PT 536 Progressive Lesions Physiology

1. growth rate

2. nuclear atypia

3. angiogenesis

Tumor aggressiveness is based on what 4 criteria?

glutamate toxicity, increasing ICP

Brain tumors are mass lesions that kill neurons through what mechanisms?

proto-oncogenes, tumor suppressor genes

what two proteins are responsible for controlling cell division?

Proto-oncogenes

which protein promotes the cell cycle (cyclins and cyclin-dependent kinases (Cdks) phosphorylate proteins to progress the cell cycle)

tumor suppressor genes

what proteins prevent the cell cyce?

DNA damage → p53 → p21 → inhibits cyclin-Cdks

how can tumor suppressor genes inhibit the cell cycle shorter term?

DNA damage → p53 → p21 → apoptosis

how can tumor suppressor genes inhibit the cell cycle long term?

oncogenes

mutations in proto-oncogenes lead to the formation of what?

lead to aberrant progression through the cell cycle

how can oncogenes contribute to the development of cancer?

unable to prevent cell cycle

how can mutations in the tumor suppressor genes contribute to the development of cancer?

p53

50% of cancers have mutations in what cancer gene?

anaplasia

mutations in the proteins that regulate cell division lead to what change in the cells?

anaplasia

presence of multiple cell differentiation state

high

anaplasia indicates a high or low grade tumor?

pleomorphic nuclei

having variation in the size and shape of cells or their nuclei.

diffuse astrocytoma; grade 2

a type of brain tumor that originates from astrocytes, with no pleomorphism present

anaplastic astrocytoma; grade 3

a type of brain tumor that originates from astrocytes, with pleomorphism present

glioblastoma; grade 4

high grade astrocytoma present with necrosis and microvascular proliferation

benign tumors

tumors that have a slow growth rate and are noninvasive; but can still grow and damage normal tissue and become malignant

malignant tumors

tumors that have a high growth rate and are more likely to metastasize

20/100,000

annual incidence of primary brain tumors

age, exposure to ionizing radiation, family history, exposure to certain infections (EBV)

risk factors for primary brain tumors

gliomas

most common primary brain tumor that affects the glia

high grade astrocytoma

most common type of glioma with the worst prognosis

low grade astrocytomas

glioma common in the frontal lobes with a prognosis of 6-8 years and prevalence of 10-12% of primary tumors

neuroma (schwann cells)

what type of glioma has the best prognosis and may not even be treated in the elderly?

12 years

prognosis of a oligodendroglioma grade II

3.5 years

prognosis of a oligodendroglioma grade III

ependymoma

type of glioma that is more likely to obstruct blood flow, involving a prognosis of >10 years

medulloblastomas

gliomas that often develop in the vermis (affecting balance and movement), involving a prognosis of 3 years for children and 6 years for adults

meninges

most common site of non-gliomas

meningioma

most common non-glioma that produces ICP signs and has a typical 10 year survival rate

pituitary adenoma

non-glioma that includes visual signs and hormonal irregularities with a typical 10-year survival

craniopharyngioma

non glioma that includes visual signs and hypopituitarism with a typical 10 year survival rate

epidermoid, dermoid

non glioma that is benign and occurs in development, with a 20 year survival rate

hemangioblastoma

non-glioma that is well-vascularized with >80% in cerebellum and a 10 year survival rate

primary CNS lymphoma

non-glioma that is deep periventricular and involves controversial surgery and only has a 1 year survival rate with RT and CT

intramedullary

rarest spinal cord tumor that gives burning diffuse pain

age, exposure to ionizing radiation, family history, exposure to certain infections (EBV)

risk factors for spinal cord tumors

extramedullary

spinal cord tumor outside of the cord and stimulating the dura; gives sharp and radiating pain

extradural spinal cord tumors

spinal cord tumors that tend to be in the posterior regions of the spine due to ease of metastasizing near valveless blood vessels

14/100,000

annual incidence of metastatic brain tumors

age, exposure to ionizing radiation, family history, exposure to certain infections (EBV)

risk factors for primary brain tumors

metastatic

do primary or metastatic brain tumors generally have a worse prognosis?

middle cerebral artery

what artery is usually associated with metastatic brain tumors?

lung

most common site of origin for metastatic brain tumors

myelin

When brain tumors are present, the pressure first "pops" what structure of a nueron?

conduction block

electrical impulses go down but encounter blocks and delays in the demyelinated internodes

insert ion channels to propagate APs

how can neurons recover from demyelination?

increase metabolic stress and free radicals

risk of inserting ion channels to propagate APs

true

true or false? if we removed the source of pressure, we can remyelinate via the reproduction of oligodendrocytes

late neuronal loss

in the presence of brain tumors, initial demyelination causes what process?

1. oxidative stress + apoptosis

2. mechanical pressure + excitotoxicity

3. tumors release glutamate + excitotoxicity

4. incomplete functional recovery

4 ways late neuronal loss can occur after initial demyelination

cystine-glutamate antiporter inhibitor (SAS)

what do tumors use to release glutmate?

CSF

liquid cushion in the brain that is in equilibrium with extracellular fluid (ions, NTs, nutrients, & wastes)

hydrocephalus

accumulation of CSF in the ventricles, compressing the midbrain and cerebral aqueduct

blockage of cerebral aqueduct from herniated brain tissue

typical causation of hydrocephalus

increased ICP

big negative consequence of hydrocephalus

ischemia

Whenever tumors occupy space and herniate brain tissue, an increase in ICP can ensue and lead to what issue with blood?

increased blood brain barrier

Other than ischemia, what specific pathophysiology of brain tumors that involves blood can happen?

edema, hemorrhage (increased ICP overall)

with increased BBB permeability, blood secreting factors leak through and lead to what two issues?

1. blood has higher levels of glutamate and K+, so leakage into brain with hyper-excite neurons

2. reactive gliosis and reduces K+ and glutamate pick-up

how can an increase in BBB permeability lead to excitotoxicity in the brain

directly, increasing ICP

how can infections kill neurons?

necrosis

physical injury involves what kind of cell death

damage-associated molecular patterns

Endogenous molecules released by damaged or dying cells. They serve as signals to alert the immune system to tissue injury and initiate an inflammatory response (stuff that should be inside the cell that is not outside the cell)

pathogen-associated molecular patterns

Molecular structures released in infections that increase inflammation to bring blood to the area of infection

increased BF, vasodilation, increased permeability, increased blood flow and blood cells

results of infection

toll-like receptors

recognize molecular patterns unique to pathogens, detecting DAMPs and PAMPs

sheddases, transcription factors

activated TLRs activate what molecules to stimulate the release of pro-inflammatory cytokines

cytokines

secreted signaling proteins that stimulate inflammation

1. VD, increase permeability via COX and prostaglandins causing smooth muscle to relax

2. chemotaxis (attracting macrophages to the area)

3. reactive gliosis

how can cytokines facilitate inflammation?

meninges

layers of connective tissue that cover the CNS

prevent nervous tissue from directly contacting bone

how do the meninges work as a physical barrier?

prevent diffusion from blood into the brain

how do the meninges work as a chemical barrier?

dura mater, arachnoid mater, pia mater

three different meninges

dura mater

tough, outermost layer of the meninges; acting as a physical barrier

arachnoid mater

CSF filled intermediated meninge; acting as a diffusion barrier

pia mater

delicate & permeable, innermost meninge; acting as an anchor

2.5/100,000

annual incidence of bacterial meningitis

11/100,000

annual incidence of viral meningitis

exposure to neurotrophic pathogens, lack of vaccination, compromised immune function, nervous system damage, age <5

risk factors of meningitis

virus/bacteria enters CSF in subarachnoid space → triggers immune response from epithelial cells in meninges

how can infection cause meningitis

edema (increased ICP) and ↑BBB permeability

infection in the meninges can lead to inflammation and cause what two main issues?

brain herniation, hydrocephalus, ischemia, mechanical depolarization

consequences of edema and increased ICP in meningitis

edema, WBC entry

consequences of increased BBB permeability in meningitis

encephalitis

inflammation of the brain

3.5-7.4/100,000

incidence of encephalitis

exposure to neurotrophic pathogens, lack of vaccination, compromised immune function, nervous system damage, age <5

risk factors of encephalitis

retrograde

in what manner do infections enter the central nervous system? (anterograde or retrograde)

increase ICP, increase BBB permeability

how can inflammation with encephalitis affect the CNS?

explode the cell membrane

how do new viruses leave their hosts?

motor neurons, thalamus, brainstem, cerebellum

where are cells targeted with the west nile virus?

motor neurons

where are cells targeted with the poliovirus ?

limbic system, temporal lobes, frontal lobes

where are cells targeted with the herpes simples virus?

prions

infectious proteins that act as potent neurotoxins

0.1/100,000

annual incidence of prion disease

ingesting infected meat or brain matter

risk factors for prion disease

- ataxia, myoclonic jerks, weakness or paralysis

- hallucinations

- cognitive/memory impairments

- emotional disturbances

- sleep abnormalities

symptoms of prion disease

none

treatment for prion disease

death within 1 year

prognosis of prion disease