Vol.6 No.2
1997 Fall

_________________________________________________________________________________________________________

Contents

· Opening comments - p. 1
· RRPF organizational information - p. 2
· RRP Remission and Network News - p. 2
· RRP National Issues - p. 3
· Patient Statistics - p. 4
· Update on Adjunct Therapies and new protocols - p. 4-6
Adjunct Therapy Survey Update - p. 4
indole-3-carbinol - p. 4-5
Immune Formula - p. 5
PDT at LIJ - p. 5-6
Cidofovir: a multi-center trial - p. 6
Treating pulmonary papillomas - p. 6
· Research Activities Update - p. 6-7
A new IC3 derivative: DIM - p. 6-7
Diet Based Studies and HPV - p. 7
· Perspective - p. 8
· RRPF Mission Statement, Information/Support Centers, subscription form - enclosure

From the Editor

I thank all of you who have expressed appreciation of our RRP related efforts and who have provided feedback regarding your particular RRP
priorities. We sincerely hope that the information and support services we provide are helping. Your comments are important, as it is
impossible for Marlene and I to contact each of the approximately 400 support network members personally.

I am urgently appealing for help from the RRP community. We need more people to actively paticipate in the RRPF and the RRP Newsletter.
First and foremost I am asking for one (or more) person(s) to take over as the RRP Newsletter Editor(s). If there are no newsletter editor
volunteers Marlene and I will make a best effort to continue to publish the RRP Newsletter, however, it will be published on an "as we can"
basis, not as a regular semi-annual publication.

With the continued growth of the RRPF we have had to devote much more of our time to database management and analysis activities. The
database is important to the research community and continued research is our hope for an RRP cure. Furthermore, Marlene, Lindsay and I
must spend more time being a family and therefore we must be able to delegate more of the RRPF activities.

The RRP Newsletter has been a vital part of the RRPF's information dissemination system. Having an editor who's efforts are not diluted
by other RRPF duties should help to enhance the quality of this publication. If you have any interest in this regard, please contact
Bill Stern (see page 2 for address information).

We also continue to welcome people who are interested in helping to gather information and write articles as well as those who have database management experience. Our thanks to all those who have responded to our appeal for help. If you would like to assist in any way, don't hesitate to contact me at the address listed on page 2.

Thank you.

Bill Stern

P..S. Thanks to Lindsay and her friends Raquel, 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 who contribute, we extend our sincere thanks to everyone who has supported our efforts.

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

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

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

We would like to take this opportunity to acknowledge donations received from the following local United Way chapters during the past year: Central Maryland, Southeastern PA, Jackson County Oregon, San Diego County, CA., Washington, DC. and Mercer County, NJ. Also we have been contacted by chapters from Southeastern PA and Oregon in anticipation of receiving donations from them. We thank all those individuals who contributed in this way. Your help is very much appreciated.

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
mstern@pucc.princeton.edu

Bill Stern
Treasurer and Director
P.O. Box 6643
Lawrenceville, NJ 08648-0643
(609) 530-1443
wfs@gfdl.gov

Henry Woo, Esq.
Secretary
Medtronic International Inc.
Suite 2002, C.C. Wu Building
308 Hennessey Rd.
Wanchai
Hong Kong
henrywoo@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
Apt 2503
Parkside and Pacific Place
88 Queensway
Hong Kong
writeus@netvigator.com

[Please see the enclosure 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 Minimum Annual Donations

RRP Newsletter

Professional/Corporate - $25
Individual - $15

RRP Newsletter plus Medical Reference Service

Professional/Corporate - $40
Individual - $25

(see RRPF subscription form enclosed)

[Note: Back issues of the RRP Newsletter and Medical Reference Service ($10/issue) are available upon request, subject to availability]

RRP Remission News

by Marlene Stern and Judy Thompson

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

Five and a half year old Martika form Alabama has been papilloma free for 2 years. Before that she endured 25 surgeries every 4 to 6 weeks until starting a treament plan involving Accutane. After 3 months on Accutane she began her current remission.

Andrea age 31 from Louisiana has been in remission since September of 1994. She took acyclovir until March 1995. She has since been through a pregnancy giving birth to a healty baby girl 7 months ago, with no recurrence of papilloma.

Others still in remission include: Trey from Maryland, age 4 1/2; Nine year old Anthony from Kentucky; Ariel from California, now
6 years old; Steph from Florida, age 24; Jeff from Illinois, age 49; Cara from Michigan at age 15; Emily from Michigan, now 9 years old; Leah from New Hampshire age 17; Lindsay from New Jersey, now 8 years old; Melissa from New York, who is also 8; Kaitlyn from Tennessee now 5;
Smokey from Virginia, age 25; Rita from Pennsylvania, now 3 1/2 years old; Jim from North Dakota, at age 44; Linda from New Jersey now age 42; Kevin from Maryland age 38 and Ralph from Pennsylvania, now age 70.

If you feel that you or your family member is in remission and would like to share this information with the RRP community, please contact:

Judy Thompson
3184 Eutaw Forest Dr
Waldorf, MD 20603
(301) 843-6378
email: jthompson@gpo.gov

PAGE 3

RRP Network News

Our international support network has grown to approximately 400 respiratory papilloma families. Patients range in age from 1 to 81 years and are located in 44 states, the District of Columbia, three Canadian provinces, the United Kingdom, Spain, Macedonia, Croatia, Morocco, Chile, Hong Kong, Brunei and Australia.

Our thanks to all who have taken the time to fill out the RRPF Patient/Therapy Survey. The copy enclosed includes a few additions which we would like to point out. First there is a box near the top of the front side which, when checked, will alert us to an address change. Secondly, 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. Finally, in the upper right of the back side, we have requested your doctor's name and address along with the name of the hospital where surgeries are being performed. As our support network has grown, we have become more dependent on the patient questionnaires to 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 note that 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. Please return the surveys to Marlene and Bill Stern. 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, please notify Bill or Marlene Stern.

Information exchange throughout the support group and the RRP community remains a primary focus of the foundation. In this regard, the use of the Internet and World Wide Web (WWW) is increasing. The RRPF maintains e-mail lists and a website located at
(http://members.aol.com/rrpf/RRPF.html) . Our page is cross linked with other WWW home pages that we feel are relevant to the RRP community. If you have some experience/expertise with the WWW and would like to help us improve our website,
please contact Bill Stern.

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 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 the names and addresses of specific key govermental officials see the RRP Newsletter Spring 97 issue.
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The table that follows summarizes information obtained by the Centers for Disease Control and Prevention (CDC) for their
RRP National Registry. site coordinators at 16 medical centers have submitted data on children with active RRP aged 17 years and younger. As of October 23, 1997, there were 269 children in the registry representing 5229 procedures (both clinic and OR).

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

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RRP Patient Stats

The statistics that follow are based on RRPF questionnaire responses. 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 4.

Tables 1 - 3 provide a breakdown of the patients in the support group based on sex and age; the sample sizes for tables 1-3 range from 315 to 358.

Table 1. Total number of patients in support group reporting

	Females	Males
All Ages	159	199

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

Age Groups	Females	Males	Total
Under 10	72	50	122
10-20	22	30	52
20-30	13	13	26
30-40	15	17	32
40-50	14	32	46
Over 50	9	28	37

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

Age Groups	Females	Males	Total
Under 10	122	121	243
10-20	5	4	9
20-30	18	20	38
30-40	5	22	27
40-50	5	23	28
Over 50	4	9	13

Table 4. Distribution of respiratory papilloma sites of involvement based on responses from 145 patients

respiratory site	no. of patients
above cords	80
at cords	145
below cords	60
tracheal	33
bronchial	13
lung	12

Table 5. Birth Statistics from Patient Support Network*:

Cesarean birth in 15 cases - 239 responses
juvenile onset: 8 of 153 responses
adult onset 7 of 86 responses
Patient is first born in 122 cases - 221 responses
juvenile onset: 94 of 144 responses
adult onset: 28 of 77 responses
Patient was adopted in 35 cases - 241 responses
juvenile onset: 33 of 156 responses
adult onset: 2 of 66 responses
Mother's ages - 120 responses (juvenile onset only)
Under 20 = 38
20 -> 25 = 37
> 25 = 45
* Juvenile onset was defined here as diagnosis age <=14.

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.

Adjunct therapy survey responses from 243 patients/families have been received. Of those responding 94 indicated that they have not used any adjunct therapies and 143 responded that they have tried adjunct treatments (many have tried more than one). The most reported therapy was indole-3-carbinol (I3C) with 108 users and next was interferon (IFN) with 65 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 at two typical surgical intervals) or a partial response (Partial).

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

Therapy	Users	None	Improve	Comp	Partial
I3C	62	31	31	13	18
IFN	35	15	20	3	17
Acyc	18	11	7	5	2
PDT	10	8	2	0	2
Ribvrn	2	1	1	0	1
Retin	10	6	4	0	4
Mumps	5	2	3	1	2
Others	11	5	5	1	5

Some notes regarding the above table:

The therapies are abbreviated as follows, I3C = indole-3-carbinol, IFN = interferon, Acyc = acyclovir, PDT = photo dynamic therapy (using Photofrin), Ribvrn = ribavirin, Retin = retinoic acid or accutane, Mumps = mumps vaccine (more details on page 6). In the category of other therapies used, improvement has been noted using the following treatments: Thuja (a homeopathic anti-viral), a mixture of vitamins including vitamin C and vitamin A, ShapeRite immune formula (more info. on page 5), topical 5-flourouracil (5FU), bleomycin and cobalt. (Please see RRP Newsletter Spring 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. Futhermore, since sample sizes are generally small and no statistical significance tests have been applied to data in the above table, one must interpret these numbers cautiously, especially when considering the natural variability of RRP. However, we do hope that this information can provide some guidance for those patients seeking adjunct therapies as well as those pursuing RRP related research.

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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 as well as Bradlow et al., 1996, J. of Endocrinology 150, S259-S265; Newfield et al.., 1993, Anticancer Research 13,337-342

If you are interested in obtaining more information about clinical trials involving I3C, please get in touch with one of the principal investigators as follows:

University of Pittsburgh:
Clark A. Rosen, MD. - (412) 647-2112

University of Tennessee:
Gayle E. Woodson, MD. - (901) 448-7677
Jerome Thompson, MD. - (901) 572-4400

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 77 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.

How to get I3C and How much to take

I3C may now be purchased from:
THERANATURALS Inc.
PO. Box 344
Orem UT 84059-0344
(801)224-8893 - Telephone; (801) 226-6064 - Fax
e-mail: www.theranaturals.com
[A credit card is requested by phone, fax, or e-mail]

Theranaturals is selling I3C in capsule form, each capsule will be guaranteed to contain 100 milligrams of I3C. Each bottle will contain 100 capsules.
Pricing as of 12-1-97 (which includes surface UPS shipping) : $40.00 for one bottle; $110.00 for a package of 3 bottles
add $16.00 to above prices for Fed X shipping.
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 bis(3-indolyl)methane (B3IM) a try. B3IM is one of the key reactive by-products of I3C. It can be ordered through Theranaturals by asking specifically for the B3IM CAPS. [See the article on a new form of B3IM in the Research Articles Update section]

There is another I3C capsule product made by Enrich that may be at least partially natural (it is also much more costly) If you would like more information about this product, please call support group member Michael Green at (206)361-8185.

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.

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Our son Jeremy, now 14 years old, has had a very aggressive case of recurrent respiratory papillomas. Diagnosed at the age of 8 months, he has had over 250 laser surgeries. He was assisted, to some degree, with interferon when he was younger but did not respond to Indole 3 Carbinol or Photo Dynamic Therapy. Surgeries becoame the focal point in which our lives revolved. His surgeries were needed every two to four weeks. Our surgeon had an RRP child who went into remission. While asking the mother if the child was on any medications or supplements, it came to light that she was using Immune Formula made by ShapeRite Concepts. The dietary supplement has been broken down by Children's Hospital LA and contains exactly what is on the label of the box; a variety of herbs including enchinacea, ginseng, gotu kola, licorice root and some others. I was surprised when doing some research that licorice root is claimed to be able to boost the body's immune function and that enchinacea has long been used tohelp the body fight viruses. Our doctor felt it would be beneficial to have Jeremy try this product. He takes one capsule in themorning and one at night. After the first 3 weeks, his surgery time was extended by one week. The following surgery, he again was extended an additional week. Now, one year later he is going every 3 months and we are still extending the surgery time gradually. He has consistently had a voice for the first time in his fourteen years. He no longer has to whisper to make other kids understand him and life for us, has blissfully, become somewhat normal. I hope the Immune Formula can benefit others too.

ShapeRite Immune Formula comes in a Blister Pack of 100 cps for $25.00 wholesale. You may use my ID#236619401 (to get the wholesale prIce) and the phone number is (800) 776-9898. Please let the RRPF know if this product is helpful to you or your child (adults can also take the product). If we could collect enough data on children who respond to the Immune Formula, Children's Hospital LA, may consider doing a study. If you would like more information you may feel free to contact me (Susan Spock, Jeremy's mom) at (760) 744-5022 .
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Five patients who have been treated with PDT using m-THPC (see Fall 95 and Spring 97 RRP Newsletter issues for more details) have now been followed for at least 9 months. Of these patients, one is free of disease and two are markedly better. One had a small epiglottic papilloma recur after 9 months, and one with tracheal disease went from onthly sugery to surgery every 4 months. All patients had severe disease at the time of treatment. two others were treated in Sweden, and both are much better. The numbers are too small to draw any conclusions, but it is encouraging. Thus far, photosensitivity appears limited to less than 3 weeks with some patients able to go outdoors in the daytime after two weeks.

LIJ is currently recruiting additional RRP patient candidates. Participation in this study will involve a 6 month pre-PDT observing period and a 12 month post-PDT follow-up at LIJ. Patients/parents interested in more information should contact Ms. Ginny Mullooly, Research Nurse Clinician, at (718)470-7011. They can also arrange to send their medical records for evaluation to the following address:

Dr. Allan Abramson
Dept. of Otolaryngology
Long Island Jewish Medical Center
270-05 76th Ave.
New Hyde Park, NY 11402

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Earlier this year a research group from Belgium reported (Wellens et al., Procedings of the XVI World Congress of Otorhinolarygology Head and Neck Surgery, Sydney, Australia) on the treatment of 17 RRP patients (mostly adult) 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 set up in the U.S. According to Janet FitzGerald, RN at the University of Alabama at Birmingham (UAB), current plans are to enroll approximately 36 juvenile patients in a Phase I/II multi-centered trial sponsored by the NIH/NIAID Collaborative Anti-viral Studay Group (CASG). Patients must be experiencing aggressive regrowth of papillomas, i.e., 8-10 surgeries per year. Laser surgeries will be performed monthly, at which time a does of blinded study medication will be injected interlesionally. After three procedures a patient who is not responding to the study medication may be allowed to cross over and receive Cidofovir. in these initial phases of the study the dosage is being kept quite low to minimize the risk of toxicity and side effects.

For participating centers, contact Jan FitzGerald, R.N., Clinical Administrator - Pediatric Studies CASG 205-934-5316.

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From correspondence and surveys that the RRPF has received, it seems that in approximately 5% of the cases some papilloma have been found in the lungs. Conventional laser excision is not possible and most sdjunct treatments to date seem to be ineffective in treating pulmonary papilloma. From a support perspective, we find this to be very frustrating, not knowing in what direction we should point people who are in very much need of help.

In this regard, we have just learned that Dr. Frank Rimell at the University of Minnesota has proposed an experimental protocol in an attempt to treat papilloma in the lungs. Drawing on experience used in some HIV treatments, he is starting to treat 2 patients at the Univ. of Minn. with a (rather potent) triple drug therapy involving methotrexate, inteferon 2B and cis retinoic acid (which may be repalced with ribavirin). Dr. Richard Smith at the Univeristy of Iowa has adopted this treatment plan for one of his patients as well.

Dr. Rimell invites patients with pulmonary papillomas to call his office at 612-626-0486 and he will work with their local ENT and a local oncologist, who will need to follow them while on the protocol.

[Ed. note: This combination of drugs could produce significant side effects.]

The RRPF invites patients and doctors to learn more about these and other experimental therapies. Before entering any experimental trial, we suggest that you make inquiries regarding details of the protocol, all possible side effects, expected impact on papilloma growth, etc.
The RRPF cannot endorse any specific therapy, as the applicability of any treatment must be assessed within the context of each individual situation. The information given above is intended to provide some guidance.

Research Activities Update

You might wonder how something named Diindolylmethane (DIM which is the same as B3IM) could be related in any way to Indole-3-Carbinol (I3C). Apart fromtheir disparate chemical names, the relationship is exceedingly close. Each DIM molecule is formed from the combining of two I3C molecules. With two identical, mirror-image rings connected by a carbon bridge, one DIM molecule is like Siamese twins of two I3C molecules. DIM is naturally formed from Indole-3-Carbinol (I3C) during the fermentation or acid digestion of cruciferous vegetables. DIM like I3C is present in broccoli, cabbage, cauliflower, Brussels sprouts , and Chinese cabbage. In some studies in which synthetic I3C was fed to animals, about 4% of what left the stomach turned into DIM. Most interesting was the fact that when I3C was injected into animals, bypassing the stomach and acid digestions, it had no effect whatsoever in changing estrogen metabolism. DIM, however, was equally as potent in changing estrogen metabolism whether injected or given by mouth. Most convincing in establishing the importance of DIM were animal experiments that compared the beneficial enzyme inducing effects of I3C versus DIM. Dietary DIM was a much more powerful inducer than I3C. Could DIM be the major active byproduct of I3C? Our development group certainly thinks so.

To back up a bit in this story, let me explain my introduction to DIM and I3C. About two years ago, I was writing on the subject of cancer prevention. In doing so I reviewed the work of H. Leon Bradlow, Ph.D. in the area of breast cancer prevention. Surprisingly, with regard to I3C, the most compelling evidence for effectiveness resided not with cancer but with Recurrent Respiratory Papilloma (RRP). The evidence for successful suppression of RRP with I3C impressed me deeply, since, as a pediatrcian-anesthesiologist, I knew firsthand of the frustration and seriousness of this condition. I was surprised that no one had worked on improving the formulation of I3C. My resolve to develop I3C into a more widely available dietary supplement led me to intense study of the chemistry of this group of food chemicals. I3C turned out to be quite unstable, with no shelf life, and productive of many breakdown products of questionable benefit. DIM, on the other hand, had none of these problems but presented its own unique challenge. It was completely insoluble in watre and only marginally soluble in oil. This required some real work in nutrient delivery. Our research and development group, BioResponse, created D-MAX^TM a delivery system to make DIM more absorbable. When taken as a supplement, D-MAX^TM , is DIM packaged in microscopic bubbles of Vitamin E and coated with starch.
When examined, D-MAX^TM has the consistency of flour. But when added to the diet it provides for the smooth absorption of DIM. We next turned the powder into granules through a food process. By adding flavor during this step, we have been able to produce D-MAX^TM Sprinkles. This form of DIM is designed to be added to food, especially to encourage DIM use by children. What became clear inour research was that D-MAX^TM was stable on the shelf, tasted better than I3C, and remained stable through the digestive process.

As we looked into its history, DIM had been used as early as the 1970's and had been shown to prevent cancer in laboratory animals. The synthesis of DIM from building block chemicals went back further to the 1950's. Although work with DIM has not been as extensive as with I3C, no evidence for negative or toxic effects has been reported. Our initial clinical tests of D-MAX^TM have shown it to be quite effective in adjusting the balance of estrogen metabolism to favor 2-hydroxy estrone in adult volunteers. During all of this, BioResponse, submitted an extensive package of information supporting the safty and advantages of D-MAX^TM to the F.D.A. Office of Special Nutritionals. This declaration will allow for the use of DIM as a "new dietary ingredient". Once the FDA review process is completed, D-MAX^TM containing products will be able to enter the marketplace. We hope this will be in the latter part of November. D-MAX^TM sprinkles, and D-MAX^TM capsules will offer RRP affected individuals absorbable DIM. The dosage is still being carefully evaluated. We know that DIM has at least twice the potency of I3C, but whether this might be stretched to 3 times the potency is under study. This would allow a reduction in the daily dosage necessary to sustain beneficial estrogen metabolism in comparison to I3C. One thing is certain, taking DIM crystals is ineffective at typical doses, since pure DIM is so poorly absorbed. D-MAX^TM and DIM have proved to be safe and non-toxic with daily doses of D-MAX^TM containing as much as 300 mg per day of DIM. We will continue to work on dosage recommendations for children and adults in the next few months. There is no question that D-MAX^TM sprinkles will be a more palatable and better dosage forms for kids than I3C powder. We also hope that some individuals who failed to respond to I3C may respond differently to D-MAX^TM . This is possible if lack of gastric acidity or absorption of naturally produced DIM, made in the process of digestion of I3C, was part of the problem. I hope to have further news in subsequent issues on the progress to be made in introducing D-MAX^TM to the RRP community. In the meantime BioResponse thanks the RRP Foundation for this opportunity to introduce readers to D-MAX^TM . Further work and experience with DIM containing formulations will tell us whether we have found a next, more effective, generation after I3C.

BioResponse L.L.C.
P.O. Box 288
Boulder, CO 80306-0288

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Assays have been developed to measure two enzymes induced by indole-3-carbinol. These enzymes favorably modulate estrogen metabolism. Measurements can be made on small amounts of cells grown in the laboratory and from small amounts of tissues such as a papilloma removed during surgery. These assays will clearly help us to define the role of these enzymes in disease and have the potential to be used diagnostically.

Certain omega-3-fatty acids (found in fish oils) inhibit the growth of papilloma cells found in the laboratory. The mechanism of this inhibition is being prepared for publication. Studies in animal models should be the next step to determine efficacy of these fatty acids as adjunct treatment for papillomavirus disease.

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Perspective

[The follwing article was written about 9 year old RRP patient Peter Curley by his 17 ear old sister, Jori Frakie. Peter's situation is
quite unique, being a victim of several unfortunate circumstances, of which RRP is only one. He was born prematurely to a 13 year old mother and was essentially abandoned. In additon to RRP, he is quite medically fragile, being affected at birth with broncho pulmonary dysplasia (BPD - a problem that closely mimics emphysema) and fetal alcohol effects.

Peter's is an individually critical situation and is by no means typical. However, his incredible ability to live life despite the ever present threat of death, and Jori's eloquence in sharing her emotional struggle about her brother and mortality, deserve publication.]

A short time ago, I set out to prove that I have accepted mortality. I wrote a four page essay detailing the strength I have garnered over the last eight years of living with my critically ill borther, Peter. By the end of the paper, I was beginning to suspect that I was lying; that my "security" with the thought of death was just an act. I put the paer aside, hoping my uneasiness would fade, and that I could convince myself I'd written the truth. This last week, though, has proven to me that my instinct was right: I am in no way prepared to face mortality. I may think about it a great deal, and maybe I even try to prepare for the all-to-significant possibility that my brother might die at any moment, but I cannot accept it.

I was nine when my family brought Peter home from the hospital. We had decided two months before to adopt him, or, rather to "foster" him, as he is a member of the Salish-Kootenai tribe and regulation discourages adoption from outside the tribal community. That August, Peter was twenty months old, but he was by no means the average toddler. He was on a respirator. He had a tracheostomy. He had to be fed through a tube in his nose. He could not talk and could hardly move. His eyes were glazed over and he withdrew whenever anyone touched him. I had no idea, then, how much I would come to love him and how dramatically he would change my life. All I knew was that he was now my brother and that the doctors had told my parents and me not to "get attached" to him. They were putting him with a foster family, they said, onlsy so that he might die in a more pleasant evvironment than the stale white rooms of Community Medical Center. They were sure he had only two or three months left.

The prognosis was wrong that time. Within a few months of Peter's arrival into our home, his health began to improve; his spirits too. For the first time in his life, he was grinning and seeking out hugs. By Christmas, he was crawling. My family was overjoyed: we had fallen head over heels in love with Peter, despite the doctors' warnings, and we did not want to lose him.

Peter has been with us for eight years now. Over this time, we have often been forced to remember the fragility of life -- Peter's especially. He is in and out of hospitals. He has surgery every couple of months. He is highly susceptible to every virus and bacterial infection that moves through his grade school and his recovery is always long and difficult. Occasionally, he has seizures for which no doctor can find a cause: He is still on oxygen; he still eats through a tube in his stomach. One lung is now so much bigger than the other - because it is the only one that has been working all these years - that it shoved his heart into the lower right side of his body, next to his stomach. This lung is wearing out. So is his heart. But his mind and soul are not. He loves people, books, trains, and laughter. He loves me.

In the story of Gilgamesh, the title character finds it hard to accept human mortality after he is told that the gods have decided to end the life of his friend, Enkidu. I can relate. I hate, in the strongest sense of the word, to think of Peter dying, yet cold medical probabilities force me to consider it every time he is wavering on the edge between life and whatever lies beyond this world. Still, during the periods when Peter's health is relatively stable, I half way forget that there is little chance he will live past puberty because of his weakening lung and heart -- if he does not succumb sooner to some disease or passing virus. When Peter is well, every aspect of him suggests life: his smile, his mischieviousness, his strong legs, his impish dimple, and huge brown eyes. I lull myself into such a state of denial that when he does become extremely sick again, I am shocked and frightened and angry.

There was a time, for example, that Peter was part of an experimental surgery in Minneapolis and it just happened that he was the one in five hundred who reacted negatively to the treatment. Those were two excruciating weeks in Intensive Care, wondering if Peter would ever recognize us again, if he did survive. I spent so much time in that hospital, I saw three people die. The unit was small enough that I had to watch their famililes react; how none of them could encompass the emotion that was coursing through their bodies, though they tried. I wondered how my own family would deal with the grief my brother's death would bring. I wondered if I, too, would cry out as did one mother, "he's too young! He's too young!" or if I would choke on dry tears as her husband did.

I found out what immediate reaction would be two years ago. Peter had started having seizures and had to be hospitalized. Each seizure was worse than the last and finally, he went into a coma. A few days later, he became agitated inhis comatose state and had another seizure. A few hours later, he had another one, this one even more severe, and the doctor told us to call our pastor up from the lobby; that it was time to start praying if we were so inclined. A nurse led Pastor Ophus into the room and he began to pray. The low hum of his voice was pierced by my Mother's sharp breaths and the erratic beeping of the machines around Peter's bed. Suddenly, all the neon green lines on the monitors would go awry and Peter would seem even closer to death. I could not cry. My Mother was sobbing against my father's chest and I could see, over his shoulder, his face, contracted in pain. I ached all over. I went over to the bed and put my cheek on Peter's forehead. Pastor Ophus pulled me away. Minutes later, Peter stabilized. Two weeks later, he had again, miraculously, recovered.

Since then, there has been just the "usual" cause for true worry until recently. I had almost convinced myself that I was ready to handle Peter's death, whenever it moght come. But it is far easier to say this than to actually be prepared.

Now that I am living far away from my family, it is even more difficult, as I've found out a short time ago. My mother called over my luch hour to tell me that Peter was once again in the hospital and that he was having seizures every few hours. Again the doctors could not pinpoint the cause of these seizsures and were worried. My Mother spent every single second at the hospital, even sleeping there, and my father did not go to work. There was no certainty as to Peter's condition or prognosis; the anxious waiting had again begun.

My mind is now tangled with emotion. Intellectually, I know that it is how we spend the time we have that counts, and not how much time we have, and I know that I am blessed to have Peter as my brother -- he has taught me ore tha anyone else could have -- but my heart is having a hard time realizing all this. Peter has a kind of strength I've rarely seen; he does not complain and is always ready to smile. He has taught me to respect all types of intelligence and beauty, and to appreciate every precious second of life. Despite all that I have learned from him, I am still selfish and, right now, these lessons and my memories are not enough. I am not prepared for his death and I am angry that I should be prepared. Perhaps I should be putting my trust in God or fate; perhaps there is a greater plan at work here than I can imagine, but I cannot accept that a nine year old boy is so close to the end of his life. I am not ready to speak about Peter inthe past tense. I have a long, long way to go in terms of following Gilgamesh on the journey towards acceptance.

All I can do for now is go on as I must. I will try to appreciate every sensation I exprience a bit more, and to use the lessons I have learned from my brother in my own lilfe. I will pray, as I always do when stress pushes me into sudden faith, that God will give Peter more time on this earth, and, if that does not fit into the Almighty Plan, he give me some way of reasoning and comprehending my grief and human mortality. Right now, I miss my brother and I do not want to be away while he is in a hospital in Montana. I want to cry out like Gilgamesh does before Enkidu's death, and I do not want this overflowing loneliness inside of me to become any greater. I do not want Peter to die yet. I do not want to feel so helpless in all of this. I know I am unreasonable. I know I feel helpless, but not hopeless. I know that I love my brother. This finally is the truth of all this ponderous experience, I guess: love. Love is what brings us tears, and song, and language, and life itself. And without love, we would not pay a single thought to death. And so I'll keep on loving, struggling to accept the tears I know must come.

Jori Lydia Frankie