Glioma Flashcards
Depending on cellular origin the glioma can make
Astrocytoma, Oligodendroglioma or Ependymoma
4 grades of gliomas
Pilocytic Astrocytoma, Low-grade Glioma, Anaplastic Glioma and Glioblastoma multiforme
Glioma features
- The most common malignant primary brain tumor in adults
- Peak age in the 6th decade (people in their 30s and 40s can have them too)
- Increasing incidence
- Without treatment fatal course within weeks
- Patients experience hemiparesis, seizures, aphasia, personality changes and die quickly
Histological features of glioma
Grade 1: low cell density
Grade 2: medium cell density and a little polymorph(?)
Grade 3: High cell density, polymorph, elevated, pathological mitosis figures
Grade 4: High cell density, high polymorph, atypic mytosis and necrosis
Neoangiogenesis
thedevelopment of new blood vessels froma pre-existing vasculature involves the migration behavior
Other than histological features, what can help us identify the grade of glioma?
Molecular features & IDH mutations (Glioblastoma can both have WT and mutated version)
Are you more likely to survive with or without a IDH mutation?
With
What is IDH?
Isocitratdehydrogenase - it’s a metabolic enzyme that’s part of the Krebs cycle that will catalyze Isocitrate → a-Ketoglutarate.
Outcomes of IDH mutations
reduces enzyme activity
additional „gain of function“
hypermethylation of DNA
silencing genes
Notes on surgery
We fix the head
There is a ring to steady the surgeons hands
we have a bipolar instrument to coagulate vessels to stop bleeding
It’s difficult to separate tumor and healthy tissue, but using 5-ALA to mark tumor tissue is useful
Neuronavigation
we can match the intraoperatively obtained pictures with MRI’s from the patients to we know where we are. We have a pen we stick into the area (?) which will show us where we are. Downside: during surgery we have shift and swelling - it get’s less and less exact over time
Tractography
all fiber tracks are different, so we therefor look at the tractography to keep neurological function - we can also preform wake-surgery. A neuropsychologist can examine the patients and tell when we’re reached the margins of the tumor and it’s better to stop there to not lose neurological function
Why do we put so much effort into removing the whole tumor?
Because survival rates are a lot longer if we do
Do patients fully recover if we remove the whole tumor?
No, the area around will still show abnormal cells
TT fields stands for?
Tumor treating fields
What are TT fields?
Alternating charges –> indicates that the poles are switching in a set frequency. The charges move back and forth and the dipoles rotate
Which part of the cell cycle does TT fields screw up?
mitosis
Phases of Mitotis
Prophase: DNA condensates and forms the chromosomes
Metaphase: the spindle fibers line up chromosomes the
Anaphase: the spindle fiber separate the chromosomes
Telophase: the cytoplasm and chromosomes are divided into two separate cells
What does the mitotic checkpoint do?
Mitotic check point makes sure the DNA is separated correctly in the anaphase. If it sees any attachment error in the spindle fibers to the kinetochores, the cell will stop and go into apoptosis
How does TT field mess up the metaphase of mitosis?
The spindle fibers depend in aligning with the electrical currents, but if that is not possible due to TT fields, it will delay mitosis and might even cause apoptosis
How does TT field mess up the telophase of mitosis?
It causes the polar component of the separating cell to be drawn into the middle again
What can TT fields do to a cell?
delay cell division & induce apoptosis –> leads to less viable cells
It also reduces cell migration
What’s the optimal intensity and frequency for TT fields?
For Glioblastoma 200 kHz and to get antimitotic effect (so cells don’t divide) is > 1 volt/cm. Generally, the larger the cell, the lower the frequency
Why do we want optimal intensity and frequency for TT fields?
Because reduction in cell viability is frequency and intensity depended
The effects of combining TTFields & irradiation?
Reduces the number of viable cells more than the components could individually (Synergistic effect)
Why are the effects of combining TTFields & irradiation strong?
might be due delayed DNA repair we have when we do TT field right after radiation
After radiation, the DNA is damaged, but it disappears after max 24 hours - if you combine the 2 methods in a short time period, it takes a long time for the DNA to fix itself
Why does combining TTFields & inhibitors for the mitotic checkpoint work?
The checkpoint detects damages to the DNA, and if we inhibit the check point, the cell is not able to stop and repair DNA damages, so it goes into apoptosis. We also get a lot of abnormalities in the cells that survive
Effects of combining TTFields with chemo?
Made patients survive 4.9 months longer than just chemo and increased survival percentages over years
Safety of combining TTFields with chemo?
Completely fine, even seizures, which might be concerning as it’s an electrical treatment, were the same across conditions
Effects of meeting with other TTFields users and relatives on anxiety, depression, everyday restrictions and social life on patients?
Anxiety and depression scores were already low, but anxiety decreased a bit.
everyday life restriction and social exposure was at 2.5 out of 5 before the meeting, but restriction dropped to 2.25 and social exposure to 1.7 (lower scores are better)
Effects of meeting with other TTFields users and the patients on anxiety, depression, everyday restrictions and social life for relatives?
Anxiety and depression scores were higher than for patients, but both decreased.
Reduced stress for patients in everyday life: 2.9 –> 2.3
Reduced sense of social exposure: 2.3 –> 1.9
Why do patients often die within 2 years?
Relapse (new tumor after surgery)
Why do we have Neoangiogenesis with Glioblastomas?
Because Glioblastomas need a lot of blood to grow
How can an inhibitor against Bevacizumab help decrease tumor size?
It binds to Vascular endothelial growth factor (VEGF) and stops it from binding to its receptor. Without VEGF we might not have Neoangiogenesis and the Glioblastoma can’t grow.
Is Bevacizumab an effective treatment against Glioblastomas?
For overall survival no, but for Progression-free survival yes
What is the challenge of new treatments against Glioblastomas?
Agents need to be able to cross the BBB
Why might Bispecific antibodies be a good treatment against Glioblastomas?
Because they tie T cells to a specific surface protein of the Glioblastoma –> The t cells destroys the tumor cell
Why might Bispecific antibodies not be a good treatment against Glioblastomas?
There are a lot of different surface protein of the Glioblastoma, so choosing the correct antibody is hard
What’s a CAR-T?
Modified T cells that recognize specific tumor antigens (surface proteins)
How do we create CAR-Ts?
CAR-Ts pass the BBB. To make CAR-T we need the patients blood and isolate T-cells - they’re modified using lentiviruses to have them recognize a specific surface tumor antigen. You can modify it to have a co-stimulatory region (hinge region), which depend on the size of the antigen. It’s re-infused into the patient.
What’s the response to CAR-Ts in patients?
Some tumor necrosis and stable disease. 29 months survival is overall seen, which is 8.1 months more than TT fields + chemo
Downside to CAR-Ts?
They again only target one tumor antigen/surface protein - BUT we can combine multiple tumor antigens and make a TanCAR
CAR-Ts vs TanCAR: function and survival
CAR-Ts target one tumor antigen and TanCAR an target 2 (maybe more?)
survival is significantly longer for TanCAR than CAR-Ts, though CAR-Ts has longer survival than just chemo
Macrophages can become which cells to help with immunosuppression of tumor growth?
M2 cells
Are elevated M2 microphage levels associated with higher or lower survival?
lower
What are the function of TAM (tumor associated microglia)?
They secrete cytokines and other growth factors promoting tumor growth
Why are there T and B cells present in the brain when we have a Glioblastoma?
Because the BBB becomes leaky due to the tumor
