Winter 2001

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Volume 8 • Number 1

The RRP Medical Reference Service is intended to be of potential interest to RRP patients/families seeking treatment, practitioners providing care, micro biological researchers as well as others interested in developing a comprehensive understanding of recurrent respiratory papillomatosis.

This issue focuses on a selection of references with abstracts from recent (2000 and later) RRP related publications.These listings are sorted in approximate reverse chronological order as indicated by the "Unique Identifier" numbers. Each listing is formatted as follows:
Journal or reference
Title
Language (if it is not specified assume article is in English)
Author(s)
Primary affiliation (when specified)
Abstract
Unique identifier

If copies of complete articles are desired, we suggest that you request a reprint from one of the authors. If you need assistance in this regard or if you have any other questions or comments please feel free to contact:

Bill Stern
RRP Foundation
P.O. Box 6643
Lawrenceville NJ 08648-0643
(609) 530-1443 or (609)452-6545
E-mail: bills@rrpf.org or rrpf@aol.com

Dave Wunrow RPh.
210 Columbus Drive
Marshfield WI 54449
(715) 387-8824
E-mail: djwunrow@charter.net

Drugs 2000 Dec;60(6):1329-52

Current recommendations for the treatment of genital herpes.

Leung DT; Sacks SL

Wake Forest University School of Medicine, Winston Salem, North Carolina, USA. dleung@wfubmc.edu

The incidence of genital herpes continues to increase in epidemic-like fashion. Aciclovir (acyclovir) has been the original gold standard of therapy. The recent addition of famciclovir and valaciclovir as antiherpes drugs has improved convenience as well as the efficacy of treatment. Although aciclovir remains a widely prescribed and reliable drug, its administration schedule falls short of the ease of usage that the newer nucleoside analogues offer, for both episodic and suppressive therapy. Suppression of symptomatic disease and asymptomatic shedding from the genitalia have both become popular approaches, if not the primary targets of antiviral therapy. Knowing that asymptomatic disease leads to most cases of transmission strongly suggests that suppression with antiviral agents could reduce transmission risk in discordant couples. Unfortunately, the role for antivirals in reducing transmission remains to be proven in clinical trials. Neonatal herpes is now successfully treated using aciclovir. Current randomised clinical trials are examining aciclovir and valaciclovir administration, as well as safety and efficacy for post-acute suppressive therapy. Prevention of recurrences in pregnancy is also a topic under investigation, with a view to reducing the medical need for Cesarean section, or alternatively (and far less likely to be accomplished) to protect the neonate. Although resistance is largely limited to the immunocompromised and a change in resistance patterns is not expected, several drugs are available for the treatment of aciclovir-resistant strains of herpes simplex. Foscarnet is the main alternative with proven efficacy in this setting. Unfortunately, administration of foscarnet requires intravenous therapy, although a single anecdote of topical foscarnet efficacy in this setting has been published. Alternatives include cidofovir gel, which is not commercially available but can be formulated locally from the intravenous preparation. Less effective alternatives include trifluridine and interferon. Future possibilities for treatment of genital herpes include a microparticle-based controlled-release formulation of aciclovir and resiquimod (VML-600; R-848). The search for an effective therapeutic vaccine for genital herpes has not been successful to date, although a live virus glycoprotein H-deficient (DISC) vaccine is currently in clinical trials. Recent data suggest that seronegative women are protected (albeit, not fully) by a glycoprotein D recombinant vaccine with adjuvant. Despite the established safety and convenience of current treatment options, better suppressive options and topical treatment options are much needed. Studies using existing agents as

potential tools to avoid Cesarean section, or transmission to neonate or partner are ongoing. Both vaccines and antivirals may eventually play a role in prevention of infection.

Unique Identifier: 21025334

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Eur Arch Otorhinolaryngol 2000 Nov;257(9):498-501

The course of laryngeal papillomatosis treated by endolaryngeal microsurgery.

Uloza V

Department of Otolaryngology, Kaunas University of Medicine, Lithuania. inviulo@medi.lt

Eur Arch Otorhinolaryngol 2000 Nov;257(9):498-501

Surgical excision of papillomas remains the mainstay of the management of laryngeal papillomatosis, as causal therapy is not yet available. Eighty-nine patients -32 with juvenile papillomatosis (JP) and 57 with adult papillomas (AP)-- underwent endolaryngeal microsurgery (EM) in our department during the last 15 years. The ENT-department in Kaunas serves most of the patients with laryngeal papilloma among the 3.85 million inhabitants of Lithuania. Therapeutic outcome was assessed as both the recurrence rate and the length of time between recurrences of papillomas in the follow-up period lasting at least 2 years. The recurrence rate was 71.9% (23 patients) in the JP group and 22.8% (13 patients) in the AP group. The interval between recurrences of papillomas ranged from 1 month to 10 years (mean 1.9 years) in the JP group and from 6 months to 9 years (mean 3.2 years) in the AP group. The number of EMs per patient ranged from 1 to 18 (mean 3.2) in the JP group and from 1 to 5 (mean 1.35) in the AP group. EM is a minimally invasive and safe technique which provides accurate removal of papillomas, although recurrence is often unavoidable. Prognosis for the disease therefore remains rather unpredictable.

Unique Identifier: 21014715

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J Clin Virol 2000 Oct;19(1-2):101-11

Public health paradoxes and the epidemiological impact of an HPV vaccine.

Garnett GP; Waddell HC

Wellcome Trust Centre for the Epidemiology of Infectious Disease, University of Oxford, South Parks Road, OX1 2JD, Oxford, UK.

Background: our understanding of human papilloma virus (HPV) and cervical cancer has improved dramatically, with a vaccine against the viral infection being a real possibility in the near future. Aims: the goal of an HPV vaccine would be to reduce the prevalence of infection and hence the risk of cervical abnormalities. However, questions arise as to how this would interact with an existing intervention, screening, which reduces the progress of cervical abnormalities to serious disease. Furthermore, will a vaccine against one genotype influence the other types within a population and will the patterns of infection and disease remain the same if the vaccine alters the timing and type of HPVs experienced within a population? What would a vaccine that only worked in one sex achieve and how widespread would the use of such a vaccine have to be? Conclusion: the above-given questions can be addressed within a theoretical framework that describes the transmission dynamics of human papilloma virus.

Unique Identifier: 20546050

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Chest 2000 Oct;118(4):1210-4

Successful treatment of juvenile laryngeal papillomatosis-related multicystic lung disease with cidofovir case report and review of the literature.

Dancey DR; Chamberlain DW; Krajden M; Palefsky J; Alberti PW; Downey GP

Division of Respirology (Drs. Dancey and Downey) and the Division of Medical Microbiology (Dr. Krajden), Department of Medicine, the Department of Laboratory Medicine and Pathobiology (Dr. Chamberlain), and the Division of Otolaryngology

Cidofovir, a nucleoside analog antiviral agent, has been used with moderate success in the treatment of juvenile laryngeal papillomatosis (JLP) by direct intralesional injection. We report the first case where IV cidofovir was used successfully to treat a rare but lethal multicystic lung disease complicating JLP. A 35-year-old woman with a history of JLP requiring multiple laser ablations of laryngeal papillomata each year presented with hemoptysis and was found on CT scan to have bilateral, multiple pulmonary nodules and cysts. The results of BAL fluid analysis demonstrated no evidence of malignancy, and cultures were negative for fungi and mycobacteria. Molecular DNA typing of a biopsy specimen obtained from a laryngeal papilloma confirmed infection with human papilloma virus type 11. She received 12 months of treatment with IV cidofovir followed by 9 months of combined treatmentwith IV cidofovir and subcutaneous interferon-alpha-2A. This therapeutic regime resulted in a markedly decreased requirement for surgical removal of laryngeal papillomata, and CT scanning documented the regression of the lesions in the lung parenchyma that persisted after the discontinuation of therapy. The results of this case demonstrate that cidofovir may be used successfully to treat JLP-related lung disease and suggest that further studies are warranted.

Unique Identifier: 20490299

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Laryngoscope 2000 Oct;110(10 Pt 1):1783-5

A pilot series demonstrating fluorescence staining of laryngeal papilloma using 5-aminolevulinic acid.

Leunig A; Betz CS; Mehlmann M; Stepp H; Arbogast S; Grevers G; Baumgartner R

Department of Otorhinolaryngology--Head and Neck Surgery, University of Munich, Grosshadern Clinic, Germany. Andreas.Leunig@hno.med.uni-muenchen.de

[No abstract available]

Unique Identifier: 20489545

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Arch Otolaryngol Head Neck Surg 2000 Oct;126(10):1239-43

Clinical update on 10 children treated with intralesional cidofovir injections for severe recurrent respiratory papillomatosis.

Pransky SM; Brewster DF; Magit AE; Kearns DB

3030 Children's Way, Suite 402, San Diego, CA 92125, USA.

OBJECTIVES: To continue assessment of the benefits and risks of intralesional administration of cidofovir, an acyclic nucleoside phosphonate, for treating severe recurrent respiratory papillomatosis (RRP) in pediatric patients, and to discuss guidelines for larger prospective multi-institutional studies of the use of cidofovir. DESIGN: Prospective case series. SETTING: Tertiary care children's hospital. PATIENTS: A total of 10 patients with severe RRP (defined as requiring debulking procedures to maintain airway patency at least once a month) underwent intralesional cidofovir therapy. The original 5 patients have received more than 1 year of follow-up since their last cidofovir injection, and 5 subsequent patients have been treated with a revised injection protocol. INTERVENTION: Microsuspension laryngoscopy with intralesional injection of cidofovir after repetitive carbon dioxide laser treatments and mechanical debulking of papillomas. MAIN OUTCOME MEASURES: Papilloma stage at the time of serial laryngoscopies. Histologic examination of biopsy specimens of laryngeal tissue obtained 1 year or more after last cidofovir injection. RESULTS: There was evidence of marked improvement in the 4 of the 5 new patients enrolled under the revised injection protocol, continuation of a disease-free state in 1 of the original 5 patients, and sustained improvement in 4 of the 5 original patients, resulting in a

significantly reduced interval of intervention. CONCLUSIONS: Intralesional cidofovir therapy continues to show benefit in the treatment of severe RRP in pediatric patients. Safety profiles have not been fully established, but current histologic data are reassuring.

Unique Identifier: 20487834

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J Infect 2000 Sep;41(2):148-51

Treatment of external genital warts in men with imiquimod 2% in cream. A placebo-controlled, double-blind study.

Syed TA; Hadi SM; Qureshi ZA; Ali SM; Kwah MS

Department of Dermatology, University of California San Francisco Box 0989, San Francisco CA, 94143-0989, USA.

Objective: The purpose of this double-blind, placebo-controlled study was to evaluate the safety, clinical efficacy and tole-rability of imiquimod (2%) in cream to cure external genital warts in males.Methods: Preselected male patients (n=60) ranging between 18 and 50 years of age (mean 24.2) harbouring 558 lesions (mean 9.3) with clinical, histopathological and polymerase chain reaction (PCR) confirmed diagnosis of human papilloma virus (HPV) infection were randomized to two parallel groups. Each patient was allocated a precoded 25g tube, and instructions on how to apply the trial medication to their lesions at home once daily for three consecutive days per week (max. 12 application in 4 weeks). To evaluate the safety, clinical efficacy and tolerance, patients were exa-mined on a weekly basis. Cure was defined as the total elimination of treated warts with PCR, and Southern blot hybridization confirmed negative HPV DNA.Results: By the end of the treatment, 40% (24/60) patients and 49.8% (278/558) warts were cured. Breaking the code revealed that imiquimod cream had cured 70% (21/30) patients and 86.8% of warts, while placebo healed three subjects and 28 warts (P=0.0001). Eleven patients (18.3%), predominantly in the imiquimod cream group, experienced mild to moderate, non-objective, drug-related side effects with no dropouts. The study was followed up for 18 months from the first day of the treatment, and among the 26 cured patients, one in the imiquimod cream group and two in the placebo had a relapse after 14 months. Conclusion: The study demonstrated that 2% imiquimod in cream with mild non-objective side effects is safe, tolerable and significantly more effective than placebo in curing external genital warts in males.

Unique Identifier: 20481370

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Clin Otolaryngol 2000 Oct;25(5):358-60

RAPID COMMUNICATION: powered laryngeal shavers and laryngeal papillomatosis: a preliminary report.

Patel RS; MacKenzie K

Department of Otolaryngology Head and Neck Surgery, Royal Infirmary, Glasgow, UK.

Carbon dioxide (CO2) laser ablation is widely accepted as the most effective first line surgical treatment of recurrent laryngeal papilloma. However, vaporization of papilloma with the CO2 laser exposes the patient and staff to a potentially infective plume. Furthermore, unsuitable pathological tissue specimens and scarring of the surrounding laryngeal architecture are inevitable consequences of the thermal energy generated by this instrument. Following their innovative use in endonasal surgery, powered laryngeal microresecting instruments (Xomed Shavers) have been developed for laryngeal surgery. We assessed the value of these new instruments in five patients who had previously undergone laser ablation. All of the patients reported that their postoperative recovery was the 'same as' or 'better than' that following laser surgery. The surgeon reported that though there was more bleeding, shaver excision of papilloma provided good clearance of disease; easy collection of pathological samples; and a potentially safer and faster alternative to laser excision.

Unique Identifier: 20467089

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Ann Otol Rhinol Laryngol 2000 Sep;109(9):812-8

Tracheobronchial extension of recurrent respiratory papillomatosis.

Blackledge FA; Anand VK

Division of Otolaryngology, University of Mississippi Medical Center, Jackson 39216-4505, USA.

Endobronchial and pulmonary dissemination reportedly occurs in 5% of patients with laryngeal papillomatosis. It is more frequently observed in the juvenile form, and carries significant implications for treatment. In this study, we review our experiences with pulmonary and endobronchial extension of laryngeal papillomatosis. The records of the 52 patients with laryngeal papillomas treated at our institution since 1980 were reviewed. Twenty-nine percent of the patients (N = 15) developed tracheobronchial extension; 7% (N = 4) demonstrated pulmonary involvement. The birth history, race, sex, age at onset of symptoms, presenting symptoms, site and type of papillomas, surgical procedures, other methods of treatment, complications, and mortality data were analyzed. Eighty percent of the patients with tracheobronchial involvement were born to mothers with a positive history of

vaginal condylomas. Pulmonary changes in 4 patients were observed on either chest radiographs or computed tomography and were manifested as multiple parenchymal nodules in 3 of the 4 patients. Pneumatoceles, cavitary empyema, and multiple recurrent pneumonias were the predominant complications of pulmonary involvement. Of the 15 patients with tracheobronchial extension, 80% (N = 12) required tracheotomy before their presentation to us. The number of multiple surgical procedures performed to remove papillomas ranged from 7 procedures in 1 patient with a solitary tracheobronchial lesion to more than 100 procedures in 2 patients with diffuse bronchopulmonary papillomatosis. As our study shows, tracheobronchial involvement continues to complicate surgical treatment in this challenging disease process.

Unique Identifier: 20460148

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J Virol 2000 Oct;74(20):9712-6

DNA vaccination prevents and/or delays carcinoma development of papillomavirus-induced skin papillomas on rabbits.

Han R; Cladel NM; Reed CA; Peng X; Budgeon LR; Pickel M; Christensen ND

Jake Gittlen Cancer Research Institute, Department of Pathology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.

Malignant progression is a life-threatening consequence of human papillomavirus-associated lesions. In this study, we tested the efficacy of papillomavirus early-gene-based vaccines for prevention of carcinoma development of papillomavirus-induced skin papillomas on rabbits. Rabbit skin papillomas were initiated by infection with cottontail rabbit papillomavirus (CRPV). The papillomas were allowed to grow for 3 months without any treatment intervention. Rabbits were then immunized by gene gun-mediated intracutaneous administration of four DNA plasmids encoding CRPV E1, E2, E6, and E7 genes, respectively. All eight control rabbits receiving vector alone developed invasive carcinoma within 8 to 13 months. In contrast, only two of eight vaccinated rabbits developed carcinoma at 12 and 15 months, respectively. Papilloma growth was suppressed in the majority of vaccinated rabbits but not completely eradicated. These results indicate that gene gun-mediated immunization with papillomavirus early genes may be a promising strategy for prevention of malignant progression of human papillomavirus-associated lesions in humans.

Unique Identifier: 20457235

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Antiviral Res 2000 Aug;47(2):103-9

Cyclic HPMPC is safe and effective against systemic guinea pig cytomegalovirus infection in immune compromised animals.

Bourne N; Bravo FJ; Bernstein DI

Children's Hospital Medical Center, Division of Infectious Diseases, 3333 Burnet Avenue, 45229-3039, Cincinnati, OH, USA.

Cidofovir (HPMPC) is licensed for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS but its use is limited by nephrotoxicity. We evaluated the safety and efficacy of 1-[((s)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine dihydrate (CHPMPC) the cyclic congener of cidofovir. Treatment was well tolerated both in normal guinea pigs and in animals immune compromised with cyclophosphamide. Further, blood chemistry analysis showed no adverse effects of CHPMPC treatment on kidney or liver function. In efficacy studies in immune compromised guinea pigs challenged with a virulent salivary gland passaged guinea pig CMV, CHPMPC treatment significantly reduced mortality resulting from disseminated virus infection. Quantitative culture showed that treatment also significantly reduced virus replication in the liver and spleen, but not the lungs of infected animals. The efficacy of CHPMPC combined with its improved safety profile appear to make it an attractive alternative to cidofovir for the treatment of herpesvirus infections. Further evaluation is warranted.

Unique Identifier: 20452541

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Otolaryngol Head Neck Surg 1982 Nov-Dec;90(6):728-35

Culture of human laryngeal papilloma cells in vitro.

Steinberg BM; Abramson AL; Meade RP

Department of Otolaryngology, Long Island Jewish-Hillside Medical Center, New Hyde Park, NY 11042, USA.

Human laryngeal epithelial cells have been grown in tissue culture in a hydrated collagen gel containing Nutrient Mixture F12 (Gibco) supplemented with 15% fetal calf serum and 10 micrograms/mL hydrocortisone. Primary cells often remain viable in culture for more than six months. They can be serially transferred two to four times before senescence. Cells derived both from normal epithelium and from laryngeal papilloma have been successfully cultured. Papilloma cells appear to contain more perinuclear granules and form fewer tight junctions than normal cells.

Unique Identifier: 20449917

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Otolaryngol Clin North Am 2000 Oct;33(5):1127-42

Recurrent respiratory papillomatosis of the larynx: current diagnosis and treatment.

Derkay CS; Darrow DH

Department of Otolaryngology-Head and Neck Surgery, Eastern Virginia Medical School, Norfolk, Virginia, USA.

Treating children with recurrent respiratory papillomatosis can be very rewarding as more information is learned about human papillomavirus. The future goals are reducing the morbidity and mortality of this disease process. The establishment of the national recurrent respiratory papillomatosis patient registry and coordinated efforts between basic scientists involved in human papillomavirus research and clinicians involved in the treatment of recurrent respiratory papillomatosis should aid the endeavor.

Unique Identifier: 20442345

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Indian J Pediatr 2000 Aug;67(8):567-9

Multiple papilloma larynx.

Yadav SP; Gera A; Singh J; Ranga RK

Department of Otolaryngology, Pt. B.D. Sharma Postgraduate Institute of Medical Sciences, Rohtak.

Multiple papilloma of larynx is caused by human papilloma virus. We treated sixteen such cases (10 males and six females) in the last 10 years. All presented with hoarseness while six presented with difficulty in respiration. Three patients needed tracheostomy, all had difficult decanulation, and one developed laryngotracheal stenosis and could not be decanulated. All were treated by surgical excision; ten had recurrence. Four patients were treated with post operative Acyclovir with no recurrence in three cases.

Unique Identifier: 20441011

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Arch Otolaryngol Head Neck Surg 2000 Sep;126(9):1119-23

Molecular identification of 7 human papillomavirus types in recurrent respiratory papillomatosis.

Penaloza-Plascencia M; Montoya-Fuentes H; Flores-Martinez SE; Fierro-Velasco FJ; Penaloza-Gonzalez JM; Sanchez-Corona J

Division de Medicina Molecular, Centro de Investigacion Biomedica de Occidente, Apartado Postal 1-3838, Guadalajara, Jalisco, Mexico.

BACKGROUND: Recurrent respiratory papillomatosis (RRP) is the most frequent benign neoplasm in childhood; it originates as a mild dysphonia and results in asphyxia. The RRP has been associated with an infection caused by human papillomavirus (HPV), mainly types 6 and 11, the latter being associated with more severe RRP. OBJECTIVES: To analyze the frequency of the association of RRP with the HPV types in our juvenile population and to classify it according to severity. DESIGN: Observational descriptive trial. MATERIALS AND METHODS: Forty-seven samples of paraffin-embedded papillomas, from 26 female and 21 male children (age range, 2 weeks to 17 years) were analyzed. DNA was isolated and a 188-base pair fragment was amplified from a consensus sequence in the E1 open reading frame of several HPVs by polymerase chain reaction. The corresponding band was recovered and reamplified. The fragment was digested with the restriction enzyme RsaI. The digestion products were compared with patterns of molecular weight markers for viral type identification. The patients' clinical records were reviewed, and RRP was classified as mild or aggressive. RESULTS: The presence of HPV types 6, 11, 16, 31, 33, 35, or 39 was confirmed in all the cases with different combinations. The chi(2) test showed no significant differences in clinical aggressiveness among the viral types. A logistic regression analysis demonstrated no association between clinical aggressiveness and any viral type or viral combination. CONCLUSION: These results show that RRP is caused by infection with HPV types 6 and 11 in addition to many other types, with no relationship between HPV type and clinical severity.

Unique Identifier: 20435376

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Vopr Onkol 2000;46(3):340-3

A comparative evaluation of treatment methods for a genital papillomavirus infection in women with different viral genotypes.

Mikhailov IG; Maksimov SIa; Novik VI; Safronnikova NR; Vishnevskii AS; Prianishnikov VA; Lyshev AA

N. N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St. Petersburg.

Such genotypes of human papilloma virus (HPV) as "malignant" (180), "benign" (49) and indeterminate (127) were identified in 356 females by PCR and cytological procedures. The following therapeutic techniques were compared: cryodestruction of the uterine cervix (60), antiviral medication (AVM) (19), combination of AVM and cryodestruction (224), and combination of AVM and laser destruction (54). In the "malignant" HPV group, AVM in conjunction with cryo- or laser destruction was significantly more effective than cryodestruction or AVM alone. Both cryodestruction alone and in combination with AVM were more effective in treating "benign" genotypes. Repeat courses showed the same tendency.

Unique Identifier: 20432802

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J Virol 2000 Sep;74(18):8700-8

Granulocyte-macrophage colony-stimulating factor priming plus papillomavirus E6 DNA vaccination: effects on papilloma formation and regression in the cottontail rabbit papillomavirus--rabbit model.

Leachman SA; Tigelaar RE; Shlyankevich M; Slade MD; Irwin M; Chang E; Wu TC; Xiao W; Pazhani S; Zelterman D; Brandsma JL

Department of Dermatology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA.

A cottontail rabbit papillomavirus (CRPV) E6 DNA vaccine that induces significant protection against CRPV challenge was used in a superior vaccination regimen in which the cutaneous sites of vaccination were primed with an expression vector encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that induces differentiation and local recruitment of professional antigen-presenting cells. This treatment induced a massive influx of major histocompatibility complex class II-positive cells. In a vaccination-challenge experiment, rabbit groups were treated by E6 DNA vaccination, GM-CSF DNA inoculation, or a combination of both treatments. After two immunizations, rabbits were challenged with CRPV at low, moderate, and high stringencies and monitored for papilloma formation. As expected, all clinical outcomes were monotonically related to the stringency of the viral challenge. The results demonstrate that GM-CSF priming greatly augmented the effects of CRPV E6 vaccination. First, challenge sites in control rabbits (at the moderate challenge stringency) had a 0% probability of remaining disease free, versus a 50% probability in E6-vaccinated rabbits, and whereas GM-CSF alone had no effect, the interaction between GM-CSF priming and E6 vaccination increased disease-free survival to 67%. Second, the incubation period before papilloma onset was lengthened by E6 DNA vaccination alone or to some extent by GM-CSF DNA inoculation alone, and the combination of treatments induced additive effects. Third, the rate of papilloma growth was reduced by E6 vaccination and, to a lesser extent, by GM-CSF treatment. In addition, the interaction between the E6 and GM-CSF treatments was synergistic and yielded more than a 99% reduction in papilloma volume. Finally, regression occurred among the papillomas that formed in rabbits treated with the E6 vaccine and/or with GM-CSF, with the highest regression frequency occurring in rabbits that received the combination treatment.

Unique Identifier: 20411444

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Arch Otolaryngol Head Neck Surg 2000 Aug;126(8):935-9

The cost of juvenile-onset recurrent respiratory papillomatosis.

Bishai D; Kashima H; Shah K

The Johns Hopkins School of Public Health, Department of Population and Family Health Sciences, Baltimore, MD 21205, USA. dbishai@jhsph.edu

OBJECTIVE: To assess the medical costs and the number of quality-adjusted life years lost owing to juvenile-onset recurrent respiratory papillomatosis (JORRP). DESIGN: We examined hospital and physician charges for JORRP surgical procedures in Maryland in 1994 adjusting for inflation and the cost-charge ratio. Centers for Disease Control and Prevention data on treatment intensity for JORRP were augmented with a review of treatment records for 18 patients with JORRP. Sensitivity analyses were performed. To illustrate the application of our cost estimates, we compare the costs of JORRP to the costs of the surgical procedures that would be necessary to prevent it. RESULTS: We find that the present value at birth of the cost of a single case of JORRP is $201,724 (range, $61,822-$474,334). The annual cost for a single case of JORRP is $57,996 (range, $32,407-$94,114). The annual cost of JORRP in the United States is between $40 million and $123 million depending on the prevalence. Cesarean section (CS) for women with condyloma has been suggested as a potential strategy to prevent JORRP, but its efficacy remains to be determined. Our results suggest that if only 1% of the CSs actually prevented JORRP, this strategy would be a cost-effective means to prevent JORRP. CONCLUSIONS: Studies to reduce the uncertainty surrounding the efficacy of CS and the effect of both CS and JORRP on families need to precede consideration of a policy of CS for women with clinically evident genital condyloma. Patients should be kept thoroughly informed about the role of CS for the prevention of JORRP and the nature of the remaining uncertainties.

Unique Identifier: 20380732

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Eur Arch Otorhinolaryngol 2000;257(5):263-9

Current advances in the basic research and clinical management of juvenile-onset recurrent respiratory papillomatosis.

Bergler WF; Gotte K

Department of Otolaryngology, Head and Neck Surgery, University Hospital Mannheim, Germany. wolfgang.bergler@hno.ma.uni-heidelberg.de

Juvenile-onset recurrent respiratory papillomatosis is a relatively uncommon disease that presents clinically with symptoms ranging from hoarseness to severe dyspnea. Human papilloma viruses type 6 and 11 are important in the etiology of the papillomata and are most probably transmitted from mother to child during childbirth. Although spontaneous remission is frequent, a rare fatal course because of pulmonary spread or malignant transformation has occurred. CO2 laser evaporation of papillomas and adjuvant drug therapy using lymphoblastoid alpha-interferon are the most common treatment modalities at present. However, several other treatment modalities have been tried with varying success. Recent advances in basic research and different therapeutic approaches are reviewed.

Unique Identifier: 20378462

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Int J Pediatr Otorhinolaryngol 2000 Jun 30;53(2):95-103

Mucosal swabs detect HPV in laryngeal papillomatosis patients but not family members.

Sun JD; Weatherly RA; Koopmann CF Jr; Carey TE

Department of Otolaryngology/Head and Neck Surgery, Laboratory of Cell Biology and Immunology, The University of Michigan, Ann Arbor 48109-0506, USA.

Seven patients, aged 2-7 years, with active recurrent respiratory papillomatosis (RRP) attending the University of Michigan Pediatric Otolaryngology Clinic were studied to determine if human papillomavirus (HPV) is harbored in sites of the upper aerodigestive tract other than in the laryngeal papilloma itself. We also determined if close family members had detectable virus in their oral cavities. Noninvasive swabs of buccal mucosa, posterior pharynx, nasal vestibule, and tonsillar pillar of patients, as well as buccal mucosa and posterior pharyngeal swabs of family members were studied. Swabs of the patients' papillomas served as the positive controls. HPV was detected using polymerase chain reaction (PCR) amplification and Southern hybridization techniques. Six of seven patients had detectable HPV in papilloma and endolaryngeal swabs. Four were HPV type 6, and two were HPV type 11. The patient whose swab was negative for HPV was found to be biopsy negative for papilloma 3 weeks after a single laser excision which was performed 6 months prior to the endolaryngeal swab. HPV types 16, 18 and 31 were not found in any of the patients. No swabs from other sites in patients or family members were HPV positive despite the presence of adequate DNA in the swabbed material for successful amplification of beta-actin sequences. The absence of HPV (other than in the papilloma itself) in the upper

aerodigestive tract of patients and caregivers is consistent with the absence of reported cases of horizontal transmission to siblings or other family members. The findings are also consistent with the conventional view that juvenile respiratory HPV is transmitted vertically from vaginal condylomas in the mother.

Unique Identifier: 20368401

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Nippon Jibiinkoka Gakkai Kaiho 2000 Jun;103(6):727-33

Effects of calcium on HPV16 gene transcription in cultured laryngeal epithelial cells.

Tsutsumi K; Iwatake H; Kuwabara D; Hyodo A; Kobayashi T; Koizuka I; Kato I

Department of Otolaryngology, St. Marianna University School of Medicine, Kawasaki.

Human papillomavirus (HPV) gene transcription is closely linked to the differentiation status of infected epithelial cells. A variety of physiological agents, including calcium, regulates the differentiation of cultured epithelial cells. The expression of cytokeratin No.13 (CK13) can be used as a marker for differentiation in cultured laryngeal epithelial cells (HLEC cells). The purpose of this study is to examine the effects of calcium on CK13 expression and HPV16 gene transcription in HLEC cells. We analyzed two types of HPV16-containing HLEC cells: HPV 16-immortalized HLEC cells (HLEC16 cells) and HPV16-positive (infected) cultured laryngeal papilloma cells (HLP16 cells). In the HLEC16 cells, the viral genes were integrated into the host cell chromosomes, while the HLP16 cells contained extra-chromosomal viral genes. The effects of increasing calcium concentrations on CK13 expression were then evaluated using immunocytochemistry. Both the HLP16 and the HLEC16 cells responded to an increased calcium concentration by inducing CK13 expression. In HLP16 and HLEC16 cells, the CK13 expression was undetectable at low calcium concentrations (0.1 mM) but became clearly detectable at high calcium concentrations (1.0 mM). The level of viral RNA was elevated in HLP16 cells with added calcium (1.0 mM) but was similar in HLEC16 cells grown in either low (0.1 mM) or high (1.0 mM) calcium concentrations. These results suggest that a calcium-induced differentiation results in the up-regulation of HPV16 gene transcription in HLP16 cells. The integration of viral gene into the host cell chromosomes may be an important determinant for the differentiation-independent transcription of HPV16 genes.

Unique Identifier: 20355775

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Clin Ter 2000;151(1 Suppl 1):35-52

Cutaneous and mucous infections from human papilloma virus: new therapeutical approach.

Verardi S; Zupy E; Marconi D; Romanini C; Casciani CU

Chair of Obstetrical (Maternity Home), University of Rome Tor Vergata, Italy.

[No abstract available]

Unique Identifier: 20335697

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J Voice 2000 Jun;14(2):278-81

The association of laryngoceles with ventricular phonation.

Dray TG; Waugh PF; Hillel AD

Department of Otolaryngology-Head and Neck Surgery, University of Washington Medical Center, Seattle 98195, USA.

Laryngoceles represent dilatations of the laryngeal saccule that may extend internally into the airway, or externally through the thyrohyoid membrane. Unilateral laryngoceles are uncommon clinical entities and bilateral laryngoceles are rare. Certain activities like glass blowing and playing a wind instrument are associated with laryngocele development, as is laryngeal carcinoma in the ventricular area. This case describes development of bilateral laryngoceles in a patient who chronically uses ventricular phonation during speech. The pathogenesis involves repetitive elevation of intralaryngeal pressure during false vocal cord approximation, exposing the ventricles to abnormally high air pressures. The pathogenesis in this case, as well as in laryngoceles associated with occupational or anatomic risk factors, is discussed.

Unique Identifier: 20331835

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Head Neck 2000 Jul;22(4):360-8

Papillary squamous cell carcinomas of the upper aerodigestive tract: a clinicopathologic and molecular study.

Suarez PA; Adler-Storthz K; Luna MA; El-Naggar AK; Abdul-Karim FW; Batsakis JG

Department of Stomatology, The University of Texas Dental Branch, Houston 77030, USA.

BACKGROUND: The limited studies and the small number of published cases of papillary squamous cell carcinoma have precluded accurate assessment of the biologic characteristics of this lesion. METHODS: Thirty-eight of the carcinomas were studied. In-situ hybridization and polymerase chain reaction were performed to detect human papilloma virus (HPV) and p53 expression. RESULTS: HPV was found in 4 of 14 assessable carcinomas by in-situ hybridization and in 5 of 14 by polymerase chain reaction. The most frequently identified HPVs were HPVs in 6/11 and 16/18 patients. In general, a reciprocal relationship was found between p53 and HPV prevalence. The most lethal site for this tumor was the sinonasal tract, whereas patients with papillary squamous cell carcinomas of the larynx had the best outlook. Eleven of 25 (44%) assessable patients died of disease (mean time interval, 2 year). CONCLUSIONS: Papillary squamous cell carcinoma of the upper aerodigestive tract is a distinct variant of squamous cell carcinoma. As such and because of its putative association with HPV, papillary squamous cell carcinoma could be an informative model for defining how viral oncogenes cooperate with other factors in genomic instability, carcinogenesis, and tumor development.

Unique Identifier: 20320809

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Antiviral Res 2000 May;46(2):135-44

Topical effects of cidofovir on cutaneous rabbit warts: treatment regimen and inoculum dependence.

Duan J; Paris W; De Marte J; Roopchand D; Fleet TL; Cordingley MG

Department of Biological Sciences, Boehringer Ingelheim (Canada) Ltd, Bio-Mega Research Division, 2100 Cunard Street, Quebec, H7S 2G5, Laval, Canada.

The present study examined topical effects of cidofovir on cutaneous rabbit warts. Based on an inoculum-dependency study, each New Zealand White rabbit was inoculated with a high and low titer of cottontail rabbit papillomavirus (CRPV) at four sites on each dorsolateral area. Inoculation with 50 ID(50) induced papillomas at 100% of the inoculation sites within 16+/-1 days, and the wart growth curve plateaued within approximately 7 weeks. With an inoculum of 5 ID(50), 80% of the inoculated sites developed papillomas within 21+/-1 days and their size plateaued at a later time. Cidofovir was applied topically twice daily on the inoculated sites at a concentration of 1% for 18 days, starting at three different time points. In the first experiment, treatment was initiated 7 days post-inoculation. One of the inoculated sides received cidofovir or the vehicle, PBS, while the other side was left untreated. With this treatment regimen, cidofovir significantly delayed the time of onset and the growth rate of papillomas induced with the high titer of inoculum. It completely prevented papilloma-induction on the sites inoculated with the low titer of CRPV. Reversible side-effects of

cidofovir were observed on the directly treated area including erythema, necrosis, and flaking. Both therapeutic and side-effects were limited to the sites of direct exposure. In the second experiment, one of the two sides in each group of rabbits received cidofovir or vehicle starting on day 29 post-inoculation. With this treatment regimen, cidofovir significantly reduced wart growth against the low titer only. Topical treatment initiated on day 49 post-inoculation was not effective on warts initiated with either viral titer. These results demonstrated that topical cidofovir could be very effective against papillomavirus-induced wart growth if it is initiated early during the infection, especially against low titers of inoculum.

Unique Identifier: 20314178

Natl Med J India 1999 Nov-Dec;12(6):274-80

The impact of new technologies on vaccines.

Talwar GP; Diwan M; Razvi F; Malhotra R

Talwar Research Foundation, New Delhi, India.

Vast changes are taking place in vaccinology consequent to the introduction of new technologies. Amongst the vaccines included in the Expanded Programme of Immunization (EPI), the pertussis vaccine has been replaced by acellular purified fractions devoid of side-effects. Non-pathogenic but immunogenic mutants of tetanus and diptheria toxins are likely to replace the toxoids. An effective vaccine against hepatitis B prepared by recombinant technology is in large-scale use. Conjugated vaccines against Haemophilus influenzae b, S. pneumococcus and meningococcus are now available, as also vaccines against mumps, rubella and measles. Combination vaccines have been devised to limit the number of injections. Vaccine delivery systems have been developed to deliver multiple doses of the vaccine at a single contact point. A genetically-engineered oral vaccine for typhoid imparts better and longer duration of immunity. Oral vaccines for cholera and other enteric infections are under clinical trials. The nose as a route for immunization is showing promise for mucosal immunity and for anti-inflammatory experimental vaccines against multiple sclerosis and insulin-dependent diabetes mellitus. The range of vaccines has expanded to include pathogens resident in the body such as Helicobacter pylori (duodenal ulcer), S. mutans (dental caries), and human papilloma virus (carcinoma of the cervix). An important progress is the recognition that DNA alone can constitute the vaccines, inducing both humoral and cell-mediated immune responses. A large number of DNA vaccines have been made and shown interesting results in experimental animals. Live recombinant vaccines against rabies and rinderpest have proven to be highly effective for controlling these infections in the field, and those for AIDS are under clinical trial. Potent adjuvants have added to the efficacy of the vaccines. New technologies have emerged to 'humanize' mouse monoclonals by genetic engineering and express these efficiently in plants. These

recombinant antibodies are opening out an era of highly specific and safe therapeutic interventions. Human recombinant antibodies would be invaluable for treating patients with terminal tetanus and rabies. Antibodies are already in use for treatment of cancer, rheumatoid arthritis and allergies. An advantage of preformed antibodies directed at a defined target and given in adequate amounts is the certainty of efficacy in every recipient, in contrast to vaccines, where the quality and quantum of immune response varies from individual to individual.

Unique Identifier: 20196979

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Virology 1999 Dec 20;265(2):365-74

Naturally occurring, nonregressing canine oral papillomavirus infection: host immunity, virus characterization, and experimental infection.

Nicholls PK; Klaunberg BA; Moore RA; Santos EB; Parry NR; Gough GW; Stanley MA

Department of Pathology and Infectious Diseases, Royal Veterinary College, Hatfield, Herts, AL9 7TA, United Kingdom. pnicholl@rvc.ac.uk

Papillomaviruses occasionally cause severe, nonregressing or recurrent infections in their human and animal hosts. The mechanisms underlying these atypical infections are not known. Canine oral papillomavirus (COPV) typically regresses spontaneously and is an important model of mucosal human papillomavirus infections. A severe, naturally occurring, nonregressing COPV infection provided an opportunity to investigate some aspects of viral pathogenicity and host immunity. In this case, the papillomas proved refractory to surgical and medical treatments, including autogenous vaccination and vaccination with capsid (L1) virus-like particles. High levels of induced anti-L1 antibodies appeared to have no effect on the infection. The papillomas spread to oesophageal mucosa, perioral haired skin, and remote cutaneous sites. Isolation of COPV from the animal and sequencing of several regions of the viral genome showed no differences to the COPV prototype. Experimental infection of beagle dogs with this viral isolate resulted in the uncomplicated development and regression of oral warts within the usual period, indicating that the virus was not an unusual pathogenic variant. These findings support the hypothesis that the recurrent lesions seen in some human papillomavirus infections, such as recurrent laryngeal papillomatosis, are associated with specific defects in host immunity rather than variations in viral pathogenicity.

Unique Identifier: 20070325

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