primary brain tumor
469
Meningioma characteristics? Tx?
- more common in women - often benign - usually grow inward putting pressure on brain and spinal cord - can grow outward and cause thickening of skull - tx: surgery and radiation
470
Meningioma prognosis?
- est 5 year survival rate is 73-94% diff to estimate due to many people found to have meningiomas die from other causes - tx: surgery and radiation
471
Sites where meningiomas can develop? Sxs?
suprasellar, optic sheath, paranasal/olfactory, foramen magnum, clivus sxs: -irritation: seizures -compression: HA, focal weakness, dysphagia, apathy, somnolence -stereotypic: CN deficits, change in mentation, visual changes, anosmia, exopthalmos, tongue atrophy - vascular: compression of cerebral arteries - misc: hydrocephalus, panhypopituitarism
472
Tumors of the cranial and paraspinal nerves?
- schwannoma - neurofibroma - perineurioma - malignant peripheral nerve sheath tumor
473
What are schwannomas?
- nerve sheath tumor composed of schwann cells - relatively slow growing - mostly benign and less than 1% become malignant - tumor cells always stay on outside of nerve (tumor itself may either push the nerve aside and/or up against a bony structure thereby possibly causing damage
474
Most common schwannoma?
- acoustic neuromas
475
Characteristics of acoustic neuromas?
- arises from 8th CN - benign - usually slow growing - can cause serious complications and even death if they grow and exert pressure on nerves and eventually on brain - other locations include spine and more rarely along nerves that go to the limbs
476
Sxs of acoustic neuromas?
- unilateral hearing loss - tinnitus - occasional dizziness - difficulty swallowing - impaired eye movement - taste disturbance - unsteadiness - HA
477
Tx of acoustic neuromas?
- surgical excision - stereotactic radiation surgery to arrest growth - in some cases tehy are followed by observation for growth: small tumor size, not sig sx, elderly, poor surgical candidates or pt declines other tx
478
Outcome and prognosis of acoustic neuromas?
- tinnitus: up to 60% of pts it is relieved - recurrence: less than 5% but observe for up to 10 years - hearing: can be preserved in up to 80% of pts - facial nerve dysfxn: incidence of facial nerve paralysis post surgery is variable depends on tumor size
479
Primary CNS lymphomas are common in what populatons? How common are these?
- pts with immunodeficiency syndromes: organ transplant, HIV, autoimmune disease - 2% of all primary brain tumors - derived from B lymphocytes - most often occurs in cerebral hemispheres: may involve eyes, CSF, or spinal cord
480
Tx of CNS lymphoma?
- steroids to decrease brain edema: may cause tumor regression - chemo and or radiation - usually inoperable due to location deep in brain \*\*\* don't give steroids until dx imaging done - b/c steroids can change tumor cells and make it undx
481
Most common cancers to met to brain?
- met tumor: most common brain tumor - can spread to brain from any peripheral tumor - most common: lung (16-20%) RCC (7-10%) malignant melanoma (7%) breast (5%) colon (1-2%)
482
Tx of met brain tumors?
- radiation and or chemo
483
What type of dx imaging should you order for eval of neoplasm in brain?
- MRI with contrast
484
Presentation of CNS tumors?
- sxs start with focal neuro signs and move to more generalized sxs as tumor size increases
485
Generalized sxs of CNS tumors?
- HAs - seizures - N/V - depressed LOC - neurocog dysfxn
486
Focal sxs of CNS tumors?
- seizures - weakness - sensory loss - aphasia - visual spatial dysfxn
487
Overall - Sxs of CNS tumor?
-HA -seizures -syncope -N/V -numbness, tingling, weakness -balance issues -cognitive dysfxn: personality changes, changes in memory, attention, altered language ability, problems with executive fxn, change in daily patterns of eating and sleeping
488
Tumor HA characteristics?
- dull, constant - usually bilateral, and not throbbing - occipital or frontal lobes - increased with coughing or straining - worse with change in body position or after lying down to rest - tend to be worse at night and may awaken pt from sleep - N/V - change in pattern from usual HA - 48% of pts with brain tumors have HAs
489
Most common sxs of gliomas and cerebral mets?
- seizures - HA is also very common
490
Medical management of HA/brain edema and seizure?
- HA/brain edema: steroids (Decadron) - seizures: anti-seizure meds: valproic acid, carbamazepine, (lorazepam for status epilepticus)
491
Tumors and bleeding?
- brain tumors bleed - bleed a lot when given anticoagulation - CI to thrombolytics - in pts with known cancer (RCC) always be on lookout for signs and sxs of cerebral mets or hemorrhage
492
Workup for brain tumors?
- Hx - PE to include complete neuro exam - visual, stereognosis, graphesthesia, testing of CNI - imaging: MRI with gadolinium, CT not as detailed and difficult to see posterior fossa structures - +/- LP to examine cells in certain cases - +/- cerebral angiogram - bx
493
Tx of brain tumors?
- surgical resection - chemo - radiation
494
Tumor staging?
- no std staging - primary brain tumors stay within the CNS
