RRP Medical Reference Service



An RRP Foundation Publication

edited by

Dave Wunrow and Bill Stern





















Winter 2000


Volume 7 • 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
Language (if it is not specified assume article is in English)
Primary affiliation (when specified)
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
210 Columbus Drive
Marshfield WI 54449
(715) 387-8824
E-mail: wunrowd@tznet.com




RRPF Selected Articles and Abstracts


Ann Otol Rhinol Laryngol 2000 Jan;109(1):72-6

Spontaneous respiration anesthesia for respiratory papillomatosis

Stern Y; McCall JE; Willging JP; Mueller KL; Cotton RT

Department of Pediatric Otorhinolaryngology, Children's Hospital Medical Center, University of Cincinnati College of Medicine, Ohio, USA.

Several anesthetic techniques for microlaryngeal laser surgery in children have been advocated. The objective of this study was to evaluate the operative conditions and safety of the spontaneous respiration anesthesia technique for carbon dioxide laser surgery in children with recurrent respiratory papillomatosis (RRP). The anesthetic and operative records of 60 pediatric patients with RRP who underwent microlaryngeal laser surgeries between 1991 and 1997 were reviewed. Papilloma location, severity of involvement, oxygen saturation, airway stability, need for intubation, duration of procedure, and complications were recorded. The patients underwent 744 surgical procedures. Two hundred two procedures were randomly studied (statistical power > or = 80%). The supraglottis and glottis were most commonly involved. Most of the papillomas were graded as moderate or severe disease. Complications occurred in 11 procedures. The surgical procedure was completed in all cases. No variable had predictive value regarding the outcome. Spontaneous respiration anesthesia is an efficient and relatively safe technique for microlaryngeal laser surgery in children with RRP.

Unique Identifier: 20114839




Am J Pathol 2000 Jan;156(1):333-7

Inverted sinonasal papilloma : A molecular genetic appraisal of its putative status as a precursor to squamous cell carcinoma

Califano J; Koch W; Sidransky D; Westra WH

Departments of Otolaryngology/Head & Neck Surgery() and Pathology,() The Johns Hopkins Medical Institutions, Baltimore, Maryland.

Inverted papilloma (IP) is a proliferative lesion of the epithelium lining the sinonasal tract. Although IP often recurs after surgical excision and is sometimes associated with squamous cell carcinoma of the sinonasal cavity (SNSCC), its presumed neoplastic nature and putative role as a precursor to squamous cell carcinoma have not been confirmed at the molecular genetic level. We analyzed the pattern of X chromosome inactivation in IPs from nine female patients. Inactivation of a single allele is seen in monoclonal proliferations and may be indicative of a neoplastic process. We also analyzed 28 IPs and 6 concurrent SNSCCs for loss of heterozygosity (LOH) on chromosomal arms 3p, 9p21, 11q13, 13q11, and 17p13. Losses at these loci occur frequently during neoplastic transformation of the upper respiratory tract and can be detected in squamous cell carcinomas and the progenitor lesions from which they arise. X chromosome analysis was informative in four of the nine IPs. All four lesions demonstrated a monoclonal pattern of inactivation. LOH was not detected in any nondysplastic areas from the 28 IPs, but LOH at one or more chromosomal loci was present in all six of the concurrent SNSCCs. We conclude that IPs are monoclonal proliferations, yet they do not fit the profile of a prototypic precursor lesion. Unlike squamous epithelial dysplasia, IPs do not routinely harbor several of the key genetic alterations that are associated with malignant transformation of the upper respiratory tract.

Unique Identifier: 20090578




Clin Diagn Lab Immunol 2000 Jan;7(1):79-85

Altered expression of TAP-1 and major histocompatibility complex class I in laryngeal papillomatosis: correlation of TAP-1 with disease

Vambutas A; Bonagura VR; Steinberg BM

Department of Otolaryngology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.

Recurrent respiratory papillomatosis (RRP) is an insidious disease caused by human papillomavirus (HPV) infection. It is characterized by a variable clinical course that can include frequent disease recurrence, significant morbidity, and occasional mortality. The mechanisms responsible for the variability in the clinical course and the persistence of latent HPV infection remain unknown. Effective T- cell-mediated clearance of HPV-infected cells may be defective in patients with RRP, leading to recurrent disease and failure to suppress latent HPV reactivation. This study describes the down-regulation of the transporter associated with antigen presentation (TAP-1) and the major histocompatibility complex (MHC) class I protein expression in laryngeal papilloma tissue biopsies and cell culture of primary explants. There was a statistically significant correlation between reduction of TAP-1 expression in biopsy tissues and rapid recurrence of disease. Patients with RRP had less frequent recurrence if their papillomas expressed TAP-1 at levels close to that of normal tissue, compared with those with very low expression of TAP-1, who had frequent recurrence (32 versus 5 weeks to the next surgical intervention). These findings suggest that HPV may evade immune recognition by down- regulating class I MHC cell surface expression via decreased TAP-1 levels. Expression of TAP-1 could be used for prognostic evaluation of disease severity. Gamma interferon was able to restore class I MHC expression at the surfaces of laryngeal papilloma cells in culture. This up-regulation of class I MHC antigen at the cell surface potentially allows the infected cell to become a target for the immune system again. This finding provides some promise for nonsurgical treatment of laryngeal papillomas.

Unique Identifier: 20087387



Int J Pediatr Otorhinolaryngol 1999 Dec 5;51(2):109-13

Cimetidine treatment for recurrent respiratory papillomatosis.

Harcourt JP; Worley G; Leighton SE

Department of Paediatric Otolaryngology, Great Ormond Street Hospital for Children, London, UK.

Effective adjuvant treatment for recurrent respiratory papillomatosis (RRP) is at present limited to alpha-interferon, which may have significant side effects including rebound growth of papillomata following its withdrawal, is given by injection and is expensive. High dose cimetidine is known to have immunomodulatory side effects and has been reported as a useful treatment for cutaneous warts. We report a case of very advanced RRP with tracheo-bronchial-pulmonary involvement treated with adjuvant cimetidine at a dose of 40 mg/kg for 4 months. The patient enjoyed a remarkable improvement in her clinical condition following treatment. The literature regarding cimetidine treatment for cutaneous warts is reviewed.

Unique Identifier: 20084642




J Hepatol 1999;31 Suppl 1:232-6

Treatment of chronic hepatitis C: comparative virologic response rates among the different interferons.

Lindsay KL

Division of Gastrointestinal and Liver Disease, University of Southern California, Los Angeles 90033, USA. klindsay@hsc.usc.edu

End-treatment and sustained virologic response rates are similar in large, comparative controlled trials which have compared the standard dosing regimens of interferon alpha-2b to interferon alpha-nl and consensus interferon, as well as to virologic response rates recently reported with interferon alpha-2b monotherapy for 24 weeks. For patients who have responded and relapsed after an initial course of alpha interferon, retreatment with consensus interferon for 48 weeks demonstrates a high sustained virologic response rate, similar to that reported with interferon alpha-2b combined with ribavirin for 24 weeks. Based on available pharmacokinetic and pharmacodynamic data, pegylation of interferon alpha-2a shows promise in demonstrating high sustained serum levels and 2',5' OAS activity. Preliminary data from a Phase II clinical trial of a 48-week treatment in naive patients demonstrates end-treatment and sustained virologic response rates similar to that seen with interferon alpha-2b combined with ribavirin for 48 weeks.

Unique Identifier: 20086306




Pediatr Emerg Care 1999 Dec;15(6):419-21

Laryngeal papillomatosis presenting as acute airway obstruction in a child.

Reeber CB; Truemper EJ; Bent JP

Department of Emergency Medicine, Medical College of Georgia, Augusta, USA.

Upper airway obstruction, regardless of cause, can masquerade or be misdiagnosed as lower airway disease in children. In such cases, therapeutic trials of antibiotics, bronchodilators, and over-the- counter medications for symptom relief routinely fail; however, the original diagnosis often goes unchallenged. If the obstructive process is progressive, then acute occlusion of the airway may occur, rapidly leading to suffocation and death if resuscitation is unsuccessful. Outlined in this report is the case of a young female with a history of asthma, poorly responsive to outpatient treatment, who presented with respiratory arrest. The cause of the respiratory collapse was later identified as a large laryngeal papilloma, a condition rarely encountered by emergency physicians.

Unique Identifier: 20074011








J Otolaryngol 1999 Dec;28(6):337-43

Clinical applications of the holmium:YAG laser in disorders of the paediatric airway.

Fong M; Clarke K; Cron C

Department of Pediatric Otolaryngology, Izaak Walton Killam-Grace Health Center, Dalhousie University, Halifax, Nova Scotia.

OBJECTIVE: The aim of this study was to review the role of the holmium:YAG laser in the management of paediatric airway disorders. METHOD: Twenty-six paediatric patients underwent 42 airway procedures between June 1993 and August 1996 in a tertiary care centre. A case series design was used. OUTCOME MEASURES: Safety, precision, hemostasis, bone-cutting properties, and accessibility of the lesion to the equipment were compared to standard therapies. Postoperative outcomes were then compared to standard therapies. RESULTS: Eight patients underwent correction of choanal atresia or revision, 10 patients underwent functional endoscopic sinus surgery, 3 underwent excision of tracheal granuloma, 2 underwent excision of tracheal web or revisions, 1 underwent excision of subglottic stenosis and bronchial stenosis, 1 underwent excision hemangioma of the tongue, and 1 underwent excision papilloma of the oral cavity. One patient in 42 procedures suffered a surgical complication. Our early success rates are comparable to other series using the carbon dioxide laser or cold instruments. CONCLUSION: The holmium:YAG laser is a safe, effective tool in the treatment of paediatric airway disorders and offers the advantage of a flexible fibre-optic system, good hemostasis, and better bone-cutting characteristics compared to the carbon dioxide laser, which is in widespread clinical use.

Unique Identifier: 20071830




Clin Immunol 1999 Dec;93(3):302-11

Recurrent respiratory papillomatosis: altered CD8(+) T-cell subsets and T(H)1/T(H)2 cytokine imbalance.

Bonagura VR; Hatam L; DeVoti J; Zeng F; Steinberg BM

Department of Pediatrics, Schneider Children's Hospital, Long Island Jewish Medical Center, 269-01 76th Avenue, New Hyde Park, New York 11040, USA. bonagura@lij.edu

Human papillomaviruses (HPVs) cause benign papillomas and squamous cell carcinomas in the genital and respiratory tracts. Recurrent respiratory papillomas (RRP) generate a high level of morbidity and significant mortality because of their location, resistance to treatment, and relentless recurrence that can vary in frequency in a given patient and between patients. We have found that T-cells from these patients, when exposed to or isolated from autologous papilloma tissue, have an elevated percentage of CD8(+), CD28(-) T-cells, and that T-cells from many of these patients express an increase in T(H)2-like cytokine mRNA in response to autologous papilloma tissue. Furthermore, both of these immunologic findings correlate with disease severity. These observations suggest that patients with RRP, and possibly others with refractory HPV-induced lesions, are unable to manage their disease with an appropriate and effective HPV-specific, T-cell response. This immune imbalance may be responsible for the development and severity of HPV- induced respiratory papillomatosis.

Unique Identifier: 20071228




Eur J Dermatol 1999 Dec;9(8):618-20

Focal dermal hypoplasia (Goltz-Gorlin syndrome) associated with obstructive papillomatosis of the larynx and hypopharynx.

Gordjani N; Herdeg S; Ross UH; Grimme H; Kleinschmidt M; Brandis M

Universitats-Kinderklinik, Mathildenstrasse 1, 79106 Freiburg, Germany. gordjani@kk1200.ukl.uni-freiberg.de

A 14-year-old girl with focal dermal hypoplasia (Goltz-Gorlin-syndrome) presented with dysphagia, hoarseness, inspiratory stridor, intermittent dry cough and a 10% weight loss. Endoscopy showed that these symptoms were caused by papillomatosis of the hypopharynx and the larynx. The papillomatous masses were resected subtotally by endoscopic laser treatment. Residual papillomas were left in the subglottic space but tracheotomy could be avoided. Complete clinical recovery with adequate weight gain as well as, resolution of dyspnoe and dysphagia resulted after the intervention. Histological examination did not show morphological signs of human papilloma virus as an etiological agent.

Unique Identifier: 20054946




Ann Otol Rhinol Laryngol 1999 Nov;108(11 Pt 1):1073-7

Characterization of human papillomavirus in airway papillomas by histologic and biochemical analysis.

Glynn M; Sanford T; Hoover L; Kinsey W; Dobbs L; Bruegger D

Department of Otolaryngology, University of Kansas Medical Center, Kansas City 66160-7380, USA.

The role of human papillomavirus (HPV) in airway papillomas has been well defined in recent literature. The chronicity and recurrence of papillomas has been postulated to be a result of residual viral genome in tissue treated with standard laser techniques. Thirteen patients with airway papillomas were selected for study with polymerase chain reaction (PCR) methods to detect viral DNA. Specimens taken prior to laser therapy and specimens taken at laser margins were consistently positive for HPV DNA by PCR. The HPV DNA is apparently present in tissues after macroscopic disease has been ablated by laser techniques. Histologic analysis of laser biopsies demonstrated fragments of squamous epithelium with cytologic features of HPV infection. Laser treatment is ineffective in eradicating HPV-infected tissues from airway papillomas, and this finding supports the notion that recurrence is a product of HPV incorporated into tissue not ablated by laser irradiation. Specific methods, results, and clinical correlation will be discussed.

Unique Identifier: 20043836




Am J Ophthalmol 1999 Nov;128(5):638-40

Treatment of recurrent conjunctival papillomatosis with mitomycin C.

Hawkins AS; Yu J; Hamming NA; Rubenstein JB

Department of Ophthalmology, Rush Medical College of Rush University, Chicago, Illinois 60612, USA.

PURPOSE: To report an effective treatment for recurrent squamous papillomas of the conjunctiva with excision and application of mitomycin C. METHOD: Case report. RESULTS: A 5-year-old African- American girl with recurrent squamous papillomas of the right bulbar and palpebral conjunctiva was treated with multiple therapies, including excision, cryotherapy, and conjunctival injection of alpha- interferon; all therapies were followed by recurrence. After treatment with excision followed by intraoperative application of mitomycin C to the involved conjunctiva, the patient had no recurrence in a 30-month period. CONCLUSIONS: Excision with application of mitomycin C was successful in managing a case of squamous papillomatosis that was resistant to traditional therapy.

Unique Identifier: 20043469




Surg Clin North Am 1999 Oct;79(5):1207-21

Chemoprevention of breast cancer.

Osborne MP

Department of Surgery, Cornell University Medical College, New York, New York, USA. osborne@strang.org

A critical question is, why do the European studies fail to confirm the US study? Clearly, the answers are complex and uncertain. Differences in power, age, risk, compliance, the use of ERT, and follow-up in the European studies may all be relevant. The efficacy of tamoxifen in BRCA 1 or 2 carriers is an important issue; recent data have shown a DNA repair defect in those with BRCA 1 gene alterations. This finding, coupled with the potential genotoxicity of tamoxifen, is of concern, but the NSABP study did show a significant reduction in breast cancer risk in those with first-degree relatives with breast cancer, including those likely to have a hereditary-predisposition gene. The issue will be clarified when the BRCA 1 or 2 status of these individuals is determined from the stored DNA samples of all participants in the NSABP study. The duration of use of an antiestrogen for prevention is uncertain; the adjuvant trial data for up to 5 years of tamoxifen use showed an effect on contralateral breast cancer prevention extending beyond 5 years, but experimental data show that stopping tamoxifen therapy results in the appearance of new tumors. The long-term use of tamoxifen for prevention carries significant risks. If raloxifene can be given long term, then continuing the prevention of tumors may be possible if raloxifene is proven safe. Should tamoxifen be used outside of a clinical trial? The FDA has approved its use to "delay" breast cancer so it can be prescribed for any patient at increased risk for breast cancer. The word prevention has been the subject of polemics. Every day that breast cancer is delayed is a day that it is prevented. Risk reduction is technically a more accurate phrase but lacks meaning to many women. Novel approaches to chemoprevention are being explored. Naturally occurring compounds or their analogues are being assessed. Based on experimental studies, the vitamin A analogue 4-hydroxyphenyl retinamide (4-HPR) was shown to delay and reduce carcinogen-induced breast cancer. A randomized clinical trial of 4-HPR is being tested in women in Italy to reduce contralateral breast cancer, but no results are available. New approaches using substances derived from plants, such as vegetables, are being pursued. Based on epidemiologic studies, investigators have proposed that an estrogen metabolite, C16 alpha- hydroxyesterone (16 alpha-OHE1), may have estrogen-stimulating and DNA- damaging properties of mammary epithelial cells. Strategies to reduce 16 alpha-OHE1 have been explored. Indole-3-carbinol, found in high concentration in cruciferous vegetables (i.e., cabbage, cauliflower, broccoli, rabe, brussels sprouts, kale, and bok choi), has been shown to reduce mammary cancer in rodent models and induces a metabolic pathway competing with 16 alpha-OHE1, which increases C-2 hydroxyesterone and thereby reduces substrate available for the 16 alpha-OHE1 pathway. Indole-3-carbinol has a good short-term safety profile. The minimum effective dose that favorably perturbs the ratio between 16 alpha-OHE1 and 2-OHE1 has been determined, and a pilot feasibility trial is in progress in women at risk for breast cancer at Strang Cancer Prevention Center. Future research will identify single or a combination of agents that may significantly reduce the risk for breast cancer without toxicity. A better understanding of the steps involved in the progression of normal breast cells toward cancer will permit the development of strategies to reduce the incidence of and mortality from breast cancer, with the ultimate goal of prevention.

Unique Identifier: 20038854




Eur Arch Otorhinolaryngol 1999;256(9):450-4

Malignant transformation in non-irradiated juvenile laryngeal papillomatosis.

Rehberg E; Kleinsasser O

Department of Otorhinolaryngology, Philipps University, Deutschhausstrasse 3, D-35033 Marburg, Germany.

A spontaneous cancer transformation of non-irradiated juvenile papillomas has been observed in a very small number of cases. We report on six more patients with juvenile laryngeal papillomatosis developing into a squamous-cell carcinoma. Three patients had childhood papillomatosis and three patients adult onsets of their papillomas. The average duration between onset of papillomatosis and cancer diagnosis was 33 years, while the average age at time of diagnosis of a laryngeal cancer was 50 years. All patients were cigarette smokers, but none of them had received prior irradiation. The typical histological picture of tumors showed an infiltrating keratinizing squamous carcinoma besides remaining benign papillomas within the larynx. Our study again illustrates the risk of malignant transformation of juvenile papillomatosis in long-lasting cases. Therefore, regular extensive biopsies and careful histopathological examination are required. The role of smoking as a co-factor in the development of carcinoma ex- papilloma is still not clear.

Unique Identifier: 20019779




Chin J Dent Res 1998 Dec;1(3):35-7

Detection of the E7 transform gene of human papilloma virus type 16 in human oral squamous cell carcinoma.

Wang J; Li J; Huang H; Fu Y

Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Hubei Medical University (HMU), P. R. China.

OBJECTIVE: To determine, with the use of polymerase chain reaction, the prevalence of human papillomavirus (HPV) 16 in 30 patients with primary oral squamous cell carcinoma (OSCC) and 30 healthy control patients. MATERIALS AND METHODS: DNA was extracted from freshly frozen tumor tissues of 30 patients with primary oral squamous cell carcinoma and from the oral mucosa of 30 controls. A pair of specific primers of the E7 early gene of HPV 16 were designed. PCR products were run by 1.5% agarose gel and the results of electrophoresis were photographed. RESULTS: HPV 16 was detected in 36.7% (11/30) of oral squamous cell carcinoma patients and 11.1% (4/30) of controls. CONCLUSIONS: HPV 16 has a significant association with oral squamous cell carcinoma. However, the role HPV 16 plays in the tumorigenesis of oral cancer and its clinical significance remain to be investigated.

Unique Identifier: 20018727




Otolaryngol Head Neck Surg 1999 Nov;121(5):668

Saccular cyst caused by recurrent respiratory papillomatosis.

Stone ME; Myer CM 3rd; Stern Y

Children's Hospital Medical Center.

[No abstract available]

Unique Identifier: 20016498




Eur J Cancer Prev 1999 Oct;8(5):449-55

Sandalwood oil prevent skin tumour development in CD1 mice.

Dwivedi C; Zhang Y

College of Pharmacy, South Dakota State University, Brookings 57007- 0099, USA. Chandradhar_Dwivedi@sdstate.edu

Sandalwood oil (SW oil) has been used for the treatment of inflammatory and eruptive skin diseases. In the present study, the chemopreventive effects of SW oil on 7,12-dimethylbenz(a)-anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate(TPA)-promoted skin tumour development and TPA-induced ornithine decarboxylase (ODC) activity in CD1 mice were investigated. Female CD1 mice (5-6 weeks old) were divided in different groups, having 30 mice in each group. One week after topical application of DMBA (200 nmole in 100 microl acetone) alone or with SW oil at different concentrations (100 microl, 1.25, 2.5, 3.75, 5% in acetone), at different times (0.5, 1, 2 h) before DMBA, the mice were treated topically with TPA (5 nmole in 100 microl acetone) alone or with SW oil at different concentrations (100 microl, 1.25, 2.5, 3.75, 5% in acetone) at different times (0.5, 1, 2 h) before TPA applications twice a week for 20 weeks. The mice were weighed and papillomas counted weekly. The results indicate that SW oil pre- treatment decreased the papilloma incidence and multiplicity in a concentration and time-dependent manner. The pre-treatment with 5% SW oil (100 microl) 1 h before DMBA and TPA treatments provided a maximum of 67% and 96% decrease in papilloma incidence and multiplicity, respectively, after 20 weeks of promotion. The mice pre-treated with SW oil at all concentrations and time period before TPA had significantly lower ODC activity than the group treated with TPA alone. The data suggest that SW oil could be an effective chemopreventive agent against chemically-induced skin cancer.

Unique Identifier: 20014437



Virology 1999 Oct 25;263(2):388-94

Induction of E6/E7 expression in cottontail rabbit papillomavirus latency following UV activation.

Zhang P; Nouri M; Brandsma JL; Iftner T; Steinberg BM

Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.

Latent human papillomavirus (HPV) infections are widespread in the genital and respiratory tracts and are a source of recurrent disease. This study used a cottontail rabbit papillomavirus (CRPV) model to determine the presence of E1, E6, and E7 transcripts in latent infection and to determine the temporal change in transcripts following UV activation. We found E1 transcripts in all latently infected sites but no detectable E6 and E7 transcripts, consistent with our earlier studies of HPV6/11 latency. These results suggest that this transcription pattern is broadly characteristic of latent papillomavirus infections. E6/E7 transcripts were detectable within 1 week of irradiation, with maximal induction (approximately 40% of sites) at 2 weeks postirradiation. Papillomas were induced in approximately 26% of irradiated sites after a 3- to 5-week lag. Sites that did not form papillomas by 3 months after irradiation were CRPV DNA positive but E6/E7 RNA negative. Thus, only a subset of latent infections can be induced to express E6/E7 transcripts and form papillomas. We propose that CRPV can be used to study the molecular processes regulating papillomavirus activation.

Unique Identifier: 20013196


Radiat Res 1999 Nov;152(5):493-8

Sensitizing human cervical cancer cells In vitro to ionizing radiation with interferon beta or gamma.

Gruninger L; Cottin E; Li YX; Noel A; Ozsahin M; Coucke PA

Laboratory of Radiobiology, Department of Radiation Oncology, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.

Human cervical cancer is often associated with human papilloma virus (HPV). HPV products, such as the oncoproteins E6 and E7, are known to disrupt the function of TP53 (formerly known as p53). The protein encoded by the TP53 gene plays a central role in managing cellular damage. Interferons are known to down-regulate E6/E7 and may therefore restore TP53 function and influence radiation sensitivity. We investigated whether IFNB or IFNG, at various concentrations (2- 300 IU/ml) and for a range of durations of exposure (from 48 h before to 8 h after irradiation), were able to modify the radiation response of HeLa, C4-1, Me-180, C33-A and SiHa cells. In parallel to the clonogenic assays, we analyzed the effect on the mRNA that encodes IFNB and E6 by Northern blotting in the same experimental conditions. A significant change in the initial slope of the dose-response curve was observed more consistently with IFNB than with IFNG. No changes in the mRNA or protein level of TP53 and E6 could be detected. Thus other mechanisms of action need to be investigated to explain radiosensitization with recombinant IFNB in cells of human cervical cancer cell lines.

Unique Identifier: 20004659




Chem Biol Interact 1999 Sep 30;122(2):89-106

Protection against 12-O-tetradecanoylphorbol-13-acetate induced skin- hyperplasia and tumor promotion, in a two-stage carcinogenesis mouse model, by the 2,3-dimethyl-6(2-dimethylaminoethyl)-6H-indolo-[2,3- b]quinoxaline analogue of ellipticine.

Skarin T; Rozell BL; Bergman J; Toftgard R; Moller L

Department of Biosciences, Karolinska Institute, Novum, Huddinge, Sweden.

The effects of topical applications of 2,3-dimethyl-6(2- dimethylaminoethyl)-6H-indolo-[2,3-b]quinoxaline (B-220), on 12-O- tetradecanoylphorbol-13-acetate (TPA) or benzoylperoxide (BPO) induced promotion of skin tumors and hyperplasia were studied in female SENCAR mice. Papillomas were induced by initiation with 7,12- dimethylbenz[a]anthracene (DMBA), followed by promotion biweekly with TPA or BPO. Administration of B-220 1 h before TPA promotion resulted in a prolonged latency period of tumor appearance and a significantly reduced (up to 15% of positive controls) papilloma yield at 20 weeks. Moreover, if B-220 treatment was terminated after 20 weeks and TPA treatment continued, papilloma development resumed indicating that initiated tumor cells were still present but were unable to grow with B- 220 present. If B-220 pretreatment was not given during the first 10 weeks of TPA promotion, incidence at 20 weeks was not reduced but tumor multiplicity was still decreased. In addition a marked reduction of the TPA induced sustained epidermal hyperplasia was observed in the long term experiment. Neither the inflammatory response nor the increase in the number of apoptotic cells seen in short term experiment after a single TPA treatment were inhibited by B-220. B-220 administration before BPO promotion had no effect on the appearance of BPO induced papillomas or epidermal hyperplasia, suggesting that TPA and BPO promote tumor formation via at least partially different mechanisms. In experiments where B-220 was applied topically 1 h before DMBA initiation, little or no effect was seen. No morphological changes in mouse skin due to long term exposure (two times/week, 39 weeks) to B- 220 were found. In conclusion, we present evidence that B-220 is a potent inhibitor of mouse skin tumor promotion by TPA, but has little effect on the initiation step or the survival of initiated cells.

Unique Identifier: 99456263




Oncogene 1999 Oct 14;18(42):5727-37

The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-alpha.

Li S; Labrecque S; Gauzzi MC; Cuddihy AR; Wong AH; Pellegrini S; Matlashewski GJ; Koromilas AE

Department of Oncology, McGill University, Montreal, Quebec, Canada.

We have examined the effects of human papilloma virus (HPV) E6 proteins on interferon (IFN) signaling. Here we show that expression of the 'malignant' HPV-18 E6 in human HT1080 cells results in inhibition of Jak-STAT activation in response to IFN-alpha but not IFN-gamma. This inhibitory effect is not shared by the 'benign' HPV-11 E6. The DNA- binding and transactivation capacities of the transcription factor ISGF3 are diminished in cells expressing HPV-18 E6 after IFN-alpha treatment as a result of decreased tyrosine phosphorylation of Tyk2, STAT2 and STAT1. However, HPV-18 E6 does not affect the induction of tyrosine phosphorylation and DNA-binding of STAT1 by IFN-gamma. In addition, HPV E6 proteins physically interact with Tyk2. This interaction takes place preferably with HPV-18 E6 and to a lesser extent with HPV-11 E6. The E6/Tyk2 interaction requires the JH6-JH7 domains of Tyk2, which are important for Tyk2 binding to the cytoplasmic portion of IFN-alpha receptor 1 (IFNAR1). These findings demonstrate an inhibitory role of HPV-18 E6 in the IFN-alpha-induced Jak-STAT pathway, which may be explained, at least in part, by the ability of E6 to interact with and impair Tyk2 activation.

Unique Identifier: 99455253




Laryngoscope 1999 Oct;109(10):1570-9

Head and neck computed tomography virtual endoscopy: evaluation of a new imaging technique.

Gallivan RP; Nguyen TH; Armstrong WB

Department of Otolaryngology-Head & Neck Surgery, University of California, Irvine, USA.

OBJECTIVE: To evaluate a new radiographic imaging technique: computed tomography virtual endoscopy (CTVE) for head and neck tumors. STUDY DESIGN: Twenty-one patients presenting with head and neck masses who underwent axial computed tomography (CT) scan with contrast were evaluated by CTVE. Comparisons were made with video-recorded images and operative records to evaluate the potential utility of this new imaging technique. METHODS: Twenty-one patients with aerodigestive head and neck tumors were evaluated by CTVE. One patient had a nasal cylindrical cell papilloma; the remainder, squamous cell carcinomas distributed throughout the upper aerodigestive tract. Patients underwent complete head and neck examination, flexible laryngoscopy, axial CT with contrast, CTVE, and in most cases, operative endoscopy. Available clinical and radiographic evaluations were compared and correlated to CTVE findings. RESULTS: CTVE accurately demonstrated abnormalities caused by intraluminal tumor, but where there was apposition of normal tissue against tumor, inaccurate depictions of surface contour occurred. Contour resolution was limited, and mucosal irregularity could not be defined. There was very good overall correlation between virtual images, flexible laryngoscopic findings, rigid endoscopy, and operative evaluation in cases where oncological resections were performed. CTVE appears to be most accurate in evaluation of subglottic and nasopharyngeal anatomy in our series of patients. CTVE is a new radiographic technique that provides surface-contour details. The technique is undergoing rapid technical evolution, and although the image quality is limited in situations where there is apposition of tissue folds, there are a number of potential applications for this new imaging technique.

Unique Identifier: 99450758




Arch Otolaryngol Head Neck Surg 1999 Oct;125(10):1143-8

Intralesional cidofovir for recurrent respiratory papillomatosis in children.

Pransky SM; Magit AE; Kearns DB; Kang DR; Duncan NO

Pediatric Otolaryngology, Children's Hospital and Health Center, San Diego, Calif 92123, USA.

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 carbon dioxide laser therapy more frequently than once a month to maintain airway patency. Each patient underwent between 12 and 33 laryngoscopies with laser treatment prior to being injected with cidofovir. INTERVENTION: Microsuspension laryngoscopy with intralesional injection of cidofovir (Vistide) in conjunction with mechanical debulking and carbon dioxide laser of papillomas. MAIN OUTCOME MEASURE: Papilloma stage at time of serial laryngoscopies. RESULTS: One patient was disease free and 3 patients demonstrated a dramatic response to adjuvant therapy with cidofovir at the 9-month follow-up visit after the last injection of cidofovir. One patient showed an improvement in papilloma stage that was possibly related to concurrent therapy with interferon. CONCLUSIONS: 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.

Unique Identifier: 99450343




Biochem Pharmacol 1999 Sep 15;58(6):1047-55

In vitro and in vivo inhibition of human flavin-containing monooxygenase form 3 (FMO3) in the presence of dietary indoles.

Cashman JR; Xiong Y; Lin J; Verhagen H; van Poppel G; van Bladeren PJ; Larsen-Su S; Williams DE

Human Biomolecular Research Institute, San Diego, CA 92121, USA. ledcash@aol.com

The effect of consumption of glucosinolate-containing Brussels sprouts on flavin-containing monooxygenase functional activity in humans was investigated in 10 healthy, male, non-smoking volunteers. After a 3- week run-in period, 5 volunteers continued on a glucosinolate-free diet for 3 weeks (control group), and 5 others consumed 300 g of cooked Brussels sprouts per day (sprouts group). Human flavin-containing monooxygenase activity was measured by determining the levels of urinary trimethylamine and trimethylamine N-oxide. In the control group similar trimethylamine to trimethylamine N-oxide ratios were observed, while in the sprouts group the trimethylamine to trimethylamine N-oxide ratios were increased 2.6- to 3.2-fold, and thus flavin-containing monooxygenase functional activity was decreased significantly. To investigate the molecular basis for the in vivo inhibition of functional human flavin-containing monooxygenase activity, in vitro studies were carried out examining the effect of acid condensation products of indole-3-carbinol, anticipated to be formed after transit of Brussels sprouts through the gastrointestinal system, on the prominent cDNA-expressed human flavin-containing monooxygenase form 3 enzymes. Two indole-containing materials were observed to be potent inhibitors of human flavin-containing monooxygenases, having Ki values in the low micromolar range. The results suggested that acid condensation products expected to be formed upon transit of Brussels sprouts materials through the gastrointestinal system were potent competitive inhibitors of human flavin-containing monooxygenase form 3 enzymes. The findings indicate that daily intake of Brussels sprouts may lead to a decrease in human flavin-containing monooxygenase activity, and this may have consequences for metabolism of other xenobiotics or dietary constituents.

Unique Identifier: 99437456




Cytokines Cell Mol Ther 1999 Jun;5(2):79-85

Molecular analysis of resistance to interferon in patients with laryngeal papillomatosis.

Garcia-Millian R; Santos A; Perea SE; Gonzalez-Cabanas R; Valenzuela C; Arana M

Department of Cellular Biology, Center for Biological Research, Havana, Cuba. farma3@cigb.edu.cu

Although interferon (IFN)-alpha has been used successfully as an adjuvant therapy in laryngeal papillomatosis, some patients are resistant to this treatment. In order to know which patients will benefit from the therapy, we have tried to find a relationship between the IFN response and the viral and host parameters in the lesion. Detection of viral type and copy numbers by polymerase chain reaction (PCR) showed that all patients infected with human papillomavirus (HPV)- 11 were sensitive to the treatment, in contrast to those infected with HPV-6. These differences could be explained in part by the inability of HPV-11 E7 to inhibit the induction of an IFN-responsive element, whereas HPV-6 E7 almost completely inhibited the activity of this promoter in transient transfection experiments. Local immune status in the lesion showed that all HPV-11-infected patients had detectable levels of interleukin (IL)-15 and IFN-gamma mRNA, in contrast to HPV-6- infected patients, in whom mRNA for these cytokines was almost absent. Viral copy numbers and levels of IL-4 mRNA could not be correlated with IFN response. Only one patient resistant to recombinant IFN-alpha2b and negative for HPV DNA presented high titers of neutralizing anti-IFN- alpha2b antibodies. This patient became sensitive when natural IFN- alpha was administered. These results suggest that response to IFN may be a complex phenomenon resulting from the interaction between viral and host elements.

Unique Identifier: 99443703




AJNR Am J Neuroradiol 1999 Sep;20(8):1445-51

Recurrent inverted papilloma: diagnosis with pharmacokinetic dynamic gadolinium-enhanced MR imaging.

Lai PH; Yang CF; Pan HB; Wu MT; Chu ST; Ger LP; Huang WC; Hsu CC; Lee CN

Department of Radiology, Veterans General Hospital-Kaohsiung, National Yang-Ming College, Taiwan, ROC, USA.

Dynamic gadolinium-enhanced MR imaging has been used successfully to identify post-treatment recurrence or postoperative changes in rectal and cervical carcinoma. Our purpose was to evaluate the usefulness of dynamic gadolinium-enhanced MR imaging for distinguishing recurrent inverted papilloma (IP) from postoperative changes. Fifteen patients with 20 pathologically proved lesions (recurrent IP, 12; fibrosis or granulation tissue, eight) were enrolled in the study. Three observers, blinded to pathologic results, independently evaluated conventional MR images, including T1-weighted (unenhanced and postcontrast), proton-density-weighted, and T2-weighted spin-echo images. Results then were determined by consensus. Dynamic images were obtained using fast spin-echo sequences at 5, 30, 60, 90, 120, 150, 180, and 300 seconds after the injection of gadolinium- diethylene-triamine penta-acetic acid. Time-signal intensity curves of suspected lesions were analyzed by a pharmacokinetic model. The calculated amplitude and tissue distribution time were used to characterize tissue, and their values were displayed as a color-coded overlay. T2-weighted images yielded a sensitivity of 67%, a specificity of 75%, and an accuracy of 70% in the diagnosis of recurrent IP. Contrast-enhanced T1-weighted images yielded a sensitivity of 75%, a specificity of 50%, and an accuracy of 65%. Pharmacokinetic analysis showed that recurrent IP had faster (distribution time, 41 versus 88 seconds) and higher (amplitude, 2.4 versus 1.2 arbitrary units) enhancement than did fibrosis or granulation tissue. A cut-off of 65 seconds for distribution time and 1.6 units for amplitude yielded a sensitivity of 100% and a specificity of 100% for diagnosing recurrent IP. Dynamic MR imaging can differentiate accurately recurrent IP from postoperative changes and seems to be a valuable diagnostic tool.

Unique Identifier: 99440778






Am J Ophthalmol 1999 Sep;128(3):362-4

Oral cimetidine (Tagamet) for recalcitrant, diffuse conjunctival papillomatosis.

Shields CL; Lally MR; Singh AD; Shields JA; Nowinski T

Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

PURPOSE: To report the efficacy of cimetidine for treatment of conjunctival papillomatosis. METHODS: An 11-year-old boy had an 8-year history of diffuse conjunctival papillomas, treated previously with standard measures of excisional biopsy and cryotherapy. He developed spontaneous conjunctival bleeding and diffuse tumor recurrence over the entire conjunctival surface. Oral cimetidine liquid (30 mg/kg/day) was prescribed. RESULTS: Within 2 months, dramatic tumor regression was noted, with nearly complete resolution by 4 months. The patient had no local or systemic side effects from the medication. CONCLUSIONS: Oral cimetidine possesses immune modulation properties and may be useful in some cases of virus-induced conjunctival papillomatosis.

Unique Identifier: 99439053




Int J Cancer 1999 Nov 12;83(4):449-55

Asian-american variants of human papillomavirus type 16 have extensive mutations in the E2 gene and are highly amplified in cervical carcinomas.

Casas L; Galvan SC; Ordonez RM; Lopez N; Guido M; Berumen J

Multidisciplinary Research Laboratory, Military School of Medical Graduates and Army School of Medicine, University of the Army and Air Force, Mexico City, Mexico.

Human-papillomavirus (HPV)-E2 protein is involved in gene-expression regulation and replication of HPV genome. Disruption of the E2 gene during viral integration has been proposed as a mechanism of tumoral progression, since the expression of E6/E7 viral oncogenes is allowed. However, retention of E1/E2 genes and high viral amplification are frequently found in HPV16-positive carcinomas of some populations. In this study, we investigated whether retention of E1/E2 and viral amplification are associated with particular HPV16 E2 variants in cervical carcinomas. HPV16 detection, E1/E2 integrity and viral amplification were explored by Southern blot in 123 cervical carcinomas. HPV16 variants were identified by Southern blot and by sequencing E6, L1/MY and E2 regions. Of 46 HPV16-positive tumors, 34 were positive for E1/E2 and 14 of them showed a variant restriction pattern by mutations in E2. All 14 were Asian-American (AA) variants and, of 11 sub-classified, 6 were AA-a and 5 AA-c. Two E1/E2-negative tumors also contained the AA-c variant, while the remaining HPV16- positive tumors contained only European variants. The E2 gene of AA variants showed 24 mutations, 19 identical in both sub-classes. The 24 mutations were distributed throughout the entire gene and 19 result in 18 amino-acid changes. The AA variants were associated with E1/E2- positive carcinomas with more than 50 viral copies/cell (p = 0.035). The association of Asian-American E2 variants with retention of E1/E2 suggests that E2 variation may be an alternative mechanism de- regulating the expression of viral oncogenes.

Unique Identifier: 99438123


Histol Histopathol 1999 Oct;14(4):1113-8

Glycoprotein CD44 expression in benign, premalignant and malignant epithelial lesions of the larynx: an immunohistochemical study including correlation with Rb, p53, Ki-67 and PCNA.

Ioachim E; Assimakopoulos D; Goussia AC; Peschos D; Skevas A; Agnantis NJ

Department of Pathology, Medical School, University of Ioannina, Greece.

CD44 is an integral membrane glycoprotein that has diverse functions in cell-cell and cell-substrate interactions. It has been suggested that it may be a determinant of metastatic and invasive behavior in carcinomas. The immunohistochemical expression of CD44 was examined in a series of 34 squamous cell carcinomas, 13 in situ carcinomas, 35 cases with various degrees of epithelial dysplasia, 10 papillomas and 17 cases of keratosis. We used the monoclonal mouse anti-human phagocytic glycoprotein-1 CD44 (clone DF 1485), on formalin-fixed, paraffin-embedded tissue. CD44 expression was correlated with the expression of Rb and p53 proteins, with the proliferative indices Ki-67 and PCNA as well as with conventional clinicopathological data. The mean value of CD44 expression was 78.84 in squamous cell carcinomas, 78.04 in situ carcinomas, 54.93 in dysplasia, 26.8 in papillomas and 24.97 in keratosis. There was no significant difference of CD44 expression between in situ and invasive carcinomas. However, a strong difference of reaction between carcinomas and the other cases was observed. CD44 expression was statistically higher in dysplastic lesions than the cases of keratosis (p < 0.0001) and papillomas (p = 0.01). In the group of invasive carcinomas, CD44 expression was statistically correlated with pRb (p = 0.011), while in preinvasive lesions it was correlated with PCNA (p = 0.016). The relationship with the degree of dysplasia or grade of carcinoma and p53 protein expression was insignificant. These observations suggest that CD44 expression may be involved in the multiple mechanism of the development and progression of laryngeal lesions and may help to predict the risk of transformation of the benign or precancerous lesions to cancer.

Unique Identifier: 99436815



J Gen Virol 1999 Sep;80 ( Pt 9):2453-9

Human papillomavirus type 16 E2-specific T-helper lymphocyte responses in patients with cervical intraepithelial neoplasia.

Bontkes HJ; de Gruijl TD; Bijl A; Verheijen RH; Meijer CJ; Scheper RJ; Stern PL; Burns JE; Maitland NJ; Walboomers JM

Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.

T-cell-mediated immune responses against mucosal oncogenic types of human papillomaviruses (HPV) are thought to play a role in the control of the virus infection and its associated cervical lesions. The in vitro production of interleukin-2 by T-helper (Th) cells in response to the C-terminal and N-terminal domains of the HPV-16 E2 protein was determined in 74 women with cytological evidence of premalignant cervical epithelial neoplasia who participated in a non-intervention follow-up (FU) study. Cross-sectional analysis at the end of FU showed that Th cell responses against the C-terminal domain were associated with evidence of previous or present HPV-16 infection as compared to patients with no evidence of any HPV infection (18.9% versus 0%, P = 0.039). Th cell responses against the N-terminal domain were not associated with evidence of HPV-16 infection. No association with disease outcome was observed with Th cell responses against either of the E2 protein domains. However, longitudinal analysis revealed that Th cell responses against the C-terminal domain frequently occur at the time of virus clearance. Whether these responses are responsible for the clearance of the virus is not known.

Unique Identifier: 99429609




J Gen Virol 1999 Sep;80 ( Pt 9):2445-51

Human papillomavirus type 6: classification of clinical isolates and functional analysis of E2 proteins.

Kovelman R; Bilter GK; Roman A; Brown DR; Barbosa MS

Virology Program, Signal Pharmaceuticals Inc., San Diego, CA 92121, USA. rkovelma@signalpharm.com

Human papillomaviruses (HPVs) cause a variety of clinical manifestations, including the most prevalent viral sexually transmitted disease, genital warts. HPV-6 is found in a greater number of genital warts than any other HPV. To increase our understanding of the structural and functional relationships between HPV-6 isolates and to provide information for epidemiological studies, the sequences of the E2, E6 and E7 coding regions of HPV-6 genomes in clinical samples were determined. This sequence analysis was performed on isolates originally designated HPV-6a on the basis of analysis of patterns generated by restriction enzyme digestion. It was found that the designation of subtype on the basis of restriction enzyme digestion correlated poorly with the designation of subtype on the basis of sequence comparison; in fact, the clinical isolates were clearly categorized into HPV-6a and HPV-6b groups, with the previously described HPV-6vc being a member of the HPV-6a group. It was also found that the HPV-6a E2 protein is a much less potent activator of transcription than the HPV-16 E2 protein, generalizing our previous results with the HPV-6b E2 protein to this second HPV-6 E2 protein. These studies indicate that the amino acid differences observed between these natural variants of the HPV-6 E2 protein do not affect its function.

Unique Identifier: 99429608




J Voice 1999 Sep;13(3):382-8

Inspiratory pressure threshold training for glottal airway limitation in laryngeal papilloma.

Sapienza CM; Brown J; Martin D; Davenport P

Department of Communication Sciences and Disorders, University of Florida, Gainesville 32611-7420, USA. sapienza@csd.ufl.edu

A single-subject design was used to determine if inspiratory pressure threshold training increases inspiratory muscle strength and reduces the sensation of dyspnea during exercise and speech. The subject was a 23-year-old female with congenital juvenile papilloma which has been in remission for 10 years. A 4-week inspiratory muscle training program was implemented using an inspiratory pressure threshold trainer. The pressure threshold of the trainer was set by the experimenter. The pressure threshold setting of the trainer was based on a percentage of the subject's maximum inspiratory pressure measured prior to training. The average range of the pressure threshold was 40 to 70 cmH2O. In order for inspiratory air to flow, the subject generated inspiratory pressure, independent of airflow rate. Maximum inspiratory pressure (MIP) was the dependent variable used as the index of inspiratory muscle strength. Exercise dyspnea was a dependent variable rated by the subject during a progressive treadmill test. Dyspnea associated with speech was rated following production of a comfortable and loud speech task. MIP increased by 57% following the training program with a 2- scale point reduction in the perception of dyspnea during exercise. Dyspnea during loud speech decreased from moderate to mild. The changes in dyspnea, both during exercise and speech, are directly related to inspiratory muscle strengthening. The results suggest that inspiratory muscle training may improve respiratory related function in patients with restrictive upper airway disorders.

Unique Identifier: 99426342



Eur Arch Otorhinolaryngol 1999;256(7):370-2

Recurrent respiratory papillomatosis associated with gastroesophageal reflux disease in children.

Borkowski G; Sommer P; Stark T; Sudhoff H; Luckhaupt H

HNO-Universitatsklinik, Ruhr-Universitat Bochum, St. Elisabeth- Hospital, Bleichstrasse 15, D-44787 Bochum, Germany.

The hallmark of gastroesophageal reflux disease (GERD) is an increased exposure of esophageal and laryngeal mucosa to gastric juice. This exposure can cause complications such as chronic laryngitis or chronic respiratory diseases. We report our experience in managing three pediatric patients with severe recurrent juvenile laryngeal papillomatosis (JLP) associated with GERD. All patients showed a high rate of recurrence requiring multiple laser surgeries. Systemic alpha interferon therapy over a period of more than 1 year and photodynamic therapy with dihematoporphyrin produced no improvement. However, after therapy for GERD, the rate of recurrence of JLP decreased significantly. Although the course of respiratory papillomatosis is known to fluctuate, our findings suggest that gastroesophageal reflux may have a role in aggravating papillomatosis.

Unique Identifier: 99406382




Food Chem Toxicol 1999 Jun;37(6):663-70

Modulatory potential of clocimum oil on mouse skin papillomagenesis and the xenobiotic detoxication system.

Singh A; Singh SP; Bamezai R

Human Genetics Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

The present study was designed to elucidate the mechanistic inhibitory efficacy of clocimum (an eugenol rich variety of Ocimum gratissimum; Labiatae) oil on murine skin papillomagensis. Topical application of clocimum oil (50 microl/animal/day) during peri-initiation stage (1 week before and 2 weeks after initiation) of 7,12- dimethylbenz[a]anthracene (DMBA)-induced papillomagenesis and/or during the tumour promotion stage reduced (P < 0.05) the (i) tumour burden to 5.00, 4.41 and 4.50 (positive control value 5.27); (ii) cumulative number of papillomas to 85, 75 and 72 (positive control value : 95); and (iii) percent incidence of mice bearing papillomas to 94, 89 and 88, respectively (positive control value 94). Significant (P < 0.01) elevation in the hepatic levels of glutathione S-transferase (GST), sulfhydryl (-SH) and cytochrome b5 (Cyt. b5) was observed by the respective topical treatment of clocimum oil. Even in the skin tissue of the mouse, the topical treatment of clocimum oil enhanced (P < 0.05) the -SH content. The results suggest the modest chemopreventive potential of clocimum oil against the murine skin papillomagenesis, and such effects may be partly due to the modulated xenobiotic detoxication system enzymes.

Unique Identifier: 99405949




Anticancer Res 1999 May-Jun;19(3A):1887-91

Inhibitory potential of Chlorella vulgaris (E-25) on mouse skin papillomagenesis and xenobiotic detoxication system.

Singh A; Singh SP; Bamezai R

Human Genetics Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

The present study assesses the modulatory potential of Chlorella vulgaris (E-25) on murine skin papillomagenesis, and the role of xenobiotic detoxication system in modulating the papillomagenesis pattern. Topical application of E-25 (500 mg/kg b.w./day) during peri-, post- or peri- and post-initiational stages of 7,12-dimethylbenz [a] anthracene (DMBA)-induced papillomagenesis, significantly modulated the a) tumor burden to 5.00, 4.33 and 3.94 (positive control value: 5.88 b) cumulative number of papillomas to 90, 78 and 67 (positive control value: 106); and c) percent incidence of mice bearing papillomas to 94, 90 and 89 respectively (positive control value: 100). E-25 treatment alone or during peri-, post- or peri- and post-initiational stages significantly elevated the sulfhydryl (-SH) and glutathlone S- transferase (GST) levels in the liver and skin tissues. However, the levels of microsomal cytochrome b5 (Cyt. b5) and cytochrome P-450 (Cyt. P-450) were not appreciably modulated by the topical treatment of E-25. The results suggest the chemopreventive potential of E-25 during peri-, post- or peri- and post-initiational stages of murine skin papillomagenesis. The possible significance of xenobiotic detoxication system in modulating the papillomagenesis pattern is discussed.

Unique Identifier: 99399118


Cancer Lett 1999 Aug 23;143(1):23-8

Imunohistochemically stained markers (p53, PCNA, bcl-2) in dysplastic lesions of the larynx.

Krecicki T; Jelen M; Zalesska-Krecicka M; Szkudlarek T; Szajowski K

Department and Clinic of Otolaryngology, Head and Neck Surgery, Medical University of Wroclaw, Poland. krecicki@orl.am.wroc.pl

The percentage of malignant transformation of laryngeal dysplastic lesions is difficult to estimate. There is a need for new histological markers which could enable more objective assessment of the premalignant stages of the larynx and help in estimation of the potential of future neoplastic progression. We performed a retrospective study to determine whether immunohistochemical staining for the proliferating cell nuclear antigen (PCNA), tumour suppressor gene protein p53 and antiapoptotic protein bcl-2 may be prognostic factors in laryngeal epithelial lesions. Staining was performed on 57 paraffin-embedded biopsies from patients with clinically detected precancerous stages of the larynx. Histopathologic examination revealed normal epithelium in six cases, mild dysplasia in 20 cases, moderate dysplasia in 18 cases, severe dysplasia in seven cases, CA in situ in four cases, papilloma in one case and CA invasivum in one case. The p53 count in mild and moderate dysplasia was 26.8 and 38.6%, respectively. This difference was statistically significant. There was significant correlation between PCNA and p53 scores. There was also a relationship between the scores of these markers and bcl-2 expression. In ten out of 45 cases of dysplastic lesions the invasive cancer developed in 4 years of follow-up. The correlation between PCNA score and malignant progression of the dysplastic lesions was on the statistical borderline. There was significant relationship between malignant transformation and age of the patients.

Unique Identifier: 99393002




Cancer Res 1999 Aug 15;59(16):3991-7

Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice.

Jin L; Qi M; Chen DZ; Anderson A; Yang GY; Arbeit JM; Auborn KJ

Department of Otolaryngology, Long Island Jewish Medical Center, The Long Island Campus of Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.

Mice that express transgenes for human papillomavirus type 16 under a keratin 14 promoter (K14-HPV16 mice) develop cervical cancer when they are given 17beta-estradiol chronically. We asked whether the antiestrogenic phytochemical indole-3-carbinol (I3C), found in cruciferous vegetables, administered at physiological doses, would prevent the cervical-vaginal cancer that is promoted in these mice by high doses of estrogen. We compared mice that were fed a control diet with those that were fed a diet supplemented with 2000 ppm I3C. In the group fed the control diet, at a dose of estradiol of 0.125 mg per 60- day release, 19 of 25 transgenic mice developed cervical-vaginal cancer within 6 months, and the remainder had dysplasia. Only 2 mice of 24 in the group fed the I3C supplemented diet developed cancer, and the remainder had dysplasia or hyperplasia. I3C reduced dysplasia in the nontransgenic mice. Similar results were obtained at a higher dose of estradiol (0.250 mg per 60-day release), and I3C helped to prevent morbidity associated with retention of fluid in the bladder that frequently occurred with the higher estradiol dose. Additionally, I3C appeared to reduce skin cancer in transgenic mice. These data indicate that I3C is a useful preventive for cervical-vaginal cancer and, possibly, other cancers with a papillomavirus component.

Unique Identifier: 99391238




Anaesthesia 1999 Aug;54(8):787-9

Acromegaly and papillomatosis: difficult intubation and use of the airway exchange catheter.

Hulme GJ; Blues CM

Specialist Registrar, Department of Anaesthesia, Salford Royal Hospital NHS Trust, Stott Lane, Salford M6 8HD, UK.

We describe the anaesthetic management of a patient with acromegaly scheduled for transsphenoidal resection of a pituitary tumour who was found at intubation to have coexisting laryngeal papillomatosis. Oral intubation was impossible using both direct and fibreoptic techniques. Nasal fibreoptic intubation was successful but precluded the transsphenoidal approach to surgery. A Cook Airway Exchange Catheter [Cook (UK) Ltd, Monroe House, Letchworth SG6 1LN] was used with a Negus bronchoscope to convert to oral intubation and allow completion of surgery without resort to tracheostomy.

Unique Identifier: 99390144








Semin Diagn Pathol 1999 May;16(2):105-16

Oxyphilic proliferations of the respiratory tract and paranasal sinuses.

Ritter JH; Nappi O

Department of Pathology, Washington University Medical School, St. Louis, MO, USA.

Neoplasms of the upper respiratory comprised primarily of eosinophilic cells are, in general, rare, and they include a diverse group of lesions. Low-grade oncocytic neuroendocrine neoplasms (so-called oncocytic carcinoids) can be encountered in several locations throughout the respiratory tract. The oncocytoma and related entities, lesions that presumably arise from minor gland tissue, can likewise be seen from the nasal cavity to the lung; differences in clinical significance may relate to the location of such lesions, and are discussed herein. Granular cell tumor is another entity that can involve both the upper respiratory tract and lungs, and specific features of this lesion in different anatomic sites are highlighted. The oncocytic variant of Schneiderian papilloma is an important nasal lesion to recognize, because of important therapeutic and prognostic implications of that diagnosis. Finally, unique oncocytic variants of glomus tumor and pulmonary alveolar adenoma are discussed, as well as eosinophilic varieties of pulmonary carcinomas and mesotheliomas.

Unique Identifier: 99379645




Pediatr Dev Pathol 1998 Mar-Apr;1(2):157-63

Juvenile-onset recurrent respiratory papillomatosis involving the lung: A case report and review of the literature.

Magid MS; Chen YT; Soslow RA; Boulad F; Kernan NA; Szabolcs P

Department of Pathology, The New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, NY 10021, USA.

[No abstract available]

Unique Identifier: 99335622


Arch Otolaryngol Head Neck Surg 1999 Jul;125(7):743-8

Initial results from the national registry for juvenile-onset recurrent respiratory papillomatosis. RRP Task Force.

Armstrong LR; Derkay CS; Reeves WC

Viral Exanthems and Herpesvirus Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Disease, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. lra0@cdc.gov

OBJECTIVE: To characterize the spectrum of juvenile-onset recurrent respiratory papillomatosis (RRP) in the United States and to obtain data about the natural course of the disease and its response to treatment. SETTING: Twenty tertiary-care pediatric otolaryngology centers throughout the United States. PATIENTS: All patients with active RRP aged less than 18 years at the participating sites. MAIN OUTCOME MEASURES: Number of surgical procedures performed per year, progression of papillomas to previously nondiseased anatomical sites, drug interventions and other adjuvant therapy, and need for tracheostomy. RESULTS: Data were collected from 399 children enrolled from January, 1, 1997, through December 31, 1998. There were 51.9% male; 62.7% white, 28.3% black, 9.0% other or unknown racial group; 10.8% Hispanic ethnicity. Mean age at diagnosis was 3.8 years (range, 0.1-16.3 years) and mean duration of disease was 4.4 years (range, 0.03- 18.9 years). The mean number of surgical procedures per child was 4.4 per year (range, 0.2-19.3 per year). Children whose RRP was diagnosed at younger ages (<3.0 years) were 3.6 times more likely to have more than 4 surgical procedures per year (P=.001) and almost 2 times more likely to have 2 or more anatomical sites affected (P=.008) than were children whose RRP was diagnosed at later ages (> or =3.0 years), after adjusting for sex, race, and years of treatment. CONCLUSIONS: Children whose disease was diagnosed before age 3 years were more likely than children aged 3 years or older to have more severe disease as measured by the mean number of surgical procedures performed and by the number of anatomical sites affected. The registry will form the basis for future analysis on the outcome of disease, natural course of RRP under management strategies, prevention strategies, and public health importance.

Unique Identifier: 99332943



Histopathology 1999 Jul;35(1):55-64

Down-regulation of p27Kip1 expression is correlated with increased cell proliferation but not expression of p21waf1 and p53, and human papillomavirus infection in benign and malignant tumours of sinonasal regions.

Saegusa M; Nitta H; Hashimura M; Okayasu I

Department of Pathology, Kitasato University School of Medicine, Kitasato, Sagmihara, Kanagawa, Japan.

Although p27Kip1(p27) is a cyclin-dependent kinase inhibitor and a contribution to tumorigenesis has been hypothesized, the possible role in tumours arising in the nasal and paranasal sinus regions is still unknown. METHODS AND RESULTS: Seventy-six sinonasal tumours, including 28 inverted papillomas (IPs) and 48 squamous cell carcinomas (SCCs), were immunohistochemically investigated, along with 46 exophytic papillomas (EPs) of upper respiratory tract and 34 samples of normal paranasal sinus epithelium. The results were also compared with expression of p21WAF1 (p21) and p53, cell proliferation assessed in terms of Ki67 labelling indices (LIs), and human papillomavirus (HPV) infection. The average p27 scores decreased from normal through to malignant lesions, while Ki67 LI scores showed a stepwise increase, the inverse correlation between scores for all categories being significant (r = - 0.639, P < 0. 0001). In the SCCs, p27 expression was significantly higher in keratinizing than nonkeratinizing type tumours (P < 0.05), while there was no association with p21 and p53 expression. Although HPV DNAs for type 16 and 18 were detected in two (7.4%) of 27 EPs, six (35.8%) of 28 IPs, and nine (28.1%) of 32 SCCs, no relation with p27 scores was evident. CONCLUSION: Loss of p27 expression correlates with increased cell proliferation in sinonasal tumours. Moreover, the expression appears to be associated with keratinization in SCCs of the paranasal sinus. These findings indicate that p27 expression may be a useful marker for the dysregulation of cell kinetics in these tumours.

Unique Identifier: 99315717




Phytother Res 1999 May;13(3):261-3

Chemopreventive action by an extract from Brassica compestris (var Sarason) on 7,12-dimethylbenz(a)anthracene induced skin papillomagenesis in mice.

Qiblawi S; Kumar A

Department of Zoology, University of Rajasthan, India.

We report the chemopreventive property of an ethanolic extract of the seeds of Brassica compestris var sarason (mustard seed) on DMBA (7,12 dimethylbenz(a)anthracene induced skin papillomagenesis in male Swiss albino mice. A significant reduction in the values of tumour incidence, tumour burden and the cumulative number of papillomas was observed in mice treated orally with the seed extract of Brassica compestris var sarason, continuously at peri and post initiational stages of papillomagenesis compared with the control groups. The latency period in the experimental group significantly increased (11.3 +/- 0.40 weeks) compared with the control group (7.8 +/- 0.17).

Unique Identifier: 99281442


Am Surg 1998 Nov;64(11):1082-7

Condyloma acuminata: a fatal disease?

Rhea WG Jr; Bourgeois BM; Sewell DR

Department of Surgery, Louisiana State University School of Medicine, New Orleans, USA.

Condyloma acuminata is a virally mediated epithelial overgrowth caused by the human papilloma virus. Its simplest form is the common wart, which may occur almost anywhere on the body surface. Its papillary lesion forms are commonly seen in the genital, perineal, and anal areas, though it also infects the conjunctiva, nose, mouth, larynx, and tracheo-bronchial tree. Malignant degeneration may occur in any of these areas. Diagnosis is established by clinical impression and biopsy. Immunoassay methods exist but are simply indicative of the presence of infection and are not useful in predicting the course of the disease. Many treatment modalities exist and all work well for minor lesions. For large lesions such as the giant condyloma acuminata, also known as the Buschke-Lowenstein lesion, only radical surgical extirpation is considered to be appropriate treatment. This case report, as well as others referenced in this study, documents the extreme complexity of management of many of these lesions and the fatal outcome of this disease process in a significant number of cases.

Unique Identifier: 99013119



































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