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

13001 Burlingame Ave.

Oklahoma City, OK 73120

(405) 749-8499

cneuberger@eti1.com

Maura Weiner

Director

4900 Fieldwood Court

Fairfax, VA 22030

(703) 691-1922

mauraweiner@serviceimpact.net

Susan Woo

Director
The Manhattan, Flat 33D

33 Tai Tam Road

Hong Kong
(852) 2812 7379

susanleewoo@hotmail.com

[Please see the support info. on page 16 for a complete list of the RRPF regional and state coordinators]

Scientific Advisory Committee

Thomas R. Broker, PhD, University of Alabama at Birmingham Schools of Medicine & Dentistry

Haskins K. Kashima, MD, Johns Hopkins University School of Medicine

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

Kathleen Sullivan, RN, Children’s Hospital of Boston

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.]

RRP Network News

Our international support network has grown to approximately 700 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 conprehensive RRP patient survey available online at http://www.rrpf.org/rrpf/survey. Development of this new survey has been a collaborative effort with Thomas Mingot, Director, Clinical Research and Operations at Stressgen Biotechnologies. We have also invited additional collaboration with the RRP ISA Center, with the goal of evolving the new survey into one that will be adopted as an RRP community standard. So even if you have already completed an older 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. Finally, even if you are not able to provide answeres to all the questions, it is important that you get the information you provide entered, by remembering to click on the “submit” button at the end of the survey. If you have more information to enter at a later time, it is easy to provide an update as outlined below,

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).

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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.

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RRPF Listserve Highlights

by Randy Sparkman

The RRPF-sponsored e-mail distribution list is now five years old. Its 220+ subscribers continue to maintain a lively and useful dialog. There have been over 500 posts over the past six months. Of recent note, there has been much discussion regarding the spread of papilloma to the lungs and whether there is a need for regular bronchoscopies, x-rays or cat scans in all cases.

RRP patients, health care providers and caregivers share technical information and opinions about the various RRP treatments and adjunct therapy. But most importantly, the “listserve” is a vital way for the newly-diagnosed and RRP veterans to know that they are not alone and that RRP can be managed.

Listserve users should be aware that the RRPF e-mail list is vulnerable to the same issues as all on-line services. Concerns among list users about patient privacy led the RRPF leadership to restrict access to the mailing list to only users who have registered with the hosting service, YahooGroups. Even though anyone may register with YahooGroups, limiting access to registered users prevents access from open Internet services like search engines, etc. In any case, subscribers with privacy concerns should not post full names, postal addresses, e-mail addresses, etc.

There have also been recent posts about 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: rsparkman@bellsouth.net

RRP Remission News

!!! A new addition to our growing list of remissions!!!

Nikole, who was born in September, 1990 in Ohio, was diagnosed with RRP at a year old in 1991, at which time her airway was almost completely blocked by the lesions.

She went a couple years with surgeries, about once every 2-3 months but in 1994 she took a dramatic turn for the worse requiring surgeries every week. This is when her doctor in Cincinnati suggested Interferon shots to boost her immune system. She received 2 doses daily for a six month period and continued with weekly surgeries. The Interferon treatment was taking its toll making her sick and weak. At first it didn't appear the treatment was working but then Nikole started to improve after she was taken off the Interferon, as her doctor had indicated would be the case. Her surgeries gradually started to spread

out.

Around 1998-1999 she was clear and only required annual check-ups at the office. Finally in 2002 her doctor told Nikole that she would only need to return if she had symptoms. She has had no problems since and is now a very active 14 year old.

RRP Patient Stats

RRP patient statistics will appear again in the next newsletter issue, as we are just starting to gather additional RRP statistics via a new comprehensive RRP patient survey available online at: http://rrpf.org/rrpf/survey

This new patient questionnaire is intended to enhance our epidemiological knowledge of RRP with expanded surveying of diseae related issues, surgical and non-surgical treatment histories/responses, plus additional questions to assess the scio-economic and public health impact of RRP. There may be a number of questions for which you do not have answers, just answer as many as you can and remember to get the information formally entered into our database by clicking on the submit button at the end of the survey.

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 Activity:

Running For RRP – 2^nd Marathon Fundraiser

On April 18, 2005, RRP patient and newsletter editor Jennifer Woo will be running the Boston Marathon for the second time to raise awareness and funds to support RRP research and networking between patients, physicians and scientists. Please see the RRP Newsletter Spring 2004 for more about Jennifer.

She encourages all Boston-area affiliates of the RRPF to contact her at jwoo@fas.harvard.edu if they would be interested in coming out to celebrate this fundraising effort for the RRP Foundation. (More to follow)

RRP Meetings

22^nd International HPV Conference
in
Vancouver, British Columbia, Canada
HPV/RRP Education and Advocacy Forum
2005 May 5-6

The 22^nd International HPV Conference will be held in Vancouver at the Hyatt Regency from 30 April to 6 May 2005. The RRP Foundation will be participating in the HPV/RRP Education and Advocacy Forum which is scheduled to be held on Thursday May 5, with a session devoted strictly to RRP during the afternoon (~ 2-4 PM). The forum will continue on Friday May 6. For more information go to: http://www.hpv2005.org/

If you are interested in attending, please contact Bill Stern at bills@rrpf.org.

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Summary of Fall 2004 RRP Task Force Meeting
Minutes prepared by Craig Derkay, MD
summarized below by Bill Stern

On Monday, September 20, 2004, a meeting of the RRP Task Force took place in conjunction with the annual AAO meeting in New York City. There were 20 members present including Chris Neuberger and Bill Stern representing the RRP Foundation.

A number of RRP research initiatives were discussed as follows:

Dr. Farrek Buchinsky’s RRP Genetics Study - for more info. see “Science and Research Activities” section.

Hsp-E7 proposed Phase III trial – at this time FDA is currently reviewing Stressgen’s proposal. It is anticipated that 25-35 centers in the U.S., Canada and abroad will participate and 130-140 children with severe RRP would be enrolled. (See update in “Science and Research Activities” section)

Merck quadrivalent vaccine (i.e., HPV 6,11,16,18) is in phase III trial showing great promise. Animal data shows antibodies to HPV 6 & 11 in the offspring of vaccinated mothers up to 13 weeks postpartum. If this applies to humans it could be very effective in preventing HPV transmission from mother to child.

Dr. Mark Shikowirtz spoke about the proposed Celebrex study at LIJ. For more information see the 2004 Focus Session highlights that follow, and an update in the “Science and Research Activities” section.

Michael Green distributed articles about two new skin papilloma agents, Artemisinin and Hamlet.

The rest of the meeting focused around two additional issues:

The first topic was Public Health issues regarding the risk in school settings for transmission of papillomas in children, especially those with tracheostomies. As a follow up, the Task Force has prepared a Public Health policy statement that concludes that patients who have RRP, with or without a tracheostomy tube, should be allowed to attend classroom programs, since the risk to both classmates and classroom personnel is viewed as being extremely low.

There was extensive discussion associated with the second topic, which revolved around the safety of cidofovir. Much of the otolaryngology community treating RRP patients have expressed enthusiam about cidofovir’s effectiveness in treating this disease. However, some studies, including one cited by a toxicologist from the FDA, are showing that cidofovir is a potent carcinogen in rats, even at doses comparable to those used for intralesional injections to treat RRP. Until more is undestood about the long-term safety profile of cidofovir in humans, the RRP Task Force is recommending that,

[patients and doctors]

1) Given the promising results reported in pediatric and adult patients, cidofovir should be routinely presented as a treatment option in moderate to severely afflicted RRP patients. i.e.; those patients whose disease is not improving on surgical therapy alone or in conjunction with less potentially morbid adjuvant measures and/or requiring surgical intervention 3 or more times a year. With appropriate consent, cidofovir therapy should be a viable option in patients whose disease severity is resulting in a need for frequent surgery, worsening airway compromise or severely impaired communication or those who otherwise may be considered candidates for tracheostomy.

2) Patients with more mild disease, particularly children, should be discouraged from seeking treatment with cidofovir, until a better understanding of the long-term implications of the use of this drug have been established. With appropriate informed consent, cidofovir could still be utilized on a case-by-case basis, at the discretion of the prescribing physician, for the more mildly affected patient.

[doctors]

3) As with all surgical procedures, informed consent should be obtained and documented in the patient's record. At a minimum, this should include a frank discussion of the nephrotoxic and carcinogenic potential of this drug.

4) Adverse responses, particularly evidence of dysplasia or malignant transformation to squamous cell carcinoma, either locally or remotely, should be reported simultaneously to the FDA (form 3500 or 3500A) and to the RRP Task Force through email communication with its Chairman, Craig Derkay, MD. (derkaycs@chkd.com)

RRP Focus Session 2004 Highlights

On September 18, 2004, in conjunction with the American Academy of Otolaryngology meeting in New York City, the RRP Foundation and the International RRP ISA Center co-sponsored a special meeting dedicated to RRP. It was the fourth RRP focus session since the first one took place in January of 1999 in Charleston, S.C. at the HPV meeting. Generous support for this meeting was provided by Medtronic Corporation and Stressgen Biotechnologies.

There were approximately 80 - 100 attendees, including about 50-70 RRP patients/family members and about 20-30 RRP doctors / researchers. In addition to the many RRP families from the New York City area, some people traveled from more distant locations such as Michigan, Oklahoma and even as far as California.

Bill Stern and Michael Green provided some introductory remarks and discussed some organizational objectives. They were followed by presentations from Thomas Mingot, Dr. Bettie Steinberg, Dr. Mark Shikowitz, Dr. Graciela Andrei (who came all the way from Belguim!), Dr. Nigel Pashley, Dr. Alan Shaw, Dr. Robert Bastian and Dr. Tom Broker. Due to the severe impact of Hurricane Ivan in the Birmingham, Alabama area, Dr. Brian Wiatrak was unable to attend, but did email his presentation, which Dr. Broker was able to cover in part during his talk. After the presentations there was time for some interesting follow-up discussion.

The following is a summary of some of the highlights from the presentations (most in”bullet point” format):

RRP Priorities, Statistics and Perspectives
Bill Stern, RRP Foundation

RRP Foundation priority activities

1) Provide RRP information, RRP physician referral, networking and emotional support primarily via the RRPF website, RRP Newsletter, RRP Reference Service, and RRPF email listserve

2) RRP Epidemiological data:
Data collected via practitioner and patient survey forms

Maintain RRPF practitioner and patient databases

Analyses of patient supplied data and assistance to researchers

New online patient survey and web based database being developed in collaboration with T. Mingot of Stressgen
Coordinate with RRP ISA Center and propose that RRP Task Force endorse and host new RRP patient survey forms.
3) Address some of the major patient/family concerns including:
Proper and early diagnosis of RRP,
Help in coping with RRP,
Help in finding proper RRP treatments – both surgical and adjunct,
Ways to preserve, restore and improve voice quality

Mortality - pulmonary involvement, malignancy
Disease transmission

4)RRP research - collaboration and support

Analysis of patient/parent assessed adjunct therapies for RRP

According to RRPF patient survey results the four leading adjunct therapies for RRP are, I3C/DIM, Interferon, Mumps vaccine (with reported efficacies of between 50% and 60% and Cidofovir (with a reported efficacy of about 80%). An indication that adjunct therapies may be having an impact on reducing surgical procedures for RRP was seen in a diagram showing a reduction over the last 6 years in the percentage of patients requiring 6 or more surgeries / year from about 35% to just over 25%.

RRP research activities with support from and/or involvement by the RRPF

Completed:

Risk factors for JORRP

Mouse study investigating I3C/DIM and BMD

Quality of life studies for JORRP patients

Ongoing/Proposed:

Assist with recruitment for HspE7 RRP trial

Assistance with study of RRP genetic susceptibility

Study of HPV vaccine applicability for RRP

Proposed for future:

Assessing genetic patterns in treatment response

Treating pulmonary RRP

International RRP ISA Center 2004 RRP Focus Session Michael Green, International RRP ISA Center

Organizational Description

The RRP ISA Center was established 1998 with a 9 person board of directors that includes a physician, an R.N., a clinical social worker, a genetics researcher, parents of children with JORRP, adult RRP patients and a representative of third world nations.

The scientific advisers include physicians and RRP researchers.

Some of the organizational goals and activities include:

Educate RRP patients and families so that they can make more informed treatment decisions

Create an empowering and supportive community network for those afflicted with RRP

Improve treatment of RRP and eventually find a cure

Make distributions to RRP-related organizations and to RRP patients and families who cannot afford medically necessary treatment

Sponsor educational forums that will provide treatment and research-related information to physicians and patients

Advocate on behalf of patients whose insurance coverage has denied benefits for RRP, and also with physicians

Develop and maintain a powerful relational database that will help us offer more personal service and enhance our understanding of the demographics , epidemiology and impact of RRP on patients and their families

Participate as an engaged member of the RRP Task Force

Sponsor research on ways of treating and curing RRP

Educate the public and raise media awareness of RRP.

Some Website Features

RRP related articles

RRP treatment related issues page

Frequently asked questions

Some Issues of Concern

Better treatment for pulmonary and tracheal RRP

In-service to healthcare providers promote better management of RRP.

Better understanding of cell-mediated immunity.

Better understanding of variability amongst RRP patients.

Better understanding of psychosocial impact of RRP on children.

Opportunity to use new approaches (HAMLET, Artemisinin, HPV vaccines).

Patient and Provider Databases

A relational database based on patient and healthcare provider surveys was made operational in July 2003.

The patient survey contains over 135 questions (fields), is completed entirely online and should take less than 15 minutes to complete. At this time 240 patients & families have responded so far, with bar graphed data available online.

An example of one type of analysis, is assessing disease severity based on surgical procedures during the first18 months following diagnosis. Approximately 34% had 1-2 surgeries and 32% had 3-5, 19% (37 out of 194 respondents) reported having 6-10 surgeries, and 4% (8 our of 194) reported having 21 or more surgeries. So, 24% of RRP patients have had at least 6 or more surgeries in the past 18 months. This would imply that about a quarter of RRP respondents have a disease status that could be called severe.

Of the many other questions, there are those that assess surgical and adjunct therapy approaches.

Future plans

As of 9/2004, these are a few of the projects that RRP ISA is working on:

Development of a study of the long-term psychosocial effects of RRP on children.

Writing grants for innovative research protocols such as the “Long-Peptide Therapeutic Vaccine for HPV” study.

Organizing local RRP focus sessions for patients, physicians and researchers. They will be modeled after the 2004 RRP Focus Session that RRP ISA co-sponsored in New York City.
Development of audio-visual materials that will help new patients and families learn about RRP, and will provide in-service training to healthcare professionals.
Data development to expand our knowledge of the epidemiology, demographics and psychosocial impact of RRP.
Expanding our capacity to offer coaching, counseling and case management tpatients and familie

Comments from Stressgen Biotechnologies

Thomas Mingot

Stressgen provided an update on their immunotherapeutic treatment for RRP, HspE7. It is currently under consideration by the FDA for a Phase III clinical trial involving ~150 RRP patients. It is hoped that the FDA approval will come before the end of the year.

[Note: On Dec. 2, 2004, Stressgen indicated that they are finalizing a protocol for this Phase III trial with the FDA.]

Immune Responses in RRP
Bettie Steinberg, PhD
Long Island Jewish Med. Ctr. Dept. of Otolaryngology

Key to treating RRP is controlling latent HPV infection

Latency is the persistent presence of HPV DNA in normal respiratory tissue.

Recurrent presentation of RRP is not due to “spread of virus” during surgery, but more likely from activation of local virus as follows:

All patients have patchy latent infection throughout airway, even if in remission for 20+ years.

Disease is due to local activation of latency

Cannot cure RRP unless latent virus is eliminated - only able to control it.

Role of host immune response in RRP

Why does immune system not prevent activation of latent infection, and why does disease severity vary from one patient to another

Approx. 5% of population carries latent HPV in larynx, but RRP prevalence is 1/100,000

RRP patients are not immunosuppressed

No more likely to have other types of infections

Standard tests show no general defect in immune system

There must be specific immune problem with HPV

Two primary types of immune response:
Humoral – Activates “B” cells to make antibodies

Cell-Mediated – Activates Cytotoxic “T-cells” to kill virus infected cells

What happens in RRP patients

Cell-Mediated immune response is necessary to control RRP

Specific defect in the ability of RRP patients to generate a cell-mediated response to HPV infection, i.e., T-Cells in papillomas of patients with severe disease don’t make cell-mediated response cytokines. This defect may be genetic, as it appears that severe RRP patients are 7 times more likely to have a particular “variant” gene than people from a national control population.

So, what appears to be happening in RRP patients is:

A generalized weak response to HPV proteins

An impaired presentation of virus protein on papilloma cells, i.e., infection hides from immune system

This allows the virus to persist as latent infection, and activate to cause papillomas repeatedly without effective immune response

Future Directions

Use this knowledge of host immune response issues in RRP patients to develop new therapies that can overcome the defects.

Recurrent Respiratory Papillomatosis (RRP): Celebrex and COX-2 Inhibition
Mark Shikowitz, MD
Long Island Jewish Dept. of Otolaryngology

What causes papilloma growth?

External signals control cell functions

EGF receptor appears to be over expressed in papilloma, and activates many signaling pathways, including COX-2.

COX-2 background info.

It appears to be elevated in inflammations and in many types of tumors including a number of cancers and also in RRP.

COX-2 induces prostaglandins such as PGE₂, which also appears elevated in papillomas.

Elevated PGE₂ levels stimulate papilloma growth

Inhibiting COX-2 with Celebrex

A selective COX-2 inhibitor

Blocks enzyme activity

Approved for treatment of familial colon polyps

Clinical trials in progress to treat breast, lung, bladder and prostate cancers

Shown to reduce both COX-2 and PGE₂ levels in papilloma cells

Increases apoptosis (cell death) of papilloma cells

Disrupts the EGF-R / COX-2 positive feedback loop

Study to treat RRP with Celebrex

Project 1. Papilloma cells in tissue culture (Steinberg)

Mechanism: effects on cell growth, EGF receptor signaling

Project 2. Celebrex trial in patients (Abramson, Shikowitz)

Prevent or reduce recurrence compared to surgery alone

If variable response, why

Can we find markers to predict who will respond

Project 3. Effects on host immune response to HPV proteins (Bonagura)

Clinical trial

Celebrex study design:

Patients: Age 18 or older, with 3 or more surgeries in past year, or tracheal/bronchial involvement

Randomized - two start times (6 and 18 months) after enrollment - late group is “control” group, all receive celebrex

Celebrex dose: 200 mg BID – max FDA approved dose

Score disease at endoscopy every 3 months for total of
2.5 years

Blood and biopsy studies – celebrex levels, COX-2, PGE2, etc.

Important that patients be treated by celebrex through study

Study goals:

Determine whether Celebrex is a good adjunct to surgery for RRP

Determine how it works

Determine which patients will benefit from Celebrex

Cidofovir Mechanisms in Suppressing Papilloma - Graciela Andrei, PhD, Rega Institute for Medical Research, Belgium

Anti-viral activity spectrum of cidofovir

Papovaviridae

Polyomaviridae

Murine polyomavirus

Human polyomavirus

Papillomaviridae

Rabbit papillomavirus

Human papillomaviruses (several types)

Adenoviridae

Herpesviridae

Poxviridae

Iridoviridae

Some examples of treating laryngeal papillomas with cidofovir

1) Cidofovir was administered by local injection (directly into the tumor) at 1.25 mg/kg

at weekly intervals. Complete regression of the tumor was achieved after 7 injections

2) Cidofovir (2.5 mg/ml) was injected directly into the tumor. Complete regression of the

tumor was achieved after 15 injections over 9 months.

3) Cidofovir (2.5 mg/ml) was injected into the tumor. Complete regression of the tumor was achieved after 15 injections every 2 to 3 weeks.

Mechanisms of anti-viral activity associated with cidofovir

Anti-proliferative effect on papillomavirus cells

The mechanism of cell death following cidofovir treatment appeared to be apoptosis, which was associated with accumulation of cells in the S-phase, increase in p53 and p21 levels and downregulation of the viral oncoproteins E6 and E7.

Further studies are ongoing to determine the selective mechanism of action of Cidofovir and other potential antiviral agents, such as PMEG, against HPV.

Mumps and MMR Vaccine for RRP - the Saga Continues Nigel Pashley, MD,
Children's Ear Head & Neck, Denver

Dr. Pashley first started using mumps in 1980, presented data at ASPO (American Society of Pediatric Otolaryngology) Meeting in May 2001, then noticed a back order on mumps in December 2001. By January 2002 no mumps vaccine was available, so he started using MMR in January 2002.

Dr. Pashley states, that to his knowledge, using a vaccine to actually treat a different disease has not been investigated before his study. (Vaccines are usually used to prevent the disease if exposure occurs). If this treatment approach were to be proven effective, he believes that there may be other virally associated diseases which could be treated in this manner.

Mumps/MMR protocol

Excise papilloma with CO2 laser, 2-5 Watts

Inject MMR/Mumps vaccine into base of where papilloma were excised

~ 1/2 ampule given as sub-cutaneous immunization

Table of results treating RRP patients with MMR:

Patient sample size = 34

24 adults (3F/ 21M), 10 children (3F/ 7 M)

Follow up = 6mo- 2yr 6 mo.

severity score MMR (amount) Remission

before after amps #treatments

Adults 19-28 1-6 7-28 1-14 21/24 = 87.5%

Child 18-24 2-6 2-15 1-16 8/10 = 80%

(Where remission is defined as two typical surgical intervals in which the RRP patient is found to be disease free.)

Remission group includes 6 mumps alone failures who became MMR successes and includes 8 for whom a single MMR treatment resulted in remission.

Mumps alone gave a 75% remission with about the same follow up, based on treating 46 RRP patients.

(Complete results from using mumps alone is reported in Archives of Otolaryngology July 2002 pp 783-786 vol 128 and is available on line at www.archoto.com).

Dr. Pashley notes that it is important to remember that this is an ongoing series and that this is the remission rate at the time of the survey, It may improve with longer treatment and follow up. Also there are no non-responders, i.e. everone gets some beneficial lengthening in their intervals and less recurrence (Dr. Pashley believes that these patients then go into remission after the study period)

Merck's HPV Vaccine Research
Alan Shaw, PhD, Merck Research Labs

Merck’s Investigational L1 VLP Vaccines

Clinical Program Conducted in 3 Phases:

Phase I & IIa

Preliminary assessment of immunogenicity and tolerability of a broad range of doses of monovalent HPV L1 VLP vaccines

Preliminary efficacy assessment of a monovalent HPV vaccine in women (proof of principle study)

Phase IIb

Immunogenicity and tolerability of a range of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine dose formulations (Preliminary indications are that immune response is 50-100 times greater than normal naturally generated response.)

Logistics for large-scale international clinical trials

Phase III

Demonstrate that HPV L1 VLP vaccines reduce risk for:

acquisition of HPV infection and early endpoints

development of a broad spectrum of HPV-related diseases

Proof of Principle Efficacy Study

Randomized, double-blind (in-house blinding), placebo-controlled study of HPV 16 vaccine pilot manufacturing material

In 2392 young women with £5 lifetime male sex partners

Primary endpoint:

Persistent HPV 16 infection (PCR) and/or

HPV 16-related CIN

Resutls:

Two Methods of Cidofovir Injection in the Office Procedure Room
Robert Bastian, MD, Bastian Voice Institute, Downers Grove, IL

The necessity to inject cidofovir in the O.R. could limit the effectiveness of a promising treatment due to:

Cost

Convenience

Scheduling

Aversion to general anesthesia

Anatomical constraints

Injection in the office offers the advantage of:

Better care due to convenience and easier logistics (no general anesthesia)

Societal mandate to control cost

Physician interest in better care

Injection Methods

Two methods are used for the interoffice treatment.

Rigid scope with a needle through the mouth

Fiberoptic scope with injection performed through the neck.

Both of the methods require the application of a topical anesthesia (either spray, drip or injection).

Rigid Scope

The scope is placed in the mouth. In addition, a needle is placed in the mouth as well. The vocal chords are visualized on a monitor and the injection is performed.

Fiberoptic Scope

The fiberoptic scope is inserted in the nose and the chords are visualized through the scope, or monitor. The needle is then inserted into the neck and the chords are injected.

Injection Procedure Results

192 procedures have been performed with the following statistics:

96% succeeded in performing the injection in one visit

1% required two visits

2% were unsuccessful and required injection under general anesthesia

There were no complications out of 192 procedures

HPV-6 and HPV-11 in RRP: Correlation of disease severity with HPV-11;
Plans for future Workshops and public education
Thomas Broker, PhD, Univ. of Alabama Birmingham, Biochemistry and Molecular Genetics

Thomas Broker from the University of Alabama-Birmingham presented his findings on the correlation of disease severity with HPV-11 and HPV-6 in RRP. Dr. Broker’s discussion covered current therapies used to treat papilloma infections, including surgical methods (LEEP, laser, microdebrider, general surgery), natural products (podophyllin, Indole-3-carbinol, diindoylylmethane), small molecule drugs (interferon-alpha, imiquimod), acids (Vitamin A, Cidofovir, Photodynamic therapy combined with laser excitation in laryngeal papillomas), and prophylactic vaccines using virus-like particles of empty viral capsids.

Analysis of Juvenile Laryngeal Papillomatosis and relation of RRP disease severity with HPV types 6 and 11

In collaboration with Brian Wiatrak MD, Audie Wooley MD, Scott Hill MD, and Lin Lewis RN at the Children’s Hospital of Alabama, Dr. Broker obtained staging sheets from all endoscopies of juvenile laryngeal papillomas and sent them to a research lab to correlate the severity of the disease with adjuvant therapies and molecular biomarkers. The research lab conducted histological assessment, HPV genotyping, and biomarker analysis on all RRP endoscopies.

The ten-year prospective study involved 73 patients, with staging performed at each surgery. A standard RRP staging system was implemented to define the severity of the disease at each stage. This study was the first longitudinal, prospective analysis of a large pediatric RRP population that implemented such a standardized staging system.

Results

The study’s results show that RRP patients with HPV-11 are more likely to have higher disease severity scores, require more frequent surgery, and require adjuvant medical treatments. They also report a higher incidence of tracheal disease, are more likely to require a tracheostomy, and develop pulmonary disease. Diagnosis of HPV-11 under 3 years of age was also shown to correlate with higher disease severity scores, more frequent surgeries, and to require adjuvant medical treatments.

International Papillomavirus Society involvement in HPV Educational Activities

Annual Clinical Workshops for physicians, health care providers, public health officials and epidemiologists – typically regional to site of Conference

All-inclusive Scientific Conferences with sessions across very diverse research, clinical & public health disciplines

Public commentary on timely HPV issues

Public advocacy concerning HPV diseases

Private assistance to physicians and patients in response to email and telephone inquiries

In-depth, special topic reviews for Papillomavirus Report

Web site: www.IPVSoc.org with comprehensive resources for the professional communities and lay public

Forum on HPV Education Vancouver, Canada : May 5 - 6, 2005 – Key Issues

I -

General consensus on what we know and what we do not know
Consistent web sites – coherent messaging

Top quality illustrations

Age-appropriate, culturally sensitive information

Translation into 15 - 30 or more languages

Coordination of efforts in targeting readership & audiences for improved efficiency

II -

Conjoined efforts concerning patient advocacy

Lobbying for federal and state funding for basic and translational research and education

Corporate partnerships and sponsorships

Broadcast and print media placements

More comprehensive and timely education for health care professionals

Greatly improved school books and teacher guides

Identification and fostering of constructive alliances in the community

De-stigmatization of HPV associated diseases

Quality of Life Issues Effecting Pediatric RRP Patients
Brian Wiatrak, MD, FACS, FAAP, Chief, Pediatric Otolaryngology The Children's Hosptial of Alabama

[Note: This talk was not presented because the impact of hurricane Ivan prevented Dr. Wiatrak from leaving Birmingham in time for our meeting. The summary of the presentation is based exclusively on a powerpoint presentation that Dr. Wiatrak was so kind to email to us.]

The main focus of this study is to define what quality of life (QOL) is, determine whether it is effected in our RRP patients and how much.

Definitions of QOL

Health - the condition of being sound in body, mind or spirit; freedom from disease or pain.

The degree to which a person enjoys the important possibilities of his or her life.

Factors - health, function, future potential, socioeconomic status

Can it be measured? YES

Use of PedsQL to Assess Health-Related Quality of Life in Children with RRP

Wiatrak, Lindmann et al (Funded by RRP foundation)

QOL instrument designed for people with chronic illness

23 questions

4 subscales (physical, emotional, social, school functioning)

Parent proxy reporting for children 4yo and under

Parent AND child reporting for older pts.

Results compared to validated “normal” healthy children AND compared to
children with other chronic illnesses i.e. cancer, renal, CF etc..

Results (27 patients ages 2-18)

RRP has a significant effect on QOL

Compared to healthy children:

Self reporting (age 5-18)

Significant (P=<.05) worse QOL for total score, psychosocial aspects, social functioning, school fx)

Parent reporting

Very significant (P=<0.0001) in ALL scales

Parents seem to perceive things worse than their self reporting children

Results Compared to Children with OTHER illnesses

Self reporting (age 5-18)

Trend towards significance in all scales

Significance (P=<0.05) in school functioning

Parental reporting

Trend toward significance in all scales

Significance in psychosocial (P=<.05) and school functioning (P=<0.0001)

Significance of study

Demonstrates in a “more” objective way the effects of RRP on a patient’s quality of life

Objective data may be used to justify more extensive RRP research which is still considered an “orphan disease.”
National based study needed utilizing field tested and validated RRP QOL instrument.

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.

Other therapies, not mentioned above, that have shown some efficacy include PDT (photodynamic therapy) and Acyclovir.

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, Retin = retinoicacid or accutane.

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, colloidal silver, topical 5-flourouracil (5FU), 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 ($3.85 up to 1 lbs.) , 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@itsnet.com

(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 product pricing as of 9-1-99 (includes shipping via USPS priority mail):

1 bottle - 100 capsules @ 100 mg -$20

3 bottles - 100 capsules @ 100 mg - $55

add $16.00 to above prices for Fed X shipping.

Kronos Pharmacy

3675 S. Rainbow Blvd, #103

Las Vegas NV 89103

Tel: 1-800-723-7455

Local: 702-873-8455

Fax: 702-873-6845

www.kronospharmacy.com

[Credit card orders may be placed by phone, fax, or web ]

For more detailed information ask to speak with Richard Fura.

Kronos Pharmacy I3C product pricing as of 9-1-99:

1 bottle - 100 capsules @ 400 mg - $59.50 + shipping

1 bottle - 100 capsules @ 200 mg - estimated ~ $33.95 + shipping

SHIPPING: UPS 3rd Day Service ($5.00) or Airborne Overnight ($8.00)

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

[Note: Kronos Pharmacy now requires prescriptions for I3C]

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

…………………………………………………………………….

Anecdotal Evidence for Optimal Cidofovir Injection and Methods

By Clark Rosen, MD

University of Pittsburgh Voice Center

As many of you are aware, Cidofovir has been shown to be, in preliminary studies, quite effective for the treatment of RRP. The introduction of the use of Cidofovir for RRP was done in a fairly non-scientific fashion. As with many inventions or great ideas the originators of using Cidofovir for RRP tried it on some patients using their best judgment on how to apply and use the medication and fortunately received favorable results. These doctors initially injected Cidofovir into RRP at a relatively low concentration (2.5 mg per cc) on an every two-week basis without removing the RRP at all. The results were positive, however, their patients had to have repeated surgery on a fairly excessive level (8-10 surgeries). Following these initial positive reports of the use of Cidofovir for RRP, other investigators started using Cidofovir and slightly changing the dose and administration protocol. Now many doctors are using Cidofovir typically in a fashion of surgical removal of the disease in combination with Cidofovir injection either immediately before or immediately after the surgical excision of the disease. No set dose of the Cidofovir injection has been tested or found to be optimal or better then the others.

A colleague of mine was recently telling me how his Cidofovir results have not been very positive and he does not understand why people are so excited about Cidofovir for RRP. I asked him to explain his exact methodology and he explained that he was using a very high concentration (75 mg per cc) right at the papilloma location following removal and because of the high dose he was using a very small volume of the medication. I explained to him that at Pittsburgh we had very good success with Cidofovir use, using the methodology of surgical excision and then Cidofovir injection in a very wide area around the larynx at lower concentration (5 mg per cc) and a higher volume injection. Typically we will inject all mucosal surfaces of infraglottis, glottis, ventricles and supraglottis with each treatment time period. Interestingly, my colleague called me back four to six months later after the original discussion and reported that his Cidofovir results had been outstanding as soon as he changed from a high-concentration, low-volume Cidofovir administration to a low-concentration, high-volume delivery method.

Now of course this is a strictly anecdotal experience however, given the HPV biology that has been so nicely elucidated by the Long Island Jewish Researchers stating that “HPV is present throughout all mucosal surfaces both normal and abnormal in the larynx” it makes some sense to apply the antiviral medication to as much of these as are possible. This can be safely done using a low concentration of Cidofovir (approximately 5 mg per cc) with a higher volume of a drug at delivery. This approach is safe and an easy way to deliver the medication in the adult larynx, however pediatric larynges are so much smaller and thus the volume of the drug delivery is a significant concern that needs to be done with greater caution.

Until exact animal studies or clinical studies are done to determine the optimal dosing and treatment regime for Cidofovir this is one small anecdotal story to lend support to a Cidofovir treatment approach consisting of lower concentration and higher volume delivery of the medication.

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

RRP Genetics Study

Principal Investigator – Farrel Buchinsky, MD, Center for Genomic Sciences, Pittsburgh, PA

The Center for Genomic Sciences, in collaboration with the RRP Task Force, is conducting a study into the genetic susceptibility to RRP. The RRPF is also involved in this collaboration and is asking for RRP patients / parents to volunteer to participate. All it will require is a Scope mouthwash. For more information go to:

http://www.rrpgenetics.org

or contact Dr. Buchinsky or Ms. Marilyn Smith (research coordinator) directly at:

Address: Center for Genomic Sciences

Allegheny-Singer Research Institute

320 East North Avenue

Pittsburgh, PA 15212

Phone: (888) 887-7729

E-mail: fbuchins@wpahs.org

…………………………………………………………………….

Study at LIJ to Treat RRP with Celebrex – Update Feb. 05
Bettie Steinberg, PhD, Long Island Jewish Med. Ctr. Dept. of Otolaryngology

As all of you know, Vioxx was recently withdrawn for sale due to a clear increase in risk of heart attacks in patients taking the drug. Vioxx is a selective COX-2 inhibitor. COX-2 is an enzyme that is elevated in all kinds of inflammation and also elevated in many benign and malignant tumors. COX-2 is elevated in respiratory papillomas, and appears to stimulate their growth. Celebrex is also a COX-2 inhibitor, and we have proposed that inhibiting COX-2 with Celebrex would be effective in treating RRP. That is the basis for our pending NIH grant on the use of Celebrex for treatment of respiratory papillomas. Celebrex appears to have much lower risk of causing heart attacks than Vioxx. Celebrex has a different chemical structure, and functions differently which is why it does not have the same problem. A number of studies with very large numbers of patients have addressed the question of Celebrex and heart disease in the last 2 years. Most shown no increased risk with Celebrex, compared to either not taking any drug or compared to other anti-inflammatory drugs like Motrin. However, two very recent studies have shown a small increase in heart attacks in people treated with the highest doses of Celebrex. We are continuing with our study of Celebrex for RRP, with the approval of the Institutional Review Board (IRB) at North Shore- LIJ. The IRB is a committee responsible for all clinical research to protect patients from unnecessary or excess risk. We have made two changes to the study. First, we have reduced the dose of Celebrex since it appears that any risk goes up with the highest dose of drug. Second, we will not enroll patients with RRP into the study if they have heart disease or high blood pressure that cannot be controlled with medication. With these changes, we believe that the risk of any problem with Celebrex will be less than the risks associated with severe RRP. If Celebrex is effective in reducing or preventing recurrent RRP it would be wonderful. Therefore, we are continuing to enroll interested patients in the study.

To be eligible, patients must be at least 18 years old and must have had at least 3 surgeries in the past year to remove papillomas. If patients are interested, they or their doctors should contact Ginny Mullooly, RN at 718-470-7011 for more information.

For more details, see RRP Focus 2004 highlights, summary of presentation by Mark Shikowitz, MD.

…………………………………………………………………….

HspE7

Recurrent Respiratory Papillomatosis (RRP) Phase III Clinical Study

Stressgen Biotechnologies, Inc., a company based in Victoria, BC, Canada, with offices in San Diego, CA, and Collegeville, PA, is developing a therapeutic vaccine, HspE7, for the treatment of recurrent respiratory papillomatosis (RRP), and is initiating a Phase III clinical study.

The Phase III clinical program in RRP is based on the encouraging results of a Phase II RRP study in children and young adults. The results of the Phase II RRP study, conducted at eight medical centers in the United States in 27 patients with moderate to severe RRP, were reported at the 21^st International Papillomavirus Conference in Mexico City, February 26, 2004.

The Phase III study registration process for local institutional review board and federal regulatory approval is under way with a goal to enroll physicians throughout the United States who are currently treating children and young adults with RRP. The start of the treatment phase in the study will occur in mid 2005.

Stressgen has contracted with PPD Development, Inc., for monitoring of the study, and you may contact them if you wish to learn more or to obtain the name of a physician in your area who will be a study investigator if you are interested in volunteering. A PPD representative may be contacted toll free at:

Information Number 1-877-654-6062

Overview of requirements for study entry and conduct of the study:

Males and females 2-18 years of age.

Must have had at least 3 debulking surgeries prior to the start of the study and 1 additional surgery at the start of the study with no interval between any of the 4 surgeries greater than 126 days.

Must be free of a significant life-threatening or serious concomitant medical condition other than RRP.

Must be free of a disease that compromises the immune system.

No adjuvant RRP therapy can be used within 30 days of the start of dosing in the study.

No immunotherapy for RRP can be used within 9 months of dosing in the study.

Total patient participation in the study is 60 weeks.

Patients will receive standard medical/surgical care of their RRP condition throughout the trial.

Study medication is administered subcutaneously at monthly intervals for 3 total doses. There is a placebo arm and patients initially randomized to placebo will be eligible to receive active drug at the conclusion of the 48-week postmedication observation period so long as the patient still meets study entrance criteria.

Stressgen Contact Information:

www.stressgen.com CanadianOffice:

350-4243 Glanford Avenue

Victoria, BC CANADA V8Z 4B9

Tel: 250/744-2811

Fax: 250/744- 2877

Principal Executive Office:

Donna Slade

Director, Investor Relations

6055 Lusk Boulevard

San Diego, CA USA 92121

Tel: 858/202-4900

Fax: 858/450-6849

dslade@stressgen.com

On April 18, 2005,

Your support for this cause is very much appreciated!

Pledge per mile or a flat amount to: marathon@rrpf.org

or send a check to the
RRP Foundation

Analysis of patient/parent assessed adjunct therapies for RRP

RRP research activities with support from and/or involvement by the RRPF

Organizational Description

Key to treating RRP is controlling latent HPV infection

Role of host immune response in RRP

What happens in RRP patients

Future Directions

COX-2 background info.

Inhibiting COX-2 with Celebrex

Study to treat RRP with Celebrex

Clinical trial

Anti-viral activity spectrum of cidofovir

Papovaviridae

Some examples of treating laryngeal papillomas with cidofovir

Mechanisms of anti-viral activity associated with cidofovir

Mumps/MMR protocol

Merck’s Investigational L1 VLP Vaccines

Proof of Principle Efficacy Study

Rigid Scope

Fiberoptic Scope

Analysis of Juvenile Laryngeal Papillomatosis and relation of RRP disease severity with HPV types 6 and 11

Results

International Papillomavirus Society involvement in HPV Educational Activities

Forum on HPV Education Vancouver, Canada : May 5 - 6, 2005 – Key Issues

II -

The main focus of this study is to define what quality of life (QOL) is, determine whether it is effected in our RRP patients and how much.

Significance of study

Anecdotal Evidence for Optimal Cidofovir Injection and Methods

On April 18, 2005,

Your support for this cause is very much appreciated!

Pledge per mile or a flat amount to: marathon@rrpf.org

or send a check to the RRP Foundation

Analysis of patient/parent assessed adjunct therapies for RRP

RRP research activities with support from and/or involvement by the RRPF

Organizational Description

Key to treating RRP is controlling latent HPV infection

Role of host immune response in RRP

What happens in RRP patients

Future Directions

COX-2 background info.

Inhibiting COX-2 with Celebrex

Study to treat RRP with Celebrex

Clinical trial

Anti-viral activity spectrum of cidofovir

Papovaviridae

Some examples of treating laryngeal papillomas with cidofovir

Mechanisms of anti-viral activity associated with cidofovir

Mumps/MMR protocol

Merck’s Investigational L1 VLP Vaccines

Proof of Principle Efficacy Study

Rigid Scope

Fiberoptic Scope

Analysis of Juvenile Laryngeal Papillomatosis and relation of RRP disease severity with HPV types 6 and 11

Results

International Papillomavirus Society involvement in HPV Educational Activities

Forum on HPV Education Vancouver, Canada : May 5 - 6, 2005 – Key Issues

II -

The main focus of this study is to define what quality of life (QOL) is, determine whether it is effected in our RRP patients and how much.

Significance of study

Anecdotal Evidence for Optimal Cidofovir Injection and Methods

or send a check to the
RRP Foundation