AMAZING NEWS !!!!!!
Due to the fantastic efforts of The Butterfly AVM Charity and all our brilliant volunteers and fundraisers,the research that we have funded has allowed for a major breakthrough to occur . The first genetic cause of AVM in the skin has been found ! and we did it !. Although this is our first step we are well on the road to finding definitive treatments to help AVM sufferers.
We still need your help , please help us take the next step forward , you can really make a Change , run a race, climb a mountain, bake a cake, or anything that you can think of !!!
Lara’s message below
Research into the genetic basis of cutaneous arterio-venous malformations (AVM)
Update September 2016
Research into AVM at the UCL Great Ormond St Institute of Child Health is progressing well. We have recruited more patients and a further set of samples were run on our next generation sequencing chip. We are confident we found the cause of the AVM in one patient, which has been a great breakthrough as it is the first genetic cause of AVM in the skin.
These exciting results will be published soon and were presented at the European Society for Dermatological Research meeting in Munich this month. For the patients in whom we don’t yet have the mutation we are currently looking using a different technique, but this requires fresh biopsy samples. This experiment takes a long time but we have results for one patient already which are under analysis.
If you have an AVM and have ever attended Great Ormond St even on only one occasion, and would like to give a fresh sample for this research (for example if you are due to have some surgery on your AVM), or if you have previously had surgery performed on your AVM and would like to give us permission to use the old sample, please contact me by e-mail email@example.com or our research coordinator firstname.lastname@example.org or do let your doctor know, as all the Dermatology department are able to recruit to the study.
This is our great AVM Researcher Lara in Munich .
If you would like to see a copy of the poster please email email@example.com
A very interesting recent article by eminent Dr Yakes on the efficacy of Ethanol when compared to bleomycin .
Use of Multiple Sclerosant Agents in Vascular Malformation Management: A World. in Endovascular Confusion and Chaos
Wayne F. Yakes, MD
‘AVM = arteriovenous malformation, LM = lymphatic malformation, VM = venous malformation
In the series of Ui Haq et al (1), 20 patients underwent
21 bleomycin foam embolization procedures, and six
procedures involved sclerosant agents in additional to
bleomycin. The authors report a per-patient complica
tion rate of 40% (30% minor, 10% major); on a perprocedure
basis, the complication rate was 29% (22%
minor, 70/n major). The authors state that all patients had
•a decrease in symptoms after treatment.
An interesting comment by the authors is that “[t]he use
of bleomycin should be reserved for locations where
post procedure swelling would be dangerous.” Yet in their
own small 20-patient series, one patient required intubation
for 4 days as a result of tongue swelling to maintain the
airway. Another patient with a tongue lesion required
prolonged intubation and hospitalization for 15 days after
treatment with bleomycin and ethanol. The authors state,
“[s]welling was seen only in the area treated with alcohol,
.not in the area treated with bleomycin foam.” This is a
difficult statement to articulate this conclusion. Having
treated numerous venous, lymphatic, and mixed venous!
lymphatic lesions in the tongue over the years, I have had
only two patients require overnight intubation secondary
to tongue swelling. I have never had a patient require
prolonged inttibation (ie, 4 d or more, as in two of 20
patientsin this series ) as these authors report. Therefore,
swelling is definitely a real possibility with bleomycin use,
as sweffing is a potential issue with any sclerosant agent.
‘In regard .to the statement that one patient had tongue
swelling only in the ethanol-treated part, but not the
bleomycin-treated part, venous malformations (VMs) of
the tongue are interconnected saccular spaces of varying
sizes, and liquid embolic agents flow through endothelial
cell—lined spaces and are never limited to specifi’: areas.
Injection of one area does not mean that the sc crosant
agent stays put: it does flow into other contiguous areas.
as does the blood within these interconnecting tubes.”
Therefore, the authors’ statement is challengin to be
accurate and definitive as stated.
Other authors have reported the use of bleonycin in
the treatment of lymphatic malformations (LI’ Is) andi
VMs. Hassan et al (2) reported a 71% effectiven~s& rate
and a 14% complication rate, with ulcerations ir five of
75 patients. Sainsbury et al (3~ reported an 82.7%
effectiveness rate with bleomycin and compl cations
that includcd ulcers, blistering, infections, swelli ig. and
recurrence. In a study of pingyangmycin (blc omycin
AS), Bai et al (4) reported a 43% effectiveness r; te with
interventional treatment alone and a 740/ effec iveness
rate with interventional treatment and surg~ry for
microcystic LMs (4). Yang et al (~ reported blcomycin
injections to be effective in 81% of macrocystic L ‘vis and:
63% of microcystic LMs, with complications including
hematoma, ulcers, fever, and soft-tissue atrophy
Regarding articles comparing bleomycin and ethanol, UI
Haq et al (1) did not include the 2013 article by Zht ng et al
(6), a 138-patient series, yet referenced the 2011 a ‘drib by
Spence et al (7) that reported only 17 patients. Intl dr 138-
patient series, Zhang et al (~ reported that 95% of patients
(71 of 75) were cured or had markedly effective or :ffective
treatment with absolute ethanol. In the bleomycir group.
65% of treatments (41 of 63) were deemed effectix e (there’
were no cures or markedly effective treatments in the
bleomycin group). The difference in these rest Its was
statistically significant, whereas the article by Sperce’ et at
(7) could not achieve any statistical significance w:’th. only
17 patients. In the large comparison study of Zha’ig et al
(6), absolute ethanol proved markedly superh ‘r. The
ethanol group had 14 cases of skin necrosis in 75 patients
and the bleomycin group had five cases of skin necrosis
among 63 patients. Therefore, the use of bleomyci n is not
http://dx.doi.orgllO.1016/j.jvir.2015.0E.002 immune to swelling or necrosis.
V&umel6 • Number 10 • October • 2015 1495
Amo ~g articles that report the use of absolute ethanol as
the prii aary sclerosing agent for low-flow VMs, several
should l:e mentioned. Lee et al (8) reported 87 patients, 399
ethanol procedures, and a 95% effectiveness rate of
significant or complete malformation ablation, with a
l2.4% complication rate. Johnson et al (9) reported the
treatme it of tongue VMs with a 100% success rate and no
major mplications. One patient who presented with
;breathiig difficulties secondary to a tongue VM re
:mained intubated for 5 days and was discharged un
eventfully. Su et al (10) reported the treatment of head
and ne.~k VMs with absolute ethanol, with 56 of 60
patients cured (four with minimal residual VM), and no
skin ne.~rosis or nerve damage issues. Orlando et al (11)
reporte(. a 94% rate of complete remission or improve
ient a symptoms in 39 patients, with 32 having no
complicitions. One had a skin ulcer that was managed
consen Ltively, and three had transient paresthesias. In a
study o 87 patients who underwent 305 ethanol injection
sessions Lee et al (12) reported 84.5% of patients with
excellent or good results, one transient facial nerve palsy,
and no episodes of tissue necrosis.
In my own vascular malformation center, over a 6-
year pc iod (January 2002 to December 2007), my team
perforn Led a prospective gathering of data regarding
ethanol einbolizations in VMs of all types in all
anatomic locations. There were 1,367 patients under
going .1,798 procedures in which a total of 133,253 mL
of .abs lute ethanol was injected. Transient complica
tions ~ ere seen in 5% of procedures (minor blisters,
transiei t nerve injuries, superficial deep vein thrombosis,
.infectio as, and disseminated intravascular coagulopa
thy). lvi ajar complications were seen in 0.4% (deep vein
thromb )si5, n = 4; pulmonary embolism, n = 3;
amputation, n = 2; pneumothorax, n = 1; gastrointest
inal blc.xling, n = 1; skin graft, n = 3; permanent nerve
injur~,.i = 1; and cardiopulmonary collapse, n = 3).
Regarding cardiopulmonary collapse with the use of
ethanol this issue has been solved by several investiga
tors.(13—16). lii a 2010 prospective study, Shin et al (13)
reporteL.l that, according to their treatment protocol with
Swan—( ianz catheter monitoring, if the injections of
ethanol do not exceed 0.14 mL/kg every 10 minutes,
cardiopulmonary collapse is avoided. This series was of
high-fk.w arteriovenous malformations (AVMs) that can
require greater ethanol dose injections. Bisdorff et al
(14), in a retrospective review of 71 patients undergoing
.162 ethanol treatments of VMs, demonstrated that an
ethanol dose/weight ratio greater than 0.24 mL/kg was
:predictwe .of systemic toxic effects. Systemic com
plicatio as were not related to repetitive sclerotherapy
sessiom. The authors determined that a maximal dose of
0.2 mL ‘kg per injection could be considered acceptable
in VM treatment indications.
In m v institution, we studied this issue as well. With
the us of Swan—Ganz catheters, we prospectively
inonito ed 200 .consecutive patients (all > 15 y of age)
who underwent ethanol embolization of their vascular
malformations. It was determined that, when ethanol
doses of 0.1 mL/kg or less are injected every 10 minutes,
increases in pulmonary artery pressures were minimal if
not negligible. Therefore, adherence to this protocol has
obviated Swan–Ganz catheter monitoring, and no car
diopulmonary collapse has occurred since. Observa
tional and published prospective data with Swan—Ganz
catheter monitoring revealed ethanol dose injections of
0.10—0.14 mL/kg to be without issue. In the retrospective
series (14), a dose of 0.20 mL/kg proved safe. One
caveat, however, requires elucidation. These dose ranges
apply only to patients whose pulmonary artery pressures
are in the normal range. In those patients with
pulmonary artery hypertension of whatever etiology,
these rules do not apply. Patients with pulmonary
hypertension, unlike patients with normal. pulmonary
pressures, have no pulmonary pressure reserves. With
the pressures already abnormally elevated, any further
evaluations could mitigate cardiopulmonary collapse in.
an already compromised patient. Therefore, in this
patient group, if ethanol embolotherapy is contem
plated, Swan—Ganz catheter monitoring is. mandatory.
After the level of pulmonary hypertension. has been
determined, ethanol embolotherapy may even be
omitted to prevent further elevations that may not be
tolerated. If ethanol treatment is determined to. be
possible, it should be immediately terminated if, during
monitoring, there is even a minimal increase in
pulmonary artery pressures. Nitroglycerin or adenosine
should be available to be administered through the
Swan—Ganz catheter into the pulmonary circulation.
Inhaled nitric oxide through the endotracheal tube, if
available at an institution, should be present if needed by
the anesthesiologist. Adenosine is usually preferred to
nitroglycerin because of its minimal effect of lowering
systemic arterial blood pressures, which is very
undesirable during cardiopulmonary collapse situations.
Despite the focus on treatment of only low-flow VMs
in the study of UI Haq et al (I), it is important to also
consider and review a 2014 Journal of Vascular and
Interventional Radiology article (i’~ that describes a
single-center experience in treating 46 patients with.
VMs and AVMs over a 13-year period! and its retro
spective analysis. Vogelzang et al (1~ reported on their
experience of serially treating 31 patients with VMs and
15 patients with AVMs with absolute ethanol.. They
reported per-patient major complication rates of 13.3%
in AVM treatment (3.9% per procedure) and 9.7% in
VM treatment (5.4% per procedure) and per-patient
minor complications rates of 6.7% in AVMs (2% per
procedure) and 16.1% in VMs (9.8% per procedure)
According to Society of Interventional Radiology
reporting criteria, the overall complication rate was
24% (11 of 46 patients). Major complications in five
patients (11%) included one permanent ulnar neuro
pathy (in a patient with a forearm VM), one digit
Commentary: Multiple Sclerosants for Vascular Malformations Yake:, • JVIR’
amputation (in a patient with a hand AVM), one leg
compartment syndrome requiring fasciotomy (in a
patient with a leg AVM), one skin ulceration requiring
wound debridement escharectorny (in a patient with a
VM), and one case of transient severe gluteal pain with
sciatic neuropathy resolving after 4 weeks (in a patient
with a pelvic VM). They further reported that 24
patients (52.2%) were totally cured, 12 patients showed
improvement (26.1%), and 10 patients showed no change
or worsening (2 1.7%). The authors concluded that
ethanol produces good outcomes, with relief of symp
toms in a majority of patients in the series (17).
‘In summary, the literature states unequivocally the
superiority Of absolute ethanol 98% or 96% in the
treatment of low-flow malformations. The vast majority
of publications state greater than 90% efficacy. Bleomy
•cin is a second-tierembolic agent, as are other selerosant
agents, in :low..flow vascular malformation treatment,
with fairly ‘consistent published results in the 60%—80%
efficacy range. The literature is very clear that, despite
rationales for the use of second-tier agents to prevent
swelling and ulcerations, these complications do still
occur and are never completely avoided.
Experience with the use of ethanol, recognition of where
•the “nidus” is (rather than a collateral vessel), and
knowledge of the vascular supply to nerves is tantamount
to lowering complication rates and achieving successful
outcomes. With the use of sclerosant embolic agents,
especially ethanol, an old adage does apply: “a poor
workman blames his tools.” The fact that these authors (1)
have published ethanol complication rates in lower ranges
than other published series is emblematic of the value
of high patient volumes and collaboration in one of
the most challenging areas of vascular medicine. The
rarity of vascular malformations, compounded by the
extreme difficulty in treating these patients, points to the
enormity of the problem. Querying many interventional
radiologists, interventional neuroradiologists, and fellows
training in these subspecialty disciplines, I hear again and
• again that they have had little or no experience with the
use of ethanol as an embolic agent during their training.
Therefore, many endovascular specialists are extremely
reluctant to use ethanol when they move on to their
practices. Often, they use the embolic agents with which
they are familiar rather than those with which they are
unfamiliar. This is only natural. However, commu
nication between individuals and centers can mutually
advance the cumulative experience and knowledge of the
endovascular specialists in each. The use of ethanol as an
embolic agent in other clinical entities can be a key to gain
more experience in its safe use as well. Its use has been
•reported suecessfi.al as a primary endovascular treattnent
for hemorrhaging angiomyolipoma (18), preoperative
embolization for renal cell carcinoma as first introduced
by ElIman et al G~) and later amplificd by Bakal et al (20),
or as a palliative treatment for inoperable cases (21).
Ethanol can also be vei’y effective as a primary treatment
modality for varicocele and its recurrences (2~ When
collaboration between centers and individuals occ urs and
experience is shared, knowledge advances, success rates
increase, and complication rates decrease, all to bei ‘efit our
only object: our patients.
1. UI Haq F, Mitchell SE, Tekes A. Weiss CR. Bleomycin foam treatment
of venous malformations: a promising agent for effective treatment with
minimal swelling. J Vasc lnterv Radiol 2015; 26:1484—1493
2. Hassan V. Osman AK. Altyeb A. Noninvasive management of heman
giomas and vascular malformations using intralesional Bleomycin injec
tion. Ann Plast Aurg 2013: 70:70—73
3. Sainsbury DC, Kessell 6, Fall AJ, Hampton FJ, Gahan A, Muir T. lntrale
sional Bleomycin injection treatment for vascular birthmarks: A 5 year
experience at a single United Kingdom unit. Plast Reconstr Surgery 2011;
4, Bai Y. Jia J. Huang XX, Alsharif MF, Zhao JH, Zhao ‘iF, Sclerotherapy of
microcystic lymphatic malformations in oral and facial regions. J Oral
Maxillofac Surg 2009; 67:251—255
5. Yang Y, Sun M, Ma 0, et al, Eleomycin AS sclerotherapy for cervico
facial lymphatic malformations, J Vasc Surgery 2011; 53:150—155
6. Zhang J, Li HE, Zhou SY, et al. Comparison between absolute ethanol
and Bleomycin for the treatment of venous malformations in children,
Exp Ther Med 2013; 6:305—30a
7. Spence J, Krings T, TerBrugge KG, Agid R. Percutaneous treatment of
facial venous malformations: a matched comparison of alcohol and
bleomycin sclerotherapy. Head Neck 2011; 33:125—130
8. Lee BE, Do VS, Byun HS, Choo 1W, Kim Dl, Huh Sh. Advanced
management of venous malformations with ethanol sclerotherapy: mid
term results. J Vasc Surg 2003; 37:533—538
9. Johnson PL, Eckard DA, Brecheisen MA. Girod DA, Tsue fl’. Percuta
neous ethanol scierotherapy of venous malformations of the tongue.
AJNR 2002; 23:779—782.
10. Su L, Fan X, Zheng L, Zheng J. Absolute ethanol sclerotherapy for
venous malformations in the face and neck. J Oral Maxillofac Surg 2010:
11. Orlando JL, Caldas JGMP, Campos HGAC, Nishinari K. Wolosker N.
Outpatient percutaneous treatment of deep venous malformations using
pure ethanol at low doses during local anesthesia. Clinics lSao Paulol
12. Lee lH, Kim KH, Jeon P. et al. Ethanol sclerotherapy for the manage
ment of craniofacial venous malformations: the interim results. Korean
Radiol 2009; 10:269—276.
13. Shin ES. Do VS. Cho HS, et al, Effects of repeat bolus ethanol injections
on cardiopulmonary hemodynamic changes during embolotherapy of
arteriovenous malformation of the extremities. JVIR 2010; 21:81—89
14. Bisdorft A, Mazighi M, Saint-Maurice JP, Chapot H, Lukaszewicz AC.
Houdart C. Ethanol threshold doses for systemic complications during
scierotherapy cf superficial venous malformations. Neuroradiology 2011;
15. Yakes WF, Baker H. Cardiopulmonary collapse: sequelae of ethanol
embolotherapy. Radiology 1993; 189:145
16. Vakes WF, Rossi P. Odink H. How I do it: arteriovenous malformation
management. Cardiovasc Intervent Radiol 1996; 19:65—71
17. Vogelzang IL, Attasi A, Vouche M, Resnick 5, Salem R. Ethanol
emborotherapy of vascular malformations: clinical outcomes at a single
center. JVIR 2014: 25:206—213
18. Kothary N, Soulen MC, Clark 1W, et al. Renal angiolipoma: Long-term
results after arterial embolization. JVIR 2005; 16:45—50
19. ElIman BA, Parkhill BJ, Curry TS Ill. Marcus PB, Peters PC. Ablation of
reanl cell tumors with absolute ethanol: a new technique. Radiology
1981: 141 :619—626.
20. Sakal CW, Cynamon J, Lakritz PS, Sprayregen S. Value of preoperative
renal artery embolization in reducing blood transfusion requirements
during nephrectomy for renal cell carcinoma. JVIR 1993; 4:727—731
21. Mukund A, Gamanagatti S. Ethanol ablation of renal cell carcinoma for
palliation of symptoms in advanced disease. J Palliat Med 2010:117—120
22. Usuki N. Nakamura K, Takashima 5, et al. Embolization of varicocele
with ethanol. Nihon Igaku ‘rioshasen Gakkai Zasshi, Nippon Acta Radi
ologica 1994: 54:870—875.
Research into the genetic basis of arterio-venous malformations (AVM)
Great Ormond Street Hospital and the UCL Institute of Child Health
Update, February 2015
This project is well underway. What we are trying to do is to work out what caused the AVM to form in the first place. This is a very good starting point for understanding the condition better, and would be really important for further research in this field. We are using all the best techniques we know, plus our experience in this sort of condition, to really attack the problem.
We are currently running the first 12 samples from patients with AVM on a specially designed panel called a next generation sequencing chip. This experiment is a way of reading the sequence of lots of genes all at once, from lots of patients all at once. The reason we want to read the sequence of these genes is that we are looking for little changes in the genes (mutations) which might have caused the AVM to form. The first chip is being run in the first week of March, although it has taken several months to prepare the samples properly. This is because it is difficult to work with samples that have been taken for histology (the normal tests that would be done on a sample of AVM), and we have had to go back a few times to try to get exactly the right amount of sample and of a sufficient quality to run on the chip.
The samples then underwent many stages of experiments to make them work on the chip – they are specially fragmented to the right lengths, then tagged with invisible molecular barcodes, then amplified to match the genes we are interested in. We are initially looking at 60 genes. The results will take many months to analyse in detail as we are looking for a mutation that is only present in a certain percentage of the cells in the sample, and this makes it more tricky to know what you are looking at. We will be doing this using special analysis programme’s. Once we think we have a list of possible candidate mutations we need to design and perform extra lab experiments to confirm or refute the changes that we find.
Research update 29/10/2014
Arterio-venous malformation research – update October 2014
Lara Al-Olabi, Veronica Kinsler
Paediatric Dermatology dept, Great Ormond Street Hospital for Children (GOSH);
Genetics and Genomic Medicine, UCL Institute of Child Health
We are very pleased to be able to report that we have the first 12 AVM samples about to be tested this week with some control samples from other patients with different vascular lesions who have very kindly agreed to be involved in the project as well. We will be using some of the money previously donated by Butterfly AVM to run these samples on a special gene panel to see if we can look at which genes are involved in the AVM lesions. It will take a long time to obtain and analyse the results, and either positive or negative results will be useful.
The more families who take part in the research the better, so if you have AVM and you would like to take part when you are next coming to Great Ormond St please do let your doctor know, as all the Dermatology department are able to recruit to the study.
Research update 16/05/2014
Great Ormond Street Hospital for children NHS Foundation Trust
Arterio-venous malformation (AVM) research update
AVM Butterfly website, May 2014
AVM research began at GOSH and the neighbouring UCL Institute of Child Health in September 2013, with a grant from AVM Butterfly charity. This grant was to half fund a full-time research assistant, Ms Lara Al-Olabi, to work with Dr Veronica Kinsler who leads the research into the genetics of rare paediatric skin conditions.
The first priority has been to recruit patients to the study, and to obtain blood and/or skin samples to test. In some instances we can even use samples that have already been taken in GOSH, so that all the patients need to do is agree to us testing those samples rather than taking new ones. Collecting samples is the whole basis for the research, and it is really important for patients to join up if they wish to help out. As such this is a very collaborative project between patients and doctors/researchers – we are doing the research together.
Six families have already been enrolled from clinics, and a further batch of 50 recruitment letters are going out to families later this month. Patients can only be recruited if they have been seen at least once at GOSH. Anyone who thinks they fall into this category and who does not receive a letter in the next few weeks can email Lara on firstname.lastname@example.org and we can arrange for one to be sent.
Once we have at least 10 skin samples together we will start to run some initial genetic tests. This work will be funded by money previously donated by AVM Butterfly charity, which we have stored for this purpose. Results of those tests may be positive or negative, but either way they will be helpful for going forward. We hope to have some preliminary results by September 2014.
Dr V Kinsler
Research Fund for Arterio-Venous Malformations at Great Ormond Street Hospital for Children NHS Foundation Trust
Nikki Christou Giving a cheque from The Butterfly AVM Charity to Dr Veronica Kinsler , Clinical Research Fellow, who will lead our AVM research & Dr Mary Glover, Consultant Paediatric Dermatologist at Great Ormond Street Hospital.
Research into rare paediatric dermatology diseases is a priority at Great Ormond Street Hospital (GOSH). The paediatric dermatology department has very recently received approval to begin collection of samples from GOSH patients with all rare skin diseases, if the families want to participate in research. This is to start building up an important resource which can then be used for research, and which ultimately makes the research process quicker and more efficient. AVM patients will be included in this project, and from February 2013 all patients in the GOSH clinics will be offered the chance to take part.
With the recent fantastic donation of £20,000 , £27,300 and £19,176.00 from the Butterfly AVM Charity researchers at GOSH paediatric dermatology department have set up a specific fund for AVM research, which will be used once sufficient samples have been collected together. This is likely to take a few years but the fact that the process has started is very exciting.
useful link below
24th May 2013
Genetic breakthrough means birthmarks affecting one in 300 could soon have advancement in treatments
- Scientists find mutation that results in red or purple marks
- Breakthrough described as ‘complete game changer’
- Condition could now be prevented in children
Birthmarks that affect thousands of newborns each year could soon be eradicated.
Scientists have found a genetic mutation which is responsible for port wine stain marks, and claim the discovery is a ‘complete game changer’ which they hope will lead to new preventative treatments.
One in every 300 children born in Britain has the condition which results in red or purple marks on the body, most commonly on the neck or face.
They are caused by the abnormal development of blood vessels in the skin, and the birthmark may become thicker, darken and develop a raised appearance in later years.
A research team in the U.S. has now proved the condition occurs because of a gene mutation, which occurs after conception.
Although laser treatment can lighten their appearance, the birthmarks are not curable. The genetic mutation discovered by researchers at Kennedy Krieger Institute in Baltimore is also responsible for Sturge-Weber syndrome (SWS), a rare disorder that affects the eyes and brain, and is associated to port wine stain.
The findings also confirm that both conditions are not inherited.
‘This is a complete game changer for those with Sturge-Weber syndrome (SWS) and the millions born with port-wine birthmarks,’ said lead author, Dr Anne Comi, director of the Kennedy Krieger Institute’s Hunter Nelson Sturge-Weber Center.
The research, published in the New England Journal of Medicine, looked at the genetic make-up of skin samples from three individuals with SWS.
Breakthrough: The genetic mutation discovered by researchers at Kennedy Krieger Institute in Baltimore
They were able to identify one mutation in the affected tissue, compared to healthy samples.
Following the discovery, researchers will now begin to search for drugs that will selectively inhibit the mutation in a bid to prevent the condition.
Co-author Dr Jonathan Pevsner said: ‘This study presents a turning point for research on Sturge-Weber syndrome and port-wine birthmarks.
‘While we suspected that a somatic mutation was the cause for decades now, the technology to test the theory didn’t exist.
‘The advancements in whole genome sequencing and the development of next-generation sequencing tools finally allowed my lab to test and prove the hypothesis.’
The team also discovered a link between the gene and a type of melanoma that occurs in the eye, raising hopes that a new method of treating it could also be uncovered.
13 February 2013
Researchers find gene responsible for rare condition that can lead to melanomas
The genetic cause of a rare condition which causes large moles to grow on the skin and brain before birth and which increases the risk of melanoma, has finally been identified in a study led by the UCL Institute of Child Health (ICH) and Great Ormond Street Hospital (GOSH).
The findings, published in the Journal of Investigative Dermatology, will help clinicians to develop tests for the condition and may help develop treatments for people living with the condition, known as multiple congenital melanocytic naevi or CMN.
CMN can be difficult to live with for children and their families, as the CMN are large dark brown marks on the skin. More seriously, they can also lead to neurological problems such as fits and developmental delay, and to malignant melanoma (skin cancer) which is usually fatal when it occurs.
No treatment is currently available for patients who have many large CMN, but doctors monitor patients carefully for signs of skin cancer, and use MRI to scan the brain for lesions. Small moles can be removed by surgery, but larger areas cannot normally be removed this way. Laser treatment is not a treatment option, as the CMN are too deep to be removed completely.
The breakthrough is the discovery that this condition is caused by a mutation in a gene called NRAS, which occurs while the baby is growing in the womb. The mutation is concentrated in specific parts of the body – it has so far been found in the skin and brain, but not in the blood. This gene mutation was found in 80% of the patients who took part in the study. The other 20% are still being investigated to determine the cause of the condition in their cases.
The gene pinpointed in the ICH-led study is known to be involved in the development of melanomas in the normal population, but has never been found before to occur during the development of a baby. It explains why patients with CMN have an increased risk of melanoma, and the researchers found that the patients need to develop a second mutation to change the moles into cancer.
Dr Veronica Kinsler, Paediatric Dermatologist at GOSH and the ICH and lead author of the study says: “This is a big breakthrough for people who have CMN. The discovery of the genetic mechanism means we can now develop tests to differentiate between people carrying this gene and those who don’t, and finally we can start to look for new ways to treat this serious condition.”
Notch4 normalization reduces blood vessel size in arteriovenous malformations.
Laboratory for Accelerated Vascular Research, Division of Vascular Surgery, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
Abnormally enlarged blood vessels underlie many life-threatening disorders including arteriovenous (AV) malformations (AVMs). The core defect in AVMs is high-flow AV shunts, which connect arteries directly to veins, “stealing” blood from capillaries. Here, we studied mouse brain AV shunts caused by up-regulation of Notch signaling in endothelial cells (ECs) through transgenic expression of constitutively active Notch4 (Notch4*). Using four-dimensional two-photon imaging through a cranial window, we found that normalizing Notch signaling by repressing Notch4* expression converted large-caliber, high-flow AV shunts to capillary-like vessels. The structural regression of the high-flow AV shunts returned blood to capillaries, thus reversing tissue hypoxia. This regression was initiated by vessel narrowing without the loss of ECs and required restoration of EphB4 receptor expression by venous ECs. Normalization of Notch signaling resulting in regression of high-flow AV shunts, and a return to normal blood flow suggests that targeting the Notch pathway may be useful therapeutically for treating diseases such as AVMs.
The article is very detailed. Please read.
New Blood-Vessel-Generating Cell With Therapeutic Potential Discovered
16 Oct 2012
This shows functional blood vessels formed in vivo in mouse by transplanted daughter cells of one single adut vascular endothelial stem cell. The endothelial cells of the cell transplant are genetically tagged by green fluorescent protein to enable their recognition and tracking in the wild type recipient animal. (Credit: Image by Petri Salvén Laboratory. Copyright: University of Helsinki)
ScienceDaily (Oct. 16, 2012) — Researchers at the University of Helsinki, Finland, believe they have discovered stem cells that play a decisive role in new blood vessel growth. If researchers learn to isolate and efficiently produce these stem cells found in blood vessel walls, the cells offer new opportunities in the treatment of cardiovascular diseases, cancer and many other diseases.
The study will be published Oct. 16, 2012 in the online journal PLOS Biology.
The growth of new blood vessels, also known as angiogenesis, is needed in adults when repairing damaged tissue or organs. Unfortunately, malignant tumours are also capable of growing new blood vessels to receive oxygen and nutrients. In other words, the treatment of diseases would benefit from two types of methods: ones that help launch the process of angiogenesis and ones that make it possible to prevent the process. Medications that prevent the growth of new blood vessels have already been introduced, but their effectiveness and long-term efficacy leave much to be desired.
For more than a decade, Adjunct Professor Petri Salvén from the University of Helsinki has studied the mechanisms of angiogenesis to discover how blood vessel growth could be prevented or accelerated effectively. He has examined the birth and origin of endothelial cells, which form the thin layer that lines the interior surface of blood vessels. Endothelial cells are necessary for new blood vessel growth. Where do these highly diversified cells come from? Can their production be prevented or increased?
For a long time, it was assumed that new cells in the blood vessel walls of an adult originate in the bone marrow. In an article published in the Proceedings of the National Academy of Sciences (PNAS) in 2008, Salvén’s research team showed that such stem cells were not found in bone marrow.
Now Salvén is ready to reveal where these mysterious stem cells originate. His team’s new study will be published in the PLOS Biology journal on 16 October 2012.
“We succeeded in isolating endothelial cells with a high rate of division in the blood vessel walls of mice. We found these same cells in human blood vessels and blood vessels growing in malignant tumours in humans. These cells are known as vascular endothelial stem cells, abbreviated as VESC. In a cell culture, one such cell is able to produce tens of millions of new blood vessel wall cells,” Salvén explains.
“Our study shows that these important stem cells can be found as single cells among ordinary endothelial cells in blood vessel walls. When the process of angiogenesis is launched, these cells begin to produce new blood vessel wall cells.”
The effects of new endothelial stem cells have also been tested in mice. The results show that the growth of new blood vessels weakens and the growth of malignant tumours slows if the amount of these cells in the organism is below normal. Correspondingly, a high number of new blood vessels quickly emerge where new stem cells are implanted.
Identifying stem cells among other blood vessel wall cells is challenging and time-consuming. Salvén and his team managed to identify a few molecular surface structures that make it easier to trace these stem cells. However, the efficiency of the identification process needs to be enhanced.
“If we can find more molecules that are characteristic of the surface structure of these rare cells, it is possible that we can increase the efficiency and accuracy of the cell isolation process by more than tenfold. This would enable numbers that are sufficient for cell transplant treatments for humans,” says Salvén.
Plenty of potential treatment applications
“The identification and isolation of an entirely new adult stem cell type is a significant discovery in stem cell biology. Endothelial stem cells in blood vessels are particularly interesting, because they offer great potential for applications in practical medicine and the treatment of patients,” says Salvén.
If an efficient method to produce endothelial stem cells can be developed, they will offer new treatment opportunities in situations where damaged tissue or diseases call for new blood vessel growth or where the constriction or dysfunction of blood vessels deprives tissues of oxygen. These cells also offer new opportunities for developing medications that seek to prevent new blood vessel growth in malignant tumours.
Sirolimus (Rapamune) – turning wrong into right? Henrik Berlin, Cecilia Andersson, Carolin Freccero Dept. for Clinical Sciences in Malmo
AVM may require treatment due to their various symptoms including cardiac failure. First-line treatment includes sclerosation but is not always sufficient. If combined with surgery, the aim is complete resection, due to their potential of rapid growth if triggered by trauma, such as partial excision. Our report describes a high-dose treatment with anti-angiogenesis drug Sirolimus following partial excision of an AVM.
We present the case of a 5-year old Swedish girl, with a very large AVM engaging her right gluteal region, causing systemic symptoms already during her first year of life. Attempts to limit the AVM’s growth, by sclerosing injections of Alcohol, were unsuccessful, leading to severe congestive heart failure, with a Left Ventricular end-diastolic dimension (LVDD) measuring +8SD, within four years requiring palliative treatment. Due to the localisation of the AVM, complete resection was impossible. For cardiac reasons, an incomplete resection was made. The patient recovered well. LVDD diminished from +8SD to +4SD post-operative, and to +2.5SD within a month. Despite the incomplete resection, the AVM did not undergo excessive growth. To reduce neoangiogenesis and prevent AVM re-growth, we decided for treatment with an antiproliferative drug, Sirolimus, normally used to prevent rejection in organ transplantation. The treatment was started 6-months post-operative, and is given in a dosing of 2.0 mg/m2/dose, twice daily, to keep a drug trough level of 10-15 ng/ml, with well-tolerated side effects.
Sometimes a complete resection of an AVM is not possible, due to advanced local growth, localisation, or the condition of the patient, but reduction may still be necessary. Our report describes a now 1.5-year high-dose treatment with Sirolimus after partial excision of an AVM. 2.5 years postoperative, the patient is thriving, tolerating treatment well and fully mobile without signs of AVM re-expansion.
Bevacizumab (Avastin) Used to Treat Hereditary Bleeding Disorder
June 9, 2009
Hereditary hemorrhagic telangiectasia (HHT) is an angiogenesis-dependent genetic disorder characterized by small vascular malformations (telangiectasia) in the skin and mucosal linings, and symptoms including nosebleeds, gastrointestinal bleeding, and iron-deficiency anemia. Internal organs can harbor malformations in larger vessels, called arteriovenous malformations (AVMs), which can result in serious bleeding episodes. HHT is a disorder of unbalanced angiogenesis. Patients have elevated plasma and tissue expression of vascular endothelial growth factor (VEGF)—the primary mediator of angiogenesis—and transforming growth factor-beta (TGF-b), which stimulates production of VEGF.
In a letter in the May 14, 2009 issue of the New England Journal of Medicine, Prithviraj Bose, M.D., and colleagues from the University of Oklahoma Health Science Center reported on the treatment of a 42-year old man with HHT using the antiangiogenic drug bevacizumab (Avastin), a humanized monoclonal antibody designed to neutralize VEGF. After treatment with 4000 mg of intravenous iron over a 6-month period, the patient received 4 cycles of bevacizumab every 2 weeks at a dose of 10 mg/kg for the first 2 cycles, and 5 mg/kg for the second two. After bevacizumab therapy was initiated, the patient’s nosebleeds decreased from 3-4 episodes per day pre-therapy to only 1-2 episodes per week. After completion of 12 weeks of treatment, the number of nosebleeds stabilized at 1-2 per day, but were of much shorter duration than pre-treatment (~10 min. vs. 30-45 min.). Serum ferritin (iron) levels increased from an average of 33 ng per mL in the 6 months prior to bevacizumab treatment to an average of 315 ng per mL in the 9 months after treatment was started. One-year follow-up of the patient indicates that the beneficial effects of bevacizumab in HHT may require maintenance therapy.
Two other cases of bevacizumab use in HHT have been reported. A patient with the condition receiving the agent for malignant mesothelioma had a dramatic reduction in GI bleeding due to AVMs; a second patient with severe hepatic HHT who received 6 courses of bevacizumab no longer required liver transplant and was doing well 6 months after completing treatment.
It should be noted that bevacizumab is not approved for the treatment of HHT or mesothelioma, and the cases described in these research reports represent off-label use of the agent.
Head and Neck Arteriovenous Malformations: Results of Ethanol Sclerotherapy
P. Salminen and
From the Department of Radiology (J.P., K.L.), University of Helsinki and HUS Radiology (Medical Imaging Center), Helsinki, Finland and Departments of Plastic Surgery (P.V.), Otorhinolaryngology (T.K., A.P.), and Pediatric Surgery (P.S.), Helsinki University Hospital, Helsinki, Finland.
BACKGROUND AND PURPOSE: Peripheral AVM is a locally aggressive disease with a high tendency to recur; its treatment is complex, especially in the anatomically delicate head and neck area. Here, we report results of ethanol sclerotherapy for head and neck AVM and discuss its potential use for peripheral AVM.
MATERIALS AND METHODS: We retrospectively assessed degree of AVM eradication, complications, and clinical or imaging signs of recurrence for 19 patients treated with ethanol sclerotherapy for head and neck AVM (1 intraosseous, 18 soft-tissue AVMs).
RESULTS: Of the 19 patients, 11 had complete eradication of arteriovenous shunting at DSA, with 1 recurrence (mean follow-up 15 months), and for 7 patients, treatment is ongoing. During 59 treatment sessions, 12 patients experienced 14 complications, 1 leading to permanent functional damage.
CONCLUSIONS: Ethanol sclerotherapy has potential for complete eradication of head and neck AVM with low recurrence within the first year after completion of treatment. Complete eradication may require several treatment sessions during which complications should be minimized with careful techniques.