____________________________________________________________________________________________________
 
 

Contents
 
 

• Opening Comments - p.1
• Special Acknowledgements -p.1
• RRPF Organization Information - p.2

RRPF Publication and Subscription Policy - p.2
• RRP Remission and Network News - p.2-3
• RRP Patient Statistics - p. 3-4
• RRP Registry - p. 4
• RRP Fundraising - p. 4
• Adjunct Therapies and Protocol Update- p.4-5

I3C/DIM Update - p.5-7
Progress with Absorbable DIM - p.5-6
Cidofovir Update - p.7-8
• Research Activities Update - p.8

Pregnancy, Hormones and RRP - p.8
I3C Bone Density Research Study - p.8
• Patient Profile - p.9
• Memorial - p.9
• RRPF Mission

From the Editor
 
 

This issue of the RRP Newsletter is dedicated to RRP patient, Allan Williams, who was a member of our support group. A short memorial can be found on page 8.

Over the past few months, we have seen a great deal of interest relating to two forums now available via the internet. The first area is the new RRP interactive positing board. This interactive part of our website is discussed further in the RRP Web News, and I would highly recommend taking a look at this portion of our website for those that haven't seen it. In addition, over the past few months, Dr. Ed Beck has developed an RRP Listserv, which is a secure web based environment for communicating RRP based information. Both of these new forums offer a great way to communicate and share RRP experiences.

Some of you may have noticed that this edition of the RRP Newsletter has fallen a bit later in the year than normal. While the distribution date of the newsletter is later than normal, we would like to take this opportunity to solicit volunteers who could help support the RRP Foundation. We could use support in database management, data gathering, assisting with articles and general research. If you are interested in assisting in some capacity, please contact Bill Stern.

Chris J. Neuberger

(405) 749-8499

Email: Cneuberger@horizonfleet.com

P.S. Thanks to Lindsay and her friends 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. A few special acknowledgments are listed below. 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.
 

The late Florence M. Fitzner, great aunt of papilloma patient Ariel Bandasch, who was so kind to remember the RRPF in her will.

Ed and Maura Weiner who have so unselfishly raised funds for the RRPF by having a birthday party for Maura and asking for donations to the RRPF in lieu of gifts.

We also thank those at Abbott Labs who have donated to the RRPF through the Abbott Labs Combined Appeal Campaign.
 
 

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 or rrpf@aol.com

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@attmysite.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, Children's 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 Hospital of Boston
 
 
 

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
 

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

The last time four year old Ashlyn, from Colorado had any papilloma removed was Nov 2, 1998, and there were very few. In 97, however, Ashlyn had aggressive RRP and was trached in August of 1997. Her surgical frequency had been 5-7 weeks until she started taking Indolplex in mid-June 98.

Seven year old Sarah from Texas has been in remission since the Spring of this year. Sarah had been on a 5 week surgery schedule until June of 1998 when the growths appeared to slow down. Three weeks before the June 98 surgery she was switched from I3C to Indolplex. Sarah also has been seeing a homeopathic doctor since 1997.

Twelve year old Andy from California had his last surgery on May 3 of this year, but they found no sign of RRP. His doctor attributes this to a combined therapy approach involving Interferon and Acyclovir, plus the fact that he is now approaching puberty.

Julie from Florida is now 25 and, has not had a recurrence of respiratory papillomas since 1985. Between 1976 and 1985 she had approximately 30 surgeries and has not had any adjunct treatments. She is currently in a graduate program studying speech pathology.

Others still in remission include: Eight year old Ariel from California; Christie from Florida now eleven years old; Steph from Florida, age 26; Jeff from Illinois, age 52; William from Illinois, at age 75; Jessica from Kansas who is now nine; Twelve year old Anthony from Kentucky; Cara from Michigan at age 16; Emily from Michigan, now 11 years old; Leah from

New Hampshire, age 19 (she has now been in remission 14 1/2 years) ; Lindsay from New Jersey, now 10; Julie from New York, who is now 22; Joe from Ohio at age 32; Six year old Rita from Pennsylvania; Ralph from Pennsylvania at age 73; Kaitlyn from Tennessee, now seven; and Smokey from Virginia, age 28. [Please let us know if you are in remission, we will happily add your name to our growing list.]
 
 

RRP Network News
 
 

Our international support network has grown to approximately 480 respiratory papilloma families. Patients range in age from about 2 to 84 years and are located in 46 states, the District of Columbia, three Canadian provinces, Australia, Brunei, Chile, Croatia, England, Germany, Hong Kong, India, Israel, Macedonia, Morocco, Spain, Sweden, United Arab Emirates, and Wales.

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 box located near the top of the front side. 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 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 now sponsors an RRP community ListServe which currently has 116 subscribers, including RRP families, doctors and researchers. If you haven't joined yet, please feel free to join by simply sending a blank email to: rrpf-subscribe@egroups.com.

The RRPF website now has 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) On-line submission of the RRPF Patient/Therapy Survey 2) an expanded library of RRP Newsletter and RRP Reference Service back issues; 3) an interactive discussion forum which allows for posting of questions, comments and replies to previous postings. We invite all members of the RRP community (i.e., patients, families, doctors, nurses and researchers) to participate. Occasionally, we have invited "expert" moderators monitor the board.

Via e-mail and the website, 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
 
 

The statistics that follow are based on RRPF 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. In addition to these data, results regarding adjuvant therapies are presented on page 5. Tables 1 - 3 provide a breakdown of the patients in the support group who have reported to us, based on sex and age; the sample sizes range from 379 to 433 for tables 1-3.

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

	Females	Males
All Ages	196	237

 

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

Age Groups	Females	Males	Total
Under 10	71	53	124
10-20	35	38	73
20-30	20	18	38
30-40	23	24	47
40-50	17	34	51
Over 50	11	35	46

 

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

Age Groups	Females	Males	Total
Under 10	132	112	245
10-20	11	6	17
20-30	21	26	47
30-40	6	31	37
40-50	7	25	32
Over 50	4	12	16

Table 4. Distribution of respiratory papilloma sites of involvement based on responses from 236 patients.

respiratory site	no. of patients
above cords	114
at cords	236
below cords	91
tracheal	43
bronchial	20
lung	16

 Table 5. Birth Statistics from Patient Support Network*:

Cesarean birth in 18 cases - 321 responses

juvenile onset: 11 of 198 responses

adult onset: 7 of 123 responses

juvenile onset: 124 of 187 responses

adult onset: 31 of 111 responses

juvenile onset: 39 of 202 responses

adult onset: 3 of 122 responses

Under 20 = 41

20 -> 25 = 53

> 25 = 54

juvenile onset was defined here as diagnosis age <= 14.

Under 20 = 12

20 -> 25 = 26

> 25 = 61

Table 6. Answers to some RRP research questions.

	Was patient nursed? J-O / A-O	Was patient exposed to smoking? J-O / A-O
Yes	49 / 53	53 / 69
No	74 / 44	62 / 29

RRP National Issues
 
 

A number of proposed scientific and clinical studies involving promising therapies for the treatment of RRP are in need of funding. Government agencies are a very significant source of support for these RRP research efforts. In this regard we continue to urge you to contact your congressional representatives and senators to make them aware of RRP and mobilize their support. For names and addresses of specific key governmental officials see the RRP Newsletter Spring 97 issue.

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

A number of people have asked about ways that they could help raise funds for RRP. I am admittedly not very good at fund raising, hence, I would rather defer this issue to others who have much more talent and creativity in fund raising than I. In this regard, Ed Weiner has accepted the role as coordinator of fund raising for the RRP Foundation. He would like to talk and brainstorm with others about ways to raise funds for RRP. He can reached in the evenings at: (703) 691-1922 or by e-mail at: serviceimpact@msn.com.

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

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 September 24, 1999 there were 496 children in the registry.
 

* Centers for Disease Control and Prevention

Mail Stop A-15, 1600 Clifton Road, NE..
Atlanta, GA 30333

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.
 
 

227 RRP patients/families have reported using at least 1 adjunct therapy. Of those responding that they have used adjunct treatments, 127 reported that they have tried only one treatment, 59 have tried two and 41 have reported using three or more treatments. The most reported therapy was I3C/DIM with 152 users and next was interferon (IFN) with 75 users responding. The patient/parent assessed impact of some adjuvant therapies is summarized in the table below. In this table the sample sizes include only the subset of adjunct therapy users who indicated some response to a treatment, either some improvement (Improve) or no impact (None). If some improvement is noted, it is further broken down into either a complete response (Comp, i.e., no new growths seen for at least two typical surgical intervals) or a partial response (Partial).

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.
 
 
 
 

Table 1. Patient/family assessed impact of adjuvant therapies reported.

Therapy	Users	None	Improve	Comp	Partial
I3C/DIM	97	44	53	21	32
IFN	46	18	28	4	24
Acyc	27	17	10	4	6
PDT*	14	10	4	1	3
Ribvrn	3	1	2	0	2
Retin	15	8	7	0	7
Mumps	12	5	7	1	6
Others	16	6	10	3	7

Experimental therapies for which the RRPF has no documented patient supplied statistics:

Cidofovir

Cimetidine (Tagamet)

HPV Vaccines

Omega-3 Fatty Acids (Fish Oil)

Some notes regarding the above table:

The therapies are abbreviated as follows, I3C/DIM = indole-3-carbinol (I3C) or Diindolylmethane (DIM), IFN = interferon, Acyc = acyclovir, PDT = photo dynamic therapy (*thus far only 1 patient has reported who has used the new agent mTHPC and they have indicated a complete response) , Ribvrn = ribavirin, Retin = retinoicacid or accutane, Mumps = mumps vaccine. In the category of other therapies used, improvement has been noted using the following treatments: Echinacea and Thuja (homeopathic anti-virals), a mixture of vitamins including vitamin C and vitamin A, ShapeRite immune formula, topical 5-flourouracil (5FU), bleomycin and cobalt. (Please see the I3C Update in this issue and previous newsletter issues, such as the RRP NewsletterSpring 97 issue regarding side effects for some of these treatments.)

Finally, we continue to remind our readers that these results are based on patient perspectives. Although the survey encourages objectivity and quantitative assessment as much as possible, these analyses cannot replace well designed clinical trials and research. Furthermore, since sample sizes are generally small and no statistical significance tests have been applied to data in the above table, one must interpret these numbers cautiously, especially when considering the natural variability of RRP. However, we do hope that this information can provide some guidance for those patients seeking adjunct therapies as well as those pursuing RRP related research.
 
 

I3C/DIM 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.
 
 

An important step forward in understanding dietary indoles and the importance of DIM was made recently by researchers at the Midwest Research Institute in Kansas City. They reported that in human subjects given 400 mg of I3C as an oral supplement, only DIM and no I3C was subsequently identified in their blood using a highly sensitive detection method (1). This important finding focuses new attention on the importance of DIM as an active principle in the benefits so far attributed to I3C. In a second, more recent report using human liver slices in organ culture, no change in enzyme activity was noted when I3C was added directly to the liver slices. However, a powerful up-regulation of enzymes was seen after addition of DIM (2). These are some of the same enzymes responsible for the beneficial shifts in estrogen metabolism seen with I3C and with DIM from Indolplex.

As you may know, we have managed a development effort that has resulted in production of a proprietary formulation of DIM, which we call Indolplex. Indolplex provides dependable and uniform absorption of pure DIM from capsules and from "Chocolate Sprinkles". Pure DIM in crystalline form is not absorbed based on direct sampling of human blood even after large oral doses. The absorption enhancing processing and formulation developed from Indolplex overcomes the barrier to absorbing DIM and allows for the sustained release of active DIM over a period of 3-4 hours after each dose. This has been consistently seen in all individuals tested, using the same technology employed in the report mentioned above. Testing of human subject's urine, before and after daily supplementation with Indolplex, has shown a beneficial shift in estrogen metabolites favoring 2-hydroxy estrone at a dose of DIM from Indolplex that is one tenth of the lowest active dose of I3C in the same test.

Most encouraging, however, are the number of individuals with RRP who have responded to Indolplex with improvement in symptoms. Over 50 individuals taking Indolplex have now completed a questionnaire after using Indolplex for at least 4 months. The vast majority of respondees reported a beneficial impact with symptom reduction and increasing interval between surgery. 15 individuals who completed the questionnaire had previously tried I3C but did not respond. 10 of these 15 did respond to Indolplex with either symptom reduction or increasing intervals between surgery. Notable among adults completing the questionnaires were two individuals who lengthened surgical intervals from every six months to over a year.

Most encouraging among the responses from parents and children was a report concerning Ashley Lawton, a 4 year old girl, whose history is summarized below with her parent's permission.

Ashley was diagnosed with RRP at 15 months of age. Before starting Indolplex, she had undergone 21 laryngoscopic surgical procedures for recurrent papillomas compromising her airway. Surgical frequency had shortened to every 2 weeks in 1997. During this time, a 6 month trial of I3C failed to produce clinical improvement or a lengthening of the intervals between surgical procedures. Tracheostomy was performed in 1998 to provide a more secure airway. Indolplex (DIM) was begun in June, 1998. Surgical frequency lengthened immediately to 2 months. After 5 months of supplementation, no new papillomas were noted. 14 months past the start of Indolplex, the patient underwent a trachael stenting, tracheostomy removal and was

found to be free of papillomas. While under anesthesia for adenoid surgery last month, her larynx and trachea were examined and found to still be completely free of any papillomas.

Frequently asked questions concerning Indolplex include the following:

Q: Should I take my entire dose of Indolplex at one time?

A: Yes, take the suggested capsules all at once, prior to a small meal. Absorption of Indolplex is further enhanced by taking the pills or sprinkles with a small amount of food.

Q: What is different about I3C and the DIM in Indolplex?

A: The DIM absorbed from Indolplex does not require any digestion to activate the cruciferous indole ingredient. Absorption is dependable and not influenced by antacids or the simultaneous presence of food.

Q: Can I get a questionnaire to complete?

A: Yes, if you have been using Indolplex for at least 4 months, please call (303)-447-3841 and request that a survey be sent to you. For individuals who have already completed the questionnaire, if it has been an additional 4 months, please call in to receive a follow up questionnaire. Upon completion of the confidential survey, you will receive a complementary bottle. Thank you to all of those individuals who continue to help us track your progress with Indolplex.

As always, we are happy to respond to any questions directly via e-mail. Please submit your questions and comments to: zeligsmd@sni.net.

References:

1. Arneson, D.W. , Jurwitz, A., et al., "Presence of 3,3' Diindolylmethane (DIM) in human plasma after oral administration of Indole-3-carbinol (I3C). Proceedings of the American Association for Cancer Research, Vol. 40, Abstract#2833, March 1999.
2. Renwick AB, Mistry H, PT, et al., "Effect of some indole derivatives on xenobiotic metabolism and xenobiotic-induced toxicity in cultured rat liver slices.", Food Chem Toxicol, 37(6):609-18, 1999

Indolplex TM products containing DIM are available from:

BioResponse
L.L.C. at P.O. Box 288
Boulder, CO 80306
Email at zeligsmd@sni.net
303-447-3841 - Telephone; 303-938-8003 - Fax

Indolplex is available in two forms:

1. Indolplex Capsules; 150 mg; 60 capsules per bottle or 75 mg; 90 capsules per bottle.

2. Indolplex 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.
 
 
 

Estimated dosages:
BioResponse has recommended that individuals with RRP choose a daily dose which is close to 4 mg/kg/day. To be close to 4 mg/kg/day a typical man weighing 70-85 kg (where 1 kg.= 2.2 lbs.) would take from 300 to 375 mg per day. A typical woman weighing 60-70 kg would take from 225 to 300 mg per day. The dose of "Sprinkles" can be individualized with each quarter teaspoon being appropriate for each 16 kg of body weight (approximately 35 pounds).

Special Note: Unlike I3C, Indolplex does not require activation by stomach acid. Indolplex can be taken by individuals
who use antacids or H2 blockers like Zantac.

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
http://www.theranaturals.com

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.

Medical Center Compounding Pharmacy
3675 S. Rainbow Blvd, #103
Las Vegas NV 89103
e-mail: mccp@mccpharmacy.com
Tel: 1-800-723-7455
Local: 702-873-8455
Fax: 702-873-6845
http://www.mccpharmacy.com

For more detailed information ask to speak with Richard Fura.

Medical Center Compounding 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
 

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

Update on Cidofovir
 
 

Cidofovir is an anti-viral drug that is being used experimentally to treat RRP. Background information on Cidofovir may be found in Snoeck et al., 1998 (J. of Med. Virology 5:219-225) and in RRP Newsletter issues Spring 98, Spring 99 . Results from some preliminary studies are encouraging. One such study is being conducted primarily at Children's Hospital and Health Center in San Diego. Below are excerpts from two current papers as follows:.
 

(Archives of Otolaryngology, October 99)

Objective. To assess the potential benefit of intralesional administration of cidofovir, an acyclic nucleoside phosphonate with activity against several DNA viruses, for treating severe respiratory papillomas in pediatric patients.

Design. Prospective case series.

Setting. Tertiary care children's hospitals

Patients. Five Pediatric patients with severe recurrent respiratory papillomatosis requiring laryngoscopy with CO2 LASER therapy more frequently than once a month to maintain airway patency. Each patient had between 12 and 33 laryngoscopies with LASER treatment prior to being injected with cidofovir.

Intervention/Methods. Microsuspension laryngoscopy with intralesional injection of cidofovir (VistideR) in conjunction with mechanical debulking and CO2 LASER of papillomas.

This pilot study consisted of five patients with RRP requiring LASER therapy more frequently than once a month to maintain airway patency. In addition to repetitive LASER treatments, these patients had failed other adjuvant medical therapy. Patients ranged in age from 2 years to 5 years and had no other medical problems, specifically renal or hepatic disease. Informed consent was obtained from the patients' parents according to the policies of Children's Hospital and Health Center of San Diego and Children's Hospital of Texas.

Papilloma stage was determined using a uniform grading format developed at the University of Alabama at Birmingham by Wiatrak (personal communication). This system is designed to quantify the extent of RRP based upon involved sites (larynx, trachea and other) and subsites with severity based on a four point rating scale (0=none;1=minimal involvement; 2=moderate involvement; 3=severe involvement). Baseline complete blood count and blood chemistries were obtained prior to the first injection and then repeated monthly. The cidofovir injection was performed under general anesthesia utilizing spontaneous ventilation using the Benjamin microsuspension laryngoscope. In some cases the inhalational anesthetic was supplemented by the use of propofol. No patient required endotracheal intubation, either before or after the injection of cidofovir. Debulking of the papillomas was done through a combination of cup forceps and CO2 laser. The cidofovir injection administrated was a maximum dose of 1 mg/kg. It was formulated initially at 2.5 mg/cc and injected in the areas most involved with the papillomas using a laryngeal needle (Karl Storz Endoscopy-America ,Inc., Culver City, Ca. Injection Needle, Luerlock, straight #8598B) The injection was performed so as not to generate airway obstruction. As we began to see a response from the medication and due to the limitation of the injectable volume in these small children, the concentration was changed to 5 mg/cc. All of the children were discharged home on the day of surgery. None routinely received systemic steroids antibiotics or probenecid.

Based upon the original data from Van Cutsem et al. and the clinical course of our patients, cidofovir was injected every 2 to 3 weeks.

Main Outcome Measure. Papilloma stage at time of serial laryngoscopies.

Results. One patient became disease free and three patients demonstrated a dramatic response to adjuvant therapy with cidofovir with 9 month follow-up after the last injection with cidofovir. One patient showed improvement in papilloma stage possibly related to concurrent therapy with interferon.
 
 

Discussion/Conclusions. This is the first report of the use of cidofovir for pediatric patients with severe RRP. The results of this preliminary report are quite promising and offer hope to those who are most severely affected with RRP. Although our report does not confirm complete eradication of disease in most of the patients, in contrast to the report of Snoeck, the marked improvement in the airway and significant reduction in the need for repetitive operative intervention (as well as improved voice) suggests that this form of therapy has tremendous value in pediatric patients with severe RRP.

The significant improvement noted in our patients after the initiation of cidofovir does not appear to be coincident with the anticipated spontaneous improvement of this disease that generally comes about after years of therapy and at adolescence. All of these patients had increasing disease demanding more frequent and aggressive operative intervention simply to maintain airway patency. Injection of cidofovir brought about an impressive response quite rapidly and seems to have permitted a sustained response in four of the five patients.

Intralesional injection of cidofovir seems to be of benefit in the treatment of severe respiratory papillomatosis in pediatric patients. Larger prospective studies with longer follow-up will be required before cidofovir can be considered an accepted means of managing this difficult disease.

Follow-up study (Presented at the 1999 ASPO meeting):

The original five patients who received cidofovir have done extremely well. Four of the five presently have no evidence of papillomatosis and one has minimal disease. This is especially notable given how severe their RRP disease was at the initiation of cidofovir injections. They have improved from needing at least monthly surgical intervention to only requiring rare operative intervention since completing cidofovir therapy. This excellent response has made a profound impact on these children and their families.

Our follow-up period on these patients now ranges from 18 to 22 months with no evidence of any rebound effect. They all remain healthy and show no clinical or laboratory evidence of any toxicity from their treatment with cidofovir.

Unpublished reports of laryngeal cancer arising in two of the patients in the series done by Van Cutsem and Snoeck has caused concern within the pediatric otolaryngology community. With this in mind, we performed biopsies of the laryngeal mucosa in four of the original five patients more than one year following their last cidofovir injection. All had evidence of chronic inflammation, but no evidence of malignancy. We also contacted the Armed Forces Institute Of Pathology (AFIP), where the original biopsies taken by Van Cutsem and Snoeck were reviewed. The AFIP reports that two of the original biopsies (taken prior to cidofovir injections) were actually not papillomatosis, but carcinoma. The pathologists at AFIP were not given patient data with the slides they reviewed, so they cannot say whether this data relates to the patients in question.

With these concerns in mind, we modified our injection protocol in our new patients in an attempt to determine an ideal injection protocol that reduced exposure to cidofovir, yet provided a substantial and prolonged response. Each patient received four injections of cidofovir, given at two-week intervals at the concentration of 5mg per 1cc.

The initial response of all of the five new patients to cidofovir was as impressive as for the original five patients. All showed a remarkable reduction in their severity scores during their injection period. Following their injections a variable response to the treatment was seen.

In comparison to the original five patients, the second group does not appear to be responding as well to treatment with respect to long term control of their RRP. This may indicate that some patients need a more prolonged treatment course with cidofovir, as was done with our original five patients and in Snoeck's original report. Nevertheless, all ten of our patients did show a significant and often dramatic initial response to the treatment, indicating that cidofovir does inhibit the growth of HPV lesions.
 
 
 
 

Research Activities Update
 

My daughter has been an RRP patient since the age of one and a half. From all outward appearances, Jenn is a normal, healthy, active teenager with a hectic schedule. Over the years we have learned to cope with this terrible disease. I still can recall the shock, disbelief, anger and guilt I felt upon discovering that my beautiful baby girl had papillomatosis. My husband and I were further dismayed by the fact that many physicians had little or no knowledge of RRP. We were told that it was an "orphan disease"; therefore little research had been done in this area. Fortunately, we found a skilled and compassionate surgeon, Dr. Steven Handler of the Children's Hospital of Philadelphia. Even though, we now live in Hong Kong, Dr. Handler has continued to be Jenn's surgeon. In 1992, we met Bill and Marlene Stern, whose daughter was also diagnosed with RRP. Through the Sterns and organizations such as the RRP Foundation (RRPF), patients and their families such as ours draw much needed support and valued advice in the medical treatment decision making process.

As a mother with a teenaged daughter, I am preparing my daughter for womanhood. I think of the many choices Jenn will be confronted with, life style choices most of us take for granted: birth control methods, children, hormonal replacement therapy, etc...What are the viable options for a woman with RRP?

After much discussion with the Sterns and medical professionals, we concluded there is insufficient, practical information in this area. So, the RRPF has decided to initiate a study to explore the effects of hormones and pregnancy on RRP in the hopes that we may gather and share information that will be useful to the RRP community. We believe that

hormones and hormonal level changes throughout a woman's life may be a significant factor in the remission or proliferation of papilloma growth. If so, this would have a tremendous bearing in the life-style choices of every female RRP patient and her family.

We invite all female RRP patients who have personally confronted these issues to share with us their experience. Of course all names will be kept confidential with regard to any future publication or dissemination of this information. You can direct your response to me through E-mail: writeus@attmysite.com, or to Bill Stern at: bills@rrpf.org

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Dr. Karen Auborn and colleagues, from Long Island Jewish Medical Center, are currently conducting a study to determine whether I3C may have a significant effect on the bone density in mice. Bones have been "harvested" from a group of mice receiving I3C as well as a control group (not receiving I3C). The bones are being sent to the Connecticut Health Center where comprehensive analyses of bone density will be performed. Both groups of mice involve males and females across a spectrum of age groups For more information regarding bone density and I3C see the Fall 98 issue of the RRP Newsletter. The RRP Foundation is a supporter of this research project.

Patient Profile
 
 

[The following profile was written by Christine Fitts about her daughter Jessica Hagemeister. In this article she presents her perspective about a very rare experience relating to RRP. Please note: the RRPF does not necessarily agree with the suggestion that RRP can be inherited.]
 
 

My name is Christine Fitts and I am a mother of a beautiful young girl that is 8 years old named Jessica Hagemeister. Jessica has RRP. She was diagnosed at the age of 2 1/2. We were in shock of the news of her condition, and we were more surprised to find out her biological father had the same condition.

When we were dating and at the age 21, his condition returned after being gone for 11 years. He suffered from the ages of 5-10 and was treated for RRP in a different country, where in fact, they did not use lasers from what his mother told me. They would wait for him to have breathing problems and perform surgery on an emergency basis to open his airway. They cut them out instead of having them lasered.

When he found out he started having problems again, I was pregnant with Jessica. So my question to his ENT Doctor was: Is this condition hereditary ? He informed that no it was not, so I had no concern of my baby possibly having the same type of condition.

Jessica's father and I were never married and did not stay together much after her birth. When Jessica started to lose her voice in the summer of 1993, I was told by my mother that she "sounded like he did". I was happy with thinking that a cold was the reason for her hoarseness, but it never got better. I finally had her checked in September of 1993. I was overwhelmed and confused. This was in fact the same doctor that told me it wasn't hereditary and to think that I, at first, was the reason. You see this doctor was convinced that I had to have had genital warts during my delivery with Jessica. I was willing to go through any testing available to find out. I did, however, have prenatal care, and I did get my regular pap smears, and I did in fact have an ob/gyn deliver my baby. I was never told by anyone that I had genital warts. At first, I guess I felt accused of her condition and was instructed if I decided to give birth to another baby to make sure that it was not delivered through the birth canal.

After the tests that I had done, there was no proof of any lesions being present and there was no indication from the tests, that I have ever had genital warts. And this may sound crazy and maybe someone else has felt this way, but there were times I wished that one of those tests would have shown something so I would know for sure why my baby girl has to go through this. But the only thing that could be said, is that maybe, just maybe she had inherited this from her birth father. Although, I believe, there is no one else who has ever reported this.

Jessica went through surgery every 6 weeks in the beginning. She had had 12 surgeries when I married my husband David. He is in the U.S Army. At this point, the military hospital wanted to do the surgery instead of having her sent to a specialist. At that point we were really hoping for some better results. But during one of the surgeries Jessica's vocal cords collapsed and she was without oxygen for several minutes. The doctors were afraid of her brain being damaged. She was in ICU for one week. She came out of that experience with good results. Her ENT doctor had performed the surgery and reported that her condition had worsened some. She was then going every 4 weeks to keep her airway open. And I believe, that was indeed due to an ENT doctor who was familiar with her condition. Through that experience, we were notified by the social worker of the RRP Foundation.

The Army announced that we were going to be stationed in Germany. We were very concerned about Jessica at that time. We did not feel comfortable taking her to another country for treatment. I had spoken with Marlene Stern about our situation and I know that there is treatment being done in Germany but the military does not guarantee where we would be. So, we put in for a transfer to Fort Benning Georgia. In hopes that we could go to The Children's Hospital of Alabama and become part of the research that they were involved in.

Unfortunately during her 20^th surgery, the laser sparked and came in contact with the oxygen tube, it had ignited and my daughter had burns from the back of her throat to the outside of her lips. I understand that this is an extremely rare occurrence and it is a risk we knew about before every surgery, but dear lord , nobody wants to see their child go through what she had already been through. There again, she was in ICU for a week. Doctors were concerned about her lungs and maybe the need for some plastic surgery, but with a lot of love and prayer she was fine with no scaring anywhere.

We then went straight to Dr. Wiatrak at UAB. Jessica was already having problems breathing within that week. They admitted her right away. Shortly we made the decision to start Accutane treatment. She started the medicine in July of 1996. Shortly after starting the treatment she showed massive improvement, with the understanding that this isn't always the outcome. She has been clear of any papillomas since. She is currently still in remission. We are no longer in the area of Alabama but do have Jessica checked every 18 months unless she has symptoms of course. She recently had surgery and was found to still be clear of papilloma.

It was not an easy choice to make, putting Jessica on the Accutane. And although she suffered minor side effects, we can now say that it was the best choice for her. I can say today that I feel I am very educated on Jessica's condition, probably not as much as some though. But I know how I felt before I knew about the RRP Foundation and the newsletters. And I know there are people out there that are feeling that same way. All I have to say is there are other people out there that are going through the same type of struggle. There is some hope. It's a fight, a tough fight. But I knew that Jessica is living a very normal life, and as unpredictable as this condition can be, you should never give up, Jessica didn't. At her most difficult times, she fought the hardest and I think everyone should try and never give up hope.
 
 
 
 
 
 
 
 
 
 

In Memory of Allan Williams
 
 

Allan Williams battled RRP since his diagnosis at 16 months of age. When he was six Allan was diagnosed with laryngeal cancer, probably one of the youngest patients in whom this has ever been observed. Despite his struggles with cancer and nearly 100 surgeries for RRP, Allan and his family maintained an active life. Allan was active right up until time he passed away on June 26, 1999 at the young age of 19. Allan will be missed so very much by many us whose lives he touched. Allan is survived by his parents Claude and Joseph and a sister Daphne.