NF1 – major optic glioama
Half of them will be affected and others not. The eye is affected even though glioma’s are not life threatening. The tumor and eye will not be matched in some cases.
Visual acuity – Vision develops in childhood – they do not see 20/20 till they are 6 years old.
Young children can look at the vertical stripes – and they are used to translate to acuity.
Visual field = extent of vision.
Tumor closer to eye can cause less issues than the one closer to brain – optic chiasma.
Optic pathway glioma – don’t treat when stable but treat when progressive vision loss is observed
Endocrine function not used as biomarker
Radiation is usually therapy of last resort – Most patients are 6 or younger, and radiation can cause cognitive issues, secondary tumors and possible visual decline.
Mostly chemo – carboplatin/vincristine. Works well for 2/3 of patient. Response rate : 46% and 5-year PFS= 69%
No second line – because concern of leukemia risk. Others therapies are those that target angiogenesis – Vinblastine, bevac
MEK inhibitor,
NF1 – uncontrolled RAS pathway.
NF1 – gene therapy work is in progress.
RAS – usually untargetable – but agents are becoming available.
Selumetinib (MEKi). Showed PFS – good at 2 year but not so great at 5 years.
Who should be treated, what are visual outcomes, what treatment regimens achieves the best visual outcome, what are true prognostic factors?
Natural history for 500 people in progress – for vision.
Optic pathway glioama – is only in children and shut themselves off after puberty.
NF1 nerve sheath tumor.
Dermal – Plexiform – (50%). low grade tumor of peripheral nerves. Atypical neurofibroma
Plexiform neurofibramas.
Benign tumors – grow along nerve and nerve branches, schwann cell that wrap around the nerve. More diffuse and are around schwann cells.
Malignant transformation is rare – more likely – pain – tumor and nerve, disfigurement, compresses other structures (vessel, spinal cord etc)
most shut them off during puberty. Treatment decision needs to be made.
Complete resection is usually curative…
No radiation or no drug therapy. As yet.
MEK inhibitor shrink PN in preclinical NF1 mouse. Selumitinib.
And about 20% reduction is defined as response. And 70% of the patients showed response.
They had to have a functional deficit because it did not cure the disease but was used to just show a response of them getting better.
NF clinical trials consortium is the one one being used….
MEK inhibitor – Mirdametinib for adults. Greater than 16 yeargs, (approved by FDA)
Another inhibitor – Binimetinib – 70%
Tumor microenvironment. Cabozantinib. (targets microenvironment and angiogenesis)
Other studies – caboantinib and selumetinib….
NF119 – repurposed drug identified through AI drug discovery platform, response in mouse model similar to MEKi,
Drug from Til Milde for senescence :
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NF2 related schwannomatosis – Schwannoma.
Hearing loss, balance forms and weakness.
Tumors of meninges, catracats, skin tumors called neurofibromas.
Bevacizumab for angiogenesis for hearing loss as one indication.
Balance between growth and death. Cannot find druggable targets.
Immunotherapy – checkpoint from CD8 cytotoxic T cells.
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Pain
Numerial pain rating scale – Numerical rating scale – NRS (1-10), Visual anolog scale 1-10.
Prevalence of pain in 30-90%. A majority of NF patients experience pain at some point in their life.
In NF – central sensitization of pain…Nervous system is ramped up.. so that in general all the pain is increased.
242 patient survey said most of them, at pain were at “6”. Opioid and GABA (anti-convulsants) were frequently used.
NF2 – merlin protein which is also a tumor suppressor.
Indications for surgery: progressive pain, neuro deficit, significant growth, diagnostic uncertainity, cosmetic.
Partial surgeries with partial resection is also possible.
Think of it like an onion – in schwanoma it can be one small area – intracapsular dissection.
In Neuroma – there can be a big defficit since they are everywhere.
Schwanoma –
25 year old myelopathy – many organs are affected vs splenopathy – very localized.
Spinal cord schwanoma…
Brachial plexus tumor – causing pain and weakness. And sometimes needed to go carefully.
Sometimes Ki67 value was low.- but it changes in time sometimes.
Pain reduction, better outcome,
Before than there was only one cell line with NF2 (now there are 2 from surgery).
MOSAIC – no specific genetic instance of a mutation – unknown.
