Recurrent Respiratory Papillomatosis
NEWSLETTER
Vol. 15 No. 1 An
RRP Foundation Publication
2006 Fall
P.O Box 6643, Lawrenceville, NJ 08648-0643
www.rrpf.org
___________________________________________________________________________________________________________________
This issue of the RRP Newsletter is dedicated to Kaitlin Redmond (13 months) and Keely Hager (18 years), both of whom have recently passed away from complications associated with their RRP.
Contents
q
Opening Comments - p1
q
RRPF Organization
Information - p2
q
RRPF Publication and
Subscription Policy - p2
q
RRP Network/Internet News - p3
q
RRP Listserve Highlights - p3
q
RRP Patient Profile -
p4-5
q
RRP Patient Statistics /
New online survey - p5
q RRPF Support and Fundraising - p5
q RRP Meetings - p6-11
Announcing RRP Focus Session 2007 – p6
Int. HPV Meeting 2005 / RRP Session - p6-7
RRP Task Force Spring/Fall 2006 Meetings Summary– p7
RRP Focus Session 2005 Summary– p7-11
q
Adjunct Therapy and
Protocol Update - p11-12
I3C/DIM
- p12
q
Science & Research
Activities - p12-16
RFP
for promising RRP research - p12
Social impact of RRP – p12-13
Update on RRP genetics research - p13
Update
on RRP research activities at LIJ - p13
HPV
vaccine update - p14-16
q
Support/Subcriber Info -
supplement
From the Newsletter Coordinator
and Editor
The RRP Foundation has been supporting and networking the RRP community for more than a decade and wants to continue to be responsive to the needs of the RRP community. In this regard we would appreciate any comments you may have regarding the RRPF. The best way to let us know what you are thinking is by email to one of the members of the RRPF Board, i.e., Chris Neuberger, Maura Weiner, Susan Woo or Bill Stern, (see addresses listed in the section on “Organizational Information”.)
We continue to seek additional help in preparing, editing and coordinating the publication of the RRP Newsletter. In particular, we are asking for a volunteer to take on the lead role of coordinating and publishing future issues. If you are interested in assisting in any way, please contact Bill Stern (bills@rrpf.org).
We hope you find this newsletter issue to be interesting and helpful.
We are most grateful to all those individuals, medical professionals
and corporations who have supported the RRPF. Although it
is impossible to publish the names of all who contribute, we extend our sincere
thanks to everyone who has supported our efforts. Future donations from
individuals, professionals or from the business community will be very much
appreciated.
Tax-deductible contributions may be made to:
RRP Foundation
P.O.
Box 6643
Lawrenceville,
NJ 08648-0643
Do you donate to the United Way through your employer? You can select a "Donor Choice"
option, which would allow you to direct a donation to the RRPF as the 501 (c) (3) of your choice. Since the RRP
Foundation is a 501(c) (3) foundation, you may specify the RRP Foundation
directly by writing in the name and address of the foundation as follows' RRP
Foundation, P. O. Box 6643, Lawrenceville, NJ 08648. If you should need to add
our Fed. ID number, it is 521798693. Thank you for your support.
Donations accepted online via Pay Pal
From the RRPF home page (www.rrpf.org)
or go dirctly to http://www.rrpf.org/donate.htm
Special Acknowledgments
We once again want to acknowledge the generous
efforts of Ed and Maura Weiner along with their friends for a very successful 4th
Annual RRP Hockey Night fundraiser
for the RRPF.
And
We would like to thank Medtronic Foundation for its generous grant to the RRP Foundation patient
support program.
To physicians and nurses: Please distribute copies of this newsletter to your RRP patients. Please register with the RRPF by completing the Practitioner Questionnaire (online or copy enclosed).
RRPF Officers, Directors & Advisors
Marlene Stern
President
P.O. Box 6643
Lawrenceville, NJ 08648-0643
(609) 530-1443
marlenelin@aol.com
Bill Stern
Treasurer and Director
P.O. Box 6643
Lawrenceville, NJ 08648-0643
(609) 530-1443
bills@rrpf.org
Henry Woo, Esq.
Secretary
Medtronic International Inc.
Suite 1602 16/F., Manulife Plaza
The Lee Gardens, 33 Hysan Ave.
Causeway Bay,
Hong Kong
henry.woo@medtronic.com
Chris Neuberger
Director
12505 Cobblestone Pkwy.
Oklahoma City, OK 73142
(405) 603-8850
cneuberger@eti1.com
Maura Burke Weiner
Director
4900 Fieldwood Court
Fairfax, VA 22030
(703) 691-1922
mauraweiner@serviceimpact.net
Susan Woo
Director
Haking Court, Flat 9B
43 Cloudview Rd.
Northpoint
Hong Kong, SAR
(852) 2812 7379
susanleewoo@hotmail.com
Scientific Advisory Committee
Thomas R. Broker, PhD, University of Alabama at Birmingham Schools of Medicine & Dentistry
Linda Miller, RN, MSN, Children’s Hospital of Philadelphia
Clark Rosen, MD, University of Pittsburgh Voice Center
Robert J. Ruben, MD, Albert Einstein College of Medicine
Keerti V. Shah, MD, DrPH, Johns Hopkins University School of Hygiene and Public Health
Bettie M. Steinberg, PhD, Long Island Jewish Medical Center
Haskins K. Kashima, MD, Johns Hopkins University School of Medicine [Emeritus]
Voice Specialist/Advisor
Julie Bowne, M.S., CCC-SLP
RRP Newsletter Editors
Chris Neuberger
Jennifer Woo
Other RRP Newsletter Contributors
Randy Sparkman
Marlene Stern
Bill Stern
RRP Reference Service Editor
David Wunrow
RRPF Fundraising Coordinator
Ed Weiner
(703) 691-1922
eweiner@weinerandassociates.com
RRPF Corresponding Secretary
Christine-Hartman Davis
RRPF Publication and Subscription Policy
The RRPF produces two publications, the RRP Newsletter and the RRP medical reference service. The RRP Newsletter focuses mainly on the human and clinical aspects of recurrent respiratory papillomatosis and in this regard targets a broad readership, including patients/families, attending physicians/nurses, as well as researchers and the general public seeking to stay in touch with RRP from a clinical perspective. The RRP medical reference service serves those in the community seeking a more comprehensive understanding of this disease. Please help us by supporting these publications and other RRP services including patient outreach, support, advocacy and research.
Subscription Policy and Suggested Minimum Annual Donations:
RRP Newsletter
Professional/Corporate
- $25
Individual - $15
RRP Newsletter plus
Medical Reference Service
Professional/Corporate
- $40
Individual - $25
[Note: Issues
of the RRP Newsletter and Medical
Reference Service are available on the
website.]
Our international support network has grown to approximately 800 respiratory papilloma families. Patients range in age from about 2 to 88 years. Domestically, patients are located in 48 states plus the District of Columbia. Outside the U.S. there are currently 33 patients from 14 countries.
Our thanks to all who have taken the time in the past to fill out the RRPF Patient/Therapy Survey. There is now a new comprehensive RRP patient survey available online at http://www.rrpf.org/rrpf/survey. So even if you have already completed a survey, help us to learn more about this disease by taking a little time to complete the new survey. Please make sure to alert us of changed addresses by checking the “new address” box. There is also a box which we ask you to check if you do or do not want your name and address information to be included in the RRPF Patient Directory. We are requesting the information contained in this survey be made available for RRP research. In this regard there is a place in the beginning of the survey to grant permission.
As our support network has grown, we have become more dependent on the patient questionnaires to maintain our mailing list and keep our database of RRP patient information up to date. If you are updating a previously filled out questionnaire, you need only identify yourself, and answer only those questions where you have new or updated information to provide. This is also the case for the new comprehensive survey, just make sure you specify the patient’s first and last names and their year of birth.
Doctors and nurses treating
RRP patients take a few minutes to fill out the practitioner
survey form.
You can find the online “patient survey” and “practitioner survey” respectively on the “patient” and “practitioner” page links from the RRPF home page (www.rrpf.org).
……………………………………………………………………
RRP Web/Internet
News
by Bill Stern
The Internet is now the most often used information exchange for the RRPF. Our website (www.rrpf.org ) has recently been redone with a totally new look, which we hope will make finding information easier. It contains a wealth of information relevant to patients, families, doctors, nurses and researchers. It includes an online database of RRP practitioners (updated through January 2005). The website has a new Interactive Discussion Forum which allows for the posting of questions, comments and replies to previous postings relevant to RRP. We also have the RRPF Email Listserve.(see below), linked to the home page. As noted above, you can find the new RRPF Patient/Therapy Survey and RRPF Practitioner Survey forms on line, which allow RRP patients and caregivers to easily submit their survey to the foundation. This is a very important aspect of the Foundation in that this information is used in analyzing RRP treatment therapies, experiences, etc. We ask that patients and practitioners update their survey at least once a year.
Also, we maintain an online library of RRP Newsletter and RRP Reference Service issues plus links with many other sites relating to RRP and much more.
If you have some experience/expertise with the WWW and would like to help us improve our website, please
contact Bill Stern.
by Randy Sparkman
Since its creation in 1999, the RRPF-sponsored e-mail distribution list has grown to over 400 members. The list continues to serve as a valuable source of information on the diagnosis and management of RRP. But it has also emerged as a vibrant community where patients and caregivers can share experiences and support.
Over the past year, the mailing list has generated 3-5 messages per day. These threads have included discussions of patient experiences, various treatment options, risks and success rates, discussions of treatment centers and resources as well as environmental considerations. Extensive discussions have taken place regarding the new HPV vaccine, its safety, efficacy and possible impact on RRP. There have been a notable number of interactions between researchers and patients. All communities are well served by these discussions.
Listserve users should be aware that the RRPF e-mail list is vulnerable to the same issues as all on-line services. Access to the list archives is limited to only those users who have registered with the hosting service, YahooGroups. But participants in the list should not assume any privacy of information posted there. Anyone can register for Yahoo Groups, for free. Subscribers with privacy concerns should not post full names, postal addresses, e-mail addresses, etc.
Users should also protect themselves and others from computer viruses. Users should not forward e-mail attachments to the mailing list and should not open any attachments within messages received from the list. This does not mean that the mailing list increases the risk of receiving a computer virus, it is simply good practice to delete e-mail messages with attachments unless you are absolutely certain of the identity of the sender and the content.
Basic subscription information and complete list archives are available on the Internet/World WideWeb at: http://groups.yahoo.com/group/rrpf. The messages may be generated and received from within your e-mail computer client or can be completely generated and received from the yahoogroups rrpf list web pages. Messages may be received one at a time or in a "daily digest". Anyone within the RRPF community that needs technical assistance with any aspect of the mailing list can send an e-mail to: jubrising@gmail.com
First an introduction, my name is Kelly and I am 27 years old.
I live in Halifax, Nova Scotia, and have a rare form of what people refer to as
“a not so bad disease”, papillomatosis.
I was diagnosed with it at age 4. Since age four there has been too many
operations to count (I believe we lost track around 100 quite a few years ago).
The disease is most common in children and its progression is said to slow down,
even to stop altogether once the juvenile in question reaches puberty and the
body’s hormone levels adjust and change. As I explained, I am 27 and still fighting
this “not so bad disease”.
This is where you come in. This is a cry for help. I need
something to inspire me, help respark the hope within me and renew the desire
to keep on fighting.
As far as treatment, I have only ever had laser surgery. I have
never talked to anyone else suffering from my disease and have developed severe
panic attacks revolving around the operations. My ENT specialist is very caring
but I have so many questions and he has very few answers.
I definitely feel
selfish writing this letter, as I know there are people who are worse off than myself.
But honestly I am burnt out, I am not sure how much fight is left within my
heart. I have been fighting what others perceive to be a manageable “not so bad
disease” for 27 years.
I struggled with this disease from birth, long before it was
diagnosed. My mother has been my angel from day 1 sensing trouble with my
crying and breathing from the minute she took me home.
My mom, was concerned that her baby girl wasn’t living the
happy healthy life a newborn deserved, the life that she was determined to give
her. Essentially her perseverance, however annoying to the doctors treating me,
SAVED MY LIFE.
My Mom’s Story
Shortly after bringing my daughter home from the hospital, I
discovered her difficulty when breathing and the odd sound of her cry. The doctors repeatedly told me I was
being an over active new mom. I
did not agree.
For 4 long years, I harassed the doctors and, pushed and pushed
them; until finally they decided to humor me by taking her into the operating room
to see if there was something going on with her throat after all. We (being her parents) waited with
great anxiety outside the OR; we didn’t wait long however, within minutes the
doctor came out and said he would see us in his office in an hour. They brought
my child out to me and said nothing more.
The anticipation was overwhelming. We rushed her home and then went to the office where we were
told she would need surgery immediately, that the growth in her throat was
closing her air way. We were told
to take her to Halifax (the biggest city in our small province of Nova Scotia)
where there was a specialist who would remove the growth.
Well here it is 24
years later and she is still having surgeries, although they have gone from
being every 6 weeks with a 2-day trip to the ICU unit (throughout her
childhood), to being able to have the surgery and go home the same day.
Today the surgeries are better and the stay in hospital shorter,
however, the trauma is much greater.
You see Kelly now suffers from extreme anxiety, panic disorder which
developed as a direct result of the many devastating surgeries and the lack of
compassion from not only cruel children who made fun of her constantly
throughout her childhood but from nurses poorly equipped to deal with Kelly’s
level of fear and anger at the amount of operations she was forced to endure at
such a young age, and then on into adulthood. She does sound and will always
sound as if she has a cold. Each
surgery is now more traumatic than the previous one and the so-called
professionals that work with her do not understand her fear nor do they try to
understand the panic. As her mom,
I have spent my life feeling guilty and sad that somehow I did this to my
child. Even today I do not know
what more I can do to make her life better. It is very draining and I pray that with God’s help you can
finally help Kelly find some sort of peace surrounding the treatment of her
disease, as there is still no end in sight.
Back To My Impute
This afternoon I had a perfect example of why my disease
supposedly “one of the better diseases you could have” wasn’t such a day at the
beach.
The first stage of the day may be described as almost pleasant,
I mean as pleasant as one could expect given the circumstances. Those
circumstances being, that I am about to be put under for well over my hundredth
procedure each exactly the same as before, however the hospital has a few
unsung heros who find just a few minutes to make the day more bearable. This
would include anyone who has been with me through it all, my doctor and some of
the nurses who remember carrying my terrified, trembling little body into the
OR. Now they hold my hand and offer true empathy and compassion as I lie, a
little bigger now, terrified and trembling still.
You think, due to
my experience with this procedure and because of trial and error, when it comes
to what does and does not work well during the procedure, I would be given some
credit or say in what I need after all these years.
Keeping with the giving credit where it’s due, I have to say a
lot of people involved in my case at one time or another humor my requests or
at least take the time to calmly, gently explain the alternatives. It is these
generous souls who have made these experiences bearable up do date. Most of the staff that knows of me or
has treated me over the past 27 years knows the trauma and anxiety levels that
take over (If you’ve never experienced one “take over” is a pretty accurate
word to describe just how little control you have of what is taking place with
your body).
There are levels in my case, to how severe my attack can get. Here
is where the trauma begins.
I have spent years conferring with psychologists,
psychiatrists, my ENT, clergy, prayer, self-help books, and through this
journey realized the solution was simpler for me. I need to feel safe in order
to avoid the panic attacks.
I feel safe with my ENT doctor by my side, my mom by my side
and there are even a few key nurses who have throughout my journey lent me
their compassion,
Understanding my fear and terror are real and the symptoms just
as intense as if brought on by a non-panic situation, I cannot stop them on
demand. I am not faking or looking for attention, truth be told, if you asked
me what I fear most in this world, it is the panic attacks and how real and
devastatingly they affect me.
I am the first to admit that doctors and nurses are too busy,
and have even sicker than me to tend to, so a few years ago we (my support team
and I) had it worked into my file (or thought we did) that if I start to feel
anxious and ask for my mother they were to allow her against policy, into
whatever the restricted area, to be by my side and help prevent the more
horrifying stages of the actual attack.
When an attack is coming on I start feeling anxious, my skin
feels tingly, I begin to hyperventilate, my heart starts to beat erratically,
sometimes I faint or urinate myself. Sometimes my muscles become rigid and even
paralyzed, sometimes times I can’t speak. The not speaking symptoms are a bit
less painful than the alternative, because when I loose control of my emotions
and the crying starts the vocal cords in need of rest after their recent
surgery become strained with terrified tears and begging for my mother to save
me from what feels in that moment to be a life or death situation.
Today after the procedure I began experiencing some slightly
different symptoms that can be scary after over a hundred procedures without
this symptom. The explanation was simple and I was appeased, however the
anxiety had already started and the nurses’ comment that “you need to get over this and just
stop,” didn’t help. Through labored breaths I asked for my mom explaining she
knew what to do. I also pointed out a note that I made sure existed on my chart
saying “get mom at the first sign of trouble.” The nurse then replied “if you
can get this under control for mom, you can get it under control for me, I am a
nurse. Stop hyperventilating now and breathe.”
Things just kept on progressing from there and I suffered a
terrifying indignity that may well have been avoided with a little compassion
for the terrified little 27 year old girl that still needs help dealing with
this “not so bad disease”.
You may be wondering what can you do. Well any support would
help I am at a loss and in need of guidance. ... honestly I am about ready to
give up. It is just emotionally tearing me apart. Also, because of my severe
panic reactions to the surgery, I find my post operative care by the nurses only
adds to the trauma of my disease.
I want you to know that the part of the story told to you today
is only a part of me. Panic disorder does not control my life. It just takes
over for a few hours maybe days, a few times a year during treatment for my “not
so bad disease”.
The rest of my life has been the best I could make it. I wanted
to see the world with no money so I joined the cruise ship and resort industry.
I worked hard at these jobs but gained confidence and a sense of others and a
sense of their challenges and formed lasting supportive relationships all over
the world.
I am enthusiastic and caring and would honestly give up
anything of myself to save anyone from anything even resembling the pain I have
endured through my “not so bad disease”.
Others describe me as outgoing, and quirky and I would like to
preserve that part of me before I loose my fight and anxiety and depression
start creeping around into non-hospital related parts of my life.
As my age progresses, thoughts of having children terrify me.
Is there any chance I could expose them to this? I have so many questions; I
have been crying since Friday after my latest treatment and haven’t convinced
myself there will be a next treatment, because when I left that hospital today
I had given up. I wasn’t going back, not to face the horrors and fear again.
This “not so bad disease” should allow me quite a few years of trauma free life
before becoming truly life threatening (the nodules would eventually cover my
airway) and I would face that possibility of death when it stared me in the
face.
That’s not me
though, that is the fear talking. I fear the panic and I fear my uncertain
future concerning this disease.
I am open to suggestions; I am willing to try anything.
The truth of the matter is in 6 months I will be expected to walk through those operating room doors once again and right now I can’t honestly say I’m up for that fight.
Kelly
ktarso@hotmail.com
Please complete or update
the comprehensive RRP patient survey available online at: http://www.rrpf.org/rrpf/survey
Very preliminary statistics may be viewed at:
http://www.rrpf.org/rrpf/survey/update/admin/
user = “rrpf”
password = “Foundation” (case sensitive)
(Caution: These are
“raw” stats and in some cases may not make sense.)
Support and
Fundraising Activities
[For support of new RRP research initiatives, please
see section on “Science and Research Activities”]
Support for RRP patient related travel expenses:
The RRPF has dedicated a limited amount of funds to provide indirect support of some travel expenses to obtain treatment for RRP families truly in need. If you would like more information please contact:
Geni Mesi
5780 Village Way
South
Ogden, Utah 84403 (801)
695-0108
e-mail: mesifam@hotmail.com
Fundraising Activities:
4th Annual
Hockey Night for RRP
On Saturday night, January 21, 2006, Ed and Maura Weiner held the 4th annual Hockey Night Fundraiser for RRP in Washington DC at the MCI Center. Ed and Maura netted the RRP Foundation over $10000.
Running For RRP
On January 7, 2006, Julie Bowne and her sister ran the Disney half-marathon in Orlando, Florida. Julie’s and her sister’s efforts helped promote RRP awareness and raised over $2000 for the RRPF.
On April 30, 2006, RRP Foundation Director, Bill Stern ran the New
Jersey Marathon for the second time to
raise awareness and funds to support RRP research and networking between
patients, physicians and scientists. Donations for this event came to about
$1000.
!!! Future meeting !!!
RRP Focus Session 2007
Washington D.C.
Tentative date is Saturday, 15 September, 2007
More details will follow
Check rrpf.org / RRPF Listserve
!!! Mark your calendars !!!
HPV 2005 Forum on Education and Advocacy
RRP Session Summary
The RRP Education and Advocacy Session took place in Vancouver, BC at the 2005 HPV Conference on Thursday, May 5th, 2005. The program was jointly sponsored and coordinated by Michael Green of The International RRP ISA Center and by Bill Stern of The RRP Foundation. A session summary follows:
1. Biology
of RRP: Role of Cox 2 – Bettie Steinberg
RRP Biology - RRP prevalence in society stands at 1 case per 100,000. Malignant conversion takes place in 3%-5% of all RRP cases (increases to 30% when Papillomas are treated with radiation). If Papillomas enter the lungs, malignant conversion increases to 80%.
RRP prevalence stands at 1 case per 100,000 in population. The incidence (or new cases) is projected to run 5 per 1,000,000.
RRP is typically caused by HPV type 6/11. A number of adjunct therapies have been used over the years with some new therapies being investigated. The newest therapy under investigation by Long Island Jewish Hospital involves the use of Celebrex (Cox 2 inhibitor).
Life Cycle of RRP
HPV virus enters the normal epithelium (in most cases of virus exposure this is where it stops). However, in cases that become RRP, the virus penetrates to the basal layer. It is in the basal layer, where cells proliferate, while the cells in the epithelium shed. Once the virus enters the basal layer, the hpv virus enters a basal cell and begins to reproduce itself. The eventual papilloma tumor is created, not due to rapidly dividing cells, but rather the cells with hpv don’t know they are suppose to die, thus, pile up on the surface as a papilloma.
Cell death-differentiation – Cells are sent signals to cause the cell to die. The signals which do this are altered, which then induce Cox 2 (which is turned on in tumors and inflammation).
Studies in mice have shown that in mice which exhibit Cox 2, that mice get skin tumors. Cancer prostoglandins, made by Cox 2, suppress the immune system, increasing tumor growth and suppress cell death.
Preliminary data has shown that if Cox 2 is inhibited, proliferation goes down and cells die. The higher the dose, the more cells that die.
LIJ has designed a study of Celebrex that will be a multicenter randomized placebo controlled study. The study will be for adults only (18 years or older), who have surgery at least three times per year. It will have two start times 6 months and 18 months after enrollment. There will be six months of observations/surgeries, and then participants will be randomized. Some will receive 400 mg of celebrex daily, while the others will receive placebo. The placebo group will later receive the celebrex. In addition, provisions have been made to unblind the study in certain situations (patient exits, remission, etc). Patients will take celebrex for one year, then crossover. Disease will be scored via endoscopy for a period of 2.5 years.
2. RRP ISA
– Michael Green
Michael Green presented information about the RRP ISA Center and the work that is underway. RRP ISA is actively involved in research and patient advocacy. Michael also discussed the interactive patient database that provides real time analysis of the information. The website is www.rrpwebsite.org. In addition, the RRP ISA is actively seeking grant proposals for funding requests. Funds are available to support worthwhile research.
3. RRP
Foundation – Bill Stern
Bill Stern presented information about the RRP Foundation, outlining the history as well as development of the organization. The RRPF currently has in excess of 750 patients in the database. In addition, a web based system using a Lagrangian Approach for Collecting RRP Epidemiological Patient Data was discussed. This database was developed with the help of Tom Mingot. The RRP Foundation is actively seeking grant proposals for funding requests. Funds are available to support worthwhile research.
4.
Efficacy if different acyclic nucleoside phosphonates in organotypic
epithelial raft cultures and cervical xenografts inathymic nude mice – G.
Andrei (presenter) J. Van Den Oord, I. Lebeau, G. Wolfgang, W. Lee, E. De
Clercq, R. Snoeck
Dr. Andrei noted that 630 million individuals worldwide are infected with HPV, this translates into 24-40 million in the U.S. with 2,000 – 2,500 new cases per year. 6,000 children per year are treated.
The use of cidofovir is being used to treat HPV infection. Current intralesional dose levels range from 2.5 to 7.5 mg/ml, up to 10 mg/ml. If cidofovir is injected in uniform intervals, the results have been better. The best response (RRP usage) has been in the supraglottic and glottic regions. Cidofovir is injected into the disease site until resolution of disease, then an additional injection is given. The more severe the disease, the better the response has been. Intralesional injections are far below levels of toxicity, and to date there have been no reported problems with the use of cidofovir.
5.
Prelimanary analysis of a 10 year retrospective review of RRP patients
– P. Campisi
Dr. Campisi is a pediatric otolaryngologist in Canada. Dr. Campisi reviewed some background information on RRP. Canadian pediatric RRP patients are generally treated at 1 of 3 hospitals in Canada. It is his goal to establish a Platform for Canadian Registry and model it after the former CDC National Registry for RRP. It is believed that it will be much easier in Canada, since the majority of the patients are treated at a limited number of facilities. In addition, once the patient outgrows the children’s hospitals, the adults are also treated at a limited number of facilities. This would simplify data gathering and fact analysis.
Dr. Campisi would also like to launch a surveillance study for the HPV vaccine.
A portion of the presentation was also devoted to the microdebrider and a discussion about the medical system in Canada.
6. RRP
Round Table Discussion – participants- Bettie Steinberg, Keerti Shah, Tom
Broker, Craig Derkay, Tom Mingot, Michael Green, Kathy Blankenship, Bill Stern,
Chris Neuberger
The participants introduced themselves to the audience.
Dr. Shah, raised the issue of a study to look at the efficacy of the HPV vaccines (once released) of new cases of JO RRP to survey if the birth mother was a recipient of the HPV vaccine. It is expected (in theory) that new cases RRP should become extinct with the introduction of the vaccine.
Dr. Broker provided a summary and update of the HPV Advocacy sessions that had been held over the course of the week. A grass roots effort is what is needed as politics are local and the politicians are the key in changing public opinion and generating necessary funding. The medical and research community need to dialog from the professional community as well. In addition, there are a number of HPV organizations and there is a need to tie together these organizations for advocacy. A website that disseminated the information and worked to coordinate the variety of HPV organizations was discussed as well.
There is a great need to de-stigmatize HPV and the consequences. It was noted that dealing with the disease outcome, such as cervical cancer would help to de-stigmatize. It was also noted, that Cervical cancer is a different focus by different cultures. There are many local and cultural barriers that need to be overcome in order to do this.
Dr. Derkay discussed a study that is proposed to analyze the viral load in the saliva of children.
……………………………………………………………………
Summary of Spring and Fall 2006 RRP Task Force Meetings
Minutes prepared by
Craig Derkay, MD
summarized below by
Bill Stern
The Spring Task Force meeting took place in May, in conjunction with the AAO Spring meeting that was held in Chicago. The Fall Task Force meeting was held in conjunction with the AAO annual meeting in Toronto.
Some of the topics
discussed were:
1) Update
on HPV vaccine efforts – With the approval of the Merck HPV vaccine Gardasil, there was
much discussion about the role that this vaccine may have with RRP. In particular:
(a) Therapeutic possibilities
-
Indications from Drs. Campisi
and Rosen, who attended
Merck investigators
meeting in July, are that Merck is not
likely to fund a
wide-scale trial using Gardasil therapeutically.
Discussions followed
regarding possible pilot studies
applying Gardasil
intralesionally in active RRP patients, intra-
muscularly to
patients in remission and using the vaccine in
patients with
involvment outside the larynx. There was a
consensus to try some
therapeutic application in a coordinated
way.
(b) Preventative possibilities
–
Dr. Froelich, attending the
HPV meeting Prague met with
Aventis/Pasteur (they own
European rights to Gardasil)
and is optimistic about a surveillance/epidemiology study of
the
preventative/therapeutic benefits the vaccine being
organized.
Discussed the
possibility of using the vaccine in pregnant
patients (not likely
in US) and in newborns at-risk of
acquiring an HPV
infection.
2) Research
Initiatives –
(a) HspE7 Phase III trial is currently on hold, as
Stressgen has
gone through some
corporate changes and is now Nventa
Corp. They are still tentatively palnning a
trial but may not
happen for 2 years.
(b) Celebrex study at LIJ
continuing with a reduced dosage (to
alay any cardiac
fears). RRP patients currently
enrolled only
at LIJ, but hoping to
expand to 6 sites.
(c) Dr. Buchinsky provided an
update on his RRP genetics
study. They have expanded the pool of patients
via
collaboration with
patient support organizations and
currently are
investigating 4 candidate genes.
(d) ICTV (a topical agent that has
shown promise in treating
plantar warts) is being
formulated for potential use with RRP.
(e) Dr. Campisi is currently
working with colleagues in
Canada to create a
registry of RRP patients there. Similar
registries are being
proposed in the UK and Sweden.
……………………………………………………………………
RRP Focus Session 2005 Highlights
The RRP Focus Session
is an event that is often convened in conjunction with the American Academy of
Otolaryngology-Head and Neck Surgery (AAO) annual convention.
The following is a summary of material that was shared at “RRP
Focus Session: Thinking Outside the Box” event
in Los Angeles on September 24, 2005.
About 45-55 RRP patients and their families attended, along
with about 10-15 physicians and researchers in addition to those who were
speakers. Four lay people presented and the other 8 speakers
(counting Mark Shikowitz who was inserted into the agenda at the meeting) were
physicians or PhD level researchers.
The meeting was very well-received and stimulated a great deal
of discussion at the dinner afterwards in honor of the speakers.
The following summaries are presented as highlights only . Details are provided in the PowerPoint and MP3 files available on the web at: http://www.rrpf.org/RRP_Focus_2005.html
Readers are strongly encouraged to listen to the MP3 recording and consult the PowerPoints for more information.
Generous support for this meeting was provided by Medtronic Corporation and Stressgen Biotechnologies.
Craig Derkay, M.D.-
“Update on RRP Research 2005”
Adjunct Therapy Update:
The
Merck vaccine works on the humoral vs. intracellular immunity. However, it is speculated that this
vaccine if used intra-lessionally could stimulate the cellular immunity.
[Ed. Note: In June 2006 Gardasil was approved
by the FDA. Currently there is NO evidence for
therapeutic effects, although this has not been rigorously tested as yet.]
Bill Stern, RRPF
Provide RRP Information; RRP Physician Referral;
Networking, Emotional and other Support
rrpf.org
RRP Newsletter (http://www.rrpf.org/newletters/RRP_Newsletter_Spring05.html)
RRPF Listserve (http://health.groups.yahoo.com/group/rrpf/)
– Provides a forum for exchange of information, ideas, opinions and
emotions related to RRP. Currently ~350 members consisting of RRP patients,
parents, practitioners and researchers (at least 5% are RRP professionals).
Identify and Address
Major patient/family concerns, i.e.,
Diagnosis issues
Coping with RRP
Treatments - surgical and adjunct
Voice - preservation, restoration/improvement
Mortality - pulmonary involvement, malignancy
Disease transmission
RRP Awareness
Are Pediatricians sufficiently aware of
RRP?
Coordinate with other HPV organizations to promote greater public (and
political) awareness of RRP and HPV
RRP Epidemiology
RRPF practitioner and patient databases
(currently >750 patients)
RRP Research
RRP Foundation encourages and supports
promising research related to RRP. Some of the studies that have received
support from the RRPF involve: RRP immunology; Quality of life of RRP patients;
Familial genetics and RRP. Furthermore, the RRPF is interested in
additional RRP research including: therapeutic role for HPV vaccines,
studies to better assess mechanisms and understanding of various adjunct
treatments and new approaches to the treatment of pulmonary RRP.
Michael Green, RRP ISA
Michael told the story of how RRP ISA came to be and he explained how ISA is an acronym for Information, Support and Advocacy. He reviewed RRP ISA’s future plans and past activities/accomplishments, which amongst other items have included:
A) Awarding of research grants to two institutions, with others in the review stage. In addition to the past grants, RRP ISA announced it would offer up to $100,000 in research grants over the next year.
B) A new website that is in development (http://rrpwebsite.modwest.com/).
C) A new message board that was just opened (http://www.rrpisa.tribe.net).
D) A new informational brochure on RRP that doctors can give to their patients (http://www.rrpwebsite.org/brochure.pdf).
E) RRP ISA’s presentation at the International Papillomavirus Society’s 2005 convention in Vancouver B.C. last May. Michael presented a synopsis of data from that presentation, entitled “RRP Patient and Family Data Trends Report” (http://www.rrpwebsite.org/report_on_the_may_2005_rrp_focus.htm).
Lotta Gustafsson, Msc, Phd
– Treatment of Papillomas with Human Alpha-Lactalbumin-Oleic Acid Complex
(HAMLET) Principle investigator
for June 24, 2004 New England Journal of Medicine article on HAMLET, Lund
University, Sweden
Aturo Avila Chavez, M.D.
“RRP in Developing Countries”
International RRP ISA Board Member and Associate Professor, National
Institute of Respiratory Diseases, Mexico City, Mexico.
Reviewed
RRP statistics. Estimated 1,500
– 2,000 RRP patients in Mexico.
The main problem in treatment is cultural, medical and economic. Voice is not treated seriously and is
typically ignored until dysphonia or respiratory problems. Due to the economic issues of health
care in Mexico, different levels of medical attention are provided. There are very few centers for
specialized medical care.
Typically a Dr. will have 80-120 patient visits per day or 10 surgeries
per day. There is a 6-8 month wait
for surgery. Some patients are
forced to wait until complete respiratory distress. Most RRP patients are handled in the public hospitals. Most Dr.’s don’t have specialized
training for handling RRP.
Equipment is lacking. A
potential solution is to utilize the RRP ISA as a platform.
Richard Schlegel, M.D. PhD – Developing
Research into Effects of Artemesinine on HPV. Professor and Chair, Department of Pathology, Georgetown
University Medical School
Artemesinine
is a Chinese herb used for the treatment of malaria. It reacts with red blood cells by creating free radicals
that kills the malaria cells. This
herb only works when converted to DHA.
It does not kill normal cells. In the Canine model artemesinine cured
the canines from papillomavirus (canine pv, not human) infection. Artemesinine is not an anti viral. It is administered topically. Future studies are planned.
Jennifer Woo, Senior
Thesis on RRP, Harvard University
Jennifer is a senior at
Harvard majoring in Anthropology.
The thesis preparation has included three months of travel interviewing
RRP patients, families, researchers and others. The thesis topic was chosen based on interest in RRP and the
cultural, economic social and political issues. A few themes have been identified thus far:
v
Voice is part of an
individual’s identity and when compromised it affects the identity of the
person.
v
Redefining the
definition of disability
v
Stigma of the disease
v
Guilt by parents
regarding disease transmission and how to cope
v
Uniting of strangers for
and due to the disease
v
Frustration of
practioners
v
Politics of research
– and the hostile political environment
The thesis will be published
in April and excerpts will be in the RRP Foundation newsletter and relevant
peer reviewed publications.
Gregory McKee, CEO of
Stressgen
Stressgen
has had success with the HPE7 drug.
Stressgen has clinical proof of the concept and is now working on the
manufacturing process. The 2nd
generation of HSPE7 looks more promising for RRP. It will also be a platform for other HPV diseases. The company was reorganized to focus on
HSPE7. Hspe7 is designed to be
therapeutic drug. It works by
making an antigen that is fused to a heat shock protein. These band together and heat shock
shepherds to small peptides, then to dendritic cells. Killer T-cells are programmed, replicate, hunt the HPV
infected cells, which are then killed.
Kathy Blankenship, “What
I’ve Learned through my Personal RRP Odyssey”, International RRP ISA Center
Research and Volunteer Coordinator
Kathy provided a very emotional and moving story on her
personal experience, which included a cancer diagnosis and the removal of her
larynx. Kathy shared her
perspective on:
The effect her RRP has had on her children and how our children
help us to realize what is truly important in life.
The importance of RRP ISA and RRPF in providing information,
support and advocacy to patients and their families; and the importance of
emotional support, health care referrals, case management and patient-friendly
websites.
Her experience with discrimination by health care providers.
Patients Beware/Caveat Emptor: The expectations RRP
patients have of their physicians to use good judgment, provide best
care possible, and be knowledgeable about RRP and current treatments.
The need for a patient to do their own research and educate
themselves about RRP and its treatment.
The importance of maintaining a sense of humor despite having
a life-threatening illness.
In conclusion, Kathy noted that despite
the removal of her
vocal cords, with the help of RRP ISA, she has learned that she very much still
HAS a voice.
Farrel Buchinsky,
M.D. “Genetic Susceptibility to
RRP: Report on Individual and Family Genetics Research Project” Pediatric Otolaryngologist Allegheny
General Hospital Pittsburgh, PA
Update
of results to date of this ongoing
study of RRP genetics. Huge
numbers of the population are exposed to HPV 6/11, however, only a few develop
RRP. As a result, genetics play a
role in who does and who does not develop RRP. A brief presentation on the genetics was presented. Presently the study has 82 enrollees
and their parent (s). This study
requires a sample of an individual’s saliva as well as that of both parents (or
one parent if both aren’t possible).
In the event parents aren’t’ available, a sample from a sibling would be
beneficial as well. This study
requires a very large data sample.
It is easy and free. Please
consider participating, see the following link for information. www.centerforgenomicsciences.org/RRPGenetics
Seth Pransky, M.D.
“Current Issues in the Management of Pediatric RRP” San Diego Children’s
Hospital
i. The mirco debrider with spontaneous ventilation
creates less trauma, however, the con is access to the ventricle and
subglottis.
ii. The pulse dye laser is new and does not destroy
underlying tissue and is very good for sensitive areas. It is not good for bulky lesions.
Cidofovir
– 50% hit rate based on 7 years of history. Non responders are 15%. Dosed at 5 mg/ml with four
injections spaced 2-3 weeks apart. Sometimes more treatments are
necessary. It is potentially
difficult for cidofovir to penetrate all areas due to scar tissue. This treatment should be reserved
for severe cases, with the caveat, severe can by in the eye of the beholder. Histological review demonstrates no
evidence of dysplasia. No change
in liver function. Typically there
is a dramatic initial response.
Once the disease does recur, it is typically easier to deal with. It is possible to achieve remission,
but certainly not universal for all.
i. RRP is a variable disease and each patient needs to be
approached differently. There are
multiple adjunct therapies and no single therapy works in all cases. Patient management requires education
of the alternatives, which must include both the pros and cons. It is
very important, from the patient perspective, to be aware of misinformation, or
chat room and internet chatter.
Just because one therapy works on one person doesn’t mean it will work
on another.
ii. RRP requires clear communication with the Physician
and Patient. Time needs to be
arranged beyond the routine office visit.
Prepare the Physician that additional time will be needed to interact,
discuss, listen and analyze.
iii. RRP Plan of action requires frequency of procedure,
surgical technique, adjunct therapy and dosing. It also requires flexibility for new approaches if
required.
i. Could remission in cidofovir patients be extended by
providing a booster dose at some point in time?
Cidofovir
is a powerful mediator and we don’t know all of the factors.
ii. What happens when Papillomas return after a cidofovir
protocol?
Don’t
know, but generally after cidofovir therapy when/if Papillomas return they are
easier to manage.
Adjunct Therapy and Protocol Update
The following reports of statistics and clinical research involving RRP therapies, represents a best effort to make an accurate and objective presentation of information from surveys, articles submitted by investigators, personal communications and reference to literature. Where appropriate, the RRPF has provided its input in a constructive manner, which we hope will best serve the RRP community.
Adjuvant Therapy Survey Update
by Bill Stern
Patient/family assessed impact of some adjuvant therapies reported.
Table 1. Patient/family assessed impact of adjuvant therapies reported.
|
Therapy |
Users |
No |
Improve |
Comp |
Partial |
|
I3C/DIM |
156 |
72 |
84 |
34 |
50 |
|
DIM † |
15 |
7 |
8 |
4 |
4 |
|
IFN |
69 |
29 |
40 |
6 |
34 |
|
MMR/Mumps |
24 |
9 |
15 |
7 |
8 |
|
Cidofovir |
40 |
8 |
32 |
10 |
22 |
† The number of users reporting they are using DIM is underestimated because many are not indicating the specific product they are using.
Experimental therapies for which the RRPF has very little or no documented patient supplied statistics:
HPV Vaccines
Omega-3 Fatty Acids (Fish Oil)
Cox-2 inhibitors (eg., Celebrex)
Cimetidine (Tagamet)
Some notes regarding the above chart:
The therapies are documented as follows IFN = interferon, I3C/DIM = indole-3-carbinol (I3C) or Diindolylmethane (DIM),Cidofovir , MumpsVax = mumps/MMR vaccine.
Other therapies with anecdotal reports of efficacy, include: Echinacea and Thuja (homeopathic anti-virals), a mixture of vitamins including vitamin C and vitamin A, ShapeRite immune formula, bleomycin and cobalt. (These treatments are generally unsubstantiated and some may involve significant side effects. The RRPF makes no recommendation for their usage.)
Finally, we continue to remind our readers that these results are based on patient perspectives. Although the survey encourages objectivity and quantitative assessment as much as possible, these analyses cannot replace well-designed clinical trials and research. Furthermore, since sample sizes are generally small and no statistical significance tests have been applied to data in the above table, one must interpret these numbers cautiously, especially when considering the natural variability of RRP. However, we do hope that this information can provide some guidance for those patients seeking adjunct therapies as well as those pursuing RRP related research.
……………………………………………………………………
I3C/DIM
For background information about the impact of indole-3-carbinol (I3C) / Diinolymethane (DIM) on estrogen metabolism and how this subsequently may act to reduce the growth rate of respiratory papillomas, see the RRP Newsletters Fall 93 through Fall 94 and Fall 97, Winter 2000-01 for DIM, as well as Bradlow et al., 1996 J. of Endocrinology 150, S259-S265; Newfield et al., 1993, Anticancer Research 13, 337-342.
How to get I3C
or DIM and how much to take
Phytosorb-DIMTM products containing DIM are available from:
BioResponse
L.L.C. at P.O. Box 288
Boulder, CO 80306
Email at etzeligs@bio-response.com
877-312-5777 or 303-447-3841 - phone; 303-938-8003 - Fax
Credit card orders (Visa and MasterCard) are being accepted
Internet ordering: You can now order the Phytosorb products on the
Internet at www.hormonalbalance.com.
If you send an email to support@hormonmalbalance.com they will set an account up for you in
the Phytosorb group to purchase on the Internet. There are additional discounts available when you order on
line. Please let BioResponse know if you are an existing customer. If you are a
new customer, please send them your phone number so they can contact you to set
up an account.
Phytosorb-DIM is available in two forms:
1. Phytosorb-DIM Capsules; 150 mg; 60 capsules per bottle or 75 mg; 90 capsules per bottle.
Estimated dosages; BioResponse recommends that individuals with RRP choose a daily dose which is close to 8 mg/kg/day (see BioResponse article on next page for recent updates on their Phytosorb-DIM product). A typical man weighing 70-85 kg (where kg. = 2.2 lbs.) would take approximately 500 to 700 mg per day. A typical woman weighing 60-70 kg would take from 450 to 600 mg per day.
2. Phytosorb-DIM Flavored* Sprinkles; 9.0 grams per bottle with directions indicating dosage per teaspoon.
At the suggested dosing below, 1 bottle should provide a two-to-four month supply for a child about 50 lbs.
* Available in orange as well as chocolate flavors.
Shipping : US priority mail , UPS, or global priority. Call or e-mail for product pricing
BioResponse has reformulated its "Sprinkles". These new formulations require lesser amounts of the powder to deliver the increased suggested dose. Detailed dosing instructions are included on the bottle label. Guidelines for children are as follows:
Weight in Pounds (lbs)
Amount of Sprinkles in
Teaspoons (tsp.) up to 25 lbs. 1/8
tsp 25 to 50 lbs 1/4
tsp, 50 to 75 lbs 3/8 tsp, 75 to 100 lbs 1/2
tsp 100 to 150 lbs 3/4 tsp
(Please consult your doctor, especially for young children.)
Special Note: Unlike I3C, Phytosorb-DIM does not require activation by stomach acid. Individuals who use antacids or H2 blockers like Zantac can take Phytosorb-DIM.
For scientific inquiries contact Michael Zeligs, MD at zeligsmd@bio-response.com
I3C may be purchased from:
Theranaturals Inc.
PO. Box 344
Orem UT 84059-0344
e-mail: theranat@fiber.net
(801)224-8893 - Telephone; (801) 226-6064 - Fax
www.theranaturals.com
[Credit card orders may be placed by phone, fax, web or e-mail]
Theranaturals I3C and B3IM product pricing as of Oct 2006 (includes shipping via USPS priority mail within US):
1 bottle - 100 capsules @ 100 mg -$20
3 bottles - 100 capsules @ 100 mg - $55
add $16.00 to above prices for Fed X shipping.
Approximate dosing information is based on preliminary results of Dr. Leon Bradlow's estrogen metabolism studies, as follows:
Estimated dosages - Adults approx. 400 mg, Children (under 50 lbs.) 100 - 200 mg
Additional I3C
Notes
The digestive process is important to properly break down I3C (see RRP Newsletter - Spring 94 ). In this regard, try to avoid taking antacids and it is probably best to take I3C at mealtime. It has also been suggested that taking ascorbic acid (vitamin C) along with I3C will produce ascorbigen, which some investigators (Preobrazhenskaya, et al., 1993, Food Chemistry, 48,48-52) speculate may be an even more important anti-carcinogen than I3C.
If you do not appear to be responding to I3C, you might want to give DIM a try.
Finally, no matter what product one is using the best way to extend the shelf life is to keep them in a cool dark location such as the refrigerator.
I3C/DIM reported side effects:
•
Occasional gastro-intestinal upset
• A couple of instances of
dizziness
• A few anecdotal instances of lowered bone density
…………………………………………………………………
Science & Research Activities
Proposed Research/Support activities:
The RRP Foundation is asking the RRP research community to apply for support of RRP related research projects. These studies may involve (but are not limited to): Immunology and RRP, genetics and RRP, RRP quality of life/public health issues and new treatment approaches for RRP (in particular pulmonary RRP).
Interested researchers should address inquiries and proposals to:
Bill Stern, Director
P.O. Box 6643
Lawrenceville,
NJ 08648-0643
Email:
bills@rrpf.org
……………………………………………………………………
Voices Unheard: The Social Experience of Illness
for Patients, Families, Clinicians and Researchers on the Recurrent Respiratory
Papillomatosis Community
Jennifer A. Woo
While recurrent respiratory papillomatosis (RRP) is an
unpredictable and devastating disease that compromises the voice and airway,
there has been little qualitative social science research exploring the social
experience of illness for afflicted individuals and their families. This study
employs medical anthropology literature and original ethnographic interview
data from over 30 patients, family members, clinicians and researchers across
the United States. Findings revealed that RRP patients and families experience
significant perceived and enacted stigma, develop numerous mechanisms to accommodate
the presence of the disease in their lives, and form strong community support
networks. Interview subjects also reported numerous social and political
obstacles currently challenging basic science papilloma research. Finally, specific
suggestions are made for the continued management of the social experience of
RRP.
Genetics of Papilloma-Induced
Voice Disturbance
Farrel Buchinsky, M.D., Center for Genomic Sciences
We all know that RRP is caused by HPV 6 or 11. Yet many millions of people are exposed to the two viruses and they do not get RRP. So then what is it about the thousands of people with RRP, that their exposure turns into a disease? Furthermore, why do some people just have a “little brush” with RRP while other suffer a crushingly aggressive course? My colleagues and I at the Center for Genomic Sciences at the Allegheny Singer Research Institute in Pittsburgh looked at the available evidence and decided that there must be a genetic susceptibility to the disease. The Center for Genomic Sciences had state-of-the-art genetic analysis capabilities and the RRP Task Force had access to many patients. Thus a collaboration was formed to enroll patients and their parents in the study to determine the genetic factors that make one susceptible to RRP. In 2003 the National Institute on Deafness and Other Communication Disorders (NIDCD) funded the study. Slowly but surely the number of trios (patient + mother + father) grew albeit not as quickly as was needed. Then in 2005 we obtained approval to recruit patients and their parents directly through the support groups. This was made possible by advances in technology that enabled us to obtain enough DNA from someone swishing mouthwash, spitting it into a tube and mailing it to our center. The enrollment rapidly rose. As of May 2006, 393 people have participated in the study with 157 of those people either having RRP currently or at some time in the past. The other 236 people are parents (and some siblings) of the 157 people with RRP.
The first gene that was investigated was, EVER1 which had been shown to be mutated in a skin disease called Epidermodysplasia Verruciformis (EV). While the rare skin condition is not caused by HPV 6 and 11, it is caused by an unusual susceptibility to HPV 5 and 8. We looked at the DNA of all the patients we had at the time to see if any of them had the mutations that were described for the skin disease. Not one person had the mutation. We concluded that the mutations causing EV was not the cause of susceptibility to RRP. We looked at other aspects of the EVER1 gene apart from the described mutations but found no convincing answers. There are many other genes that we want to explore since we know that the proteins they encode have something to do with the way HPV lives in human cells. However, our focus is on a genome-wide approach. We have already analyzed the first few people on a chip that looks at 6000 different spots in the human genome (collection of all of one’s genetic code). The field of genetic discovery is rapidly advancing. It is now possible to look at not just 6000 spots at a time but to analyze 100,000 or 300,000 or even 500,000 of the 3 billion spots that exist in the human genome. Getting so much information from each person will greatly speed up the process and increases chances of discovering the underlying genetic susceptibility. Statistical techniques have been developed that help us make sense of the overwhelming amount of data. One thing is clear though; in order to take advantage of the science and technology the number of enrollees needs to increase a lot (more than double) and must do so in the near future. We need to make the most of the opportunity that the NIDCD has afforded.
A big “Thank You” is due to the 393 people who have participated so far and another big “Thank You” to the NIDCD and for funding the study.
When we have a greater understanding of this disease we will hopefully be able to offer better management of RRP.
For more information please look at the flier that accompanies the newsletter or visit www.rrpgenetics.org or e-mail info@rrpgenetics.org or call the Center for Genomic Sciences at (888) 887-7729 and from outside the United States call + 1 (412) 359-4707
……………………………………………………………………
Bettie Steinberg,
PhD, Long Island Jewish Med. Ctr.
Dept. of Otolaryngology
The physicians at LIJ are continuing to enroll patients in their study of celecoxib as an adjunct therapy for moderate to severe RRP (3 or more surgeries in the past year, or tracheal or pulmonary disease) . It is a controlled study, with the patients randomized to the drug for one year, followed by a year on placebo, or placebo for one year followed by drug for a year. The investigators do not know whether the patients are taking the drug or the placebo at any given time. Several patients have shown marked improvement in papilloma growth, and one is in remission. However, because of the design, we cannot say until the end of the study whether this is due to the drug. Patients who are interested in participating should contact Dr. Allan Abramson, 718-470-7553, or Ginny Mullooly, RN at 718-470-7011. (For more details, see Spring 05 RRP Newsletter issue).
We are continuing to study the role of the immune system in controlling HPV infections. We have found that white blood cells from patients with RRP react to viral proteins by making a group of signaling molecules (called cytokines) that suppress an effective immune response. There is a strong correlation between the level of these cytokines and the severity of disease. We have also found that there is a correlation between production of these suppressive cytokines and certain variations in genes that regulate the immune response. Taken together, these studies suggest that there may be a genetic susceptibility to either having RRP following airway infection with HPV, or to the severity of the disease. This could help explain why one person has severe disease, while another has mild disease, or why most people with airway HPV infections (5% of the population) have no problem while one person in 30,000 has RRP.
……………………………………………………………………
HPV
Vaccine Update – 2006
[The following article is
being reprinted, nearly in ts
entirety, with the kind permission of Maney Publishing. It first appeared in the November
2005Paillomavirus Report- Vol. 16 no. 6.
Since its original publication the Merck HPV vaccine has been approved
by the FDA, which should provide impetus for pursuing a number of proposed
studies discussed in this article.]
Recurrent respiratory papillomatosis:
bright prospects for vaccine-based prevention
Keerti V. Shah1, Elizabeth R. Unger2,
Craig S. Derkay3, Bettie M. Steinberg4
1Johns Hopkins Bloomberg School of Public Health,
Baltimore, MD
2Centers for Disease Control and Prevention,
Atlanta, GA
3Eastern Virginia Medical School, Richmond, VA
4Long Island Jewish Medical Center, New Hyde Park,
NY
Key features of JORRP
The estimates of the annual number of JORRP cases in
the US,
extrapolated from data from questionnaires (1,4) and
from a
small population-based study (5) are imprecise and have
varied
from a low of 80 to a high of 2300 cases. The number of
reported
cases of JORRP in one survey, without extrapolation,
was
840 for the year 1976 (4). Among congenital and
perinatal
infectious diseases in the US, the number of JORRP
cases is
similar to that of neonatal herpes (463–2809
cases) and far
exceeds the number of cases of rubella syndrome (9
cases),
gonococcal ophthalmia (45 cases) and HIV infection (175
cases) (6). Maternal condyloma during pregnancy has
been
identified consistently as the overwhelming risk factor
for
JORRP. This association was first suggested in 1956 in
a case
report (7) and then confirmed in subsequent clinical
studies
(4,8,9). About 50% of mothers of children with JORRP in
these studies give a history of genital warts during
pregnancy.
A population-based estimate of the magnitude of the
relative
risk of maternal condyloma for JORRP was made by
Silverberg et al. (10) for Denmark. They used data from Danish
registries over a 20-year period to identify children
who were
born with a maternal history of genital warts during
pregnancy,
and reviewed medical records from all ear, nose and
throat
departments in Danish hospitals to identify cases of
JORRP. In
this study, which was relatively free of recall bias
because it
used data previously recorded in national registries,
maternal
condyloma during pregnancy increased the risk of JORRP
in
the child by more than 200-fold. However, the risk of
JORRP
for a child born to a mother who had condyloma in
pregnancy
was quite low, and estimated to be less than 1%.
Maternal
condyloma accounted for 37% of the cases identified in
the
country. Thus, a majority of the JORRP cases apparently
resulted from clinically unrecognised HPV-6 and HPV-11
infections
in the mother.
In the genital tract, HPV-6 infections are more
frequent
than HPV-11 infections but HPV-11 infections account
for a
majority of JORRP, suggesting that HPV-11 is
transmitted
more readily from mother to child than HPV-6. Also,
HPV-11
is associated with more severe disease (11) as well as
with a
greater likelihood of malignant conversion (12). In the
child
with JORRP, HPV is maintained as a latent, subclinical
infection
throughout the respiratory tract, and is readily
recovered
from clinically normal mucosal tissues (13–15).
Prevention of recurrent disease has been difficult.
Treatments are directed at maintaining the airway
rather than
elimination of disease. Success is measured as an
increase in the
time interval between surgeries. Many new treatment
modalities
are being explored for JORRP as adjuvants to surgery.
Treatments currently in use or under evaluation include
indole-
3-carbinol, intra-lesional mumps vaccine, cidofovir
injections,
interferon therapy, celecoxib therapy and a potentially
therapeutic
HspE7 vaccine.
Is caesarean delivery protective?
The generally accepted intra-partum nature of the
transmission
raised the possibility that JORRP might be prevented by
caesarean
delivery of the at-risk child. Caesarean delivery is
recommended
to protect the newborn from neonatal herpes virus
infection when the mother has genital herpes lesions at
the time
of delivery. However, it has not been possible to
obtain direct
evidence to evaluate this possibility for JORRP because
the disease
is rare, the frequency of occurrence of JORRP even in
the
highest-risk group (mothers with condyloma during
pregnancy)
is low, and many years of follow-up would be required
to
assess the protective effect of a caesarean delivery.
As mentioned
earlier, most of the JORRP cases have onset of disease
in the first 4 years, but cases with onset as late as
14–15 years
are still classified as JORRP. Indirect evidence of the
effectiveness
of caesarean delivery was sought by comparison of
observed caesarean delivery rates in mothers of JORRP
cases
with expected caesarean deliveries based on national
caesarean
rates or caesarean rates in control groups (Table 1).
In three of
the four studies listed in Table 1, the numbers of
observed caesarean
deliveries were significantly fewer than the numbers of
expected deliveries and the estimates of the
effectiveness of caesarean
delivery in reducing JORRP ranged between 78% and
90% (16–18). In the Danish study, however, seven
of 56 JORRP
cases were born by caesarean delivery (12.5%) as
compared to
8.9 expected cases, corresponding to a non-significant
22%
reduction associated with caesarean delivery (10). If
the analysis
in this study was restricted to the group at highest
risk (i.e.
mothers with condyloma during pregnancy), JORRP
occurred
in 2 of 471 women delivered by caesarean (0.42%) as
compared
to in 19 of 2559 women (0.74%) delivered vaginally
(Silverberg
M, unpublished data). This 43% reduction associated
with caesarean
delivery in the highest risk group was also not
statistically
significant. The study did not have enough power for
making
a reliable estimate in this analysis.
Caesarean delivery carried out before the rupture of
the
membranes should be protective for infections that are
acquired intra-partum. Of the 15 JORRP cases born by
caesarean
delivery in the four studies listed in Table 1, several
were
delivered prior to the rupture of the membranes,
suggesting
that there may be other possible routes of
transmission. In
addition, there are reports in the literature of JORRP
(1) or
condyloma (19) being present at birth, an indication
that sometimes
an infant may become infected in utero prior to delivery.
In summary, caesarean delivery appeared to afford some
protection
against JORRP, but the data were inconsistent across
the different studies.
Options for a woman who has condyloma during
pregnancy
JORRP resulting from subclinical HPV-6 or HPV-11
infection
in the mother (i.e. a majority of the cases) are essentially unpreventable.
But even when the mother has the overwhelming risk
factor of condyloma during pregnancy, she does not have
many
satisfactory options for preventing the disease in her
child.
Treatments for condylomas are seldom fully effective
and some
of them are not recommended for pregnant women. While a
treatment may reduce the numbers and size of
condylomas, the
viral infection may persist. The mother is often
willing to
undergo the risks and financial costs associated with
caesarean
delivery in order to reduce, even to a small and
uncertain
extent, the risk of JORRP in her child. However, the
obstetrician
is generally not supportive of this strategy for a
number of
reasons, including the low probability that the child
will have
JORRP, the evidence that caesarean delivery is not
fully protective,
the risk of surgery to the mother and the goal of health
professionals to reduce the number of caesarean
deliveries in
the US (20,21). Guidelines for Perinatal Care of the
American
College of Obstetrics and Gynecology (22) state that
caesarean
section is not recommended solely to protect the
neonate from
HPV infection.
The situation is also frustrating from the perspective
of clinical
care. The cause of the disease is known with certainty,
the
manner of transmission is known for the most part, and
the
period of exposure during birth is no more than a
fraction of
an hour to a few hours. Yet, there is no strategy
available to prevent
the disease.
HPV vaccines will change the landscape
This dismal situation will undergo a dramatic
improvement with
the anticipated availability of an FDA-approved HPV
vaccine in
2006 that can protect not only against HPV infections
that cause
cervical cancer, but also against HPV-6 and HPV-11
which cause
genital warts and RRP. HPV vaccines are based on
virus-like particles
(VLPs), which consist of the major viral capsid protein
(L1)
of HPVs expressed by recombinant DNA technology in
yeast or in
baculovirus cultures. The expressed L1 protein
self-assembles into a
VLP which is not infectious (because it does not
contain the viral
DNA) but is conformationally very similar to the
authentic virion.
Parenteral immunisation with VLPs results in an
antibody response
in humans which is 10–100-fold greater than that
after natural infection.
Antibody titres do decline with time. For previously
uninfected
women, the vaccines provide virtually 100% protection
against
incident persistent infections with the viral types
included in the vaccine
(23–25). The vaccines may also provide some
cross-protection
against related types which are not included in the
vaccine.
Two HPV vaccines are expected to be commercially
available in
the near future. The Merck vaccine (24), which is
expected to be
the first to come on the market in 2006, is
quadrivalent and contains
VLPs not only of HPV-16 and HPV-18, the types which are
responsible for a large majority of cervical cancers,
but also of
HPV-6 and HPV-11, the types responsible for most of
genital
warts and virtually all cases of JORRP and AORRP. In a
recent
phase 2, randomised, double-blind, placebo-controlled
efficacy
trial of this vaccine in over 500 young women monitored
for 36
months, HPV-6 and HPV-11 infections or associated
disease were
encountered 16 times in the placebo group but 0 times
in the vaccinated
group (24). The second vaccine, from GlaxoSmithKline
(25), is a bivalent vaccine and contains only HPV-16
and HPV-18
VLPs; this is expected to be available in Europe a few
months after
the Merck vaccine.
Both vaccines are expected to reduce the incidence of
cervical
cancer and cervical cancer precursors, but the
quadrivalent vaccine
has the additional potential of having a profound
effect in
reducing the burden of genital warts and of AORRP and
JORRP.
It is estimated that there are almost one million
annual visits to private
physicians for genital warts in the US (26). The
Advisory
Committee on Immunization Practices (ACIP) will develop
recommendations
for vaccination only after the vaccine has FDA
approval. Merck is developing the vaccine for both men
and
women and will provide data on immunogenicity in both
sexes,
although the efficacy of prevention of infections and
disease in
men will not have been addressed in the first FDA
application. If the
Merck vaccine gains wide acceptance, it will decrease
the circulation
of HPV-6 and HPV-11 in the community and will decrease
the
chance of a woman having condylomas during pregnancy.
Vaccine for young women
In the clinical trials, the vaccines have been shown to
be effective
in women, aged 16–26 years, who have not been
previously
infected with the corresponding viruses (23–25).
Such women
receiving the Merck vaccine will be protected against
condyloma
as well as against subclinical infections with HPV-6
and
HPV-11, so their risk of having a child with JORRP
should be
reduced to virtually zero.
Vaccine for older women
While discussion about target groups for vaccination
have
focused on young women before they become sexually
active, a
large majority of older women in their reproductive
years are
also likely to have been not infected with HPV-6 and
HPV-11.
Serological studies of a representative sample of the
US population
suggest that only 6.3% of 30–39-year-old women
have
been previously infected with HPV-11 (27), as compared
to
17.8% previously infected with HPV-16 (28). In Finland,
the
prevalence of antibodies to HPV-6 and HPV-11 in
23–31-yearold
women in the 1980s and 1990s was 9–12% as
compared to
17–24% for HPV-16 (29). The actual number of
women previously
infected by HPV-6 and HPV-11 is likely to be greater
than
that suggested by the serological studies because not
everyone
infected with HPVs mounts a durable immune response.
Nevertheless, a majority of adult women have probably
not
been previously infected with HPV-6 and HPV-11 and
could
benefit from the vaccine as much as the younger women
and, if
vaccinated, would also be protected against both
genital warts
and the risk of having a child with JORRP.
The vaccine may be of benefit even for the woman who
has
been previously infected with HPV-6 or HPV-11. The
vaccine
manufacturers have not yet disclosed if the vaccines
provide
protection against disease to women who are already
infected,
but the vaccine does boost the immune response in
previously
infected women. The protection conferred by the vaccine
is
antibody-mediated; in animal models, serum transferred
from
an immunised animal to a naïve animal provides protection
against tumour formation by challenge with infectious
virus
(30,31). The child born to a mother who has
vaccine-induced
high antibody titres against HPV-6 and HPV-11 could be
expected to receive large amounts of antibodies
transplacentally,
and these may help contain the infection and decrease
the
risk of developing JORRP. In neonatal herpes virus
infection,
the risk of intra-partum transmission to the child is
about 30%
if the mother is undergoing a primary HSV infection but
3% if
the mother has recurrent HSV infection (32). This
markedly
decreased risk of HSV transmission is attributed to the
lesser
severity of recurrent maternal infection and to the
high amounts
of antibodies transferred to the infant
transplacentally (33).
Vaccine for pregnant women with condyloma
In view of the above, it would be worthwhile to
consider immunisation
of a previously unvaccinated (or vaccinated) pregnant
woman with condyloma in order to reduce her risk of
having
JORRP in the child. The immune response in these women
is
already primed due to the previous infection and the
vaccine
will boost it and generate high titres of antibodies
which, after
transplacental transfer, may provide protection to the
newborn.
Vaccine for the newborn
The possibility of post-exposure prophylaxis against
JORRP
by immunising the newborn with a maternal history of
condyloma
should also be considered. Such a strategy has been
spectacularly
successful in protecting infants born to mothers
viraemic with hepatitis B virus. A hepatitis B virus
vaccine routinely
used to immunise newborn infants has provided virtually
complete protection against hepatitis B infection (34).
With
JORRP, there is a time interval of several months to
several
years between exposure at birth and onset of disease.
Immunisation with HPV-6/11 vaccine at birth may,
therefore,
be successful in generating immunity prior to the onset
of disease
and in decreasing the risk of JORRP in the child.
Surveillance of JORRP to evaluate vaccine efficacy
The quadrivalent HPV vaccine is expected to be on the
market
in the summer of 2006. Depending on the recommended age
of
vaccination, children born to vaccinated mothers may
first
appear in 2007. If the vaccine is effective in reducing
the risk of
JORRP, mothers of children with JORRP will be less
likely to
have been vaccinated than their age-matched cohort.
This
could be monitored in 2007 and beyond.
Because of the rarity of the disease, the most
efficient way
to obtain data needed to evaluate vaccine effectiveness
would
be to set up national surveillance for newly diagnosed
cases of
JORRP. Each new case could be investigated to ascertain
the
diagnosis of JORRP, collect a detailed history of the
mother’s
HPV vaccination and of condyloma during pregnancy,
obtain
a serum specimen from the mother for HPV-6 and HPV-11
antibody determination, and procure a tissue section
from the
patient’s diagnostic biopsy to identify the HPV type
responsible
for the JORRP. There is an extensive network of
patients who
communicate with each other through the web sites of
the RRP
Foundation (RRPF) and the RRP-ISA Foundation. There is
also a network of paediatric otolaryngologists who have
already worked together on the Respiratory Papilloma
Task
Force. Together, these two networks could provide ready
access
to new patients and collaborating physicians, enhancing
the
feasibility of the proposed study. The vaccination
histories of
one or more groups of appropriate control mothers would
need
to be obtained to estimate the ‘expected’ number of
vaccinated
mothers. Assuming the vaccine is 100% effective in
preventing
infection, if 10% of the control mothers gave a history
of vaccination
and none of the mothers of JORRP cases were vaccinated,
it would require investigation of as few as 35 cases of
JORRP to show a statistical difference between expected
and
observed numbers of immunised mothers. It should be
possible
to identify and investigate several times that number
of JORRP
cases in 3–5 years. If immunisation is accepted
by a significant
fraction of young women, a reliable estimate of the
vaccine efficacy
could be made by surveillance over a few years.
Continuation of surveillance would permit the estimate
of
duration of protection. Investigation of JORRP cases
that may
occur despite maternal immunisation will help identify
weaknesses
in the preventive strategy and ways to improve it.
Conclusions
JORRP can cause life-long disability and is a
tremendous burden
for the patient and his or her family. The disease is
very difficult
to treat or to prevent. The anticipated availability of
a
vaccine which has the potential to prevent this disease
greatly
brightens the prospects for reducing the burden of
JORRP.
Reference list available
at: www.rrpf.org/newletters/RRP_Newsletter_Fall06_Shah_refs.pdf
[The following report is primarily based on phone
conversations during the Spring and Summer of 2006 with Mr. Gregory McKee,
President and CEO of Nventa Corp. (formerly Stressgen)]
Status
of the Nventa (formerly Stressgen) Therapeutic Vaccine for HPV: HspE7
by Bill Stern
The much anticipated Phase III trial of HspE7 for the treatment
of RRP will be delayed at least a year.
For those with aggressive RRP who have not responded to available
therapies, this news is certainly disappointing. However, after recent conversations with Nventa President
and CEO, Gregory M. McKee, I am somewhat optimistic that RRP patients can look
forward to a new therapeutic option that promises a high degree of efficacy.
Nventa/Stressgen apparently spent the last year re-evaluating HspE7 and
improving its financial situation.
They remain highly committed to the development of a reformulated HspE7
compund that, according to Mr. McKee, has “dramtically increased potentcy”,
when compared to the original formulation. This reformulated product has shown some “impressive
results” in some pre-clinical case studies involving genital warts. In a more
recent press release (also presented at the recent Int. Papillomavirus
Meeting), results of a Phase II study of 30 men with anal/genital warts
indicated an 81% positive response (after 48 weeks “complete response” in 33%
and some improvement in another 48%), the full press release may be viewed at: http://www.nventacorp.com/news/pr20060907_HspE7_warts_data.htm.
Mr. McKee is hoping that a Phase II/III clinical trial involving approximately
200 RRP patients might begin near the end of 2007.
In 2005 the original HspE7 product
was evaluated for efficacy in treating ~27 RRP patitents via a Phase II trial.
Results indicated an approximate doubling of surgical intervals on
average. With the prospect of a
significantly improved HspE7 vaccine product, the RRP community will continue
to wait for its availability, hoping for a new therapeutic break through.
More information about Nventa may be found at their
website: http://www.nventacorp.com
---------
Mucosal
vaccines against HPV ?
[as interpreted by Bill Stern]
Nardelli-Haefliger and Revaz (2005, Papillomavirus Report, Vol. 16 no.6) suggest that enhancement of mucosal immunity, rather than systemic immunity, may be more effective against HPV infections. A key aspect of mucosal immunity is the presence of lymphocytes which, when activated, may preferentially migrate in mucosal sites. Furthermore, there exists an immulogical network operating on mucosal surfaces that might allow for immunological activity at distal mucosa. Hence, it is speculated that vaccines aerosolized for delivery to mucosa may be more effective than intra-muscular injections. With virtually no trials as yet to test this hypothesis, it is obviously very speculative and unproven, but it will be interesting to pursue this approach for future treatment / prevention of HPV/RRP.