general Flashcards
what Q’s are important in a change in bowel habit presenting complaint?
blood? mixed ? weight loss? appetite? abdominal pain? family Hx of bowel cancer? have you taken part in bowel screening programme?
when and whom is bowel screening offered?
men and women aged 50-74 every 2years
what is the bowel screening test?
Faecal immunochemical test (FIT)
- a kit sent to pt’s home
- simply unscrew cap of the test, dip the end of the stick into the bowl motion, then replace the stick in the tube and screw the lid shut
what is the level for a +ve FIT test and what happens with a positive result?
80ugHb/g faeces or above will generate a letter to the participant referring them to their local NHS Board for a follow-up assessment for colonoscopy
what are the referral guidelines for symptoms suggestive of colorectal cancer?
the following are high risk:
>bleeding - repeated rectal bleeding without an obvious anal cause. any blood mixed with the stool
>bowel habit - persistent (>4weeks) change in bowel habit especially to looser stools - not simple constipation
> mass - unexplained abdominal mass. palpable ano-rectal mass
>pain - abdominal pain with weight loss
>iron def anaemia - unexplained iron deficiency anaemia
what Ix can be done in the GP?
abdo exam
PR
bloods (FBC to check for anaemia and thrombocytosis, U+Es and LFTs), diagnostic FIT
what examination is used to examine the bowel in hospital and what further tests may be necessary?
colonoscopy (±biopsy)
further:
- CT scan of CAP to determine is there is any distant metastases
- CEA level (tumour marker)
- lymph node samples
what treatment options might be available for colorectal cancers?
surgery (aim = curative) and/or chemotherapy
what is the TMN staging?
Tumour (t) describes the size of the tumour:
T0 = no evidence of primary tumour
T1 = only in the inner layer of the bowel (submucosa)
T2 = grown into the muscle layer of the bowel wall (muscular propria)
T3 = grown into the outer lining of the bowel wall (subserosa)
T4 = grown through the outer lining of the bowel wall (into another part of the bowel, nearby organ or structure)
Node (N) describes whether the cancer has spread to the lymph nodes:
N0 = no lymph nodes containing cancer cells
N1 = 1 to 3 LNs close to the bowel contain cancer cells
N2 = cancer cells in 4 or more nearby LNs
Metastatis (M) describes whether the cancer has spread to different parts of the body:
M0 = no spread
M1 = spread
define the following
a) Neo-adjuvant therapy
b) adjuvant therapy
c) chemoradiation
d) palliative chemotherapy
a) chemotherapy given before surgery or radiotherapy to shrink the tumour
b) chemotherapy used to help destroy any cancer cells that may remain after surgery or radiotherapy. the aim is to reduce the likelihood of cancer returning in the future
c) chemotherapy combines with radiotherapy
d) if the cancer has spread to other parts of the body, the chemotherapy drugs carried in your bloodstream can reach these cancer cells. the aim is to help relieve symptoms and slow the growth of the cancer
define the inheritance patterns of familial adenomatous polyposis (FAP)
- AD
- gene defect in APC gene (adenomatous polyposis coli) = tumour suppressor gene
- chromosome 5q21-22
- nonsense or frameshift mutations
- results in truncated/ shortened proteins
- numerous adenomatous polyps (100s or more from adolescence) from mainly in the epithelium of the large intestine
- while these polyps start out benign, malignant transformations into colon cancer occurs when left untreated
- not definite = penetrance
define the inheritance pattern of hereditary non-polyposis colon cancer (HNPCC)/ Lynch syndrome
- AD
- number of genes involves: common function = working to help with dna mismatch repair
- low number of polyps
distinguish between oncogenes and tumour suppressor genes
tumour suppressor gene:
- recessive mutation (loss of function)
- normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die
- if genes don’t work properly, cells can grow out of control –> cancer
- no effect of mutation in one gene copy
- two inactivating mutations functionally eliminate the tumour suppressor gene, stimulating cell survival and proliferation
- e.g. defects in APC gene predispose to cancer, but need a second mutation (might arise by chance) then there is complete loss of function
oncogene:
- dominant mutation (gain of function)
- single mutation event in porto-oncogene creates oncogene
- activating mutation enables oncogene to stimulate cell survival and proliferation
- e.g. EGFR always switched on
describe the evidence supporting the multi-step model of carcinogenesis
- doesn’t happen over night. steady accumulation of lots of different mutations
- initially the colon is normal -> polyps -> larger -> tumour
- precursor lesion to cancer takes about 10-15yrs
- cells of origin thought to be stem cell in the base of crypts
- progression result from multiple genetic mutations and epigenetic alterations
- can take samples at different stages + compare genetically
differentiate between genetic tests for FAP and HNPCC
FAP:
- test via protein truncation test or direct sequencing
HNCC:
- study microsatellite’s in the genome and see if they are stable or unstable
- immunohistochemical protein staining (looking at which protein involved in dna mismatch repair is mutated)
describe the molecular mechanisms underlying FAP and HNPCC
FAP:
- APC normally binds beta-catenin and microtubules
- beta-catenin is a TF and is normally present at low levels by APC control (degrades it)
- accumulates when not bound to APC and cells want to proliferate
- part of wider pathway known as wnt signalling pathway: if wnt is present, this results in inactivation of APC and stable B-C
- wnt pathway only normally active in the bottom of crypt cells. in tumours, would have active wnt signalling all the way up the vilus.
- B-C also binds to microtubules; if not happening properly, results in disordered cytoskeleton
+ chromosomal instability -> chromosomes won’t attach to microtubules properly during mitosis
HNPCC:
- mismatch repair gene products normally recognise when dna bases haven’t matched dup properly e.g. G->T and attract other proteins that can cut out that region of dna, repair and stick back together again
- MSH6 and MSH2 recognise the damage
- MLH1 and PMS2 cut away section ready for repair
- repetitive regions are more susceptible to errors = microsatelite instability (MIN)
- TGF-beta pathway is an example of a protein with lots of repeats + subject to mismatch repair. it is involved in regulating cell proliferation by inactivating it
compare FAP and HNPCC and screening
FAP va HNPCC:
- large number of polyps vs low number
- low mutation rate vs high mutation rate
- high cancer risk because of high number of polyps VS high cancer risk despite low numbers of polys
- average age of onset similar (approx 40)
- life-time risk (entrance) close to 100% for VS approx 80%
- both offered regular screening from young age
- patient often elect to have colon removed
- biannual colonoscopy from 25yrs if known FAP/HNPCC
- high to moderate risk - colonoscopy every 5yrs from 50-75
why is aspirin considered a preventative measure for colorectal cancer?
- inhibit COX-2
- cox-2 increased in early stages of colorectal cancer
- increased prostaglandin synthesis
- stimulates proliferation and angiogenesis
- inhibits apoptosis
- BUT CV risk
what are the risk factors of colorectal cancer?
- non-modifiable:
- age
- sex
- IBD
- family history
- polyps in colon (tubulovillous adenoma)
modifiable:
- diet (eating too little fibre; too much 🥩 )
- lack of exercise
- smoking
- alcohol
- obesity
what is the clinical presentation of colorectal cancer?
- early stage is usually asymptomatic
- occult or overt rectal bleeding
- iron def anaemia
- change in bowel habit (constipation/ diarrhoea/ alternating)
- pain and discomfort in bowel
- weight loss/ loss of appetite
- family Hx (FAP, HNPCC)
how is colorectal cancer diagnosed?
endoscopy:
- most common, but invasive, method to diagnose colorectal Ca
- colonoscopy is gold standard
imagine:
- CT colonography - sometimes adjunct to colonoscopy
Bowel screening program (BSP)
lab:
- complete blood count, s checking carcinoembryonica antigen concentrations at the time of diagnosis )high CEA = worse prognosis)
Pathology:
- histological assessment is on the basis for pathological diagnosis and staging of the disease
- mismatch repair testing (immunohistochemistry) used for diagnosis of Lynch syndrome (HNPCC)
- adjuvant immunotherapy decision making
what is the prognosis of colorectal cancer?
1 yr survival = 80%
5 yr survival = 60%
what affects prognosis and survival:
- TNM staging
- other histopathological features
- health and fitness
- effectiveness of surgery and treatment
other prognostic factors:
- differentiation (architecture and specifically gland formation/ how normal it looks)
- tumour deposits (discrete nodules of Ca in the tissues LNs drainage area)
- venous invasion (tumour invades vessels)
- lymphatic invasion
- perineurial invasion
describe the progression sequences of colorectal disease progression
2 major pathways –> adenocarcinoma or serrated neoplasia
- adenoma to carcinoma sequence (chromosome instability) (70-90%):
- FAP or sporadic -> (germline for FAP)APC mutation -> micro-satellite stable colorectal cancer - serrated neoplasia sequence (10-20%):
- traditional serrated -> KRAS and BRAF mutation -> microsattelite stable and unstable colorectal cancer
- sessile serrated -> BRAF mutation -> micro satellite stable and unstable colorectal cancer - micro satellite instability (2-7%)
- Lynch syndrome
- germline mutation in MMR genees -> microsatelliet instable colorectal cancer
what molecular subtype of CRC exist and what is the significance
CIMP (CpG island methylation phenotype)
MSI/MSS (micro satellite instable/stable)
BRAF/KRAS (mutation status)
*prognosis and treatment decisions can be made on molecular sub typing and not just histopathological staging and features
explain some of the reasons why the NHS has become over-stretched year on year
- increase in life expectance -> healthcare is concentrated at end of life
- increase costs of treatment -> advancements, but don’t come cheaply
- patients expectations increase increase -> some conditions what were once not seen as a problem, now has treatments e.g. menapause. understanding of conditions has increased
- increased cost of admin and salaries -> employs 1.7million people. huge amounts of admin and salaries
- increase in negligence cases
explain the different strategies that could be used in NHS resource allocation
- equal access to to treatment (deprive pt’s from beneficial treatment)
- rationing according to clinical need (life preserving trump life enhancement?)
- maximising health gains (QALY)
- discriminating according to age (tragedy to be cut off early)
- taking individual responsibility for ill health into account (hard to decide list)
- rationing according to ability to pay (high risk might not get insurance. low risk might not buy into insurance)
- singling out certain types of excluded treatment (produce a package of care - decide that nhs will pay for and some that they won’t)
- dilution of care (we dont have enough resources to go round so we will dilute what er have e.g. dont just do a whole battery of tests)
- ransom allocation (when ever there is a random decision that nobody wants to make do a lottery. ethically hard to justify)
describe NICE and outline its role in technology appraisals and NHS rationing
- produce evidence based guidance for health and advice for health, public health and social care practioners
- e.g. clinical guidelines, technology appraisals, public health, interventional procedures
technology appraisal = recommendations on the use of new and existing medicines and treatments within the NHS
outline the role of SMC and describe its involvement in NHS rationing
Scottish medicines consortium - national source of advice on the clinical and cost-effectiveness of a new medicines for NHS Scotland. aim to ensure people in Scotland have timely access to medicines that provide most benefit based on best available evidence
evaluates whether the benefits for patients may be considered an acceptable use of NHS resources
when SMC accepts a new medicine, NHS boards are expected to make it, or an equivalent
describe what a QALY is, and its use in the decision-making process to purchase health care resources, and evaluate its strengths and weaknesses
- quality adjusted life year
- theory = consequentialism
- generic measure of disease burden, including both the quality and quantity of life lived
- QALYs are calculated by estimating the years of life remaining for a patient following a particular treatment or intervention and weighting each year with a quality-of-life score (on a 0 to 1 scale)
- years of life x utility value (perfect health)
give an example of controversial uses of healthcare budget
- treatments to assist reproduction (is this a healthcare need)
- cosmetic surgery
- long-term nursing for elderly
- health education in schools
- provision of traffic-calming measures
- reversal of sterilisation
- insentives
what is rationing on the NHS?
because everyone does not get the same fixed amount of resources. Rationing refers to the discretionary allocation of scarce resources
what is the role of clinical trials in drug development process?
assess the safety of the drug, obtain a thorough knowledge and understanding of the drug’s pharmacokinetic profile and potential interactions with other drugs (drug-drug interactions), and estimate pharmacodynamic activity.
describe different categorisation methods for adverse drug reactions
- traditional ABCDE classification:
- type A = ‘augmented’; ADRs are predictable from the pharmacology of the causative agent and are dose-related e.g dehydration with diuretics
- type B = ‘bizarre’; ADRs are unpredictable from pharmacology of the causative agent and are not dose-related
- type C = ‘chronic’; effect that need prolonged period of exposure to develop e.g. osteoporosis
- type D = ‘delayed’; dont arise until prolonged period after exposure.g. lymphomas are increased in frequency in people who have had previous chemo
- type E: ‘end of use’; effects of medicine withdrawal - DoTS classification:
- Dose relatedness:
- > hypersusceptibility (ADR occurs below SE/ standard therapeutic dose - e.g. anaphylaxis to penicillin)
- > SE (standard therapeutic dose - e.g. osteoporosis with steroid use)
- > toxic effects (if ADR at higher dose than for therapeutic effect)
- Time:
- > rapid (occurs when drug is administered too quickly e.g. red man syndrome with vancomycin)
- > first dose (anaphylaxis)
- > early only (improves with continued risk e.g. nitrates headache)
- > intermediate (occurs in the middle and resolves)
- > late (risk increases with duration)
- > delayed
- Susceptibility:
- > depends on age, gender, pregnancy, disease, drug interactions, exogenous factors, genetics
define pharmacovigilance
the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.
The main aim of pharmacovigilance is to identify, evaluate and prevent adverse effects from medicines.
