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PBL Y2 S4 > Case 4- Bowel cancer > Flashcards

Case 4- Bowel cancer Flashcards

1
Q

What are some structural features of small intestine?

A
  • Plicae circularis: mucous folds that increase SA
  • Villi and microvilli: villi contain an arteriole, venole and lacteal,
  • Crypts: tubular glands that open between villi (bases). The duodenal glands (of Brunner) are seen in the mucosa
  • Lymphatic follicles: aggregated lymphoid follicles throughout SI and LI, in the ileum they are called Peyer’s patches
  • Paneth cells: secrete antimicrobial peptides, i.e. Defensins and lysozymes
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2
Q

how can you distinguish between the jejunum and ileum

A

Jejunum has thicker wall, is larger and red in colour as it is more vascular. It has longer vasa recta with less prominent arterioles (from SMA)
[ileum has shorta vasa recta and more arteriole arcades]

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3
Q

How can brush border enzymes enter the SI? Give an example of one

A

Brush border enzymes are present on microvilli and break down materials when they come into contact. Epithelial cells absorb the breakdown products, then shed and disintegrate in the lumen. This releases intracellular and brush border enzymes
Example = enteropeptidase (enterokinase) - then activates trypsingen after entry

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4
Q

What causes peristaltic contractions of the duodenum after chyme enters?

A

Myenteric reflexes - stimulated by distention of food. It contracts the muscle behind the stimulus and relaxes the muscle in front of it = push food in one direction

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5
Q

When is gastrin secreted by the duodenum and what does it lead to?

A

Secreted by enteroendocrine G cells when exposed to large quantities of peptones. Increases stomach motility and production of gastric acid
(also produced by the stomach)

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6
Q

When is secretin secreted by the duodenum and what does it lead to?

A

Released when chyme enters the DD. Increases secretion of buffers:
- pancreas to increase pH
- Stimulates bile secretion from liver
- reduces gastric motility and secretory rates

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7
Q

When is GIP secreted by the duodenum and what does it lead to?

A

Secreted when fats and CHO enters. Inhibits gastrin and stimulates insulin release (promotes FA/ glu uptake)

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8
Q

What is the role of vasoactive intestinal peptide (VIP)?

A

Stimulates secretion of intestinal glands
Inhibits acid production in the stomach
Dilates capillaries

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9
Q

What does enterocrinin stimulate the secretion of?

A

Stimulates alkaline mucus secretion from submucosal glands

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10
Q

What happens when there isnt any food in the SI?

A

Motilin is released episodically, activates the migrating motor complex (MMC) = clears the SI of any debris

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11
Q

What are 3 distinguishing features of the large intestine?

A
  • Omental appendices: small pouches of peritoneum filled with fat
  • Teniae coli: 3 strips of muscle run along its surface = mesocolic, free and omental colic
  • Haustra: formed when the teniae coli contract to shorten the wall of the bowel, producing sacculations (pouches)
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12
Q

Briefly state the functions of the colon

A
  • Resorption of water
  • Reabsorption of bile salts and vitamins
  • Motility and defecation reflex
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13
Q

What is the short intrinsic myenteric feedback loop in the defecation reflex?

A

Afferent fibres from stretch receptors in rectum –> myenteric plexus to increase peristaltic contractions in sigmoid colon and rectum. Increases distention of rectum. When contractions reach the anus, the intrinsic anal sphincter relaxes

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14
Q

What is the long, parasympathetic defecation reflex?

A

Long reflex of enteric NS: stretch receptors stimulate parasympathetic motor neurons in the sacral spinal cord, to stimulate peristalsis of sigmoid + rectum. Increases rectal pressure. Stimulated motor neurons send efferent impulses in pelvic nerves so intrinsic anal sphincter relaxes

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15
Q

What determines release of faeces from the anus?

A

Activation of the somatic NS (pudendal nerves) to relax the external sphincter

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16
Q

At what rectal pressure do you get an urge to defecate?

A

15 mmHg

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17
Q

What is the lymphatic drainage of the large colon?

A

Ascending and transverse –> superior mesenteric nodes
Descending and sigmoid –> inferior mesenteric nodes

From here, lymph passes into intestinal lymph trunks then -> cisterna chyli -> thoracic duct

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18
Q

Where are the epiploic and paracolic lymph nodes found?

A

Epiploic = wall of colon
Paracolic = between marginal artery and bowel

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19
Q

Where is the most common area for metastases of colon cancer?

A

Liver
Other common areas= lungs, brain, distant lymph nodes and peritoneum

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20
Q

What is the effect of CCK after its release?

A
  • Travels in blood to stimulate the gall bladder to contract
  • Stimulates vagal afferents to travel to the brain to dorsal-vagal complex and release ACh (vago-vagal reflex), which also causes contraction of gall bladder
  • PNS fibres also cause release of NO and VIP to relax the sphincter of Oddi
  • Produces satiety in CNS
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21
Q

What are some stimulatory and inhibitory neurotransmitters released from enteric neurons?

A

Stimulatory = substance P, gastrin releasing peptide (GRP)
Inhibitory= vasoactive intestinal peptide (VIP), NO

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22
Q

How is motility achieved by the colon? (2 movements)

A

Segmentational movement: Peristaltic waves of the teniae coli (longitudinal muscle) and circular muscles contract, form haustra (bag-like sacs) = churns the food, mixing content of adjacent haustra
Propulsive (mass) movement: slow but persistent haustra contractions

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23
Q

What is the importance of segmentational movement of the colon?

A

Allows all fluid and dissolved substances to come into contact with the mucosal surface of the LI, so it can be absorbed. Also is very slow to maximise absorption

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24
Q

Where is sodium absorbed and how?

A

Ileum and large intestine:
- Na+/H+ antiporter on luminal membrane
- Epithelial Na+ channels (ENaC)- main way
- With SCFA via SMCT1 (Na+ coupled)

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25
Q

How is chloride absorbed in the colon?

A

Na+ absorption creates an electrochemical gradient to sitmulate Cl- absorption:
- Voltage dependent Cl- = across tight junctions driven by the charge or through Cl- channels
- Cl-/ HCO3- exchange: Cl- is absorbed and HCO3- secreted

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26
Q

How is water absorbed in the colon?

A

The NaCl absorption creates an osmotic gradient across the LI mucosa, so water is absorbed

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27
Q

What endocrine mechanisms increase absorption in the colon? How?

A
  • Aldosterone= stimulates basolateral Na+/K+ ATPase (increases electrochemical gradient), also increases transcription of ENaC
  • Glucocorticoids and somatostatin: increase action of basolateral Na+/K+ ATPase
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28
Q

How does the enteric NS affect secretion/ absorption of the intestine?

A

Sympathetic = promotes net absorption
Parsympathetic= promotes net secretion

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29
Q

What does the commensal microbial flora of the colon produce from the digestion of chyme?

A

short-chain fatty acids, crucial B vitamins (such as B6 and B12) and vitamin K

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30
Q

Compare metaplasia, dysplasia, and anaplasia

A

Metaplasia= change in differentiation, an adaptive response to stimuli
Dysplasia= proliferation of abnormal (metaplasia) cells
Anaplasia= loss of intracellular structural differentiation within a cell, often with increased capacity for multiplication (i.e. malignant tumour)

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31
Q

Which phase of the cell cycle is the cell sensitive to GF or anti-proliferative factors?

A

G1 - determines whether it enters the cycle (i.e. GF= enters, AP= doesnt)

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32
Q

Describe how clonal expansion can lead to cancer

A

1: Intitiating mutation = cell grows faster than neighbouring cells (1st clonal expansion)
2: One cell acquires a second mutation (2nd clonal expansion)
3: Leads to subclones of clonal expansions (Darwinian evolution)
- If lots of different subclones (i.e. dynamic) = tumour heterogenity

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33
Q

What is an oncogene? How many copies do you need to have a dominant effect?

A

Leads to gain-of-function effects. Mutation in 1 copy = sufficient for dominant effect

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34
Q

Give examples of oncogenes relevant to colorectal cancer

A

B-catenin and KRAS (family including Ras)

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35
Q

What is a tumour suppressor gene? How many copies do you need for a dominant effect?

A

Leads to loss of function. Need 1 copy for familial disease (as already acquire 1 mutant allele), but 2 for sporadic disease (‘2 hit hypothesis’)

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36
Q

Give examples of TSG’s relevant to colorectal cancer

A

APC and p53

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37
Q

What is Ras? How does it act as an on/off switch?

A

An oncogene which has GTPase activity: it binds to GTP (active), can hydrolyse GTP –> GDP releasing Pi (=inactive). It can reactivate by releasing GDP then bind to GTP (acts as on/off switch)

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38
Q

What can activate Ras?

A

Growth factors - to stimualte proliferation and cell growth

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39
Q

What happens when there is a single mutation of Ras? Give an example of one

A

I.e. G12V, it locks Ras into its active form, so proliferation is stimulated int the absence of proliferative signals (self-sufficiency).

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40
Q

What does progression through hte cell cycle depend on?

A

Cyclin-dependent kinases (CDK), which have to bind to cyclins [cyclin levels alter]

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41
Q

Give the CDK/Cyclin complexes present at each point of the cell cycle

A

Entry into G1: CDK4/ CDK6 + Cyclin D
Entry into S: CDK2 + Cyclin E
Progression through S: CDK2 + Cyclin A
Drive cell into mitosis: CDK1 + Cyclin B

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42
Q

What can inhibit CDK/ Cyclin complexes? Give an example

A

CKI’s (cyclin-dependent kinase inhibitors) such as p21

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43
Q

What can be thought of as a break in the cell cycle? Why?

A

Rb - as its normally bound to E2F, thus preventing its gene transcription. If there’s no Rb, E2F will be liberated and active = cell cycle progression

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44
Q

Describe how growth factors and Wnt signals can lead to progression through the cell cycle

A

Growth factors activate Ras, Wnt signals activate B-catenin. These oncogenes lead to gene transcription of cyclin D1 (and other targets).
Cyclin D1 binds to CKD4, then this complex then phosphorylates Rb-E2F complex
Rb then releases E2F (transcirption factor)
E2F leads to transcription of Cyclin E
Cyclin E binds to CDK2, which has positive feedback on Rb to increase E2F release, and also facilitates progression into S phase

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45
Q

In un-stimulated cells, why are levels of B-catenin low?

A

The complex with APC is intact, so GSK-3B phosphorylates (degrades) B-catenin = levels are low

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46
Q

How do Wnt signals drive cell proliferation?

A

Wnt signals engage with the receptor, which disrupts the complex and inactivates GSK-3B. Therefore B-catenin isnt phosphorylated and builds up int he cell. It moves to the nucleus to stimulate gene transcription

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47
Q

What is often referred to as the guardian of the genome? Why?

A

p53 - helps induce cell cycle arrest to give the cell time to repair when there’s damage (i.e. after UV radiation). It does this by activating p21 (CKI), and can induce apoptosis by Noxa genes.

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48
Q

How does hyperproliferation lead to CRC?

A

one crypt becomes bigger than the others due to hyper-proliferation. over time this leads to formation of a polyp, which protrudes into the lumen. This can develop into an adenocarcinoma

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49
Q

What cells are found at the bottom of crypts?

A

Stem cells, contain Lgr5+

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50
Q

What is the main gene mutated in sporadic CRC? Whats another common mutation?

A

APC (a tumour supressor gene) - mutated in 80-90%
B-catenin was mutated in 10-20%

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51
Q

What are the 2 main types of familial CRC?

A

Familial adenomatous poylposis (FAP)
Hereditary non-polyposis colon cancer (HNPCC)

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52
Q

What is the pathogenesis of familial adenomatous poylposis?

A

Individuals inherit one mutated copy of APC on gene 5q21. The other allele undergoes loss of heterozygosity = no functional copies left (autosomal dominant)

Leads to hundreds of polyps forming on the luminal surface of the colon. They then develop into carcinomas

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53
Q

Describe the migration of cells through the crypts

A

Stem cells are at the bottom of the crypt, and respond to Wnt signals secreted from stromal cells surroundnig. Wnt activates B-catenin, so the stem cells migrate up and out of the crypt whilst proliferating. Once out of the zone with stromal cells, wnt signals stop so theres no further proliferation and stem cells are differentiated

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54
Q

What is the implication of losing APC?

A

Loss of function of APC stabilises B-catenin. Therefore, stem cells can divide in the absence of Wnt, i.e. proliferation is driven beyond the normal zone (B-catenin is active above the normal zone)

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55
Q

What are the repair proteins for DNA?

A

MutS-alpha and MutL-alpha

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56
Q

What promoter may be silenced in sporadic CRC?

A

MLH1

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57
Q

What is the pathogenesis of hereditary non-polyposis colon cancer (HNPCC)/ Lynch syndrome?

A

Characterised by very few polpys but progression is fast (2-3yr instead of 8-10yr). Autosomal dominant condition!!

Mismatch repair defect in MSH2 = loss of function means mutation rate is increased and theres an accumulation of mutations in the cell = predisposes you to cancer

58
Q

What is the normal effect of TGF-B on a cell?

A

It binds to its receptor, activates CKI and inhibits Myc to block the cell cycle

59
Q

How can mismatch repair defects lead to increased mutation rates?

A

Defect = the polymerase can skip and delete, leading to a frameshift and premature stop codon, thus truncation of the TBF-B receptor (unstable so it is degraded). This means proliferation from TGF-B signals continues and the cell becomes unresponsive to anti-proliferative signals

60
Q

With the mismatch repair defect, how does the colon become predisposed to CRC?

A

It becomes sensitised to inflammation, leads to upregulation of NF-kB, causing:
- Proliferation, via cyclin D1
- Anti-apoptosis, via BCl-X
- Synthesis of pro-inflammatory prostaglandins, via COX2
= Chronic inflammation
= Ulcerative colitis
= increased risk of CRC

61
Q

What type of instability is FAP and HNPCC?

A

FAP = chromosomal instability
HNPCC = microsatellite instability, i.e. nucleotide mutation rate is increased

62
Q

Which tumours are more likely to respond to immune checkpoint therapy? Why?

A

Hypermutated tumours, i.e. mismatch repair defects:
- Have high mutation loads = thus express mutant proteins to interact with T cells
- Tumour cells express PD-L1 to suppress T cells
Could therefore block this interaction

63
Q

What drug may be prescribed as immune checkpoint therapy?

A

Pembrolizumab - if it has a mismatch repair defect that elevates mutation rates

64
Q

What are the 3 subtypes of CRC?

A

POLE ultra-mutated (<1%): driven by mutations in DNA polymerase, i.e. FAP
MSI: hypermutated due to microsatellite instability (9%)
MSS: microsatellite stable (90%)

65
Q

What has been proposed to be an effective biopsy for early detection of CRC?

A

Blood to measure:
- Circulating tumour cells
- Cell free DNA
As tumour cells burst and release these

66
Q

What is a hypothesised personal treatment approach for CRC?

A

Could grow Lgr5+ stem cells in a lab to grow organoids. then screen these and see what chemotherapy they respond to

67
Q

What are the 3 most common symptoms of CRC?

A
  • Rectal bleeding
  • Persisting change in bowel habit
  • Anaemia
68
Q

What are some advanced signs of CRC?

A
  • Weight loss
  • loss of appetite
  • abdominal pain
  • Palpable abdominal mass
  • palpable lymph nodes
69
Q

What can alter symptomatic presentation of the disease?

A

Whether the cancer is right sided (absorption disorder) or left sided (storage disorder)

70
Q

Compare right vs left sided CRC

A

Right side = weight loss, reduced haemoglobin, abdominal pain, obstruction is unlikely!
Left side= bleeding, altered bowel habit or obstruction, tenesmus (feeling like you need to evacuate bowel)

71
Q

What can cause sporadic CRC?

A

Caused by point mutation, followed by mutations:
1- mutation of APC, triggers formation of non-malignant adenomas (polyps)
2- polyps may go into malignant state if mutations in k-Ras, t-p53, and DCC

72
Q

What are some non modifiable risk factors for CRC?

A
  • Age: >50
  • Inflammatory bowel disease, i.e. Crohns or ulcerative colitis = chronic inflammation
  • Family history of CRC
  • APC mutation
  • Lynch syndrome (HNPCC)
73
Q

How does presence of innate lymphoid cells change in CRC?

A

ILC3’s are lost in CRC, which usually express ROR-yt (transcription factor), which is thought to have an anti-tumour response at epithelial surface
ILC2’s increase in CRC = produce IL-5 and IL-13 (seen in allergy)

74
Q

What lifestyle factors can icnrease risk of CRC?

A
  • Sedentary lifestyle
  • Obesity: diet may be involved in dysbiosis (disrupts microbiome)
  • Type 2 diabetes (increases risk by 50%)
  • Lack of dietary fibre
  • Acromegaly
  • Low vitamin D
  • red and processed meat
  • Smoking and alcohol
75
Q

How would investigation for CRC differ for a patient with and without a comorbidity?

A

Without -> colonoscopy
With -> flexible sigmoidoscopy then barium enema

76
Q

What is the epidemiology of CRC?

A

CRC= 44,000 cases/ year, 16,187 deaths/year
Probablity of suffering CRC = 4-5%, risk increased with age, chronic disease history and lifestyle

77
Q

What are some investigations you may perform for CRC?

A
  • Full blood count: look for microcytic anaemia (present in most R side cancer) and high Ca2+ (indicates bone metastases)
  • Liver function test: bilirubin and alkaline phosphatase
  • Colonoscopy: biopsy suspicious lesions and remove polyps
  • CT colonography
  • CT of chest, abdomen and pelvis
  • Genetic testing
  • Biopsy to confirm diagnosis, then MRI to check for metastases (lungs etc.)
  • Barium enema
78
Q

What is a CT colonography? When is it done?

A

Non-invasive investigation, pump CO2 (and sometimes contrast dye) into the bowel to outline the lining, then use a CT scan.
Often used if colonoscopy is contraindicated

79
Q

What is barium enema?

A

Liquid-containing barium is pumped into the lower gut via the rectum. It coats the mucosal lining so it is highlighted on an X-ray. Identifies polyps

80
Q

What is a typical sign seen on a barium enema with CRC?

A

Applecore sign

81
Q

Why is a liver function test done to investigate CRC?

A

Check for bilirubin and alkaline phosphatase, as if levels are high it can indicate liver metastases

82
Q

What would an abnormally high erythrocyte sedimentation rate indicate?

A

High levels of inflammation

83
Q

What can low ferritin indicate?

A

iron-deficiency anaemia (common in absorptive disorders, i.e. R sided colonc ancer)

84
Q

What is a faecel immunochemical test? What would be the next step if positive result?

A

Looks for occult (hidden) blood in the faeces, as blood vessels in larger polyps or cancers are fragile so easily damaged by passage of stool.
Screening test done every year, if positive then refer for colonoscopy

85
Q

What is the guaiac-based faecal occult blood test?

A

tests for blood in the stool via a chemical reaction

86
Q

Other than the gFOBT and faecel immunochemical tests, how else could stool be tested?

A

Stool DNA testing - look for DNA in stool for evidence of cells shed from the tumour

87
Q

How is CRC screened for?

A

Involves testing the faeces for blood: * All men and women aged 56-74 are sent a bowel screening test every 2 years. (Age range may expand to 50 over next 4 years)

88
Q

What is the staging TNM system for cancer?

A
  • T= size of Tumour, or how far it extends (T1 to T4)
  • N= extent of lymph node involvement (N0 to N3)
  • M= distant metastasis (M0, no evidence, or M1 if there is evidence)
89
Q

How does grading stage cancers?

A

Depends on what cells look like under a microscope. and how fast they’re growing:
- Grade 1 = cancer cells resemble normal ones
- Grade 2 = cancer cells dont look normal and are growing faster than normal
- Grade 3 = cancer cells look abnormal and grow/spread aggressively

90
Q

How might you treat a patient with no metastatic disease, or resectable metastases ?

A

Surgical resection, i.e. laparoscopic resection

91
Q

How might you treat a patient with potentially resectable metastases?

A

Induction chemotherapy for 5 weeks, usually cytotoxic doublet or triplet, with anti-VEGF or anti-EGFR (reduces number and size of metastases)
12 week break, then surgical resection

92
Q

How might you treat a patient with non-resectable disease?

A

Aim is palliative - reduce symptoms and aggressiveness. Give cytotoxic doublet and anti-VEGF or anti EGFR

93
Q

What drugs are typically used in a cytotoxic doublet?

A

FOLFOX = 5-FU (Flourouracil), folinic acid and oxaliplatin
FOLFIRI = 5-FU, folinic acid and irinotecan

94
Q

Give examples of anti-VEGF and anti-EGFR

A

Anti-VEGF= bevacizumab
Anti-EGFR= cetuximab or panitumumab

95
Q

What drugs are used in a cytotoxic triple therapy/

A

5-FU, folinic acid, oxaliplatin, irinotecan

96
Q

What are some side effects of chemotherapy drugs (used in doublet/ triplets)?

A

increased risk of infections, breathlessness and paleness (anaemia), bruising, bleeding gums or nosebleeds, loss of appetite, feeling of being sick

97
Q

What is the MOA of oxaliplatin?

A

inhibits synthesis of DNA

98
Q

What is the MOA of 5-FU?

A

Anti-metabolite medication, i.e. inhibits thymidylate synthase, which reduces dTMP production (essential for DNA repair and replication).
Low levels of dTMP induce cytotoxicity

99
Q

What is the MOA of folinic acid?

A

Reduced form of folic acid - it potentiates cytotoxic effects of 5-FU. It is used in palliative treatment and for resectable CRC = prolongs survival

100
Q

Compare a right and left hemicolectomy

A

Right: removes caecum, ascending and proximal 2/3 of transverse colon tumours (midgut)
Left: distal 1/3 transverse colon, descending colon (hindgut)

101
Q

What is the Hartmann’s procedure?

A

Colectomy that removes part of the colon and sometimes rectum (proctosigmoidectomy). The remaining rectum is sealed, creating what is known as Hartmann’s pouch. The remaining colon is redirected to a colostomy

102
Q

What do palliative treatments include?

A
  • Chemotherap: i.e. 5-FU - taken with folinic acid to make it more effective, Oxaliplatin, Capectibaine (converted into 5-FU by the body, may be taken before or after surgery ), Irinotecan – taken with 5-FU and folinic acid
  • Radiotherapy – in attempt to improve symptoms
  • Biological therapies
  • Pain relief
103
Q

What are the potential roles of chemotherapy in CRC?

A
  • Before surgery, to reduce size and number of metastases = easier to remove
  • After surgery, to kill any left over cells
  • Palliative, to relieve symptoms and control the cancer to improve QoL

It cannot cure CRC alone

104
Q

What is acceptance and commitment therapy (ACT)?

A

Developed from CBT, asks whether one’s thought is helpful, and if they align with their values in life

105
Q

Compare CBT and ACT

A

Unlike CBT, ACT does not challenge distressing thoughts or emotional responses, but teaches mindfullness and acceptance to reduce troubling thoughts

106
Q

How does CBT work?

A

Aims to change thought patterns and eliminate unpleasant feelings by recognising emotions, then targeting how you feel by acknowledging fear

107
Q

How does mindfulness work?

A

Aim to slow down to pay attention to whats around you, helps reduce stress, anxiety and depression. Love your favourite food, go for a walk, self-reflection etc.

108
Q

What psycholigical interventions may be used to alleviate pain?

A

biofeedback and hypnosis

109
Q

What psychological interventions may be used to alleviate feelings of nausea and vomiting?

A
  • Respondent conditioning
  • Visual imagery
  • Relaxation
  • Hypnosis
  • desensitisation
110
Q

With regards to the 4 level self help model, who can provide support at each stage?

A

Level 1: all health & social care professionals
Level 2: health and social care professionals with expertise
Level 3: trained and accredited professionals
Level 4: mental health specialists

111
Q

What assessment occurs at each stage of the 4 level model?

A

1: recognition of psychological needs
2: screen for psychological distress
3: assess psychological distress and diagnose some psychopathology (counselling)
4: diagnosis of psychopathology (i.e. CBT)

112
Q

What physiological changes can stress initiate?

A
  • Sympathetic activation (usually with acute stress): Adr, NA released, increases BP, sweating, HR, pupil dilation, immune function
  • Hypothalamic pituitary adrenocortical axis (HPA) - more likely with chronic stress = cortisol released, changes in CHO stores, inflammation, immune function (can impair wound healing)
113
Q

How does stress lead to altered bowel habits?

A

Stress causes release of corticotrophin-releasing factor (CRF) from hypothalamus, which acts on the gut via 2 receptors:
- CRF1 = stimulates colonic contractions
- CRF2 = reduces upper gut activity
Stress can also alter GI secretion and permeability

114
Q

How does serotonin influence gut motility?

A

1- stimulus, i.e. distention of food
2- 5-HT release, stimulates afferent neurones in enteric NS
3- stimulates efferent neurones
4- Excites and inhibits SM; i.e. contracts muscle behind the food, but relaxes the muscle in front

115
Q

Where is serotonin released from? How is the signal removed?

A

From enterochromaffin cells
Signal removed by SERT

116
Q

How do cytotoxic drugs lead to vomiting?

A

Cause release of excessive 5-HT, which stimulates vagal afferents via activating 5-HT3 receptors (‘vomiting centre’) in the medulla.

117
Q

What type drugs may be given as an anti-emetic to reduce nausea from cytotoxic drugs?

A

5-HT3 antagonists (prevent activation of vomiting centre in medulla), i.e. ondansetron
NK1 antagonist: inhibits substance P
Nabilone: targets CB1 receptor

118
Q

What drugs may be given for motion sickness?

A

H1 antagonists (anti-histamines)
M1 antagonists

119
Q

What brain area is implicated in emetic stimuli?

A

CTZ area/ area postrema

120
Q

Which opioid receptors are found in the GI tract and which is most important?

A

μ, δ, κ
μ = most important

121
Q

What does stimulation of opioid receptors lead to?

A

Activation of G0 proteins:
- Activates K+ channels = decreases synaptic transmission
- Inhibits Ca2+ channels = “”
- Stimulates Gi = reduced fluid secretion (of gastric, biliary, pancreatic and intestinal secretions)

122
Q

What are the 3 main side effects when opiates are used for cancer? Why do they occur?

A

1: vomiting= direct stimulation of CTZ area
2: dysphoria (agitation) = reduced synaptic transmission
3: constipation = low GI motility (inhibits inhibitory motor neurons so colon doesnt relax) and reduced secretion from pancreatic/ biliary/ intestinal & longer time in transit (means more water is absorbed into the body = stool is harder)

123
Q

Give 2 examples of endogenous opioids

A

Enkephalins
Endomorphins

124
Q

What drug may be given to a patient who is constipated from taking opioids?

A

Naloxone: opioid receptor antagonist, increases motility and intestinal secretion

125
Q

What is the MOA of anti-diarrhoea drugs? Give an example

A

μ receptor agonists: Loperamide (immodium)

126
Q

What is Lazarus and Folkman’s model of coping?

A

Says how we experience stress depends on our appraisal:
1. Primary appraisal – how stressful is the situation?
2. Secondary appraisal – how capable am I of coping with this?

127
Q

What are some psychological responses to cancer?

A
  • Anxiety
  • Depression – does it cause cancer or is it a response? Can cause neuroendocrine changes, and influence our health behaviours (I.e. smoking) which may also influence cancer
  • Body image
  • Coping strategies: problem-focused or avoidant strategies
128
Q

What is the cognitive adaptation theory?

A

3 processes thought to be important when coping with illness:
1.Search for meaning – ‘I know what caused by illness’
2. Search for mastery – ‘I can control my illness’
3. Process of self-enhancement – ‘I am better off than most people’

129
Q

What are the 3 major defence surfaces of the GI tract?

A

1st line: pre-epithelial
2nd line: epithelial (simple columnar)
3rd line: sub-epithelial = innate and adaptive defences

130
Q

What are the 4 pathogenic characteristics of H.pylori?

A
  • Flagellae = allows it to move away from acid of the lumen, through mucus to neutral pH of epithelia
  • Adhesins = allows it to stick to epithelia
  • Urease = breakdown urea and neutralise stomach acid by producing ammonia
  • Mucinase = degrade mucous
131
Q

Where are paneth cells found and what do they secrete?

A

Granular epithelial cells found at the bottom of crypts. They secrete antimicrobial peptides, i.e. alpha and beta defensins

132
Q

What does the pre-epithelial (first line) of defence include?

A

Mucus
Secretory antibodies (i.e. IgA) microbiome

133
Q

What are the 2 important cell types for sub-epithelial defence?

A
  • Intestinal macrophages = engulf antigens, express them. Non-migratory, replenished by monocytes
  • Dendritic cells = prime the T cells and start adaptive response, migratory cells (from surface to lymph nodes)
134
Q

What signals are required for a T cell to interact with a dendritic cell?

A
  • Cytokines
  • T cell receptor
  • MHC complex
  • CD28 interaction
135
Q

What is responsible for inactivation of T cells?

A

CTLA-4
PD-1 expression by T cell

136
Q

What cells might express CTLA-4 and PD-1?

A
  • By infected cells
  • on APCs and tissue = prevents self-recognition
  • tumour cells
137
Q

What is the proportion of CRC caused by sporadic, HNPCC and FAP?

A

95% sporadic, 5% are HNPCC and 1% are FAP

138
Q

When should patients be referred for an urgent investigation for CRC?

A
  • Age >40 with unexplained weight loss and abdominal pain
  • Age >50 with unexplained rectal bleeding
  • Age >60 with iron-deficiency anaemia, or changed bowel habit
  • Positive occult blood screening test
  • Age <50 with rectal bleeding and any of the other symptoms (i.e. anaemia)
139
Q

What is a carcinoma in situ?

A

Abnormal cells, but has not spread!! i.e. haven’t passed the mucosa/ invaded other tissues. Has potential to be cancerous. Stage 0

140
Q

Where is the most likely location of metastases for rectal cancer?

A

Lung (compared to the liver for colon cancer!)

141
Q

What are the stages of CRC (briefly)?

A

Stage 0= carcinoma in situ
Stage 1= beyond mucosa, no lymph nodes
Stage 2= invaded entire wall, may have reached nearby organs/tissues but no lymph nodes
Stage 3= spread to lymph nodes, but not distant organs
Stage 4 = metastatic, reached distnt organs

PBL Y2 S4 (9 decks)

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