Vol.8 No.1 An RRP Foundation Publication 1999 Spring
P.O Box 6643, Lawrenceville, NJ 08648-0643
 
 

__________________________________________________________________________________________________________
 
 

Contents
 
 

ï Opening Comments - p. 1

ï RRPF Organization Information - p. 2

ï RRP Remission and Network News - p. 2-3

ï RRP Web News - p. 3

ï RRP Patient Stats - p. 3-4

Estimating Lifetime Surgeries - p. 3-4

ï RRP Registry - p. 4

ï Highlights of the HPV International Conference - p. 5-6

RRP Foundation Support Meeting - p. 5

Scientific Session Summaries - p. 5-6

ï Adjunct Therapies & Protocol Update - p. 6-9

Interferon Efficacy and Brands of Interferon - p. 6

Cidofovir Update: Multi-center Clinical Trial - p. 7

I3C/DIM Update - p. 7-8

HPV International Conference: Adjunct therapies - p. 8-9

Cidofovir General Discussion - p. 8

Ribavirin - p. 8

Photo Dynamic Therapy - p. 9

Indole-3-Carbinol and RRP - p. 9

ï Research Activities Update - p. 9

Predicting the Behavior of RRP: Clinical Study - p. 9

Coordination of Research Pulmonary Papillomas - p. 9

ï Patient Profile - p. 10

ï Memorials - p. 10

ï RRPF Mission Statement

ï Information/Support Centers, subscription form
 
 

From the Editor
 
 

This issue of the RRP Newsletter is dedicated to RRP patients, Tom McGrane, Jennifer Nicosia and Eric Skerlak, who were members of our support group. All three died of complications associated with pulmonary papillomas. Short memorials can be found on page 10.
 

During the month of January, the 17Th Annual International Papillomavirus Conference was held in Charleston, S.C. During the conference, I had the opportunity to meet other patients and families of patients who suffer with this disease. For me, it was the first opportunity to meet other patients as well as their families. It was a very eye opening experience sharing with others the common ground and experiences of RRP. Perhaps one of the most beneficial items was knowing that we are not alone in the world with this disease. It is also quite encouraging to see as many doctors and others who are involved in the fight against RRP.

This issue of the newsletter has a great deal of information that was presented at the 17Th Annual International Papillomavirus Conference. As a patient, progress can seem slow in the making, however, as you will see in this newsletter, there are many studies going on as well as collaboration on adjunct therapies. While a cure is the ultimate goal, there are a number of treatment options that are offering some potential relief and encouragement in fighting this disease.

I would like to personally thank Bill Stern, JoEllen Bender, Caroline Dugger and Renee Randall as a great deal of the content of this newsletter came from their summaries of the conference.
 
 

Chris J. Neuberger

(405) 749-8499;

Email: Cneuberger@horizonfleet.com
 
 

P.S. Thanks to Lindsay and her friends Sara, Megan, Allison, Sadie and Katie who helped stamp, address and stuff these newsletter mailing envelopes.
 
 
 
 

We are most grateful to all those individuals, medical professionals and corporations who have supported the RRPF. Although it is impossible to publish the names of all that contribute, we extend our sincere thanks to everyone who has supported our efforts.

Future donations from individuals, professionals or from the business community will be very much appreciated. Tax deductible contributions may be made to:
 
 

RRP Foundation
P.O. Box 6643
Lawrenceville, NJ 08648-0643

Do you donate to the United Way through your employer? You can select a "Donor Choice" option which would allow you to direct a donation to the RRPF as the 501 (c) (3) of your choice.

We would like to take this opportunity to acknowledge the friends and families of Tom McGrane, Jennifer Nicosia and Eric Skerlak, who were most generous in their memorial donations.
 
 

To physicians and nurses: Please distribute copies of this newsletter to your RRP patients.
If you are not registered with the RRPF, please do so by completing the Practitioner Questionnaire enclosed.
 
 

RRPF Officers, Directors & Advisors
 
 

Marlene Stern
President
P.O. Box 6643
Lawrenceville, NJ 08648-0643
(609) 530-1443
marlenelin@aol.com

Bill Stern
Treasurer and Director
P.O. Box 6643
Lawrenceville, NJ 08648-0643
(609) 530-1443
bills@rrpf.org

Henry Woo, Esq. 
Secretary
Medtronic International Inc.
Suite 2002, C.C. Wu Building
308 Hennessey Rd.
Wanchai
Hong Kong
henry.woo@medtronic.com

Diane Burke, RN 
Director
Department of Otolaryngology
The Univ. of Iowa Hospitals and Clinics
E230 GH, 200 Hawkins Drive
Iowa City, IA 52242
(319) 356-1765
diane-burke@uiowa.edu

Susan Woo
Director
101 Repulse Bay Road
Apt. A3/1St floor
Hong Kong
852-2812-7379
writeus@netvigator.com

[Please see the support center web page 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, ChildrenÇs Hospital of Philadelphia

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 Boston (Off-site) Medical Ctr.

The RRPF produces two publications semi-annually, 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 and advocacy.
 
 
 

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

RRP Remission News
 
 

By Patti Mandl, Marlene and Bill Stern
 
 

These very brief patient profiles are intended to let you know that some of those with RRP are doing quite well.

Eight year old Alex from Nevada has now been in remission for nearly 3 1/2 years. His early surgeries after he was first diagnosed (at 18 months) were at approximately 3-4 week intervals. Alex went into remission without the help of any adjunct treatments, only laser surgeries, love and prayers. [ You can see a picture of Alex included in the RRPF website gallery - http://www.rrpf.org]

Eight year old Jessica from Kansas has been in remission since late 1996, shortly after she began treatments with Accutane. Before that time, since her diagnosis in the mid 1993 she had had about 20 surgeries.

Ten year old Christie from Florida has now been in remission since June of 1998. Since diagnosis at age 2 1/2, she has had between 50 and 60 surgeries. Her surgeon believes that her remission may be the result of painting her larynx with podophyllum after each surgery. According to Christie's mom, you will be able to see a picture of Christie in the June issue of Glamour magazine.

Thirty-two year old Joe from Ohio, has not had a recurrence of respiratory papillomas since May 1997. He was diagnosed in September of 1994 and was having surgery about every 3-4 weeks for a period of time after that. Joe tried I3C and also PDT with no response. In April of 1997 he traveled to Denver, Colorado to have a mumps vaccine treatment from Dr. Nigel Pashley . He had a second treatment in May of 1997 and has been in remission ever since.

Arthur from California, age 58, has now been in remission since early in 1998. In July 1997 Arthur was treated with PhotoDynamic Therapy, using mTHPC. Prior to that he had over 30 surgeries in a ten-year period.

Others still in remission include: Seven and a half year old Ariel from California; Steph from Florida, age 26; Jeff from Illinois, age 51; William from Illinois, at age 74; Eleven year old Anthony from Kentucky; Andrea age 32 from Louisiana; Cara from Michigan at age 16; Emily from Michigan, now 10 1/2 years old; Leah from New Hampshire, age 19; Lindsay from New Jersey, now 9 1/2; Julie from New York, who is now 21; 5 1/2 year old Rita from Pennsylvania; Ralph from Pennsylvania at age 72; Kaitlyn from Tennessee, now 6 1/2; and Smokey from Virginia, age 27. [ Note: Several people who appeared in the Fall 98 Remission News are not currently listed because we were not able to contact them.]
 
 

RRP Network News
 
 

Our international support network has grown to approximately 450 respiratory papilloma families. Patients range in age from about 2 to 84 years and are located in 44 states, the District of Columbia, three Canadian provinces, the United Kingdom, Spain, Macedonia, Croatia, Morocco, India, Israel, Chile, Hong Kong, Brunei and Australia.

Our thanks to all who have taken the time to fill out the RRPF Patient/Therapy Survey. Please note the additional questions regarding adjunct therapy side effects. Also there is a box near the top of the front side which, when checked, will alert us to an address change; there is 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 fill out the form enclosed. If you have previously filled out a questionnaire, you need only identify yourself, mark UPDATE along the top front of the form and answer only those questions where you have new or updated information to provide. Please return the surveys to Marlene and Bill Stern. (See "RRP Web News" article below for information on completing and submitting surveys via the World Wide Web) In addition, RRP families, please review the Patient Directory listings and notify us regarding any corrections, omissions or additions. If you are not included in the directory and would like to be (or vice versa), please notify Bill or Marlene Stern.

....................................................................................
 
 

Information exchange throughout the support group and the RRP community remains a primary focus of the RRP Foundation (RRPF). In this regard, we very much encourage the use of the Internet and World Wide Web (WWW) as an effective and efficient means of disseminating, sharing and collecting information throughout the RRP community.

The RRPF maintains e-mail lists and a website with a new easier to locate URL address, i.e., http://www.rrpf.org. We have a "Bulletin Board" page for posting announcements and happenings relevant to the RRP community, so if you have an announcement related to RRP, please let us know about it by e-mailing us (see page 2 for addresses). Some additional features include: 1) the capability of filling out and submitting the RRPF Patient/Therapy Survey 2) an expanded library of RRP Newsletter and RRP Reference Service back issues; 3) a Q&A with RRP Experts section which allows members of the RRP community to have questions and comments posted with responses posted from a variety of RRP experts; 4) a Gallery of RRP Patients - if you want others to see what you look like, e-mail us a GIF or JPEG picture file. Via e-mail and the website headlines/bulletin board, we will keep you informed of any new features. Links are maintained with other sites relevant to RRP, including the RRP Website and the website of the ALPF.

If you have some experience/expertise with the WWW and would like to help us improve our website, please contact Bill Stern.
 
 

RRP Patient Stats
 
 

[In this issue we will be publishing a special article on estimation of the number of lifetime surgeries for RRP patients, based on statistics from the RRPF database. A general updating of RRP patient statistics will be deferred until the Fall 99 issue]

RRP is characterized by significant morbidity with the need for repeated surgeries. An ability to make an estimate of "lifetime" surgeries that an RRP patient might anticipate, would be a useful part of the disease prognosis process. Unfortunately, this is extremely difficult to do for any individual patient, as there is great variability in the frequency of these surgical procedures especially among juvenile onset RRP (JORRP) patients (see fig. 1, p. 5, Fall 98 RRP Newsletter, hereafter referred to as F98f1).

The data used in this study comes from the RRP Foundation patient database (Shah et al., 1998). In particular, 197 RRP patients or parents have provided information regarding total surgical procedures, diagnosis age and birthdate as part of the RRPF patient questionnaire forms. From F98f1 there is a suggestion that those most likely to experience a large number of lifetime surgeries would be JORRP patients who are diagnosed in the first few years of life, while those diagnosed as adults (AORRP) might anticipate significantly fewer surgeries. However, because F98f1 includes patients who have had RRP from less than 1 to over 60 years, it is virtually impossible to obtain a statistical estimate of lifetime surgeries from this diagram alone.

The procedure used for estimating lifetime surgeries in this report is as follows: 1) Separate estimates will be made for AORRP and those with JORRP. 2) The JORRP and AORRP groups are each binned into 5 sub-groups based on years with RRP, i.e., >0, >5, >10, >15, >20. 3) The mean and 95% confidence intervals are computed for total surgeries in each sub-group, assuming that they are part of a population that is normally distributed. These data are plotted in figures 1a and 1b for JORRP and AORRP respectively, with sample sizes for each sub-grouping indicated in brackets. In figure 1a it is seen that for those with more than 10 years of JORRP, the mean number of expected lifetime surgeries appears to be asymptoting to about 80, with a 95% confidence range of 60 to 100. For AORRP (figure 1b) a nice convergence in the mean number of surgeries is not as evident as time with RRP increases, but it still suggests a mean number of expected lifetime surgeries of 20-25 within a range of about 13 to 35.

Caution is urged in using this statistical information to attempt to predict the number of expected surgeries for an individual RRP patient, as each case is somewhat unique. However, this information could be beneficial for providing a priori public health cost estimates associated with RRP including cost benefit analyses of this disease.
 
 

Fig. 1a. JORRP total number of surgeries versus years with RRP.
 
 
 
 

Fig. 1b. AORRP total number of surgeries versus years with RRP.
 
 
 
 
 
 
 
 

RRP Registry
 
 

The table that follows summarizes information obtained by the Centers for Disease Control and Prevention (CDC) for their RRP National Registry. Site coordinators at 22 medical centers have submitted data on children with active RRP aged 17 years and younger. As of April 26, 1999 there were 459 children in the registry.
 

* Centers for Disease Control and Prevention
Mail Stop A-15, 1600 Clifton Road, NE..
Atlanta, GA 30333
(404) 639-4400
 
 

Lori Armstrong has announced, effective May 10, 1999, that she will begin a new position in the Division of Cancer at CDC. Katherine Swanson, an MPH student from Emory University, will replace Lori.

We would like to welcome Katherine, as we thank Lori for her fine work with the RRP Registry and wish her well in her new endeavors.
 
 

The 17Th International HPV Conference was held in Charleston, SC from 9-15 January, 1999. There were 18 patients/family members who attended. All of the attendees indicated that they appreciated the opportunity to meet other RRP patients and families, face to face, and hear about the issues and emotions that they have faced in dealing with this disease. It was clearly a positive experience to be among other people who could understand what RRP can do to your life. Most RRP family members welcomed the opportunity to meet with RRP doctors outside of the office environment. Another major highlight, from the RRP perspective, was the 1 1/2 hour scientific session devoted to RRP. We believe it was the first time RRP was exclusively scheduled as part of the HPV conference.
 
 

Sunday morning the RRPF held a meeting that was attended by about 13 doctors and/or researchers in addition to all 18 RRP patients/parents. Each of the patients or a parent of a patient introduced themselves and told a brief history of their respective disease experience. Caroline Dugger, who was the only one in attendance with a tracheostomy, brought along draft copies of her book, " A tracheostomeeÇs guide to care and well being".

Dr. David Bishai, a health economist from Johns Hopkins who is quite interested in the economic impact of RRP, asked about the costs of living with the disease as well as the pain and other issues of coping. Some of the patients expressed some of the cost issues in terms of lost time at work, forced retirement for one person as well as some stories of those with jobs that are very flexible in terms of taking time off to handle treatment of RRP. With regard to pain, most patients and parents indicated that it was not a significant factor.

Other discussion issues included the fears of dealing with RRP. Some parents of RRP children mentioned that fear of surgery was a major problem. Some of the patients expressed that it is harder to recover from surgery as an adult, while others were intimidated by the IV. Other issues included a discussion as to when should a patient be operated on and who should be the judge. Some folks believe in delaying surgery as long as possible, while others feel it is appropriate to have surgery sooner than later since it shortens the recovery time. The fear of a fire related to the laser igniting the endotracheal tube was raised by one adult patient. According to Dr. Mark Shikowitz, of L.I.J., todayÇs technology makes this virtually impossible. He also stated that if a patientÇs anesthesiologist is not using some of the newer techniques, he will be happy to have his anesthesiologist discuss this with them.

There was a brief discussion with regard to the ability to "cough off papilloma", especially in the case of some patients with tracheostomies. Most doctors seemed skeptical.

There was a discussion regarding the value of specifically typing the papilloma. By knowing the specific HPV types, it was suggested that it might be possible to identify those patients who might be more likely to have aggressive disease.

One doctor suggested that with the current turmoil of the insurance system and HMOÇs refusing care to some patients, that it might be better to leave the typing unknown. Thereby, providing fewer reasons to exclude a patient from insurance coverage. On the other hand it was suggested by at least one researcher, that knowledge of the specific types could lead to more effective treatment options.

Some patients expressed some frustration with the time and process of getting certain therapies approved. Dr. Jerome Thompson, from the University of Tennessee, explained the reasoning behind the stringent requirements and what the medical community is looking for. The point of his discussion was to point out that it is only through stringent standards of trials do we get improved medical procedures vs. therapies that are not successful. While this may be frustrating to us a patients, it is ultimately in the best interest of all.
 
 

Following the RRP support group meeting, the conference held a scientific session dedicated exclusively to RRP. This session on RRP began with an introductory clinical description of the disease by Dr. Haskins Kashima, from Johns Hopkins. The presentations were divided into two groups. The first part focused mainly on epidemiological aspects of the disease and was chaired by Dr. Bettie Steinberg, from L.I.J. Dr. Kashima chaired the second group of presentations which dealt mostly with RRP therapies and treatments. Summaries of the therapy discussions can be found under the heading Adjunct Therapies, later in the newsletter.

Bill Stern of the RRP Foundation, opened the presentations with a talk about the major impacts of RRP on the lives of patients and their families. The disease can be life threatening and is often characterized by great morbidity. Nearly everyone with RRP experiences a degree of voice disorder. Some so severe that they have virtually no voice, others are only slightly affected. Perhaps the most relentless aspect of this disease is the need for repeated surgeries. A chart of the total number of surgeries for 17 juvenile onset patients with RRP (JORRP) for more than ten years (mean disease duration was 32 years, with a range from 14.5 - 62 years) indicated a mean of 89 surgeries with 95% confidence interval of + or - 33. Perhaps the most life threatening aspect of RRP was the spread of the disease to the lungs, which occurred in about 5% of the cases according the RRPF data.

Dr. Lori Armstrong from the Centers for Disease Control, followed with a presentation of the initial results from their JORRP registry. Data has been collected from 21 medical centers (at the time of the conference) nationally for active cases of RRP in children up to the age of 17.

Dr. David Bishai from Johns Hopkins, presented preliminary results of a cost benefit analysis of preventing JORRP. The purpose being to quantify the cost of doing, or not doing a cesarean section (CS). The study looks at the medical costs of CS and medical costs associated with JORRP and makes an assumption of a mean of about 20 lifetime surgeries for JORRP patients. In summary, based on a variety of assumptions (including cost of pain and suffering to patients and parents ), even with an efficacy as low as 50 CS to prevent one case of JORRP, the value of the social benefit of JORRP prevention would outweigh the cost associated with necessary CS.

Dr. Keerti Shah from Johns Hopkins, discussed the risk factors for JORRP and the rationale for a multi-center study. Key points he outlined are as follows:

JORRP is preventable, since we are confident that in most cases transmission of HPV-6 or HPV-11 occurs in the infected maternal genital tract. In this regard it is quite similar in transmission of herpes. He speculates that the chances of developing RRP in a child born to "high risk" mothers presenting is about 1 in 35. A general population risk is estimated at about 1 in 3,500. At present there are no guidelines on how JORRP might be prevented. In order to help establish some guidelines, a randomized trial is proposed to follow condylomatous mothers for five years (since 75% of all cases present within five years). If a formal trial is not possible, "we can at least observe". It does appear that CS would prevent 90% of all cases.

[The remaining issues during this conference session dealt with adjunct therapies and can be found under the heading Adjunct Therapies, later in the newsletter.]

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Adjunct Therapy and Protocol Update
 
 

The following reports of statistics and clinical research involving RRP therapies, represents a best effort by the RRPF to make an accurate and objective presentation of information obtained from a variety of sources. The RRPF does not endorse any particular product but will make suggestions when deemed appropriate.

[Support network adjunct therapy statistics will next be updated in the Fall 99 RRP Newsletter issue - see the Fall 98 issue for previous statistics.]
 
 

It has been suggested that there might be a substantial difference in the effectiveness of two types of interferon due to the formation of neutralizing antibodies. Specifically, evidence that a much higher percentage of patients (Leukemia and Hepatitis C) being treated with Roferon-A developed neutralizing antibodies than those being treated with Intron-A. (It should be noted that Roche has produced a reformulated Roferon after 1996. It is not yet known whether this new Roferon has less of a tendency to develop neutralizing antibodies). Thus far we cannot see this impact in data reported to the RRPF. Of 43 patients indicating on their RRPF surveys that they are using or have used interferon regularly, 17 treatments with brands have been reported (see table 1). Furthermore, in a careful reading of the Leventhal et al., 1991 article, detailing the Johns Hopkins 66 patient interferon study for RRP patients, it is evident that they were concerned about the possibility that neutralizing antibodies might result in a loss of effectiveness, however, in this study the presence of neutralizing anti-bodies did not appear to have a significant impact.
 
 

Table 1: Interferon Efficacy vs. brands from RRPF Database
 

Brands	Treatments Reported		Complete Response	Partial Response	No Response
Intron	9	0		6	3
Roferon	4	0		3	1
Alferon	1	1		0	0
Wellferon	3	0		2	1

We asked an expert on interferon and HPV, Dr. William Bonnez from the University of Rochester, for his comments on neutralizing antibodies and interferon, the following is an excerpt of some of his comments:

"...These neutralizing antibodies appear to have an adverse effect on in vivo interferon activity. Several reports have indicated that the presence of interferon neutralizing antibodies was associated with treatment failure (e.g., multiple sclerosis and interferon beta, hepatitis C and interferon alpha,...) and that the administration of a different interferon, typically a natural interferon alpha, could overcome treatment resistance (this has been shown in the case of hepatitis C). Natural interferon alpha is constituted by several species of interferon molecules. Antibodies directed to one species, e.g. alpha-2, do not seem to cross-react with another species, e.g. alpha-1. This is why presumably natural alpha interferon retain most of its efficacy..."

"... I have been involved in the only three studies that have looked comparatively at the efficacy of different interferons, either intralesionally or systemically administered, for the treatment of genital warts ...We did not observe any differences in efficacy, or lack thereof, among interferon preparations..."

"... However, if in a given patient one observes there is lack of clinical efficacy, I think it would then be appropriate to try a different interferon preparation, preferably moving from a recombinant interferon to a natural interferon..."

Based on Dr. Bonnez's comments, it is somewhat surprising that most RRP patients being treated with interferon are not using a natural product. In this regard, Alferon (a human leukocyte derived alfa-n3 interferon produced by Interferon Sciences) , is readily available. In addition, it is approved for treating genital HPV and is very similar to the interferon used in the Cuban national study involving 125 RRP patients (Deunas et al., 1997), which showed significant efficacy.

Although there has been some differing opinions between the RRPF and the RRP Website (and in scientific literature) regarding the extent to which neutralizing antibodies may impact the efficacy of some interferon products, both organizations currently see Alferon as a potentially promising interferon product for the treatment of RRP.

*[A more complete report on interferon is available from the RRPF website at: http://www.rrpf.org/rrpf/therapies/Interferon.htm ]
 
 

Update on Cidofovir
 
 

In 1997 a research group from Belgium reported (Wellens et at., Proceedings of the XVI World Congress of Otorhinolaryngology Head and Neck Surgery, Sydney, Australia) on the treatment of 17 RRP patients (mostly adults) using cidofovir (also known as HPMPC). The procedure involved intralesional injections during laser surgery. After follow up periods ranging from 2 to 27 months, it was reported that 13 of the 17 patients were in remission.

Based on these early encouraging results a clinical trial is being proposed in the U.S. It will be a Phase I/II mulit-centered trial sponsored by the NIH/NIAID Collaborative Anti-viral Study Group (CASG). The purpose of this study is to define the safety of cidofovir infiltration of laryngeal lesions following debulking. Enrollment in this dose escalating, double blind study will be offered to pediatric RRP patients with aggressive disease, meeting strict eligibility requirements.

If you are interested in obtaining additional details of this proposed study, it is suggested that attending physicians contact:

David Kimberlin, MD or
Jan Kiell, RN
205-934-5316, 205-939-9595
Fax: 205-934-8559

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I3C / DIM - Update
 
 

For background information about the impact of indole-3-carbinol (I3C) 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 for DIM, as well as Bradlow et al., 1996 J. of Endocrinology 150, S259-S265; Newfield et al., 1993, Anticancer Research 13, 337-342. Much of this information is also available from the RRPF website at: http://www.rrpf.org/rrpf/therapies/I3C_DIM.htm.
 
 

[ The following article on I3C stability contains excerpts from a joint cautionary statement by the RRP Website and the RRPF
(see -http://www.rrpf.org/rrpf/RRPF_bulletin.htm#I3C_announce for more details) ]

I3C is reportedly very unstable when exposed to heat and light, and concern has been expressed in scientific literature about some of its condensation products when it breaks down. We have recently learned that Theranaturals is currently shipping I3C that was made about a year ago and reportedly has no plans to make up any new batch for at least another 6 months. Theranaturals states that it has reviewed the scientific literature and believes that I3C is stable for up to two years when stored in an air filled bottle and when stored away from light in an air conditioned environment. [Note that Sigma, which distributes a highly purified I3C (mostly for experimental animal studies), considers the product so unstable that it stores it under argon gas at 2-8 degree C (refrigeration).]

We have had samples from a recently acquired bottle of Theranaturals I3C analyzed by mass spectroscopy. Analysis results do indicate that the product is still mostly I3C (excluding insoluble filler). Given I3C's known instability this result was somewhat surprising to us. We still have unanswered questions relative to the test results and the testing process (see below) If you are currently taking the Theranaturals product with positive results, we suggest that you continue using the product. We are also suggesting the possibility of a combined therapy approach. (A number of patients in the RRP community are successfully following a regimen of using both I3C and DIM/Indoleplex on alternate days.)

Although our two tests suggest that the Theranaturals I3C product does not appear to be degraded, it is not clear whether the analyses by mass spectroscopy are capable of identifying and resolving all trace condensation by-products, some of which might be problematic. We will continue to investigate these issues. Further discussion is needed with those responsible for the two tests conducted thus far, and we may be submitting other samples of the Theranaturals product for more testing. We strongly encourage Theranaturals to produce I3C on a much more frequent basis to better assure the full potency and purity of their product.
 
 

This study is now over four years old and clinically, we have seen very good responses to I3C and no toxicity. We are presently finalizing all data in order to submit the results to a medical journal. At present, we are missing 40% of the patient group due to "lost to follow up". This is skewing the data because most likely only responder patients have kept in contact. We are looking for all people even remotely involved in the study.

If you were involved in this study in any way, please contact the following individual:

Jamie Osborne
412-647-8094
osborne@unix.cis.pitt.edu

The RRPF continues to encourage research studies involving I3C as an RRP adjunct therapy. In this regard we suggest that those patients who are interested in I3C as an adjunct treatment for RRP become part of a clinical trial. For those who are unable to participate in an I3C trial, but who would like to pursue this therapy on their own, we have been providing information regarding how and where to get I3C and how much to take. In addition, we continue to supply urine analysis testing information and supplies to RRP patients upon request. Thus far we have had requests for and have mailed out approximately 100 test kits. Along with the kits detailed instructions are included for collecting urine samples and sending them to Strang Cancer Prevention Center for analysis. In this regard we ask for your patience. These analyses are being performed as part of a research program by a limited number of scientists who depend on various funding sources to cover laboratory expenses. The RRPF will continue to assist their efforts.

Indolplex TM products containing DIM are available from:

BioResponse
L.L.C. at P.O. Box 288
Boulder, CO 80306 (303) 447-3841
Email at zeligsmd@sni.net

Indolplex is available in two forms:

Important: For this pricing you must let Theranaturals know that you are an RRP patient/family and they will assign you a special customer number.

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 (Please consult your doctor)

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 meal time. 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 (Indolplex) 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:
ï Occasional gastro-intestinal upset.
ï A couple of instances of dizziness
ï Some speculation that I3C/DIM might affect bone density (see RRP Newsletter - Fall 98)

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Adjunct Therapy Presentations and Discussions from the International Papillomavirus Conference-1999
 
 

A discussion during the RRP Foundation Support Net meeting, led by David Kimberlin, MD, David Malis, MD and Dr. Tom Broker centered on recent developments utilizing cidofovir as well as a general discussion of how cidofovir works. In particular, cidofovir is absorbed by the host cell, which converts into an agent that kills cells which have HPV in it. It is essentially not absorbed by non HPV cells. This is called a pro-drug, which converts into an active drug. The selectivity is quite remarkable, such that, there is three orders of magnitude more absorption in papilloma cells vs. non disease cells. Thus it is speculated that this conversion to an active form will take place only in cells that have active HPV. It is also worth noting, that Dr. Broker feels that this is a very promising drug and the trials will tell us much more.
 
 

Results from a double blind, crossover clinical trial using Ribavirin for the treatment of RRP were presented. Positive preliminary results involving Ribavirin as an adjunct for RRP had been established in animal studies and in a small uncontrolled pilot study involving human patients. This was a very well designed study, which was tightly controlled. Despite low enrollment (approx. 10-11 patients), it was possible to show that an increase in the interval between surgeries for those in the group using Ribavirin was statistically significant. Furthermore, while Ribavirin may have an impact in less than six months for some patients, its effect may be delayed or continue beyond its administration period for others.
 
 

There are currently 16 patients enrolled in this protocol, 7 juvenile and 9 adults. At this time 8 patients have been studied long enough (defined as at least 12 months after treatment) to draw some preliminary conclusions. Five are said to be free from disease and two others have shown marked improvement. Improvement was not immediate, but rather, there appears to be a lag response. All patients continue to show disease at 3 months after treatment, with significant improvement occurring at 6 or 9 months post PDT. The new PDT keeps the patient light sensitive for 2-3 weeks vs. the older drug which was often 2-3 months.
 
 

This presentation outlined how estrogen plays at least a partial role in the susceptibility of the larynx to HPV. Animal models clearly support this. There are two competing estrogen metabolites, i.e. C-2 and C-16a. It was found that 16a hydroxylation was significantly increased in laryngeal papillomas. Dr. Auborn discussed how I3C agents bind the AH receptor which includes 2 hydroxylation. Several clinical studies have since demonstrated this. First in mice and more recently in a human RRP patient trial. Unfortunately, in some patients I3C does not induce 2 hydroxylation. Although it appears quite safe, long term studies of the anti-estrogen I3C, at pharmacological doses are needed. In summary, I3C and newer derivatives continue to show promise in treating papillomavirus induced diseases.

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Research Activities Update
 
 

Despite our understanding of HPV types responsible for the great majority of juvenile-onset RRP, the behavior of this disease in children remains frustratingly unpredictable. As those familiar with this disease can attest, some children with RRP have a relatively benign course, while others have extremely aggressive disease with distal spread and frequent recurrences. At the extreme of this clinical spectrum can lie malignant transformation or even death from uncontrollable disease.

In order to target pediatric patients with RRP at high risk for aggressive disease, investigators have tried to identify individual factors to reliably predict severity of disease. The possible prognostic significance of several markers in papilloma tissue has been reported: as of yet, however, no easily obtainable blood tests have been identified to predict the course of RRP in an individual child.

Cytokines, circulating proteins produced by white blood
cells, have long been know to play critical roles in the bodyÇs disease response. Of special interest in the context of RRP, is the effect of cytokines on tumor growth. Interleukin-2(IL-2) is a key player in the cytokine response and stimulates the proliferation and activation of the bodyÇs T-cells. T-cells may be directed against virus-infected or neoplastic tissue. In this regard, IL-2, may have significant anti papilloma activity.

The predictive role of IL-2 and its soluble receptor, SIL-2R has been investigated in patients with genital HPV-related tumors. An inverse correlation has been reported between IL-2 levels and recurrence rate of genital HPV, and a direct correlation between IL-2R levels and recurrence rate. To date, there have been no studies investigating the predictive value of IL-2 or IL-2R in HPV infection of the upper respiratory tract.

The objective of our study is to determine whether levels of serum IL-2 and IL-2R in patients with RRP have value in predicting the frequency of surgical intervention. Currently, a pilot study is underway at the University of Tennessee comparing our population to a group of age-matched controls.

RRP is an uncommon disease, and the majority of patients who have it are spread throughout the country. Therefore, we are in the process of requesting serum samples from patients with RRP at other centers to assay for interleukin-2 and soluble IL-2 receptor. In this way, we can accumulate a subject population large enough to establish statistical significance. Interested health care providers, families, or patients are encouraged to contact:

Jerome W. Thompson, MD
UTMG Pediatric Otolaryngology
777 Washington Avenue, Suite P110
Memphis, TN 38105-4526
901-572-4400
jwthompson@utmem1.utmem.edu

The untimely deaths of three members of our support network in approximately the past three months has brought a shocking reminder of how RRP can indeed be life threatening. Pulmonary papillomatosis represents one of the great treatment frustrations to the RRP medical community. Although there are a few clinical researchers who have shown an interest in trying to develop treatment protocols for pulmonary papillomas, I am not aware of any coordinated efforts. In this regard, the RRPF is proposing to coordinate information from existing studies involving pulmonary papillomas and encourage ideas for future studies. To date a pulmonary papilloma study group consisting of about a dozen members of the RRP doctor/researcher/patient community has been established.

If you have an interest in pulmonary papillomas and have not been included in the pulmonary papilloma e-mail list, please contact Bill Stern at bills@rrpf.org.
 
 

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Patient Profile
 
 

Writing about my story, I feel like I am writing one of those police dramas I watched as a child. You know the story. Only the details are different. But I am hoping that by sharing the details of my personal story it will make the details of your own story less painful and let you know that you are not alone. We know, we share the same hurts and hopes, and we care.

I was born in Charleston, West Virginia 46 years ago. (I donÇ t mind whispering when it comes to my age! Looking younger is every womanÇs dream.) Everything was fine for the first 18 months of my life. But by then it was obvious that I was losing my voice and having trouble breathing.

My parents began the pilgrimage of taking me from one doctor to another until we finally found an eye, ear, nose, and throat specialist who knew what the problem was. The doctor did not call this RRP. He just said that I had warts on my vocal cords.

That wasnÇt all the excitement I was due for, however! The problem got compounded when I was about 2. The car I was riding in was involved in a car accident and I was left with 50% paralysis on my left side. To this day, I have only partial use of my leg, arm and hand, and eye control on this side.

Over the years, there have been many surgeries for RRP. It has continued to block my airway and put extra strain on the use of my vocal cords. Regular visits to the doctor will always be a part of my life until a cure for this disease is found.

The hardest part of my various disabilities over the years have been the loss of my voice. It might have been comical if it hadnÇt been such a nuisance, when Social Services repeatedly called my parents in to tell them that I needed to see a doctor for my sore throat, or laryngitisÖ I was forced to take speech therapy classes that I didnÇt need because the school system just didnÇt know how else to handle someone with this condition.

When puberty came, some changes that the boys seemed to appreciate came too! Doctors said that puberty would stop the RRP, but that didnÇt happen at that time or later.

Years later, there were short periods of remission from time to time but it was never a permanent remission. Between the age of 30 and 38 I had eight years of relief and life was wonderful.

In January of 1988 my husband had a job transfer, so our family moved to Columbia, South Carolina. I had to have emergency surgery because the RRP growths seemed to start growing at a very rapid pace. Another surgery followed close behind and then another after a couple of months. Surgery throughout the 1990Çs has averaged about once every year or two, with the most recent operation in August 1998.

So that is where I am today. I work as a sales associate in a retail store and must admit it can still be a hassle from time to time as customer after customer asks, "WhatÇs wrong with your voice?" "Do you have laryngitis?" "It hurts my voice to listen to YOURS"! I feel like wearing a button that says, "Yes I always talk this way"! Instead, I just use some humor, I may wink and say,ÖÖ.. "This is my SEXY voice" and let it go with a smile.

IÇve learned that, in no matter what condition you find yourself, whether it is RRP, or paralysis, for that matter, or whatever it may be, you can still have a full and rich life. It can only take control of your life and your emotions if you let it.

So when the 10,000th person asks you, "WhatÇs wrong with your voice?" feel free to use my "sexy voice" line, or some other funny line. It helps.

I know who I am and what I have. I have been married to the same wonderful man for 25 years of ups and downs which are just part of the realities of life. We have three beautiful children (2 sons, 1 daughter), I am also a student in the paralegal program at the local college, and I have RRP. It is just one color in the rainbow that is my life. You may be dealing with RRP, but that is only one small part of the person you are.

As a Christian, I know the LORD gave us the rainbow as a sign of encouragement. I hope that my life will encourage those around you, to face life with courage and joy, whatever the circumstances. Your voice may only be a whisper, but you can still speak in a voice of love that comes out loud and clear from the heart.
 
 

 

In Memory Jennifer Nicosia battled RRP since her diagnosis at 11 months of age. In all she underwent over 150 surgeries. The first evidence of pulmonary papillomas were first noted when Jennifer was nine, but it was in recent years that the papilloma in the lungs progressed significantly. Despite all this she never complained - her courage touched many of us. She passed away in December 1998 at the young age of 25. Jennifer is survived by her parents and a younger sister.     Tom McGrane struggled with pulmonary papillomas for a number of years and had well over a hundred surgeries since he was diagnosed with RRP at the age of 12. Those who knew Tom well said he was kind, uncomplaining and never wanted any special treatment because of his disease. Despite his aggressive disease, Tom was able to pursue a successful career as an attorney for the Attorney General's office in the state of Iowa for 27 years. He passed away in early January 1999 at the age of 58. Tom is survived by his wife, two daughters, one son and a grandchild.     Eric Skerlak endured more than 120 surgeries for RRP, since his diagnosis at the age of 15 months. He had papillomas in his lungs for at least the last 6 1/2 years. Despite his extremely poor lung function, he tried as much as possible to be a normal active boy. At the end of March 1999 he passed away cutting his life terribly short at the age of 17. Eric is survived by his parents and three older sisters. We will miss all three of these courageous members of the RRP community very much.