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

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 13 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 Secretaries

Jenny Shamblin

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, see RRP Web News.]

RRPF Support and Fundraising Activities

Past Research/Support activities:

Research collaboration with Dr. K. Shah et al., from Johns Hopkins using RRPF patient data to better determine risk factors for J-O RRP.

Provided support to Strang-Cornell center for testing urine of RRP Patients to determine the impact of I3C/DIM on estrogen metabolites.

Supported research by Dr. K. Auborn and associates from LIJ North Shore Research Inst., to study the impact of I3C/DIM on bone density in mice.

Funded a study by Lin Lewis, RN, et al. from Univ. of Alabama to study biases against children with RRP.

Funded research by Dr. Lindman, et al. from Univ. of Alabama to utilize the PedsQLTM 4.0 Generic questionnaire to evaluate the impact of RRP on the quality of life of children affected by this disease.

Current Research/Support activities:

Reseach collaboration with Thomas Mingot, Director, Clinical Research and Operations at Stressgen Biotechnologies Inc. This involves the development of a comprehensive web based RRP survey and database, which is also part of PhD. Research project. It is anticipated that the information gathered from this survey will: 1) Help to convince funding agencies of the public health importance of RRP and hopefully get more funds committed to RRP research. 2) Assist the RRP Task Force and other RRP practitioners in refining treatment and practice guidelines for RRP.

RRPF website redesign, ongoing development and maintenance.

RRPF patient and practitioner database management.

RRP Newsletter publication and dissemination.

RRP Reference Service publication and dissemination.

Assistance to the Cody Pate Foundation (more info below)

Proposed Research/Support activities:

The RRP Foundation is asking the RRP research community to apply for funding a pilot study dedicated to finding a new treatment for pulmonary RRP, which is perhaps one the greatest challenges in dealing with this disease. Interested researchers should address inquiries to:

Bill Stern, Director

P.O. Box 6643

Lawrenceville, NJ 08648-0643

Email: bills@rrpf.org

Fundraising:

Cody Pate Foundation to Become Part of the RRP Foundation

The RRP Foundation is pleased to announce that we will be directly supporting the efforts of the Cody Pate Foundation to raise funds to help defray travel and some other expenses related to obtaining treatments for RRP. The Cody Pate Foundation will become a division of the RRP Foundation, but Lynette Pate will continue to spearhead activities with the goal of raising and disseminating funds for RRP families in need and also help create greater RRP awareness. For more information contact Lynette Pate at: Buddie4breathing@aol.com

3^rd Annual RRPF Hockey Night a Great Success

On January 31, 2004 the 3rd annual RRPF Hockey Night took place at the MCI Center in Washington, DC. The hard work of Ed and Maura Weiner (and their friends) netted the RRP Foundation over $15,000. It is largely due to their efforts that we now feel that we can afford to fund a pilot study for research into treating pulmonary RRP.

Running For RRP

On April 19, 2004, RRP patient and newsletter editor Jennifer Woo will be running the 2004 Boston Marathon to raise awareness and funds to support RRP research and networking between patients, physicians and scientists. Since her diagnosis at infancy, Jennifer has undergone over a dozen surgical procedures at the Children's Hospital of Philadelphia to remove papilloma growths. Her experiences as a patient in the operating room have motivated her involvement in the RRP Foundation as well as her dreams of someday becoming a pediatrician. A native of Washington DC and Hong Kong, Jennifer is currently a sophomore at Harvard University. She has grown accustomed to running in hot, tropical Asian climates as well as the frigid ice and slush of New England, and looks forward to running her first full marathon from Hopkinton, MA, to the center of Boston.

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 on the next page)

RRP Remission News

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

by Bill Stern

Heather who lives in Oregon and is now 18, has now been in remission about 14 years. However, she had a very aggressive first 4 years with RRP. During that time Heather was trached and endured over 100 surgeries. She was treated with interferon for a while, but is not really sure that it was the interferon that put her in remission. Her voice today is remarkably good.

RRP Network News

Our international support network has grown to approximately 670 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 to fill out the RRPF Patient/Therapy Survey. Please make sure to alert us of changed addresses by checking the “new address” box. There is also a box below the name and address section, which we ask you to check if you 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 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. So if you haven't completed a questionnaire in the past, please take a few minutes to complete the patient survey. If you have previously filled out a questionnaire, you need only identify yourself, and answer only those questions where you have new or updated information to provide.

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. 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 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, or “Listserve” continues to be very active. With 200+ subscribers made up of RRP patients, health care providers, and caregivers, this low volume list is a valuable resource for the whole RRP community.

Recent significant discussion topics included: dealing with insurance companies for RRP treatment, availability and dosing of adjunct therapies like DIM and Cidofovir, information about emerging adjunct therapies like Celebrex, assistance in locating experienced RRP physicians, HPV/RRP transmission issues and, most important, discussions among RRP patients and caregivers about the daily experience of dealing with RRP.

Listserve users should be aware that the RRPF Listserve is vulnerable to the same issues as all on-line services. Concerns among Listserve users about patient privacy led the RRPF leadership to restrict access to the Listserve to only users who have registered with the Listserve hosting service, YahooGroups. Even though anyone may register with YahooGroups, limiting access to registered users prevents Listserve access from open Internet services like search engines, etc. In any case, Listserve users 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 Listserve and should not open any attachments within messages received from the Listserve. This does not mean that the Listserve 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 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

[Ed. Note: The following article was posted on the RRPF listserve by RRPF scientific advisor, Dr. Bettie Steinberg, in an attempt to address many concerns expressed about HPV/RRP transmission, infection and disease expression. Because of the importance of this topic to many RRP patients and families we have published it in this newsletter issue with Dr. Steinberg’s permission]

Cause of RRP

I would like to try to clear up some of the confusion that has been expressed on the RRPF egroup site in the last few days, and hopefully answer some of your questions (although I assure you that researchers who spend all their time studying this disease have many of the same questions you do).

First, RRP is definitely caused by Human Papillomaviruses (HPVs). There is no question about that. However, infection does not always, or even usually, cause disease. Most of the time, HPVs cause silent or "latent” infection with no evidence of any problem. The virus just sits in the tissue, where it probably stays for life. Many, many people carry HPV in their throats without having RRP In a few people, the virus becomes active and then you get RRP. Why this happens to one person and not another is only starting to be understood - one of the questions scientists and physicians have. Clearly, it has something to do with the way the immune system sees (or doesn't see) the virus in this tissue. This appears to be at least partly genetic. It does not mean that people with RRP have a "bad" or "weak" immune system, just that their immune system does not respond to HPVs in an effective way. The genetics is complicated, and involves many genes. Recent studies suggest that you need just the right combination to be susceptible. Since people in the same family are not genetically identical (except for identical twins), even two children from the same parents would not have equal susceptibility.

HPVs are a very large family of related viruses (more than 100 types) that cause warts or papillomas in many parts of the body. Some types cause skin warts. In fact, everyone carries latent or silent HPVs in their skin, and recent studies have shown that every square inch of skin has these silent HPVs. We now know that these viruses are really just part of us. As far as we know, when these infections are latent they are not contagious, because there is no production of new virus. However, it is possible that small amounts of virus might be made from time to time. When the virus is active, and a wart is present, virus is produced and released from the surface of the wart, and it can then infect another site on the same person or infect other people. Skin warts, especially those plantar warts on the bottom of your foot, tend to make a lot of virus, and are therefore quite contagious.

Different HPV types cause warts or papillomas on mucous membranes, like those of the respiratory tract and the genital tract. There are at least 15-20 different types that can cause mucous membrane papillomas. Most of the time, they also cause silent infections. When the virus is active, andcausing RRP, it can make new virus. However, most papillomas in the throat make very little or no new virus. "Why" is another question where we don't have answers, but it means that those papillomas are not very contagious if they are contagious at all.

Of all of the HPV types that exist, just two are most commonly found in RRP, type 6 and type 11. These same two types are also present in many genital warts, although the most common HPV infection of the cervix in women is type 16. (Yes, HPV 16 is considered more likely to cause cancer, but it is also the most common HPV in the genital tract and usually does not cause cancer). Another question we cannot answer: if HPV 16 is most common in the genital tract, how come it is rare in the throat? Only explanation we have right now is that subtle differences in the mucous membrane tissues that we don't understand affect susceptibility to different HPV types. We know that skin HPV types don't normally cause mucous membrane papillomas, and vice versa. People are studying this question, but no answers yet. See - I told you scientists have lots of questions too.

Now to the whole STD question. Yes, genital warts are an STD. That just means that the HPV virus that causes genital warts can be transferred by sexual contact. Does not say what type of contact - between a husband and wife is still sexual contact and clearly appropriate behavior. Also does not say that is the only way to transfer it. Many, many people (probably at least half) have had a genital HPV infection. Some know they do, many do not even know it. Again, the virus can cause a silent or latent infection.

Physicians and researchers do believe that most babies with RRP get the virus from their mothers - usually while being born. If the mother has large genital warts that are making lots of virus the baby is more likely to get infected than if only a small amount of virus is being made from a wart you don't know is there. Young mothers are more likely to have an active infection, because the immune system seems to get better at handling genital tract HPV infections with time and keeping the virus latent. Therefore young mothers would generally make more virus - this could explain why a disproportionate share of babies with RRP are first born and had young mothers. Also, first babies usually take longer to be born, and therefore are exposed longer. A few babies with RRP were born by C-section. We think, but have not proven, that the virus occasionally gets up into the uterus during pregnancy and infects the baby before it is born - one more of our unanswered questions.

Finally, HPVs are completely unrelated to the viruses which cause herpes, which are Herpes Simplex Viruses (HSVs). Confusing because the abbreviations both start with H and end with V but completely different viruses.

Hope this answers some of your questions, and doesn't confuse you more. Bottom line - we should all support each other, not try to blame anyone for the wrong combination of genes and exposure to a virus that is very widespread. I like the idea of sending people with questions to the RRPF URL. The more we can educate people, the better.

Bettie M. Steinberg, Ph.D.

Chief, Otolaryngology Research

Associate Director and

Chief Scientific Officer

North Shore - LIJ Research Institute

Long Island Jewish Medical Center

RRP Patient Stats

The statistics that follow are based on RRPF patient questionnaire responses. Although suggestive trends are apparent, there has been no attempt to determine statistical significance, so caution is urged in drawing conclusions from the numbers below. (Also, see adjuvant therapy stat on page 7)

Table 1. Total number of patients in support group reporting.

	Females	Male
All Ages	281	350

Distribution of patients based on current and diagnosis age brackets and sex (sample sizes range from 563 to 591)

Table 2. Distribution of patients based on current age brackets and sex.

Age Groups	Females	Male	Total
Under 10	29	41	70
10-20	99	82	181
20-30	27	20	47
30-40	48	47	95
40-50	23	41	64
Over 50	34	72	106

Table 3. Distribution of patients based on diagnosis age brackets and sex.

Age Groups	Females	Male	Total
Under 10	186	173	359
10-20	15	10	25
20-30	27	40	67
30-40	17	48	65
40-50	16	34	50
Over 50	7	18	25

Table 4. Distribution of respiratory papilloma sites of involvement based on responses from 447 patients.

Site: sitesite	J-O	A-O	Total patients
above cords	148	61	209
at cords	242	184	426
below cords	119	50	169
tracheal	60	20	80
bronchial	32	8	40
lung	24	6	30

Table 5. Distribution of surgeries in laast 12 months reported based on responses from 421 (250 J-O, 171 A-O)

patients.

Number of surg. sitesite	J-O	A-O	Total patients
1	36	68	104
2	48	32	80
3	33	28	61
4	28	18	46
5	17	5	22
6 +	88	20	108

RRP Meetings

2004 RRP Focus Session in NYC on September 18, 2004

The RRP Foundation and the International RRP ISA Center will be co-sponsoring the 2004 RRP Focus Session in New York City on September 18th, in conjunction with the AAO (American Academy of Otolaryngology) Convention. We have received confirmation that the following physicians and RRP researchers have accepted our invitation to present: (1) Robert Bastian, MD (on two methods of transdermal cidofovir injection + results); (2) Bettie Steinberg, PhD (research into RRP molecular biology/immunology); (3) Mark Shikowitz, MD (Celebrex and COX-2 inhibitors); (4) Seth Pransky, MD (cidofovir and JORRP); (5) Nigel Pashley, MD (mumps/MMR vaccine) and (6) Thomas Broker, PhD. (HPV vaccine research and creating greater RRP/HPV awareness). We are anticipating a stimulating meeting with interesting presentations and discussion. There should be a signficant turnout of RRP patients, families and practitioners. We will keep te RRP community informed, as we finalize the details.

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	66	28	38	6	32
MMR/Mumps	22	9	13	7	6
Cidofovir	37	7	30	9	21

^†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.

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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

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

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BioResponse Spring 2004 Update for Phytosorb DIM^Ò products

Children: We continue to receive calls from parents seeing improvement with their children. Kim Smith reports that her 15-year-old daughter Emily has gone from a 4-6 week surgical interval from August to January to currently doing well more than 11 weeks since her last surgery. She had increased her dose from 450mg a day to 750 mg a day in January 2004 at her last surgery. She takes the supplement twice a day. She will be evaluated again at the end March. She has reported no side effects at this higher dosage. All the best to Emily and her family.

Chocolate Sprinkles: The Sprinkles look at bit different this time. The granules are slightly larger and there is more of a speckled look to the material. We have changed suppliers of the Cocoa and Fructose ingredients-hence the change in appearance. Please be assured that the Sprinkles are identical to the Chocolate Sprinkles in the past in quality and potency, they just look a bit different.

BioResponse encourages all parents to call and discuss the current dosage regimens for their growing children. It is always a good idea to intermittently review their weight and daily dosage. We have a toll free number 1 877 312-5777 or you can email us at orders@bioresponse.com .

Adults: Jason Jordan reports that he has not had surgery for going on 11months. Prior to taking Phytosorb DIM, he was having surgeries every 8 months with papilloma regrowth visible at 4 weeks. He began taking 750 mgs a day in October of 2002 and since February, 2004 he takes 900 mg a day or 9/mg/kg/day. He takes the product just before bedtime on an empty stomach with no side effects. His checkup last week showed only a tiny papilloma after 11 months.

If you are new customer, please call to determine what would be the best starting dose based on your specific situation. If you are an existing customer, please feel free to call and review your current regimen to make sure it is optimal. Starting at the 8mg/kg/day initially is a good approach and increasing if necessary.

Upcoming Survey: We are preparing a survey that we will send out to try and collect information on how our RRP families are doing. We will offer 2 free bottles to anyone that fills out the form, and we would be glad to take your answers over the phone if that makes it easier. We will be sending out the survey to everyone in our database in May and encourage you to participate.

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 we can set an account up for you in the Phytosorb group. There are additional discounts available when you order on line. Please let us know if you are an existing customer and we will set up an account for you to purchase on the Internet. If you are a new customer, please send us your phone number so we can contact you to set up an account.

Science & Research Activities

Reflux Diagnosis and Management

Julie L. Bowne, M.S., CCC-SLP

Reflux has recently been among the many RRPF listserve discussions. In my experience, many patients do not clearly understand reflux. This article will provide an overview of reflux, associated symptoms/conditions, and potential treatment.

There are two classifications of reflux: gastroesophageal reflux (GER) and laryngopharyngeal reflux (LPR). GER is the backflow of stomach contents to the esophagus, and LPR is the backflow of stomach contents into the throat.^1,2 The following chart breaks down each classification by symptoms:^1,2,3

GER

LPR

Heartburn

Burning sensation behind breastbone

Regurgitation of acid into mouth

Difficulty swallowing

Pain with swallowing

Chest pain

Hoarseness

Chronic cough/throat clearing

Global/lump sensation in throat

Excess phlegm

Sore throat

Difficulty swallowing

Voice breaks/fatigue

Patients that do not experience heartburn have difficulty understanding why they have been diagnosed with reflux, but as you can see, LPR affects the throat and heartburn is not typically an associated symptom.

Testing for LPR can include a variety of diagnostic measures, including barium swallow studies, esophageal manometry, and, the newest, double-probe pH monitoring. Although pH monitoring is highly sensitive and specific for LPR, many physicians diagnose LPR based upon laryngeal examination. Findings of LPR can include: edema (swelling) and erythema (redness) of the posterior larynx, edema of the vocal folds, airway stenosis, and thick mucus in the laryngeal area.^3,4

LPR has also been associated with the development of vocal fold polyps, nodules, granulomas, contact ulcers, exacerbation of asthma, and sinusitis.¹ According to the San Diego Voice Center, LPR has recently been associated with papilloma.⁵ However, there is still uncertainty regarding this association--whether reflux contributes to the development of papilloma or if papilloma predisposes one to reflux. Regardless, many physicians believe that the development of laryngeal growths is associated with the repeated exposure of gastric acid on the laryngeal mucosa.

Treatment of reflux varies depending on its severity, but typically involves dietary/lifestyle changes, use of antacids, and/or proton pump inhibitor therapy (PPI). Dietary recommendations usually consist of avoiding/reducing consumption of citrus, tomato-based food, spicy food, fatty food, chocolate, mints, caffeine, and alcohol. Lifestyle changes include cessation of smoking, losing weight (if needed), avoiding tight-fitting clothing, and avoiding meals/snacks 2-3 hours before bed. PPI therapy (e.g., Nexium/Aciphex) is often used in conjunction with the above recommendations. PPIs inhibit the production of gastric acid by targeting key enzymes produced by cells in the stomach, thus, reducing the acidic environment and allowing damaged tissues to heal. Length of treatment may vary depending on severity of reflux, laryngeal findings at follow-up visits, and/or patient's symptoms, but PPI therapy usually lasts 3-6 months.

Although, there is not a definitive cause and effect relationship between LPR and papilloma, reflux management may be a necessary adjunctive treatment prescribed by physicians.

References:

Koufman, JA, Aviv, JE, Casiano, RR, & Shaw, GY (2002). Laryngophayrngeal reflux: Position statement of the Committee on Speech, Voice, and Swallowing Disorders of the American Academy of Otolaryngology-Head and Neck Surgery. Otolaryngol Head Neck Surg, 127: 32-35.
Koufman, JA (2002). Laryngopharyngeal reflux is different from classic gastroesophageal reflux disease. ENT-Ear, Nose &Throat Journal, 81, suppl 2: 7-9.
Belafsky, PC, Postma, GN, Amin, MR, & Koufman, JA (2002). Symptoms and findings of laryngopharyngeal reflux. ENT-Ear, Nose &Throat Journal, 81, suppl 2: 10-13.
Cohen, JT, Bach, KK, Postma, GN, & Koufman, JA (2002). Clinical manifestations of laryngopharyngeal reflux. ENT-Ear, Nose &Throat Journal, 81, suppl 2: 19-23.
San Diego Voice and Swallowing Center. Laryngeal papillomas, obtained March 2004, www.sandiegovoice.org/papilloma.html.

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Clinical Trial at LIJ to Treat RRP with Celebrex

The Department of Otolaryngology at Long Island Jewish Medical Center has received FDA and IRB approval to conduct a 2 year research study for the treatment of RRP with Celebrex (celecoxib), a Cox-2 inhibitor that is a widely used for treating arthritis ( see Summer 2003 RRP Newsletter for more background information http://www.rrpf.org/newletters/RRP_Newsletter_Summer03.html#COX2 ).

In addition to surgery to remove the papillomas, patients will be given Celebrex for one year and a placebo for 6 months. Celebrex has been shown to be effective in treating other types of benign tumors. Enrollment of patients for this study is underway.

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.

They strongly urge patients not to take Celebrex on their own for RRP, since the dosing is non-standard and, therefore, should be used as part of a study with appropriate monitoring and evaluation of effects.

Cidofovir Study Update

J. Scott McMurray, MD and Charles Ford, MD

Dept. of Pediatric Otolaryngology

University of Wisconsin Medical School

There is no cure for RRP. The standard treatment for RRP is vaporization of the growths with a laser but the result is generally temporary. Medical therapies include: (1) drugs that affect the immune system such as interferon, (2) chemotherapeutic drugs such as methotrexate, podophyllin, bleomycin sulfate and fluorouracil, (3) antiviral drugs such as ribavirin and acyclovir, and (4) hormonal drugs such as indol-3-carbinol.

Cidofovir (Vistide; acyclic nucleoside phosphonate) is an antiviral drug with broad activity against herpes-type viruses, including human papilloma virus. Cidofovir is currently FDA-approved to treat cytomegalovirus retinitis in AIDS patients. In recent reports, Cidofovir injection had favorable results when injected intralesionally in adult and pediatric RRP patients (Van Cutsem et al., 1995; Snoeck et al., 1998; Pransky et al., 1999)).

The impact of the disease on patients and their families, due to the frequent recurrences, can be tremendous. It would be highly beneficial to these patients to develop effective medical therapies that would work together well with surgery, with the goal of reducing the number of times the disease reoccurs. Use of Cidofovir injection may represent such an effective medical therapy, but a controlled study is required to determine its usefulness.

At the University of Wisconsin Hospital and Clinics in Madison Wisconsin, we are nearing the end of a placebo controlled study evaluating the effects of cidofovir on laryngeal papilloma in both children and adults. Briefly, our patients are randomized into either a treatment (Cidofovir injection) or a placebo group. A placebo is a solution that resembles the drug but contains no active medication and is used in an experiment as a control. Assignment to either the treatment or placebo groups is done randomly, in a similar way as tossing a coin. The concentration of cidofovir that we are injecting is 5 mg/mL. The following measures are made at each of 6 data collection time points, over the course of one year: (1) tumor load, based upon a published staging system for papilloma, (2) degree of respiratory obstruction for phonation, as assessed by phonation threshold pressures (PTP), and (3) general health, on validated health inventories (SF12 and Voice Handicap Index (VHI) for adults; Peds QL for children) and via measures of height, weight and days absent from school or daycare, where applicable, for children. A repeated measures analysis will allow examination of time by treatment interactions to determine if the Cidofovir injectiongroup has fewer or less severe, recurrences than the placebo group.

At the completion of our study we hope to answer the following questions in this investigation:

Does cidofovir injectionreduce the frequency of RRP recurrences?

Does cidofovir injectionreduce the magnitude of RRP, as assessed with a proposed staging system for RRP (Derkay et al., 1998) and measures of phonatory threshold pressure?

Does cidofovir injectionimprove general health, as assessed by height, weight and days absent from school in pediatric patients and health inventories (general health and voice-related) in children and adults?

Currently, we have 16 patients enrolled in this study. Thirteen patients have completed the year of study, and 3 patients are currently participating. There have been no serious adverse events or deleterious effects as a result of study participation this year.

Because this study includes a placebo control, we are confident that we will be able to add meaningful information regarding the efficacy of cidofovir in the treatment of RRP.

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Clinical Research Study in Pediatric Recurrent Respiratory Papillomatosis (RRP) using aVaccine for HPV
HspE& Update

A Phase II clinical trial, conducted by Stressgen BioTechnologies, involving children with Recurrent Respiratory Papillomatosis (RRP), using the immunotherapeutic vaccine, HspE7, has been completed There continues to be some increase in the number of patients having achieved a doubling in their surgical interval with longer follow-ups. A copy of the full poster presented at the International HPV meeting held in Mexico City is available from the Stressgen website or at:

http://www.rrpf.org/rrpf/therapies/HspE7_HPV2004_Final.pdf

The following excerpts from a Stressgen press release provide updated information since earlier result reports in June and September 2003.

STRESSGEN REPORTS HSPE7 RESULTS FROM

TWO CLINICAL TRIALS

FOR IMMEDIATE RELEASE February 24, 2004

San Diego, California USA – Stressgen announced today the results from two clinical trials for its lead compound, HspE7. The trials were designed to confirm previous results and primary endpoints for future Phase III pivotal trials. The Company reported that its Phase II trial for recurrent respiratory papillomatosis (RRP) showed high statistical significance in its primary endpoint of lengthening the interval between surgeries. Stressgen has been pursuing RRP as its primary strategic focus and first indication for HspE7 since interim results were first available in early 2003, and plans to file a Biologics License Application for RRP in mid-2007. The Company also reported that its clinical trial for anal dysplasia showed a treatment effect. Although the secondary endpoints of physician’s global assessment for anal dysplasia and a subset of patients with concomitant genital warts reached statistical significance, the trial did not meet its primary pathology endpoint. Twenty-eight percent of the time there was a disagreement, or discordance, in the results of the adjudicated read process among the pathologists reading the biopsies to determine whether the dysplasia downgraded from high grade to low grade or no dysplasia. In the adjudicated read process, if two pathologists disagreed on the level of dysplasia, a third pathologist arbitrated. The difficulty in obtaining consensus suggests caution in the design of any pivotal Phase III dysplasia trial with a pathological endpoint.

RRP Clinical Trial Results:

The Company reported that its Phase II clinical trial testing HspE7 in the treatment of patients with RRP met its targeted primary endpoint of lengthening the time between surgeries following treatment with HspE7. These results were highly statistically significant and support Stressgen’s plans to begin a pivotal trial and submit a Biologics License Application for RRP as the first indication for the Company’s lead product, HspE7 in mid-2007. The RRP study was a 27 patient single arm, open label trial evaluating the length of time between surgeries following treatment with HspE7; the comparison for each patient was the baseline inter-surgical interval established during the months preceding treatment. In the overall population, the first post-treatment interval increased 93 percent over baseline (p<0.02). The median of all post-treatment inter-surgical intervals compared to pretreatment increased 107.6 days, as compared to 55.3 days at baseline, representing a mean increase of 95 percent. This increase is statistically significant (p<0.02). The annualized surgical rate was reduced significantly (p<0.003). In addition, the median interval of all surgeries reported following treatment suggests that the 27 child patient population experienced 87 fewer surgeries during the first year post treatment. A standard clinical assessment tool, the Derkay-Coltrera Scale Score, adjusted for interval between surgeries, is a measure of the growth rate of RRP. The children in this study showed a statistically significant decreased Derkay-Coltera Score by the end of the study (p<0.04). Final data from the Company’s Phase II clinical trial with HspE7 to treat will be presented as a “late breaker” oral presentation in the plenary session on February 26 at the 21st International Conference on Papillomavirus to be held in Mexico City, Mexico.

"As a surgeon who treats these sick children with RRP, I find a 95 percent mean increase in the interval between surgeries to be very encouraging," said Craig Derkay M.D., Professor of Otolaryngology and Pediatrics at Eastern Virginia Medical School in Norfolk, Virginia, and a leading investigator in the study. "Equally remarkable are the several children with very long surgery-free periods. If these results are confirmed in a Phase III trial, HspE7 could be the breakthrough we have been waiting for in the treatment of these children."

HspE7 is produced by Stressgen BioTechnologies

Stressgen Contact Information:

www.stressgen.com CanadianOffice: Jennifer Matterson

Communications Coordinator

350-4243 Glanford Avenue

Victoria, BC CANADA V8Z 4B9

Tel: 250/744-2811

Fax: 250/744-3331

jmatterson@stressgen.com Principal Executive Office:

Donna Slade

Director, Investor Relations

6055 Lusk Boulevard

San Diego, CA USA 92121

Tel: 858/202-4900

Dir: 858/202-4945

Fax: 858/450-6849

dslade@stressgen.com

On April 19, 2004,

On April 25, 2004,

An(old)RRP parent

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

BioResponse Spring 2004 Update for Phytosorb DIM^Ò products

On April 19, 2004,

On April 25, 2004,

An(old)RRP parent

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

BioResponse Spring 2004 Update for Phytosorb DIMÒ products

or send a check to the
RRP Foundation

BioResponse Spring 2004 Update for Phytosorb DIM^Ò products