Human papillomavirus prevalence among women with cervical intraepithelial neoplasia III and invasive cervical cancer from Goiânia, Brazil

This study estimated the prevalence and distribution of human papillomavirus (HPV) types among women with cervical intraepithelial neoplasia (CIN) grade III and invasive cervical cancer from Goiás (Brazil Central Region). Seventy-four cases were analyzed and consisted of 18 CIN III, 48 squamous cell carcinomas, 4 adenocarcinomas, 1 adenosquamous carcinoma and 3 undifferentiated carcinomas. HPV-DNA sequences were examined in formalin-fixed and paraffin-embedded tissues using primers from L1 region GP5+/GP6+. Polymerase chain reaction products were typed with dot blot hybridization using probes for HPV 16, 18, 31, 33, 45, 54, 6/11, 42/43/44, 51/52, 56/58. The prevalence of HPV was estimated to be 76% (56/74). HPV 16 was the most frequently found type, followed by HPV 33, 18 and 31. The prevalence of untyped HPV was 6%; 79% percent of the squamous cell carcinoma cases and 61% percent of the CIN III were positive for HPV and the prevalence rate of HPV types was the same for the total number of cases. According to other studies, HPV type 16 is the most prevalent virus in all Brazilian regions, but there is variation regarding to other types. Type 18 is the second most prevalent HPV in North, Southeast and South Brazil regions and types 31 and 33 are the second most prevalent HPV in Northeast and Central Brazil, respectively.

Beating cervical cancer: information for girls in Year 9, aged 12-13 (English and eight translations)

This leaflet is distributed to girls in Year 9 and explains about the HPV vaccine which can help protect against cervical cancer.

Beating cervical cancer. The HPV vaccine - questions and answers for parents of girls in Year 9 (English and eight translations)

This leaflet provides more detailed information in a question and answer format about the HPV vaccine offered to girls in Year 9 which can help protect against cervical cancer.

Cervical cancer: it's best to take the test

From January 2011, the Northern Ireland cervical screening programme no longer invited women aged under 25 to attend for screening. In addition, the screening interval for women aged 25-49 was reduced to every three years. This leaflet is one of a series of new information materials that was developed to reflect the policy changes and to give information to increase the uptake of information and interventions offered to protect and maintain the health of women in the target group. It gives information about cervical screening in Northern Ireland and helps women to understand why it is important to be screened.

Beating cervical cancer. The HPV vaccine - questions and answers for parents of girls in Year 9 (English and eight translations)

This leaflet provides more detailed information in a question and answer format about the HPV vaccine offered to girls in Year 9 which can help protect against cervical cancer.

Beating cervical cancer: information for girls in Year 9, aged 12-13 (English and eight translations)

This leaflet is distributed to girls in Year 9 and explains about the HPV vaccine, which can help protect against cervical cancer.

Cervical cancer: it's best to take the test (English and 11 translations)

Testing for high-risk human papillomavirus (HR-HPV) as triage and test of cure was introduced into the Northern Ireland Cervical Screening Programme on Monday 28 January 2013. This policy change will significantly alter the screening pathway for women with a mild dyskaryosis or borderline smear result.

HPV vaccination: the beginning of the end of cervical cancer? - A Review

Human papillomavirus (HPV) is responsible for all cases of cervical cancer, as well as a great percentage of other anogenital tumors and oropharyngeal tumors. Since the main etiologic factor for these diseases is a virus, prophylactic measures are the best way to reduce the burden caused by the infection and associated disease. This review brings up to date information on the two commercially available prophylactic HPV vaccines against HPV, as well as presenting the ongoing research on HPV peptide, protein and dendritic cell based therapeutic vaccines.

High prevalence and low E6 genetic variability of human papillomavirus 58 in women with cervical cancer and precursor lesions in Southeast Mexico

Infection with some genotypes of human papillomavirus (HPV) is the most important risk factor associated with cervical cancer (CC). Throughout the world, HPV type 58 prevalence varies from one region to another; it is higher in women from certain countries in Asia and Latin America, such as China and Mexico. Although intratypic variants have been reported on a few occasions, our knowledge about HPV 58 genetic variation remains limited. Therefore, this work aims to (i) determine the prevalence of HPV type 58 amongst Mexican women with invasive CC or precursor lesions and (ii) identify HPV 58 sequence variants. One hundred and forty five colposcopy clinic patients were studied. Genotyping of HPV 16, 18 and 58 was determined by specific nested PCR and HPV 58 variants were detected by direct sequencing. The general prevalence of HPV was 51.7% (75/145). HPV 16 was found in 30.6% (23/75) and HPV 58 in 24% (18/75) of the patients. HPV 18 was not identified in patients with cervical intraepithelial neoplasia (CIN) grade I; it was only found in those with CIN II, with a prevalence of 6.8% (3/44). In patients with CC, the prevalence of HPV 16 and 58 was 78.9%. Regarding HPV 58 variants, 94.4% of the HPV 58 sequences were identical to the prototype strain, whereas one sample showed changes at a single nucleotide. This study demonstrates a high prevalence of HPV 58 and a low genetic variability of E6 sequences amongst Mexican colposcopy patients.

Novel immunotherapeutic strategies against human papillomavirus type 16 (HPV 16) induced lesions and cervical cancer

RESUME Le cancer du col de l'utérus, deuxième cause de mort par cancer chez la femme, a pu être associé à une infection par plusieurs types de virus du Papillome Humain (HPV), et en particulier HPV 16. Les vaccins prophylactiques sont efficaces à prévenir le cancer du col utérin alors que les lésions de haut grade sont généralement traitées par ablation chirurgicale et par d'éventuels traitements additionnels. Les risques de récurrence liés aux ablations et le taux de mortalité (50%) lié au cancer, démontrent le besoin de développer des stratégies alternatives afin de cibler les lésions précancéreuses. A ce jour, les vaccins thérapeutiques ont démontré peu de résultats cliniques, contrastant avec les régressions de tumeurs ectopiques observées après vaccination dans des modèles murins avec tumeurs associées à HPV. L'induction de réponses immunitaires protectrices dans la muqueuse génitale semble être cruciale pour l'efficacité des vaccins thérapeutiques HPV et évaluer leur efficacité dans un modèle murin avec tumeurs-HPV génitales représente un pré-requis important avant de procéder à des études cliniques. Par conséquent, nous avons établi un modèle murin orthotopique où des tumeurs se développent dans (a muqueuse génitale après une instillation intra-vaginale (i.vag) de cellules tumorales exprimant les oncogènes E6/E7 d'HPV 16 et transduites par un vecteur lentiviral codant la luciferase afin de suivre le développement de ces tumeurs in vivo par imagerie. La caractérisation histologique a démontré que les tumeurs grandissaient dans l'épithélium vaginal et en accord avec leur localisation, des cellules Τ CD8 spécifiques à E7 induites par la tumeur n'étaient détectées que dans la muqueuse génitale et les ganglions drainants. Une infiltration de cellules Τ régulatrices a aussi été mise en évidence, empêchant la régression spontanée de ces tumeurs. Par conséquent, ce modèle devrait être plus adéquat pour tester des stratégies thérapeutiques, étant donné qu'il partage certaines similarités immunologiques avec les lésions génitales naturelles causées par HPV. Etant donné que les oncogènes E6 et E7 d'HPV sont nécessaires à la maintenance du phénotype cancéreux des cellules cervicales, elles représentent des antigènes cibles pour la vaccination thérapeutique. Nous avons démontré que des souris immunisées par voie sous-cutanée (s.c.) avec une dose d'un vaccin à base de polypeptide E7 d'HPV 16 et d'adjuvants, présentaient de nombreuses cellules Τ CD8 sécrétant de l'IFN-γ spécifiquement à E7 dans leurs organes lymphatiques mais également dans la muqueuse génitale. De plus, le manque de corrélation entre les réponses spécifiques mesurées dans la périphérie et dans la muqueuse génitale souligne la nécessité et l'importance de déterminer les réponses immunitaires localement là où les lésions dues à HPV se développent. Si une vaccination par voie muqueuse est plus propice à traiter/régresser des infections génitales/tumeurs que le voie parentérale est un sujet débattu. Nos données montrent que seule la voie s.c. était capable de régresser la quasi totalité des tumeurs génitales chez la souris bien que des réponses CD8 spécifiques à E7 similaires étaient mesurées dans la muqueuse génitale après des vaccinations intra-nasale et i.vag. Afin d'augmenter la réponse spécifique au vaccin dans la muqueuse génitale, des immunostimulants ont été administrés par voie i.vag après vaccination. Nous avons démontré qu'une application i.vag d'agonistes des Toll like receptors après une vaccination s.c. induisait de manière significative une augmentation des cellules Τ CD8 sécrétant de l'IFN-γ spécifiquement à E7 dans la muqueuse génitale. Plus précisément et concernant les CpG et Poly l:C, l'effet était probablement associé à une attraction locale des cellules Τ CD8 et deuxièmement dépendait respectivement des voies de signalisation TLR9 et TLR3/Mda5. Finalement, cette stratégie combinatoire a permis de régresser des grosses tumeurs génitales chez la souris, suggérant qu'une telle immunothérapie pourrait adéquatement traiter des lésions dues à HPV chez les femmes. SUMMARY Cervical cancer is the second leading cause of cancer mortality in women worldwide and results from an infection with a subset of Human Papillomavirus (HPV), HPV 16 representing the most prevalent type. The available prophylactic vaccines are an effective strategy to prevent cervical cancer while already established high grade lesions usually require surgical ablation of lesion with possible additional treatments. Recurrence risks linked to conventional ablations and the high mortality (50%) related to cervical cancer demonstrate the need for alternative strategies like immunotherapies to target pre¬cancerous lesions. Until now, therapeutic vaccines only showed limited clinical results, which strongly contrast with the regression of ectopic tumors observed in the available murine HPV tumor models after vaccination. Induction of protective immune responses in the genital mucosa (GM) may be crucial for efficacy of HPV therapeutic vaccines and evaluating their efficacy in a murine model with genital HPV- tumors represents an important prerequisite for clinical trials. Thus, we have here established an orthotopic mouse model where tumors in the GM develop after an intravaginal (i.vag) instillation of HPV 16 E6/E7 oncogenes-expressing tumor cells transduced with a luciferase encoding lentivirus vector for in vivo imaging of tumor growth. Histological characterization showed that tumor grew within the vaginal epithelium and according to their mucosal location tumor- induced E7-specific CD8 Τ cells were restricted to the GM and genital draining lymph nodes together with high Τ regulatory cells infiltrates preventing spontaneous regression. Consequently, sharing several immunological similarities with natural genital HPV lesions, this novel genital tumor model may be more adequate to test therapeutic strategies. As E6 and/or E7 HPV oncogenes expression is required for the maintenance of the cancerous phenotype of cervical cells, they represent target antigens for therapeutic vaccination. We reported that mice subcutaneously (s.c.) immunized once with an adjuvanted HPV 16 E7 polypeptide vaccine harbored high E7-specific IFN-γ secreting CD8 Τ cells in their lymphoid organs and more importantly in the GM. In addition, the lack of correlation between specific responses measured in the periphery with those measured in the GM highlighted the necessity and relevance to determine the immune responses locally where HPV 16-induced lesions develop. Whether a mucosal route of immunization is better to treat/regress genital infections/tumors than parenteral immunization is still debated. Our data shows that although similar E7-specific IFN-γ secreting CD8 Τ cells responses were measured in the GM upon mucosal routes of E7 vaccine delivery (nasal and vaginal immunizations), only the s.c immunization was able to regress at least all genital tumors in mice. To further increase the vaccine-specific responses in the GM, immunostimulatory agents were i.vag administrated after vaccination. We demonstrated that a single i.vag application of toll like receptor (TLR) agonists after a s.c. E7 vaccination induced a significant increase of E7-specific IFN-γ secreting CD8 Τ cells in the GM. More precisely, regarding CpG and Poly l:C, the effect is most probably associated with a local attraction of total CD8 Τ cells and secondly depends on TLR9 and TLR3/Mda5 signaling pathways, respectively. Finally, this combinatorial strategy induced tumor regression in mice harboring large genital tumors, suggesting that such an immunotherapy could be adequate to treat HPV-induced lesions in women.

Incidence of invasive cervical cancer in the Swiss canton of Vaud, and a note on screening.

Age adjusted incidence rates (World standard) from invasive cervical cancer in the Swiss canton of Vaud decreased from 17.7/100,000 in 1968-70 to 9.9/100,000 in 1983-85. The decline was substantial in younger middle age, but no appreciable trend was observed in women over 70. This is consistent with available interview based information on the pattern of cervical screening in the Swiss population. Although there was no organised screening programme in Switzerland, over 80% of women aged 20-44 and 65% of those aged 45-64 reported one or more screening smears over the previous 3 years, compared to only 22% of women aged 65 or over. In the last calendar period, there was an apparent increase in the incidence of invasive cervical cancer (from 2.5 to 6.1/100,000) in women aged 25-29. Although based on small absolute numbers, this is in agreement with incidence and mortality data from other countries, and may therefore confirm a change in risk factor exposure in younger women.

Cervical cancer: incidence and survival in migrants within Spain

This study examined the incidence of cervical cancer and survival rates according to migrant experience of women from different regions of Spain to Girona, Catalonia (Spain). DESIGN--Using data from the population based cancer registry of Girona for the period 1980-89, crude and age adjusted incidence rates were calculated for local-born and first generation migrants from other Spanish regions. The age standardised rate ratio (SRR) was calculated and Cox's regression model was used to adjust survival according to migrant status for age and stage at diagnosis. MAIN RESULTS--The incidence of cervical cancer was significantly higher in first generation Spanish migrants compared with locally born women (SRR: 2.02; 95% CI 1.40:2.92). The stage at diagnosis was more advanced among migrants. Survival probability was significantly associated with stage at diagnosis, but age and region of birth were not. CONCLUSIONS--Migrants from the southern Spanish regions show a twofold excess in the incidence of cervical cancer compared with the Girona-born female population. Cases of cervical cancer in migrants are diagnosed at a more advanced stage and as a consequence have a poorer prognosis.

[(18)F]FDG-PET Standard Uptake Value as a Metabolic Predictor of Bone Marrow Response to Radiation: Impact on Acute and Late Hematological Toxicity in Cervical Cancer Patients Treated With Chemoradiation Therapy.

PURPOSE: To quantify the relationship between bone marrow (BM) response to radiation and radiation dose by using (18)F-labeled fluorodeoxyglucose positron emission tomography [(18)F]FDG-PET standard uptake values (SUV) and to correlate these findings with hematological toxicity (HT) in cervical cancer (CC) patients treated with chemoradiation therapy (CRT). METHODS AND MATERIALS: Seventeen women with a diagnosis of CC were treated with standard doses of CRT. All patients underwent pre- and post-therapy [(18)F]FDG-PET/computed tomography (CT). Hemograms were obtained before and during treatment and 3 months after treatment and at last follow-up. Pelvic bone was autosegmented as total bone marrow (BMTOT). Active bone marrow (BMACT) was contoured based on SUV greater than the mean SUV of BMTOT. The volumes (V) of each region receiving 10, 20, 30, and 40 Gy (V10, V20, V30, and V40, respectively) were calculated. Metabolic volume histograms and voxel SUV map response graphs were created. Relative changes in SUV before and after therapy were calculated by separating SUV voxels into radiation therapy dose ranges of 5 Gy. The relationships among SUV decrease, radiation dose, and HT were investigated using multiple regression models. RESULTS: Mean relative pre-post-therapy SUV reductions in BMTOT and BMACT were 27% and 38%, respectively. BMACT volume was significantly reduced after treatment (from 651.5 to 231.6 cm(3), respectively; P<.0001). BMACT V30 was significantly correlated with a reduction in BMACT SUV (R(2), 0.14; P<.001). The reduction in BMACT SUV significantly correlated with reduction in white blood cells (WBCs) at 3 months post-treatment (R(2), 0.27; P=.04) and at last follow-up (R(2), 0.25; P=.04). Different dosimetric parameters of BMTOT and BMACT correlated with long-term hematological outcome. CONCLUSIONS: The volumes of BMTOT and BMACT that are exposed to even relatively low doses of radiation are associated with a decrease in WBC counts following CRT. The loss in proliferative BM SUV uptake translates into low WBC nadirs after treatment. These results suggest the potential of intensity modulated radiation therapy to spare BMTOT to reduce long-term hematological toxicity.

The role of PET/CT in cervical cancer.

In locally advanced cervical cancer, (18)F-fluorodeoxyglucose (FDG) positron emission tomography - computed tomography (PET/CT) has become important in the initial evaluation of disease extent. It is superior to other imaging modalities for lymph node status and distant metastasis. PET-defined cervical tumor volume predicts progression-free and overall survival. Higher FDG uptake in both primary and regional lymph nodes is strongly predictive of worse outcome. FDG-PET is useful for assessing treatment response 3 months after completing concurrent chemo-radiotherapy (CRT) and predicting long-term survival, and in suspected disease recurrence. In the era of image-guided adaptive radiotherapy, accurately defining disease areas is critical to avoid irradiating normal tissue. Based on additional information provided by FDG-PET, radiation treatment volumes can be modified and higher doses to FDG-positive lymph nodes safely delivered. FDG-PET/CT has been used for image-guided brachytherapy of FDG-avid tumor volume, while respecting low doses to bladder and rectum. Despite survival improvements due to CRT in cervical cancer, disease recurrences continue to be a major problem. Biological rationale exists for combining novel non-cytotoxic agents with CRT, and drugs targeting specific molecular pathways are under clinical development. The integration of these targeted therapies in clinical trials, and the need for accurate predictors of radio-curability is essential. New molecular imaging tracers may help identifying more aggressive tumors. (64)Cu-labeled diacetyl-di(N(4)-methylthiosemicarbazone) is taken up by hypoxic tissues, which may be valuable for prognostication and radiation treatment planning. PET/CT imaging with novel radiopharmaceuticals could further impact cervical cancer treatment as surrogate markers of drug activity at the tumor microenvironment level. The present article reviews the current and emerging role of PET/CT in the management of cervical cancer.