A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / The role of viruses in most common cancers is undoubtedly important, yet highly underestimated. Human Papilloma Virus (HPV) has been implicated with 99.7% of cervical cancers and its oncogenic mechanism has been clearly identified. The association of cervical cancer with 90% of triple negative breast cancer (TNBC) cases in African countries creates an intriguing possibility of HPV being a candidate oncovirus for breast cancer. In fact, numerous recent tissue studies conducted throughout the world detected HPV DNA in breast cancer tissues of patients with cervical cancer, while high‐risk HPV types (16, 18, 33) were present in invasive ductal carcinomas. 5,6 Prevalence of HPV varied from 4% in Mexican to 86% in American women. The virus was noted to be present in tumor tissue only, with the exception of one study, which identified lower concentration of HPV in normal tissue. 7 Although substantial evidence exists supporting involvement of HPV in breast cancer, no clinical studies have been conducted to elucidate this relationship. The goal of our retrospective chart review was to examine the association of breast cancer and HPV‐related cervical dysplasia in a cohort of women in urban setting. 15% (39/260) had abnormal Pap‐smear, while 8% (16/198) were HPVpositive. No statistically significant difference of Pap‐smear abnormality or of HPV positivity were detected among the groups in all categories. However, we noticed that non‐luminal breast cancers, double negative and triple negative (DN and TN), have higher rate of HPV positivity: 13.3% non‐luminal vs. 6.3% of luminal breast cancers, 12.5% DN breast cancers and 11.5% of TN vs. 6.4% of luminal A and 6.3% of luminal B. This creates an intriguing possibility that HPV might be associated with more than 50% increase of incidence rates of non‐luminal breast cancers, suggesting a need for larger scale studies to confirm this association.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / The human microbiome is the collection of microorganisms in the body that exist in a mutualistic relationship with the host. Recent studies indicate that perturbations in the microbiome may be implicated in a number of diseases, including cancer. More specifically, changes in the gut and vaginal microbiomes may be associated with a variety of gynecologic cancers, including cervical cancer, uterine cancer, and ovarian cancer. Current research and gaps in knowledge regarding the association between the gut and vaginal microbiomes and the development, progression, and treatment of gynecologic cancers are reviewed here. In addition, the potential use of probiotics to manage symptoms of these gynecologic cancers is discussed. A better understanding of how the microbiome composition is altered at these sites and its interaction with the host may aid in prevention, optimization of current therapies, development of new therapeutic agents and/or dosing regimens, and possibly limit the side effects associated with cancer treatment.

Orientador: Regina Helena Garcia Martins / Resumo: Mercuri G. Incidência e Prevalência da Papilomatose Laríngea no Estado de São Paulo [dissertação]. Botucatu, SP: Faculdade de Medicina de Botucatu, Universidade Estadual Paulista; 2019. Introdução: A papilomatose respiratória recorrente ou papilomatose laríngea recorrente é a neoplasia benigna da laringe causada pelo Papiloma Vírus Humano, caracterizando-se pela presença de lesões proliferativas exofíticas recorrentes. A ausência de tratamento curativo, os custos relacionados ao diagnóstico, prevenção e tratamento das doenças causadas pelo HPV apresentam importante impacto econômico em todo mundo. No entanto, a falta de dados epidemiológicos nacionais, quanto à incidência e prevalência da papilomatose laríngea no Brasil não nos permite analisar o comportamento da doença em nossa população, bem como os benefícios da vacinação. Objetivo: Estimar a incidência e a prevalência da Papilomatose Laríngea no Estado de São Paulo. Métodos: Estudo populacional que objetivou levantar todos os casos diagnosticados de Papilomatose Laríngea do Estado de São Paulo, considerando os principais centros de diagnóstico desta enfermidade. Foram mapeados e selecionados os principais serviços de residência e especialização em Otorrinolaringologia do Estado de São Paulo, a partir dos dados fornecidos pela Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial (ABORL-CCF). Através do preenchimento de um questionário obtivemos os dados para estimar a prevalência e a incidência mínimas p... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Mercuri G. Incidence and Prevalence of Laryngeal Papillomatosis in São Paulo State [thesis]. Botucatu, SP: Faculty of Medicine of Botucatu, Universidade Estadual Paulista; 2019. Introduction: Recurrent respiratory papillomatosis or recurrent laryngeal papillomatosis is a benign laryngeal neoplasm caused by Human Papilloma Virus, characterized by the presence of recurrent exophytic proliferative lesions. Without curative treatment, costs related to the diagnosis, prevention, and treatment of HPV-related diseases have a significant economic impact worldwide. However, the lack of national epidemiological data on the incidence and prevalence of laryngeal papillomatosis in Brazil does not allow us to analyze the behavior of the disease in our population, as well as the benefits of vaccination. Objective: To estimate the incidence and prevalence of Laryngeal Papillomatosis in the State of São Paulo. Methods: A population study was conducted aiming to raise all the diagnosed cases of Laryngeal Papillomatosis of the State of São Paulo, considering the main centers of diagnosis of this disease. The main services of residence and specialization in Otorhinolaryngology of the State of São Paulo were mapped and selected, based on the data provided by the Brazilian Association of Otorhinolaryngology and Cervical-Facial Surgery (ABORL-CCF). By completing a questionnaire we obtained the data to estimate the minimum prevalence and incidence for the State in 2017. Results: The questionnaire wa... (Complete abstract click electronic access below) / Mestre

Bakgrund    HPV, humant papillomvirus, är den vanligast sexuellt överförbara sjukdomen i världen. HPV kan orsaka kondylom, vilket innebär könsvårtor, men det kan även ge gynekologiska cellförändringar som kan leda till livmoderhalscancer. Syfte            Syftet var att undersöka vilken kunskap och inställning gymnasieelever, som inte ingår i vaccinationsåldern, hade till HPV och HPV-vaccination samt om det fanns några könsskillnader. Metod   En kvantitativ enkätstudie genomfördes på en gymnasieskola i Uppsala, Sverige. Enkätdistribueringen skedde vid två tillfällen och 58 (98,3 %) ifyllda enkäter kunde inhämtas, varav 38 var flickor och 20 var pojkar. Resultat    Flickorna på skolan hade en generellt högre andel rätt svar på enkäten, och totalt var det 21 (55,2 %) av flickorna som var vaccinerade medan endast 1 (5 %) av pojkarna. Av samtliga elever var det 22 (37,9 %) som kunde besvara frågan rätt angående hur många typer av HPV-virus det finns, dock kunde 51 (87,9 %) besvara frågan rätt om hur man skyddar sig mot HPV-viruset. Signifikant könsskillnad hittades i kunskapsfrågan gällande om HPV kan orsaka livmoderhalscancer (p<0,045) där flickorna hade flest rätt svar på frågan. Det var fler vaccinerade flickor jämfört med pojkar (p<0,001) och signifikant fler pojkar som kunde tänka sig att vaccineras (p<0,019). Majoriteten, 68 %, av eleverna var positiva till den befintliga HPV-vaccinationen. Slutsats     Eleverna hade generellt sett en låg kunskapsnivå gällande HPV men trots det var det ändå mer än hälften av flickorna som var vaccinerade. Behov av ytterligare kunskap om HPV och HPV-vaccination till befolkningen behövs. / Background HPV, human papilloma virus, is the most common sexually transmitted disease in the world. HPV can cause genital warts and gynaecological dysplasia, which can lead to cervical cancer. Objective The objective was to describe the amount of knowledge the students had regarding HPV and the HPV-vaccination. Another objective was to describe how many of the students who were vaccinated and to study the existing attitudes towards HPV and the HPV-vaccination. The last objective was to compare whether there was any gender differences. Methods  A quantitative survey study was conduced at an upper secondary school in Uppsala, Sweden. The distribution of the surveys occurred on two occasions and 58 (98,3 %) completed surveys were collected. Results The girls had a generally higher percentage of correct answers on the survey. About 55 % (n=21) of the girls were vaccinated but only 5 %(n=1) of the boys. Regarding how many types of HPV there are 22(37,9 %) of the students answered correctly, although 51 (87,9 %) knew how to protect themselves against a possible infection. Significant differences in gender were found in the question whether HPV can cause cervical cancer or not (p=0,045) and whether the students would be willing to take the vaccine or not (p=0,019). The majority of the students, 68 %, were in favour of the existing HPV vaccination. Conclusion Although the students generally had poor knowledge regarding HPV the majority of the girls had taken the vaccine. The need of further knowledge is vast.

Introduction: Human papillomavirus (HPV) is changing the prevalence, survival and treatment paradigms in oropharyngeal squamous cell carcinoma (OPSCC). Improved survival of patients with HPV positive compared to HPV negative OPSCC has led to trials of treatment de-escalation. Current HPV detection methods are imprecise, therefore standardised assessment of transcriptionally active HPV in OPSCC is required. Furthermore, the differences in immune characteristics and/or the hypoxia response/effects could explain observed differences in prognosis between HPV positive and negative OPSCC. Rigorous HPV detection and subsequent biomarker evaluation should provide additional information required before introduction of treatment de-escalation in broad patient groupings. Methods: The study cohort was 218 patients with OPSCC who received radiotherapy with curative intent. HPV status was determined on pre-treatment, formalin-fixed paraffin-embedded blocks using: 1) polymerase chain reaction (PCR); 2) in-situ hybridisation (ISH) and 3) immuno-histochemistry (IHC). QuantiGene multiplex assay was designed to detect mRNA of reference sequences of the common high-risk HPV types (16, 18, 33, 35, 45, 52 and 58). HPV detection methods were compared with mRNA quantification. Multimarker IHC of immune cell markers using chromogenic and fluorescent staining was performed, analysed and compared with single marker IHC using automated multispectral image analysis. A validated multiplex IHC method was used for a) chromogenic (CD3, CD4, CD8, and FoxP3) and b) fluorescent (CD8, CD68 and PD1/PD-L1) evaluation in tumour and stroma compartments. Single marker IHC was used to investigate tumour hypoxia markers (HIF-1α and CA-IX) in HPV positive and negative OPSCC. Results: p16 IHC and ISH were the most sensitive and specific, respectively, for classifying HPV status. The combination of the three tests had the highest positive/negative predictive values compared with QuantiGene mRNA detection. Multiplex validation showed that, for serial sections up to 6 μm apart, there were highly significant correlations (P<0.0001) between single and multiplex counts for both chromogenic and fluorescent IHC. Overall there was less variation in cell counts with fluorescent staining when compared to chromogenic staining. Multiplex IHC of TILs in HPV positive and negative OPSCC showed higher infiltration in both tumour and stromal areas of CD3+CD4+ and CD3+CD8+ T cells but not CD4+FoxP3 Tregs in HPV positive compared with HPV negative OPSCC. Only CD3+CD8+ stromal and not tumour area infiltration was associated with increased survival (P=0.02). PD-L1 expression was higher in HPV negative OPSCC and this was related to macrophage (CD68) expression of PD-L1. In HPV negative tumours infiltration with CD68+PD-L1 was associated with a good prognosis. HPV negative patients had higher expression of HIF-1α but not CA-IX. High expression of both markers was associated with a poor prognosis irrespective of HPV status. Conclusions: There are other prognostic factors operating in the larger subdivision of HPV positive and negative OPSCC. Precise HPV detection and inclusion of other prognostic factors is required before treatment de-escalation is used. Expression of immune inhibitory factors (PD1/PD-L1) alone without contextualisation with immune cell density is insufficient for patient prognostication and potential selection for therapy using immune checkpoint inhibitors. Hypoxia modification of radiotherapy should be explored in both HPV positive and negative OPSCC.

Denna studie undersökte kvinnors upplevelser när de fick ett HPV-positivt screeningresultat brevledes. Den svenska screeningen för förebyggande av livmoderhalscancer meddelar resultatet i ett kort, standardiserat brev. Efter att ha inkluderat humant papillomvirus (HPV) i analysen år 2014 verkade kvinnor bli mer oroliga för resultatet som kunde meddela en sexuellt överförd infektion (STI).En intervjustudie genomfördes med åtta kvinnor och empiriska data analyserades med receptionsteori. Resultaten visade vilka känslor kvinnor kämpade med, om de upplevde en negativ inverkan på deras sexualitet och om de var nöjda med ett brev som kommunikationssätt.Okunnighet om HPV och rädsla för cancer var centrala resultat. Kvinnor beskrev till och med en förändring i attityd till andra sexuella praktiker än vaginalt samlag. Resultatbrevet ansågs vara för kort och inte så informativt som nödvändigt. Detta fick samtliga kvinnor att söka efter mer information främst på internet för att hitta svar på deras frågor.Sammanfattningsvis finns det ett behov av grundlig och strukturerad information relaterad till HPV och påverkan på livmoderhalsen. Personal inom hälso- och sjukvårdssystemet bör vara lyhörda för kvinnors oro över deras screeningresultat. / This study explores women´s experiences when receiving their HPV-positive pap smear result as a letter. The Swedish screening programme for the prevention of cervical cancer notifies of the result in a short, standardised letter. After including human papilloma virus (HPV) in the analysis in 2014 women appeared to become more worried about the result showing a sexually transmitted infection (STI). An interview study was performed with eight women and the empirical data was analysed with reception theory. The study-results show which feelings women struggled with, whether they experienced a negative impact on their sexuality, and whether they were content with a letter as communication method for their results. Ignorance of HPV and fear of cancer were central findings. Women even described a change in attitude towards sexual practices other than vaginal intercourse. The result letter was considered to be too short and not as informative as needed. This caused all the women to look for more information foremost on the internet in order to find answers to their questions.In conclusion there is a need for thorough and structured information related to HPV and impact on the cervix. Healthcare system personnel should have a sensitive ear for women´s concerns about their pap smear results.

Cervical cancer represents an enormous health, psychological and social stress for every woman. The most important risk factor in the development of cervical carcinoma, which the second most common malignant cancer in women, is infection with a high-risk strain of human papillomavirus - a very frequent sexually transmitted disease. More than 100 types of HPV are acknowledged to exist, with HPV 16 and 18 being classified as high-risk types in particular. Worldwide, 500,000 new cases of cervical cancer are diagnosed every year. In the Czech Republic, there are 1,000 new cases of cervical cancer each year, out of which up to 400 women die. It is estimated that there will be up to 1,000,000 new cases of cervical cancer by 2050 unless the prevention is improved. Every woman is at risk of developing cervical cancer. HPV is sexually transmitted, however not only by sexual intercourse but also by skin-to-skin-contact with infected areas. Other risk factors in the development of the disease are: first sexual intercourse at early age, the number of sexual partners, smoking, other sexually transmitted diseases and a long term use of hormonal contraception. Use of condoms, which protects against sexually transmitted diseases, reduces the transmission of HPV by up to 70%. Having regular gynaecological check-ups with Pap smears is crucial for cervical cancer screening, as the screening suggests the presence of cytological abnormalities and pre-cancer. However, it cannot detect all types of premalignant changes and early stages of the carcinoma. Two vaccines have recently been developed, effective against the most frequent oncogenic strains of HPV (16 and 18), which currently cause about 70% of cervical cancer cases. Active immunisation against human papillomavirus is the first vaccination against carcinoma. Together with screening, it represents the best prevention method against cervical carcinoma. Based on the research of technical literature, the first part of the dissertation gives an overall view of the issue of cervical carcinoma. The second part of the dissertation deals with the research, eliciting the knowledge and attitude of women from Southern Bohemian towns in the field of cervical carcinoma prevention in the period of December 2008 - March 2009 and comparing it to technical literature.

Human papillomavirus (HPV) is the most common cause of sexually transmitted diseases. It is the causative agent of cervical cancer, anal, and penile cancers. The purpose of the study was to determine the knowledge, attitude and behaviour of parents towards HPV and HPV vaccine in preventing cervical cancer in girls aged 9 to 13 years and HPV vaccine uptake. The study was conducted in Sefhare village, in the Central District of Botswana. The researcher selected a quantitative, descriptive cross-sectional research design and data was collected using a questionnaire in face-to-face interviews. The study population consisted of parents of adolescent girls of ages 9-13 years living in four wards of Sefhare village. Data was analysed using SPSS version 19. The study found a high level (71.8%) of knowledge about HPV infection, cervical cancer and HPV vaccine and a positive attitude (81.5%) and behaviour (62%) towards the HPV vaccine. / Health Studies / M.P.H.