Cancer Pathophysiology and Cachexia

Question 1

regional lymph nodes

Answer 1

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

Question 2

Metastasis

Answer 2

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)

Question 3

for solid tutors how do we assess staging of cancer?

Answer 3

TNM

Question 4

what is TNM

Answer 4

tumor-node- metastases

Question 5

TNM - T?

Answer 5

from T1-T4 depending on the size of the tumor

Question 6

TNM-N?

Answer 6

NO -N3 - depending on how many lymph nodes are affected

Question 7

TNM-M?

Answer 7

has it metastasized?

M0 (no) or M1 (yes)

Question 8

as soon as there is even one metastasis, what stage is it?

Answer 8

last stage (IV) - advanced cancer

Question 9

chemotherapy agents will lead to what kind of side effects? why?

Answer 9

systemic side effects- bc it does not only target the cancer cells but other rapidly proliferating cells such as epithelial, hair follicles, taste buds

Question 10

other common side effects of chemo

Answer 10

bone marrow suppression (anemia), N/V, anorexia, renal toxicity, cardiotoxicity, hepatoxicity, alopecia (spot baldness)

Question 11

biological and targeted therapy side effects

Answer 11

generally less severe, for example estrogen receptor modulateers- hot flashes, but some may be more severe such as flu-like symptoms and organs damage

Question 12

cachexia a disease or syndrome?

Answer 12

syndrome

Question 13

def of cachexia

Answer 13

complex metabolic syndrome associated with an underlying illness characterized by weight loss ( of muscle with or without fat loss)

Question 14

main difference between cachexia and starvation

Answer 14

trajectory of time of weight loss

Question 15

chronic illness leads to ????

Answer 15

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)

Question 16

consequences of muscle wasting

Answer 16

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

Question 17

% of patients with lung or gastro-intestinal tumour suffer from?? * watch for in case study

Answer 17

Sarcopenia-obesity - these outcomes are worse than obese or sarcopenia patients - they are less responsive to treatment

Question 18

prevalence of cancer cachexia

Answer 18

50-80%

Question 19

differentiate undernutrition, malnutrition, starvation and sarcopenia

Answer 19

insufficient food intake - undernutrion, insufficient or improper intake or one or more nutrients- malnutrition, starvation- total food deprivation, sarcopenia- decreased muscle mass

Question 20

2 main components of cachexia

Answer 20

metabolic changes and reduced food intake

Question 21

metabolic changes in cacheixa

Answer 21

hyper catabolism ( increased protein degradation) and hypo anabolism ( less responsive to anabolic stimuli)

Question 22

what are metabolic changes driven by?

Answer 22

systemic inflammation and catabolic factor secreted by the tumour or host

Question 23

differentiate primary and secondary anorexia

Answer 23

primary - physiological changes due to illness , secondary - from treatment

Question 24

how do we measure hyper-catabolism or hypo anabolism to diagnose cancer cachexia??

Answer 24

weight loss, acute phase protein response, anorexia, appetite, satiety, hyper metabolism, inflammation

Question 25

describe the different in starvation and cachexia in terms of metabolic shifts

Answer 25

1. lean mass is lost greater in cachexia and fat loss is in starvation 2. REE; starvation reduces metabolism to adapt positively to a lower state, cachexia REE is increased 3. protein synth and degradation are decreased in starvation (less REE) but in cachexia degradation is increased and synthesis may be reduced or unaltered 4. insulin; decreased n starvation, increased or level in cachexia 5. cortisol increase in cachexia ( must also in starvation??)

Question 26

refractory (resistant to a stimulus, stubborn or unmanageable) cachexia

Answer 26

less than 3 months to survive- nutrition can do nothing here

Question 27

pre-cachexia

Answer 27

almost impossible to diagnose bc less than 5% weight loss

Question 28

cachexia

Answer 28

weight loss more than 5% or BMI less than 20 and weight loss > 2% - often reduced food intake and systemic inflammation

Question 29

how to detect inflammation

Answer 29

acute phase proteins (not specific to cancer) - modulated by cytokines released by the tumor o host

Question 30

cytokine actions

Answer 30

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

Question 31

cytokines induce proteolysis which may be used for what?

Answer 31

to synth acute phase proteins, gluconeogenesis or get excreted in urine (net protein loss- muscle wasting)

Question 32

hyper metabolism - how to detect?

Answer 32

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

Question 33

decrease the cachexia individual

Answer 33

increase in REE, decrease in PAL and reduced TEF

Question 34

insulin in cachexia individuals? what other anabolic factors are affected?

Answer 34

insulin increased but IR | - IGF-1, GH, TH, testosterone all decreased

Question 35

what catabolic factors get increased?

Answer 35

glucagon, cortisol, pro-inflammatory cytokines, tumor-derived factors

Question 36

lipid metabolism in cachexia

Answer 36

- increased lipolysis --> more FFA and VLDL --> hyperTG but coming from an endogenous source - cytokines decrease LPL, decreased fat storage

Question 37

glucose metabolism in cachexia

Answer 37

- 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

Question 38

protein metabolism in cachexia

Answer 38

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

Question 39

intracellular protein degradation

Answer 39

3 pathways of proteolysis | - lysomal, calcium-dependent, but the bulk is ATP-dependent uboquitin-proteosime pathway

Question 40

UbqE3 ligase regulation

Answer 40

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

Question 41

what proteolysis inducing factor does a tumour secrete

Answer 41

inflammatory cytokines ( TNF-alpha and PIF)

Question 42

what ATP dependent pathways do tumours induce

Answer 42

1. Cori-cycle 2. proteolysis (Ubiquitin pathway) 3. gluconeogeneis 4. synthesis of acute phase proteins 5. also induce lipolysis (not sure if ATP dependent)- but leads to hyperTG and increase in VLDL

Question 43

why anorexia in Cachexia

Answer 43

obstruction, pain, malabsorption, depression, constipation, chemo/rad, inflammation- cytokines, hypothermic disregulation

Question 44

early satiety in cachexia?

Answer 44

results from reduced GI mortalility, opined analgesics, deregulation of signalling

Question 45

why nausea and chemosensory abnormalities in cachexia

Answer 45

direct consequence from antineoplastic therapies- side effects of drugs

Question 46

what do we have to be careful about with chemosensory?

Answer 46

may be caused by treatment- but could also be a nutrient def- so have to rule this out

Question 47

how to define the severity of cachexia and the phenotype

Answer 47

1. reduced food intake; administer questionnaire ( are they below 70% usual food intake0 2. catabolic drive; CPR as indicator of inflammation 3. Muscle mass and strength; DXA, BIA, MAMA, handgrip strength 4. functional and psychosocial effects; questionnaire