general Flashcards
list some red flags in a pt presenting with backpain
trauma unexpected weight loss neurological symptoms >50y/o fever IVDU steroid use Hx of Ca
what is myeloma?
neoplastic plasma cells accumulate in the bone marrow and produce a monoclonal protein that is detected in the blood or urine; this causes organ or tissue impairment
what is the test for myeloma?
- serum and urine protein electrophoresis
- bone marrow sample - aspiration shows plasma cells, blue cytoplasm, pale Golgi, nucleus at the edge of the cell
- plain XR skeletal survey - shows multiple osteolytic areas typical of myeloma
what causes bone disease and hypercalceamia in myeloma?
imbalanced bone remodelling in the myeloma bone marrow is caused by increases osteoclast activity, together with reduced osteoblast function. myeloma cells cause an increased production. of osteoclast activating factors and cytokines that inhibit osteoblast differentiation. the unopposed osteolysis is also responsible for hypercalcaemia.
how does myeloma cause renal impairment?
in most cases malignant plasma cells produce a paraprotein - monoclonal immunoglobulin - typically IgG or IgA. plasma cells also produce varying amounts of monoclonal free light chains which are filtered in the glomeruli and reabsorbed in the proximal tubules - when the light chain load exceeds this the reabsorbtive capacity they precipitate out as casts in the distal tubules causing tubular obstruction, inflammation and –> AKI
other causes = amyloid deposition, dehydration, hypercalcaemia, hyper viscosity, nephrotoxic drugs, NSAIDs
how does myeloma present?
common presentation are symptoms of anaemia, renal impairment and bone disease
bone disease - painful lytic lesions, vertebral crush fractures, long bone fractures, spinal cord compression
Bortezomib
dexamethasone
thalidomide tx
…..???
drug-induced peripheral neuropathy can be a SE of the Tx of myeloma. list some causes of peripheral neuropathy
- alcohol
- diabetes
- drug induced e.g. some chemo and anti-HIV
- B12 deficiency
- connective tissue disease e.g. RA or lumps
list clinical symptoms of peripheral neuropathy
altered sensation to touch, pain, position sense, muscle weakness, autonomic symptoms e.g. bladder control and dizziness on standing
list some signs of peripheral neuropathy
objective sensory loss in spinal level of peripheral nerve distribution, muscle wasting and weakness, reduced tone and reflexes, postural hypertension
which of the following are long acting opiates?
a) oxycodone M/R
b) diamorphone
c) oramorph
d) fentanyl patch
e) tramadol
f) MST
a) oxycodone modified release
d) fentanyl patch
f) MST
what are some causes of hypercalcaemia?
most of causes are due to either primary hyperparathyroidism (as a result of hyperplasia, adenoma or carcinoma) or malignancy
less common:
- drugs e.g. antacids, vic D
- tertiary hyperparathyroidism (in advanced renal disease)
- greanulomatous disease (sarcoidosis, TB)
- familial hypocalciuric Hypercalcaemia
what is the indications for considering starting dialysis in a pt with progressive CKD?
- no absolute cut off in terms of eGFR for starting dialysis in its with CKD
- in UK, average eGFR at time of start of dialysis is 7ml/min/1.73
- different factors need to be considered including blood tests, examination findings and symptoms
- hyperkalaemia, acidosis and refractory fluid overload are indications for starting treatment
what are the effects of CKD?
1) Na+ and H2O balance:
- decrease GFR leads to increase sodium and water retention
- increase BP
- peripheral oedema
2) K+ balance:
- decrease GFR leads to hyperkalaemia
- muscle weakness, ECG changes, fibrillations
- NB loss of nephrons –> decrease in RENIN –> decrease in aldosterone –> distal Na+/K+ pump not functioning –> potassium retention
- promote the problem if using K+ sparing diuretics + ACEi
3) metabolic acidosis:
- diminished capacity to excrete H+ and generate HCO3 as nephron maintains the bodies pH by secreting H+ or synthesising HCO3
4) mineral and osteodystrophy:
- loss of nephron –> decrease in GFR –> hyperphosphateamia
- loss of nephron –> can’t produce calcitriol –> decrees Ca++ reabsorption from GIT and kidneys –> hypocalcaemia –> secondary hyperparathyroidism –> osteodystrophy
5) uraemia
- neurological signs and symptoms eg hiccups
6) others:
- decrease RENIN –> decreased BP
- decreased in EPO –> anaemia
- decrease calcitriol –> renal osteodystrophy
describe the role of the immune system in the body defence against malignant disease
immuno surveillance:
- physiological function of the IS to recognise and destroy clones of transformed cells before they grow into tumours
- eliminated in immune-competent host. process known as immunoediting
- IS can also specifically identify and eliminate tumour cells on the basis of their expression of molecules on their surface
what cells contribute to the IS’s pro and anti-tumour effects
- the immune system can attack but also promote the tumours
PRO:
- inflammation
- M2 macrophages
- Bcells (high presence of B cells promote tumour progression. can promote angiogenesis and tumour cell proliferation by secreting molecules like interleukin
ANTI:
- CTLs
- M1 macrophages
what are the 4 main types of tumour cell antigens
- neoantigens
- antigens of oncogenic viruses
- over expressed cellular proteins
- abnormally expressed proteins
what are the receptors expressed on lymphocytes involves in the immune checkpoint pathways
- immune checkpoints are signalling pathways that inhibit the immune response/keep it in check
- if uncontrolled can cause tissue damage
- the 2 most understood T cell inhibitory pathways are: CTLA-4 and PD-1
- the expression of both these receptors on Tcells inhibits their cytotoxic function
- tumours can secrete PD-1 which inactivates T cells before they can kill the Ca cells
describe what checkpoint blockage therapy is and how it re-activated cytotoxic lymphocytes ability to kill cancer cells
- antibody therapy that bind to checkpoint receptors and blockade their Cell inhibitory action
- T cell capable of killing tumour cells
- CTLA-4 was the first monoclonal drug approved - Ipilimumab - to treat advanced melanoma pt’s
- anti-PDL-1/PD-1 therapy seems more effective at promoting CTLs to killl tumour cells (e.g. Nivolumab and atezolizumab) has been approved in cancers including colon, bladder, melanoma, lung, renal
what are the hallmarks of cancer?
malignant phenotype results from basic hallmarks of Ca
- sustaining proliferative signalling
- evading growth suppression
- activating invasion and metastasis
- enabling replicative immortality
- inducing angiogenesis
- resisting cell death
- avoiding immune destruction
- deregulating cellular energetics
- tumour promotong inflammation
- genome instability and mutation
discuss the hallmark of cancer ‘inducing angiogenesis’
- multiple cell types originating in the bone marrow play roles in pathological angiogenesis (including innate IS: macrophages neutrophils, mast cells, myeloid pro generators).
- infiltrate malignant lesions and larger tumours
- help to trip angiogenic switch in previously quiescent tissue and sustains ongoing angiogenesis associated with malignant growth
- can also protect the vasculature from the effects of drug targeting the endothelial cell signalling (e.g. anti-VEGF therapy)
- cancers need new blood vessels to grow
what is the immunoscore used for?
histopathological study to assess the prognosis of cancer by assessing the density of immune cells
- > high CD8, high CD4 and high M1 macrophages = good prognosis
- > high M2 macrophages = poor prognosis
what are the most prominent anti-tumour cells and most important contributors to host immune defence against tumours?
cytotoxic (CD8+) T cells
how do CD4+ helper T cells contribute to antitumor immune response?
- role in priming and activating the CTL response
- also activate macrophages
- increase tumour cell sensitivity to lysis by CTLs through expression of cytokines
how are macrophages capable of both inhibiting and promoting the growth and spread of cancers?
- depending on their activation state
M1 macrophages:
- anti-tumourogenic
- they are activated by tumours (unsure of mechanism)
- kill by direct (produce NO or tumour necrosis factor as well as by phagocytosis) or indirect (recruiting other immune cells like CTLs) killing
M2 macrophages:
- promotes tumour growth and spread
- promote angiogenesis through vascular endothelial growth factor (VEGF)
- promote invasion through production of (EXM) matrix metalloproteinases (MMPs)
define evidence-based medicine
the integration of the best research evidence combined with clinical expertise and patient values and circumstances.
not data drive - but it is incorporated into decision making
briefly define lymphomas and leukaemia
leukaemia:
- haematological malignancies that are in the bone marrow and blood, that may or/may not be in organs like the liver/spleen.
- malignant neoplasms of the haemopoietic stem cells, characterised by diffuse replacement of the bone marrow by neoplastic cells that can spill into the blood and infiltrate organs
lymphomas:
- based within LNs but easily in other organs like the skin, salivary glands etc
- B and T cell malignancies of the lymphoid system
- classified into NHL (common in older people) and HL (more common in younger) based on histological appearance
discuss acute leukaemia
AML and ALL
- characterised by clonal proliferation of myeloid or lymphoid precursor cells (myeloblasts, mono blasts or lymphoblasts) with reduced capacity to differentiate
- increase in leukaemia cells in the bone marrow, peripheral blood and other tissues
- decrease in RBCs (anaemia), platelets (thrombocytopenia) and neutrophils (neutropenia)
- commoner with increasing age but ALL has childhood incidence (1-10yrs)
- present as result of bone marrow failure - anaemia/ tiredness/ bruising/ infection
- FBC normally raises strong suspicion - blast cells (myloblast/lymphoblast)
