Cancer Pathophysiology and Cachexia Flashcards
regional lymph nodes
malignant cells will escape from tumours and get released in blood, where lymph nodes start getting activated, inflamed and enlarged ( trying to limit the progression of cancer spread) - gets classified according to the distance from primary tumor
Metastasis
invasion of distal tissues and organs - it has left the primary site (could be to the same organ but different spot - for example left lung to right lung is still metastasis)
for solid tutors how do we assess staging of cancer?
TNM
what is TNM
tumor-node- metastases
TNM - T?
from T1-T4 depending on the size of the tumor
TNM-N?
NO -N3 - depending on how many lymph nodes are affected
TNM-M?
has it metastasized?
M0 (no) or M1 (yes)
as soon as there is even one metastasis, what stage is it?
last stage (IV) - advanced cancer
chemotherapy agents will lead to what kind of side effects? why?
systemic side effects- bc it does not only target the cancer cells but other rapidly proliferating cells such as epithelial, hair follicles, taste buds
other common side effects of chemo
bone marrow suppression (anemia), N/V, anorexia, renal toxicity, cardiotoxicity, hepatoxicity, alopecia (spot baldness)
biological and targeted therapy side effects
generally less severe, for example estrogen receptor modulateers- hot flashes, but some may be more severe such as flu-like symptoms and organs damage
cachexia a disease or syndrome?
syndrome
def of cachexia
complex metabolic syndrome associated with an underlying illness characterized by weight loss ( of muscle with or without fat loss)
main difference between cachexia and starvation
trajectory of time of weight loss
chronic illness leads to ????
anorexia, inflammation, IR, hypogonadism and anemia which in turn leads to fat and muscle loss therefore leading to weight loss ad weakness and fatigue ( reduced muscle strength, VO2 was and PA)
consequences of muscle wasting
predicts poorer cancer associated outcomes - increase treatment toxicity (decreased lean mass can’t metabolize them as efficiently), decreased host response to tumor - less immune cells, decreases survivala and preformance status
% of patients with lung or gastro-intestinal tumour suffer from?? * watch for in case study
Sarcopenia-obesity - these outcomes are worse than obese or sarcopenia patients - they are less responsive to treatment
prevalence of cancer cachexia
50-80%
differentiate undernutrition, malnutrition, starvation and sarcopenia
insufficient food intake - undernutrion, insufficient or improper intake or one or more nutrients- malnutrition, starvation- total food deprivation, sarcopenia- decreased muscle mass
2 main components of cachexia
metabolic changes and reduced food intake
metabolic changes in cacheixa
hyper catabolism ( increased protein degradation) and hypo anabolism ( less responsive to anabolic stimuli)
what are metabolic changes driven by?
systemic inflammation and catabolic factor secreted by the tumour or host
differentiate primary and secondary anorexia
primary - physiological changes due to illness , secondary - from treatment
how do we measure hyper-catabolism or hypo anabolism to diagnose cancer cachexia??
weight loss, acute phase protein response, anorexia, appetite, satiety, hyper metabolism, inflammation
describe the different in starvation and cachexia in terms of metabolic shifts
- lean mass is lost greater in cachexia and fat loss is in starvation
- REE; starvation reduces metabolism to adapt positively to a lower state, cachexia REE is increased
- protein synth and degradation are decreased in starvation (less REE) but in cachexia degradation is increased and synthesis may be reduced or unaltered
- insulin; decreased n starvation, increased or level in cachexia
- cortisol increase in cachexia ( must also in starvation??)
refractory (resistant to a stimulus, stubborn or unmanageable) cachexia
less than 3 months to survive- nutrition can do nothing here
pre-cachexia
almost impossible to diagnose bc less than 5% weight loss
cachexia
weight loss more than 5% or BMI less than 20 and weight loss > 2%
- often reduced food intake and systemic inflammation
how to detect inflammation
acute phase proteins (not specific to cancer) - modulated by cytokines released by the tumor o host
cytokine actions
decrease appetite, induce systemic inflammation, IR, inhibit LPL (less fat storage), decrease GI function, delay gastric emptying, decrease blood flow, inhibit growth hormone and IGF-1 signalling –> deceasing anabolic factors (hypo anabolism), inducing proteolysis
cytokines induce proteolysis which may be used for what?
to synth acute phase proteins, gluconeogenesis or get excreted in urine (net protein loss- muscle wasting)
hyper metabolism - how to detect?
very hard to detect - and not a characteristic o all cancer pateints
- careful- hyper metabolism is defined as n increase in REE not nessasarily TEE
decrease the cachexia individual
increase in REE, decrease in PAL and reduced TEF
insulin in cachexia individuals? what other anabolic factors are affected?
insulin increased but IR
- IGF-1, GH, TH, testosterone all decreased
what catabolic factors get increased?
glucagon, cortisol, pro-inflammatory cytokines, tumor-derived factors
lipid metabolism in cachexia
- increased lipolysis –> more FFA and VLDL –> hyperTG but coming from an endogenous source
- cytokines decrease LPL, decreased fat storage
glucose metabolism in cachexia
- prefered fuel for tutors (glycolytic pathways), produce lactate, which is recycled in the cori cycle (using more ATP)
- need more glucose–> proteolysis increased
- IR leads to decreased glycogen storage and decrease in anabolism
protein metabolism in cachexia
negative nitrogen balance (secreting more than intaking- catabolism )
- increased basal protein turnover
- increased or unchanged muscle proteolysis -> aa for gluconeogeneis, acute-phase proteins and tumor growth
intracellular protein degradation
3 pathways of proteolysis
- lysomal, calcium-dependent, but the bulk is ATP-dependent uboquitin-proteosime pathway
UbqE3 ligase regulation
this step links ubiquitin with a protein fragment and is highly regulated by inflammatory cytokines.
inflammatory cytokines (TNF-a and IL-1) increase the gene expression of EbqE3= increased proteolysis
what proteolysis inducing factor does a tumour secrete
inflammatory cytokines ( TNF-alpha and PIF)
what ATP dependent pathways do tumours induce
- Cori-cycle
- proteolysis (Ubiquitin pathway)
- gluconeogeneis
- synthesis of acute phase proteins
- also induce lipolysis (not sure if ATP dependent)- but leads to hyperTG and increase in VLDL
why anorexia in Cachexia
obstruction, pain, malabsorption, depression, constipation, chemo/rad, inflammation- cytokines, hypothermic disregulation
early satiety in cachexia?
results from reduced GI mortalility, opined analgesics, deregulation of signalling
why nausea and chemosensory abnormalities in cachexia
direct consequence from antineoplastic therapies- side effects of drugs
what do we have to be careful about with chemosensory?
may be caused by treatment- but could also be a nutrient def- so have to rule this out
how to define the severity of cachexia and the phenotype
- reduced food intake; administer questionnaire ( are they below 70% usual food intake0
- catabolic drive; CPR as indicator of inflammation
- Muscle mass and strength; DXA, BIA, MAMA, handgrip strength
- functional and psychosocial effects; questionnaire
