Pioglitazone, Nuclear Receptors, and Aerodigestive Prevention.

There has been intense interest in nuclear receptor targeting for cancer prevention. With the exception of estrogen antagonism in breast carcinoma there has not been widespread adoption or success of this strategy in clinical cancer prevention. Keith and colleagues have performed a careful study, which utilized the PPARγ nuclear receptor agonist, pioglitazone, a common type II diabetes agent, in subjects at risk for lung carcinoma. Although the results are not promising with this strategy, the study provides evidence for feasibility accrual and biomarker strategies that could be utilized to gain additional insight in future trials.

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.

Re-evaluation of the WHO (2010) formaldehyde indoor air quality guideline for cancer risk assessment.

In 2010, the World Health Organization (WHO) established an indoor air quality guideline for short- and long-term exposures to formaldehyde (FA) of 0.1 mg/m3 (0.08 ppm) for all 30-min periods at lifelong exposure. This guideline was supported by studies from 2010 to 2013. Since 2013, new key studies have been published and key cancer cohorts have been updated, which we have evaluated and compared with the WHO guideline. FA is genotoxic, causing DNA adduct formation, and has a clastogenic effect; exposure-response relationships were nonlinear. Relevant genetic polymorphisms were not identified. Normal indoor air FA concentrations do not pass beyond the respiratory epithelium, and therefore FA's direct effects are limited to portal-of-entry effects. However, systemic effects have been observed in rats and mice, which may be due to secondary effects as airway inflammation and (sensory) irritation of eyes and the upper airways, which inter alia decreases respiratory ventilation. Both secondary effects are prevented at the guideline level. Nasopharyngeal cancer and leukaemia were observed inconsistently among studies; new updates of the US National Cancer Institute (NCI) cohort confirmed that the relative risk was not increased with mean FA exposures below 1 ppm and peak exposures below 4 ppm. Hodgkin's lymphoma, not observed in the other studies reviewed and not considered FA dependent, was increased in the NCI cohort at a mean concentration ≥0.6 mg/m3 and at peak exposures ≥2.5 mg/m3; both levels are above the WHO guideline. Overall, the credibility of the WHO guideline has not been challenged by new studies.

Papilomatosis respiratoria recurrente y el rol de la vacunación antiVPH / Recurrent respiratory papillomatosis and the role of HPV vaccination

La papilomatosis respiratoria recurrente es una enfermedad infrecuente de la vía aereodigestiva, que afecta a niños y adultos, causada por el virus papiloma humano subtipos 6 y 11. La enfermedad tiene un curso impredecible y ha sido reportada la extensión pulmonar y la transformación maligna. Actualmente todos los tratamientos disponibles, tanto médicos como quirúrgicos, son sólo paliativos, enfocados a mantener una vía aérea adecuada y una calidad de voz aceptable. Se han desarrollado dos vacunas contra el virus papiloma humano con el fin de prevenir el cáncer cervicouterino causado por éste. Una de estas vacunas también incluye los subtipos asociados a la papilomatosis, por lo que la vacunación masiva podría disminuir drásticamente la incidencia de la enfermedad.

Recurrent respiratory papillomatosis is a rare disease of the aerodigestive tract that affects children and adults, caused by the human papiloma virus subtypes 6 and 11. The disease has a unpredictable course and pulmonary spread and malignant transformation have been reported. All the medical and surgical treatments available are only palliative and are focused on keeping a adequate airway and an acceptable voice quality. Two vaccines have been developed against the human papilloma virus for the prevention of cervical cancer. One of these vaccines also includes the subtypes associated with papillomatosis so widespread vaccination could drastically diminish the incidence of the disease.

Program, policy, and price interventions for tobacco control: quantifying the return on investment of a state tobacco control program.

OBJECTIVES: We examined health effects associated with 3 tobacco control interventions in Washington State: a comprehensive state program, a state policy banning smoking in public places, and price increases. METHODS: We used linear regression models to predict changes in smoking prevalence and specific tobacco-related health conditions associated with the interventions. We estimated dollars saved over 10 years (2000-2009) by the value of hospitalizations prevented, discounting for national trends. RESULTS: Smoking declines in the state exceeded declines in the nation. Of the interventions, the state program had the most consistent and largest effect on trends for heart disease, cerebrovascular disease, respiratory disease, and cancer. Over 10 years, implementation of the program was associated with prevention of nearly 36,000 hospitalizations, at a value of about $1.5 billion. The return on investment for the state program was more than $5 to $1. CONCLUSIONS: The combined program, policy, and price interventions resulted in reductions in smoking and related health effects, while saving money. Public health and other leaders should continue to invest in tobacco control, including comprehensive programs.

[Preventing cancer of the upper respiratory and digestive tracts]. / Prévenir le cancer des voies aéro-digestives supérieures.

In 2003, the Prévart association, in collaboration with community practitioners and the hospital, set up in Béthune, then in Lens, a plan for the detection and prevention of cancers of the upper air and digestive passages particularly widespread in the Nord-Pas-de-Calais department. Thanks to a central appointment desk and to the detection work of nurses, patients have been able to benefit from fast and adapted treatment.

[Tobacco smoking--what we know and what we do with our knowledge?]. / Palenie tytoniu--co wiemy i co robimy z nasza wiedza?

Since the industrial production of cigarettes in XIX century became possible, cigarettes price decreased and their availability increased significantly. Beside the economical income of the industry owners, the wide accessibility to tobacco products became connected to increased incidence of some diseases. Among "tobacco-related" disease we should mention: atherosclerosis (mainly coronary arteries), arterial hypertension, respiratory tract tumors, urinary tract tumors, digestive tract tumors, uterine cervix cancer, restrictive lung disease, consequences of hormonal abnormalities in women, and abnormalities of fetal, newborn and child development. Due to basic research we understood the diseases mechanisms. Although, the number of evidences of adverse effects of tobacco smoke on human health, the number of smoking population is still high. What activities should be taken for promoting life without tobacco smoke?

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.

Impact of prophylactic human papillomavirus vaccines on dermatology and venereology.

Prophylactic HPV L1 VLP quadrivalent and bivalent vaccines have a great importance for patients seen by dermatologists and venereologists. Both vaccines protect against HPV16- and HPV 18-associated anogenital cancers, as well as cancers of the mouth, the upper respiratory tract and skin, especially of the fingers and periungual region. The quadrivalent HPV6, 11, 16, 18 vaccine also prevents anogenital warts (condylomata acuminata) which are the most common benign tumors of this body region. HPV-vaccination (Gardasil) has been approved in Germany and other European Countries since October 2006 for young girls between 9-16 and young women between 16-26 years of age. Many experts feel that boys and young men should also be vaccinated. Men would profit from a vaccine that protects against HPV infections, especially anogenital warts, as well as penile and anal carcinomas. In immunosuppressed organ transplant recipients and HIV-positive patients. HPV disease can be widespread, chronic and often may rapidly progress to malignant tumors. Thus, these individuals would greatly benefit from prophylactic HPV immunization.

The potential health and economic benefits of preventing recurrent respiratory papillomatosis through quadrivalent human papillomavirus vaccination.

We estimated the health and economic benefits of preventing recurrent respiratory papillomatosis (RRP) through quadrivalent human papillomavirus (HPV) vaccination. We applied a simple mathematical model to estimate the averted costs and quality-adjusted life years (QALYs) saved by preventing RRP in children whose mothers had been vaccinated at age 12 years. Under base case assumptions, the prevention of RRP would avert an estimated USD 31 (range: USD 2-178) in medical costs (2006 US dollars) and save 0.00016 QALYs (range: 0.00001-0.00152) per 12-year-old girl vaccinated. Including the benefits of RRP reduced the estimated cost per QALY gained by HPV vaccination by roughly 14-21% in the base case and by <2% to >100% in the sensitivity analyses. More precise estimates of the incidence of RRP are needed, however, to quantify this impact more reliably.

Prevention of recurrent respiratory papillomatosis: role of HPV vaccination.

Recurrent respiratory papillomatosis is a rare, but devastating, cause of airway lesions in children and adults. This disease is caused by human papilloma virus subtypes 6 and 11. At this time there are two vaccines in late stages of development seeking Food and Drug Administration (FDA) approval to prevent cervical cancer, which is also caused by human papilloma virus. One of these vaccines has been developed to stimulate immunity to the most common subtypes that cause cervical cancer but also includes those responsible for recurrent respiratory papillomatosis. With the possibility this could drastically reduce the incidence of RRP, the otolaryngology community should advocate for implementation of a vaccine program that provides effective prevention of HPV infection with subtypes 6 and 11.

Retinoid receptor cross-talk in respiratory epithelium cancer chemoprevention.

The rationale for using retinoids in the prevention of respiratory epithelium cancers is based on their ability to coordinately regulate differentiation, proliferation and apoptosis. The complex retinoid signaling pathways and their cross-reactions are modulated by multiple mechanisms that are gradually being elucidated. It is possible that significant molecular changes take place during the very early stages of respiratory epithelial carcinogenesis, which enable cancer cells to escape apoptosis and result in unimpeded proliferation. Here, we propose that a "switch on/off" model dictates the cross-talk between retinoid receptors and other signal transducing pathways during respiratory epithelium carcinogenesis. This model might contribute to the development of novel selective retinoids and their clinical evaluation in combinatorial chemopreventive strategies.

Dietary risk factors for upper aerodigestive tract cancers.

We examined the association between whole-grain intake and incident upper aerodigestive tract cancer in a cohort of 34,651 postmenopausal, initially cancer-free women. We also studied established risk factors for upper aerodigestive cancers, including fruit and vegetable intake, smoking and alcohol intake. A mailed questionnaire at baseline in 1986 included a food-frequency questionnaire and assessment of other cancer risk factors. During the 14-year follow-up period, 169 women developed cancer of the upper aerodigestive tract. For all upper aerodigestive cancers together, significant inverse associations were observed for the highest compared to the lowest tertile of whole grains [relative risk (RR) = 0.53, 95% confidence interval (CI) 0.34-0.81] and yellow/orange vegetables (RR = 0.58, 95% CI 0.39-0.87). In addition, those in the highest compared to lowest tertile of fiber intake from whole grain were less likely to develop upper aerodigestive tract cancer (RR = 0.56, 95% CI 0.37-0.84); fiber intake from refined grain was not significantly associated with upper aerodigestive tract cancer. Findings were generally similar for oropharyngeal (n = 53), laryngeal (n = 21), nasopharyngeal/salivary (n = 18), esophageal (n = 21) and gastric (n = 56) cancers, though numbers of cases were too small for statistical testing within individual cancers. These findings confirm previous observations that high intake of fruits and vegetables and that intake of whole grains and the fiber derived from them may reduce risk of upper aerodigestive tract cancers.

Genetic instability in epithelial tissues at risk for cancer.

Epithelial tumors develop through a multistep process driven by genomic instability frequently associated with etiologic agents such as prolonged tobacco smoke exposure or human papilloma virus (HPV) infection. The purpose of the studies reported here was to examine the nature of genomic instability in epithelial tissues at cancer risk in order to identify tissue genetic biomarkers that might be used to assess an individual's cancer risk and response to chemopreventive intervention. As part of several chemoprevention trials, biopsies were obtained from risk tissues (i.e., bronchial biopsies from chronic smokers, oral or laryngeal biopsies from individuals with premalignancy) and examined for chromosome instability using in situ hybridization. Nearly all biopsy specimens show evidence for chromosome instability throughout the exposed tissue. Increased chromosome instability was observed with histologic progression in the normal to tumor transition of head and neck squamous cell carcinomas. Chromosome instability was also seen in premalignant head and neck lesions, and high levels were associated with subsequent tumor development. In bronchial biopsies of current smokers, the level of ongoing chromosome instability correlated with smoking intensity (e.g., packs/day), whereas the chromosome index (average number of chromosome copies per cell) correlated with cumulative tobacco exposure (i.e., pack-years). Spatial chromosome analyses of the epithelium demonstrated multifocal clonal outgrowths. In former smokers, random chromosome instability was reduced; however, clonal populations appeared to persist for many years, perhaps accounting for continued lung cancer risk following smoking cessation.

Inhibition of cyclooxygenase-2: an approach to preventing cancer of the upper aerodigestive tract.

Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2), an inducible form of COX, represents a potential pharmacologic target to prevent cancer. Key data suggesting a causal relationship between increased COX-2 activity and carcinogenesis and possible mechanisms of action of COX-2 in this context will be discussed. The possibility that COX-2 represents a pharmacological target for preventing upper aerodigestive cancers (head and neck, lung) will be emphasized. Importantly, clinical trials have been initiated to assess the chemopreventive properties of selective COX-2 inhibitors.

Nuclear retinoid acid receptor beta in bronchial epithelium of smokers before and during chemoprevention.

BACKGROUND: Retinoids can reverse neoplastic lesions and prevent second primary tumors in the aerodigestive tract. These effects are thought to be mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs), each receptor group including three subtypes (alpha, beta, and gamma). Previously, we found that RARbeta expression was suppressed in lung cancer. In this study, we investigated whether expression of RARbeta is modulated by chemopreventive intervention. METHODS: Using in situ hybridization, we analyzed RARbeta messenger RNA (mRNA) expression in bronchial biopsy specimens from heavy smokers, at baseline and after 6 months of treatment with 13-cis-retinoic acid (13-cis-RA) or placebo. Since we had previously detected RARbeta expression in 90% of bronchial specimens from nonsmokers, we considered loss of RARbeta mRNA expression in at least one of six biopsy specimens at baseline in this study to be aberrant. RESULTS: RARbeta mRNA expression was aberrant in 30 (85.7%) of 35 subjects in the 13-cis-RA group and in 24 (72.7%) of 33 subjects in the placebo group. After 6 months of 13-cis-RA treatment, the number of subjects who were RARbeta positive in all six biopsy specimens increased from five of 35 to 13 of 35 (2.6-fold), so that the percentage of individuals with aberrant RARbeta expression decreased to 62.9% (22 of 35), which represents a statistically significant difference from baseline expression (two-sided P =.01). In the placebo group, no statistically significant difference in RARbeta expression was observed between baseline and 6 months. RARbeta expression was not related to current smoking status or reversal of squamous metaplasia. CONCLUSIONS: These results indicate that RARbeta is an independent marker of response to 13-cis-RA and may serve as an intermediate biomarker in chemoprevention trials of upper aerodigestive tract cancers.