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Neurofibromatosis 2 and Treatments

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#1 tham

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Posted 22 December 2010 - 07:30 PM

I started this post to reflect treatments
I had researched for a couple of local
friends with neurofibromatosis 2, or NF2.


Bevacizumab (Avastin) has shown effectiveness
in vivo, but is quite toxic, with bowel perforation
a significant risk.



The tyrosine kinase inhibitors are relatively
less toxic, but generally only in vitro trials
so far.

Imatinib (Gleevec), the prototype drug in this class.


Erlotinib (Tarceva).



Sorafenib (Nexavar).


Lapatinib (Tykerb).


#2 tham

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Posted 26 December 2010 - 07:52 PM

NF2 tumors are caused by a loss of
function of the merlin tumor suppressor
gene and the subsequent upregulation of
EGFR pathways.

Thus the above tyrosine kinase inhibitors,
which act on the same signalling pathways
of cancerous tumors, would also reduce
the benign tumors in NF2.

" Schwannomas and all NF2-related tumors
are caused by loss of the tumor suppressor
merlin. "




Quercetin and resveratrol, both of
which inhibit P13K, ERK, and AKT,
would also likely suppress the
growth of NF2 tumors.


Sodium valproate upregulates merlin.


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#3 tham

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Posted 31 December 2010 - 09:12 PM

This is one of the local Malaysian girls
who has NF2, whose website I have
just done up, out of three in the country
know to me at the moment. All three
are females.


This is my first attempt at website
building, not very well done. The free
Webs.com engine also has lots of
bugs, worsened by a revamp last week.

I have been having a hard time
communicating with her as :

1. She is deaf, hearing destroyed
by schwannomas.

2. She is not literate in English, having
had just junior Chinese education,
conversant only in Mandarin and broken
Malay, while I can't understand Mandarin.

I have to SMS or email her in Malay,
and she is not very computer literate
as well.

3. Her main caretaker is her aged father,
already 70, pretty much illiterate too.
After he's gone, she is pretty much on
her own. (She has a surviving younger
brother, the only NF2-free offspring,
very much in his own world. )

Her mother and both elder silblngs
have long passed away from NF2.
NF2 does not skip generations, so
this would have come from her mum.

I wrote a letter for her to take to her
neurosurgeon on her visits some
time ago, along with printouts of the
above drug studies, emphasizing their
promising effectiveness for NF2, and
suggested that he refer her to their
oncologists for a trial of one of them.

Unfortunately, the surgeon told her
father that the studies were all
" very experimental, not proven ....
were all cancer drugs, not meant
for NF2 ..... heavy side effects ....
she would vomit, go dizzy, lose her
hair, bleed, etc. "

Her father obviously chose to follow
her doctor's advice, not realizing
that schwannomas are recurrent
and she couldn't keep on going for
repeated surgeries with their
inherent risks and morbidities for
the rest of her life.

She went with her dad to consult
another reputatable neurosurgeon
in private practice earlier this week,
who told them that multiple surgeries
would be required to take out all the
tumors in her brain and spine.

#4 rwac

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Posted 04 January 2011 - 06:44 AM

I suggest adding a translated link to her blog, It's surprisingly readable.

English translation.

#5 tham

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Posted 05 January 2011 - 07:31 PM

I suggest adding a translated link to her blog, It's surprisingly readable.

English translation.

Thanks. I have added a translated version in her page.


I tried Babelfish, but it wasn't much better.

Babelfish translation.




" Rapamycin: The Cure for all that Ails. "


The NF2 Merlin gene.


#6 tham

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Posted 16 January 2011 - 05:11 PM

The other two Malaysian girls with NF2,
Yvonne Foong and Keisha Petrus.


Yvonne Foong has had surgery at
Good Samaritan Hospital in LA a few
times, I believe.


Keisha Petrus has also has surgery
quite a few times.. She lives at the
housing estate where I work.

#7 tham

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Posted 17 November 2012 - 05:17 PM

The above NF2 patient, Lim Pei Lee, passed away at 6.30 pm this Thurday, 15 November 2012,
Malaysian time.


I had not kept in touch with her for the past year, but found ouf from Yvonne Foong's
(one of the four NF2 patients in the country that I know of) website that she had gone
for surgery at the local General Hospital by the Chief Neurosurgeon there for multiple
tumors along her brainstem and spine.

I called her home, and her father related that she lost the use of her left arm after the
surgery, as the surgeon had to cut thru some nerve fibers at critical regions to take out
a tumor. Her dad said the tumors were "quite large".

She had in fact lost the use of both legs this April, which coincides with the last entry
in her own blog. She was supposed to have been operated on by her primary neurosurgeon
at the local University Hospital in Petaling Jaya at the end of last year, but the guy seemed
to be "too busy" and then went for some seminar in the US for a month. Returning, he told
them that he had changed his mind and declined to operate.

She became crippled not too long after that.

Inevitably, her dad said a huge bed sore, some 4 inches wide and very deep, exposing
her spine, developed at her back. Several days ago, she developed a fever and lost
consciousness. Her dad admitted her into the local poorly equipped district hospital
in Klang town, near where she lived.

She recovered consciouness the next day, but then deteriorated. Apparently urosepsis
had set in, and her airways became clogged with mucus. She had been placed in the
packed women's ward, on a free bed placed along the walkways as there were numbered
beds left.

Her father complained to me that nobody was attending to her, and he was told to buy
his own mucus suction pump when he asked for one. (You can find such simple pumps
in any small private clinic around here.)

I called up the hospital, demanding to speak to the administrator or Chief Medical Officer,
but was told by a dumb half-past-six Malay female operator that "everyone was on leave
as it was a public holiday". She extended me to her ward, where nobody answered.

Further calls asking for the assistant administrator or MO fell on the idiot woman's ears,
and I was passed all over the place like a football. Fed up, I tried the ambulance line, hoping
to speak to any emergency MO there. NOBODY answered.

Finally, I asked for the Sister-On-Call, where luckily a professional sounding Chinese woman
answered. Relating the situation, I told her that if I made a complaint to the Health Ministry that
her dad had been told that the entire hospital had no suction pump, and that no one answered
their ambulance line, the hospital would be in serious trouble.

She promptly promised that she would go straight up to her ward and made sure Pei Lee was
attended too, and said she would call me back to keep me updated. However, her own busy
schedule resulted in her calling me only around 7 pm, informing that the girl was "very critical"
and asking her dad to come down to see her, as he was not around earlier at 4 pm when she
went up.

I called her dad, coudn't reach him. I drove down to the hospital, some 20 miles away, asking
for directions along the way, as I hadn't been there since 1988, reaching there at about 9.30 pm.
Going up into her ward was like entering a 19th century sanitorium filled with coughing slum
dwellers infested with the plague. Staffed by young interns looking like kids, most of them and
the nurses wore masks. I was wondering if I might catch some serious Klebsellia or
Pseudomonas infection.

Enquiring about her at the nurses' counter, I was told that she had already passed away at 6.30 pm.
Probing about the cause of her death revealed urosepsis. This dangerous superinfection, which
tends to affect women, and even in the best of times with a team of experenced specialists
treating it aggressively in the ICU, carries a mortality rate of 40 per cent.

With her pathetic treatment surroundings, looked after by interns who had never even
heard of NF2, she didn't stand a chance.

#8 tham

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Posted 19 November 2012 - 10:00 PM

A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor.


Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of
the p21-activated kinase, Pak1.


Validation of the p21-activated kinases as targets for
inhibition in neurofibromatosis type 2.


p21-Activated kinases are required for transformation in
a cell-based model of neurofibromatosis type 2.


Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent
growth of human ovarian cancer and NF2 tumor cell lines.


Edited by tham, 19 November 2012 - 10:04 PM.

#9 rwac

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Posted 20 November 2012 - 04:51 AM

tham, I know you very much want to help people. I seriously recommend you read Ray Peat, he's fantastic for badly defined illnesses. I know you will find him to have very unorthodox views, and some likely diametrically opposed to your current stream of thought.
Nonetheless, I have found Ray Peat to be extremely helpful in treating my CFS, and his advice is pretty damn effective. Most of his advice involves only diet, and a few medicines for specific things. I have been convinced about the effectiveness of his advice on me, so feel free to ask me anything here or on PM.


#10 tham

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Posted 20 November 2012 - 10:06 PM

Thanks, RWAC.

I have been quite depressed these few days because so much more could been
done for Lim Pei Lee - her death was quite tragic and could have been avoidable,
at least for a few more years.

I still can't really understand why, all these years, she was unable to secure a place
in St Vincent's Medical Center in LA for surgery there.

I wished I had had the chance to put her on the following, which activate/inhibit the Merlin,
p21, RAS, PAK1 and EGFR pathways linked with her type of tumors. Explaining this to
her and her illiterate father, however, was far easier said than done.

I am certain virtually nobody else in this country - none of the neurosurgeons nor any of
those dumb oncologists - know about the involvement of these complex signalling pathways
in her disease, let alone researched them, because NF2 is so damn rare. They probably
wouldn't even have heard of Merlin.

Sodium valproate
Fish oil
Kyolic, for its diallyl disulfide content
Imatinib or erlotinib

I have been reading Ray Peat's article on "Regeneration and Degeneration" and
ti does seem quite interesting and revolutionary. I shall PM you if I need further

#11 tham

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Posted 24 November 2012 - 08:16 AM

The NF2 gene, merlin, or schwannomin, has malfunctioned in NF2.




Sodium valproate appears to upregulate merlin.


HDAC is involved in the ploliferation of both the vestibular schwannomas and
meningiomas of NF2, as shown in these studies on a new HDAC drug, AR-42.




Sodium valproate is also a well-known HDAC inhibitor.

" ..... insulin-like growth factor-I receptor (IGF-IR) is strongly overexpressed
and activated in human primary schwannoma cells. "


Celecoxib blocks IGF-1R, as well as PDK-1, a protein in the PI3K/Akt pathway,
in the earlier study given by Joel Cairo in the glioblastoma thread.

" .... celecoxib acts directly on 3’-phosphoinositide-dependent kinase-1 (PDK-1),
a component of the insulin/IGF-1 signaling (IIS) cascade to increase lifespan. "


Cyclooxygenase-2 supports tumor proliferation in vestibular schwannomas.


Celecoxib is of course a selective COX-2 inhibitor.

OSU-03012, now called AR-12, a celecoxib analog, on these tumors.




However, AR-42 outperformed AR-12 in the HDAC study above.


#12 tham

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Posted 25 November 2012 - 05:35 AM

Curcumin activates merlin.

Combining Curcumin (Diferuloylmethane) and Heat Shock Protein
Inhibition for Neurofibromatosis 2 Treatment:
Analysis of Response and Resistance Pathways

" Curcumin also activated MYPT1-pp1δ (a merlin phosphatase), which was
associated with dephosphorylation of merlin on serine 518, an event that
results in the folding of merlin to its active conformation. "


" .... the cell-signaling pathways inhibited by curcumin alone include NF-kappaB,
AP-1, STAT3, Akt, Bcl-2, Bcl-X(L), caspases, PARP, IKK, EGFR, HER2, JNK,
MAPK, COX2, and 5-LOX. "


Activation of ERK, AKT and JNK signalling pathways in human schwannomas in situ.


Edited by tham, 25 November 2012 - 05:38 AM.

#13 tham

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Posted 11 June 2013 - 09:33 AM

Corrected link for the above study.

Activation of ERK, AKT and JNK signalling pathways in human schwannomas in situ.


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#14 tham

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Posted 11 June 2013 - 10:49 AM

Trials of sodium valproate with the VEGF inhibitor bevacizumab,
tyrosine kinase inhibitors erlotinib, lapatinib, sunitinib, sorafenib,
ras inhibitor salirasib and the mTOR inhibitor temsirolimus.

Treatment of patients with advanced neurofibromatosis type 2 with novel
molecularly targeted therapies: from bench to bedside.


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