Relationship between inflammation and the severity of Recurrent Respiratory Papillomatosis.

OBJECTIVE: To characterize inflammatory cells in Recurrent Respiratory Papillomatosis (RRP) and to correlate it with severity using the Derkay laryngoscopic scale. MATERIALS AND METHODS: The data and biopsies from 36 patients with Juvenile (JRRP) and 56 patients with Adult (ARRP) were collected and analyzed under light microscopy. The patients were separated into groups according to the Derkay index: ≥20 for the most severe and < 20 for the less severe cases. Immunohistochemical analysis using CD3, CD4, CD8, CD15, CD20, CD68, FoxP3 and MUM-1 antibodies was performed, and the inflammatory cells were quantified. All the clinicopathological characteristics and the results of the immunohistochemical analysis were compared among the groups proposed using the Chi-Square test and correlated through the Spearman correlation test. RESULTS: The ARRP showed significantly higher quantities of CD3+, CD8+ and MUM1+ cells (p < .05) than the JRRP samples. The presence of CD15+ cells showed positive correlation with the Derkay index (p < .05), while the MUM-1+ cells showed an inverse correlation (p = .01). CONCLUSION: There are differences between the inflammatory cells population in the juvenile and adult groups and it can be related to disease severity.

The involvement of liquid crystals in multichannel implanted neurostimulators, hearing and ENT infections, and cancer.

Liquid crystals (LCs) consist of assemblies of molecules, between one and tens of nanometers, grouped in identifiable cohorts according to orientation and structure, which is often lamellar with varying chirality. The term liquid phase (Lo phase) designates certain such mesophases. This variety in geometry corresponds to a variety of functions. Some molecules, both organic and inorganic, used in applied engineering, and association with LCs confer new properties. Applying these aspects of LCs in manufacturing implantable material is a growing technology, especially in the interfaces of differentiated multichannel electro-neurostimulation. We highlight the involvement of LCs in the head and neck region, and the role mesophases play in outer hair cell electromotility (mechanotransduction). We summarize implications of LCs this for multichannel electroneurostimulation implant engineering, and highlight their role importance of LCs in early oncogenic process, HPV, and latency in (Epstein-Barr) and other pathogens. Our approach should help give rise to new therapeutic perspectives. Focusing on upstream nanometric phenomena needs to take on board classic determinism, quantum probability, and statistical complexity.

Prophylactic human papilloma virus vaccination in head and neck: indications and future perspectives.

PURPOSE OF REVIEW: To gain the evidence-based knowledge concerning the efficacy of HPV vaccination for oropharyngeal sites and to highlight the trials and strategies for vaccine administration in HPV-dependent head and neck diseases. RECENT FINDINGS: Vaccination can be provided in two injections. There is increasing anecdotal evidence that therapeutic vaccination is effective in treatment of recurrent respiratory papillomatosis. SUMMARY: The availability and broadening spectrum of HPV vaccines make possible the prevention of cervical and other HPV-dependent diseases. Vaccination is now included in the national immunization programs of most industrial countries and will be used, it is hoped, in developing countries within the next few years. In developing countries, few women are screened for cervical precancerous lesions, making immunization even more important. In affluent countries and matured societies, with high coverage of cervical screening, the focus of interest will shift to other HPV-related diseases. The HPV vaccination is effective in preventing oral infection with types targeted by the vaccines.

Fungal mannosylation enhances human papillomavirus 16 E7 therapeutic immunity against TC-1 tumors.

Cervical cancer, resulting from infection with human papillomavirus (HPV)16, remains the fourth most common cancer in women worldwide. Recently, three prophylactic HPV vaccines targeting high-risk HPVs (particularly HPV16 and HPV18) have been implemented to protect younger women. However, individuals with pre-existing infections have no benefit from prophylactic vaccines. Thus, there is an urgent need to develop therapeutic vaccines. HPV16 E7 has been widely utilized as a target for immune therapy of HPV16-associated lesions or cancers, reflecting the sustained existence of this virus in cancerous cells. We developed mannosylated HPV16 E7 (mE7) expressed from Pichia pastoris as a therapeutic vaccine against HPV16-associated cancer. Unmannosylated E7 (E7) was also generated from Pichia pastoris as a control. Mannosylation enhanced the uptake of mE7 by mannose receptors of bone marrow-derived dendritic cells (BMDCs), while the uptake of E7 was unaffected. mE7-uptake BMDCs in vitro induced more IFN-γ secretion by splenocytes of immunized mice than E7. Vaccination of C57BL/6 mice with mE7 combined with adjuvant monophosphoryl lipid A (MPL) elicited stronger Th1 (type 1 T helper cell) responses and E7-specific T cell responses than E7. The mE7 vaccine induced the increased production of IFN-γ, IL-2 and TNF-α, elicited more E7-specific IFN-γ-secreting CD8+ T cells in spleen and peripheral blood mononuclear cells (PMBCs) and promoted stronger E7-specific cytotoxic CD8+ T cell responses compared with E7. Furthermore, TC-1 tumor challenged mice were used to confirm the antitumor activity of the vaccines. As a result, mE7 generated complete antitumor activity against TC-1 tumors, while E7 only provided partial antitumor activity. Taken together, mE7 can be a promising immunotherapy for treating cervical cancer.

[HPV (Human Papilloma Virus) implication in other cancers than gynaecological]. / Impact de l'HPV (Human Papilloma Virus) dans les carcinomes autres que gynécologiques.

Worldwide, approximately 5 to 10% of the population is infected by a Human Papilloma Virus (HPV). Some of these viruses, with a high oncogenic risk (HPV HR), are responsible for about 5% of cancer. It is now accepted that almost all carcinomas of the cervix and the vulva are due to an HPV HR (HPV16 and 18) infection. However, these viruses are known to be involved in the carcinogenesis of many other cancers (head and neck [SCCHN], penis, anus). For head and neck cancer, HPV infection is considered as a good prognostic factor. The role of HPV HR in anal cancer is also extensively studied in high-risk patient's population. The role of HPV infection in the carcinogenesis of esophageal, bladder, lung, breast or skin cancers is still debated. Given the multiple possible locations of HPV HR infection, the question of optimizing the management of patients with a HPV+ cancer arises in the implementation of a comprehensive clinical and biological monitoring. It is the same in therapeutics with the existence of a preventive vaccination, for example.

Degrees of dysplasia based on viral typing in patients with cidofovir use and recurrent respiratory papillomatosis.

OBJECTIVES/HYPOTHESIS: To evaluate the degree of dysplasia following cidofovir injections while documenting human papillomavirus (HPV) type in patients with recurrent respiratory papillomatosis (RRP). STUDY DESIGN: Retrospective chart review. METHODS: Demographic data, operative reports, and pathology results were reviewed from 25 patients with RRP who had had cidofovir injections. All patients included had adult onset RRP, no history of immunosuppression, well-controlled laryngopharyngeal reflux, and no current smoking history. Eight patients were excluded because they did not meet the inclusion criteria. RESULTS: Seventeen patients had adequate data for analysis and 40 subsites were identified with sufficient data for analysis. Patients negative for both low and high risk did not have progressive dysplasia at the conclusion of the study. Of the patients with positive viral typing, 70% had progressive disease at the conclusion of the study. No patients progressed to carcinoma or carcinoma in situ. The average pre- and post-treatment dysplasia scores were analyzed using a Student paired t test. There was no difference in mean dysplasia score, indicating that there was no increased risk of dysplasia following cidofovir treatment. CONCLUSIONS: To our knowledge, this is the first study looking at the degree of dysplasia while documenting HPV types in RRP. Our study suggests that HPV type appears to be relevant in the disease progression of RRP and that cidofovir does not increase the risk of dysplasia.

Significance of human papillomavirus 16/18 infection in association with p53 mutation in lung carcinomas.

INTRODUCTION: The role of high-risk human papillomavius (HPV) 16/18 in the development of lung cancer has recently been explored, and p53 mutation is a finding in lung cancer; however, its association with HPV infection is not well studied. OBJECTIVES: To investigate HPV 16/18 infection and p53 mutation in lung carcinomas and their association with tumor behavior. METHODS AND RESULTS: We expanded our prior study to include 107 squamous cell carcinoma (SCC), 63 adenocarcinoma (AC) and 91 non-cancer control cases of lung from a population of Western China. The results confirmed that HPV infection is more prevalent in SCC (59.8%) comparing with that of AC (17.5%) and the control cases (23.1%) (P<0.001), and genotyping demonstrated predominant HPV 16/18 infection in the carcinomas and HPV 6 in the control cases. By immunohistochemistry, p53 mutation was detected in 67.3% of SCC and 60.3% of AC, in comparison with 9.9% in the control (P<0.001). Within the group of SCC, the p53 mutation rate is significantly higher in those with HPV infection (78.1%) than that of the non-infected carcinomas (51.2%, P=0.004). However, this difference is not proven to be significant in the groups of AC and the controls. Clinicopathological analysis demonstrated that the coexistence of p53 mutation and HPV infection was associated with lymph node metastasis (P=0.001) and high-clinical TNM stage of SCC (P=0.001). As there was no sequencing data, the evidence for HPV 16/18 E6 induced p53 mutation is still indirect. CONCLUSION: This study indicates that p53 mutation and HPV 16/18 infection might coordinate in the development of lung squamous cell carcinomas, and their coexistence is associated with poor prognosis.

Adjuvant antiviral therapy for recurrent respiratory papillomatosis.

BACKGROUND: This is an update of a Cochrane Review originally published in Issue 4, 2005 of The Cochrane Library and previously updated in 2010.Recurrent respiratory papillomatosis is a condition characterised by benign papillomatous (wart-like) growths in the upper airway. It can affect both adults and children causing airway obstruction and voice change. Treatment usually involves repeated surgical debulking of the papillomata. Several agents have been proposed as adjuvants to surgical debulking, including antivirals, administered systemically or injected into the lesions. OBJECTIVES: To assess the effectiveness of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis in children and adults. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 24 February 2012. SELECTION CRITERIA: Randomised controlled trials. DATA COLLECTION AND ANALYSIS: We identified 143 references from the searches. Forty-three were appropriate for retrieval and assessed for eligibility by the authors. One randomised controlled trial met the inclusion criteria, involving 19 participants. We contacted the authors to obtain additional data to facilitate the review. MAIN RESULTS: The included study was a single-institution, randomised, double-blind, placebo-controlled trial of intralesional cidofovir administered at the time of surgical debulking. Adults (n = 15) and children (n = 4) were included. We judged the study to have a reasonably low risk of bias. After a 12-month trial period, no difference was found between the cidofovir and placebo groups. Both groups showed a significant reduction in disease extent (as assessed at the time of surgery using the Derkay Scoring System), but no significant change in health-related quality of life. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the efficacy of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis in children or adults. The included randomised controlled trial showed no advantage of intralesional cidofovir over placebo at 12 months. The study was limited by a small sample size and a change in the cidofovir concentration midway through the trial, from 0.3 mg/ml in children and 0.75 mg/ml in adults, to 5 mg/ml in both adults and children. An adequately powered randomised controlled trial of intra-lesional cidofovir, consistently using higher concentrations of cidofovir in comparison with injected placebo, would be required to determine effectiveness convincingly. Future studies must include health-related quality of life and symptom-based outcome measures.

Swimbladder Leiomyosarcoma in Atlantic salmon (Salmo salar) in North America.

Leiomyosarcoma with associated retrovirus were found in North America for the first time in adult Atlantic salmon (Salmo salar) held in a quarantine facility at the North Attleboro National Fish Hatchery (NANFH), Massachusetts, USA. The fish had been collected as age 1-2 yr animals from the Pleasant River, Maine, and were to be used as brood stock in a population augmentation program for that river. Neoplastic disease was observed at NANFH initially in older (age 4 yr) fish, followed by age 3 yr fish. Disease was not observed in age 2 yr fish. The mortality pattern was chronic.

Recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare, benign disease with no known cure. RRP is caused by infection of the upper aerodigestive tract with the human papillomavirus (HPV). Passage through the birth canal is thought to be the initial transmission event, but infection may occur in utero. HPV vaccines have helped to provide protection from cervical cancer; however, their role in the prevention of RRP is undetermined. Clinical presentation of initial symptoms of RRP may be subtle. RRP course varies, and current management focuses on surgical debulking of papillomatous lesions with or without concurrent adjuvant therapy.

Association between toll-like receptor expression and human papillomavirus type 16 persistence.

The mechanisms involved in mucosal immune control of cervical human papillomavirus (HPV) infection remain ill defined. Because toll-like receptors (TLRs) are key players in innate immune responses, we investigated the association between TLR expression and viral persistence or clearance in young women with incident infections with oncogenic HPV types 16 or 51. Messenger RNA expression of TLR1, TLR2, TLR3, TLR4, TLR6, TLR7, TLR8 and TLR9 was measured by quantitative reverse transcription-PCR using human endocervical specimens, collected before and after viral acquisition, in a cohort well characterized for HPV infections. Wilcoxon rank sum test was used to compare the change seen from preinfection to incident infection between women who subsequently cleared infection with those who did not. HPV 16 infections that cleared were significantly (p < 0.05) associated with an increase in expression of the four viral nucleic acid-sensing TLRs (TLR3, TLR7, TLR8 and TLR9) as well as TLR2 upon viral acquisition. Similar associations were not observed for HPV 51. In women who subsequently cleared their HPV 16 infection, changes in TLR1, TLR3, TLR7 and TLR8 expression levels between preincident and incident visits were significantly correlated with parallel changes in the levels of interferon-α2, measured by immunoassay in cervical lavage specimens. This study suggests that dampened TLR expression in the cervical mucosa is a type-specific mechanism by which HPV 16 interferes with innate immune responses, contributing to viral persistence, and that TLR upregulation and resultant cytokine induction is important in subsequent viral clearance.

Sarcomatoid carcinoma of the upper aerodigestive tract: an immunohistochemical analysis demonstrating latent Epstein-Barr virus in a subset of eight cases.

BACKGROUND: Sarcomatoid or spindle cell carcinomas are rare malignancies which are considered as a poorly differentiated variant of squamous cell carcinoma. Epstein-Barr virus (EBV) is associated with a wide variety of malignancies. MATERIALS AND METHODS: We examined the expression of EBV latent membrane protein-1 (LMP-1) and EBV EBNA-2 as well as the immunohistochemical profile of AE-1/AE-3, vimentin, desmin, CK 5-6, smooth muscle actin (SMA), p63, S-100, p53 and CD-117 with the clinicopathological correlation of eight patients of sarcomatoid carcinoma (SC) in the upper aerodigestive tract. RESULTS: Four cases showed EBV LMP-1 positivity (50%) and there was no EBV EBNA-2 positivity. However, the EBV LMP-1 results of our series could be considered only as a coincidental finding in the SCs of the upper aerodigestive tract. CONCLUSIONS: This finding supports the idea that further studies based on larger series might be helpful enlighting the role played by EBV in carcinogenesis of SC.

Recurrent respiratory papillomatosis: an overview.

Recurrent respiratory papillomatosis (RRP) primarily caused by human papillomas virus is a rare and benign neoplasm, primarily involving the epithelium mucosae of the respiratory tract. RRP may occur anywhere in the respiratory tract with a predilection to the laryngeal area and may potentially threaten life. Because of the absence of specific clinical manifestations, the diagnosis of this disease is easily delayed. The high awareness of RRP and performing endoscopy as soon as possible in suspected patients are the prerequisites for early diagnosis. Surgical removal on endoscope is still a fundamental treatment. Adjuvant treatment is required only in some patients. Because of the potential of malignant transformation and recurrence, careful follow-up for RRP is required for early detection and treatment.

Adjuvant antiviral therapy for recurrent respiratory papillomatosis.

BACKGROUND: This is an update of a Cochrane Review originally published in Issue 4, 2005 of The Cochrane Library.Recurrent respiratory papillomatosis is a condition characterised by benign papillomatous (wart-like) growths in the upper airway. It can affect both adults and children causing airway obstruction and voice change. Treatment usually involves repeated surgical debulking of the papillomata. Several agents have been proposed as adjuvants to surgical debulking, including antivirals, administered systemically or injected into the lesions. OBJECTIVES: To assess the effectiveness of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis in children and adults. SEARCH STRATEGY: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; mRCT and additional sources for published and unpublished trials. The date of the most recent search was 30 September 2009. SELECTION CRITERIA: Randomised controlled trials. DATA COLLECTION AND ANALYSIS: We identified 143 references from the searches. Forty-three were appropriate for retrieval and assessed for eligibility by the authors. One randomised controlled trial met the inclusion criteria, involving 19 participants. We contacted the authors to obtain additional data to facilitate the review. MAIN RESULTS: The included study was a single-institution, randomised, double-blind, placebo-controlled trial of intralesional cidofovir administered at the time of surgical debulking. Adults (n = 15) and children (n = 4) were included. After a 12-month trial period, no difference was found between the cidofovir and placebo groups. Both groups showed a significant reduction in disease extent (as assessed at the time of surgery using the Derkay Scoring System), but no significant change in health-related quality of life. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the efficacy of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis in children or adults. The included randomised controlled trial showed no advantage of intralesional cidofovir over placebo at 12 months. The study was limited by a small sample size and a change in the cidofovir concentration midway through the trial, from 0.3 mg/ml in children and 0.75 mg/ml in adults, to 5 mg/ml in both adults and children. An adequately powered randomised controlled trial of intra-lesional cidofovir, consistently using higher concentrations of cidofovir in comparison with injected placebo, would be required to determine effectiveness convincingly. Future studies must include health-related quality of life and symptom-based outcome measures.

Malignant transformation of a highly aggressive human papillomavirus type 11-associated recurrent respiratory papillomatosis.

OBJECTIVE: The objective is to present an uncommon case of squamous cell carcinoma (SCC) arising from extensive recurrent respiratory papillomatosis (RRP) involving the upper and lower airway and temporal bone. STUDY DESIGN: This is a case report and a review of the literature. METHODS: We describe a case of a 24-year-old woman with a history of human papillomavirus (HPV) type 11 since childhood originating in the larynx and trachea, then progressing to involve the distal pulmonary alveoli and right middle ear through the eustachian tube. Papillomatous growth was treated with multiple surgeries including laser cytoreduction of laryngotracheal papillomatosis and radical mastoidectomy, followed by a trial of chemotherapy. Despite this aggressive treatment regimen, papillomatous growth progressed with recurrence in the right eustachian tube, middle ear, and mastoid eventually extending to involve the calvaria and scalp. RESULTS: The patient underwent a composite resection of involved tissues, including the scalp, auricle, and lateral temporal bone, with reconstruction using a latissimus dorsi free flap. Final pathologic analysis revealed an extensive infiltrative well-differentiated SCC arising from the papilloma. A review of the literature on aggressive respiratory papillomatosis suggests that malignant transformation of juvenile-onset RRP occurs exclusively in cases positive for HPV-11. CONCLUSIONS: We report an unusual case of SCC originating from extensive RRP involving the airway, temporal bone, and scalp and describe the medical and surgical management. Although the incidence of juvenile-onset RRP transformation to SCC is very low, the presence of HPV-11 as a risk factor for malignant transformation of RRP is becoming evident.

Prognostic factors of recurrent respiratory papillomatosis from a registry of 72 patients.

CONCLUSIONS: The database revealed severity factors relating to human papillomavirus (HPV) type and age at diagnosis. While not exhaustive, the database is easy to use and could serve for a European multicentre epidemiological study. OBJECTIVES: To propose a database as a starting point for a national registry and to estimate prognostic factors in recurrent respiratory papillomatosis (RRP). MATERIALS AND METHODS: This was a retrospective study carried out in a tertiary care teaching hospital. From January 2005 to July 2007, epidemiological, clinical and treatment information on patients undergoing endoscopy for RRP in the department was entered in a database. Data were collected on three forms: the first comprised information about disease history before assessment in the department, the second about the disease and its treatment in the department, and the third about evolution after treatment. RESULTS: Data on 72 patients were entered into an RRP database between January 2005 and July 2007. In all, 82% had already been treated for RRP in a different centre; 24 had juvenile-onset (JORRP) and 48 adult-onset (AORRP) papillomatosis. Cidovir injections had been administered to 91% of the patients. Histology found nine cases of dysplasia, one of carcinoma in situ and one of invasive carcinoma. Subglottic and tracheal locations were significantly more frequent in JORRP than in AORRP, as were the maximum Derkay scores and annual numbers of endoscopies. Patients with type 11 HPV had significantly more endoscopies per year than those with type 6.

Palliative aspects of recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a chronic, frequently debilitating, and potentially life-threatening disease. Therapy for RRP has evolved from simply inserting a tracheotomy to provide an airway and plucking out papillomata with cup forceps to provide some degree of voice to the present-day far more sophisticated approaches, along with preventative measures that may someday offer the potential dramatically to decrease disease prevalence. Family dynamics and support and intentional structuring of office protocols to accommodate the unique nature of RRP are as essential as any operative intervention for saving and prolonging life. This article reviews recent developments in the management of RRP and highlights palliative approaches to case management for those patients who are not easily cured with initial endoscopic interventions.

Recurrent respiratory papillomatosis: update 2008.

PURPOSE OF REVIEW: Recurrent respiratory papillomatosis (RRP) is the most common benign neoplasm of the larynx in children. Over the past several years some exciting new therapeutic options as well as some relevant research into the disease process has emerged that may offer new insight and methods in managing this frustrating disease. RECENT FINDINGS: Recent investigations have resulted in the following findings: more accurate prevalence estimates of human papilloma virus in women in the United States; correlation of socioeconomic status and disease severity; the malignant potential of human papilloma virus in head and neck cancer; the role of the host immune system in RRP; the efficacy of a vaccine preventing human papilloma virus; the emergence of pulsed dye laser and potassium-titanyl-phosphate laser as a therapy for RRP; the efficacy of cidofovir as an adjunctive therapy for RRP; and the role of cyclooxygenase-2 in the molecular biology of RRP. SUMMARY: The management of RRP is ever evolving. Despite several new therapies discussed in this study, it is still a disease with the potential for high morbidity. As the focus of therapy shifts from treatment to prevention, it will take many years to determine whether prevention strategies are effective in limiting the spread of this disease. In the mean time, further research is needed to gain better control of this disease process.