[Show abstract][Hide abstract] ABSTRACT: Human papillomavirus (HPV) infection has traditionally been regarded as a sexually transmitted disease (STD), but recent evidence implicates that an infected mother can transmit HPV to her newborn during pregnancy, at delivery, perinatal period or later. Given the lack of any studies on HPV-specific immune responses in children, we conducted HPV16-specific cell-mediated immune (CMI) monitoring of the mother-child pairs with known oral and genital HPV follow-up (FU) data since the delivery. In the Finnish Family HPV Study, 10 out of 331 mothers developed incident cervical intraepithelial neoplasia (CIN) during their 14-year FU. Our hypothesis according to the common dogma is that there is no HPV16 specific immune response in offspring of the CIN mother as she/he has not started the sexual life yet.
We used overlapping 30-35 mer peptides covering the entire HPV16 E2, E6 and E7 protein sequences. Assays for lymphocyte proliferation capacity, cytokine production and HPV16-specific Foxp3 + CD25 + CD4+ regulatory T-cells were performed.
HPV16-specific proliferative T-cell responses were broader in children than in their mothers. Nine of 10 children had responses against both E2 peptide pools compared to only 4 of the 10 mothers. Six of the 10 children and only 2 mothers displayed reactivity to E6 and/or E7. The cytokine levels of IL-2 (p = 0.023) and IL-5 (p = 0.028) induced by all peptide pools, were also higher among children than their mothers. The children of the mothers with incident CIN3 had significantly higher IFN-gamma (p = 0.032) and TNF-alpha (p = 0.008) levels than other children.
Our study is the first to show that also children could have HPV-specific immunity. These data indicate that the children have circulating HPV16-specific memory T-cells which might have been induced by previous HPV16 exposure or ongoing HPV 16 infection.
Journal of Translational Medicine 02/2014; 12(1):44. · 3.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This retrospective study included 92 consecutive patients with locally advanced or metastatic pancreatic cancer treated in the Turku University Hospital in 2010. The diagnosis of pancreatic cancer was verified by either histological samples (adenocarcinoma) or by imaging or both, excluding other known histological types of tumours. Median patient survival was 11 months. Smokers had a better median overall survival (20 months) than non-smokers (10 months) (p=0.029). Patients with carcinoma of the head of pancreas had the best survival rates (15 months), whereas those with cancers of the tail of pancreas reached a median survival of only 3 months. The importance of this small trial resides in its retrospective and non-randomized nature, analyzing real-life patients, as encountered in daily practice, out of which, unfortunately, a substantial proportion would not be eligible for any randomized clinical trial.
Anticancer research 12/2013; 33(12):5491-4. · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1) associates with treatment resistance and adverse outcome in several human cancers. We studied ALDH1 expression in rectal cancer, with special emphasis on its association with treatment response and disease outcome. Immunohistochemical staining for ALDH1 was conducted for 64 biopsies and 209 operative samples from rectal cancer patients treated with short- (n = 89) or long-course (n = 46) (chemo)radiotherapy plus surgery, or with surgery only (n = 74). The staining results were compared to clinicopathological variables, tumor regression grade (TRG) and disease outcome. Nuclear β-catenin expression pattern was analyzed from 197 operative samples. Positive ALDH1 expression was present in 149 operative samples (71%), correlating with deficient nuclear β-catenin regulation (P = .018). In a pairwise comparison of respective biopsy and operative samples, ALDH1 expression remained stable or increased after preoperative (chemo)radiotherapy in most of the cases, while it decreased in few cases only (P = .02 for positive/negative category; P <.001 for intensity). ALDH1 expression did not, however, relate to tumor regression grade. In node-negative rectal cancer, ALDH1 expression was an independent predictor of short disease-free and disease-specific survival (P = .044; P = .049), specifically among patients treated with adjuvant chemotherapy. We conclude that ALDH1 associates with deregulated β-catenin signaling, supporting the role of ALDH1 in rectal cancer stemness. ALDH1 expression relates to poor outcome in early stage rectal cancer, a group where new prognostic tools are particularly needed, and may indicate chemo- and radioresistance.
[Show abstract][Hide abstract] ABSTRACT: To investigate the prognostic value of CD44 variant 6 (CD44v6), a membranous adhesion molecule, in rectal cancer.
Altogether, 210 rectal cancer samples from 214 patients treated with short-course radiotherapy (RT, n = 90), long-course (chemo) RT (n = 53) or surgery alone (n = 71) were studied with immunohistochemistry for CD44v6. The extent and intensity of membranous and cytoplasmic CD44v6 staining, and the intratumoral membranous staining pattern, were analyzed.
Membranous CD44v6 expression was seen in 84% and cytoplasmic expression in 81% of the cases. In 59% of the tumors with membranous CD44v6 expression, the staining pattern in the invasive front was determined as "front-positive" and in 41% as "front-negative". The latter pattern was associated with narrower circumferential margin (P = 0.01), infiltrative growth pattern (P < 0.001), and shorter disease-free survival in univariate survival analysis (P = 0.022) when compared to the "front-positive" tumors.
The lack of membranous CD44v6 in the rectal cancer invasive front could be used as a method to identify patients at increased risk for recurrent disease.
World Journal of Gastroenterology 09/2012; 18(33):4549-56. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cofactors of high-risk (HR) human papillomavirus (HPV) in the progression of cervical intraepithelial neoplasia (CIN) are incompletely characterized. In this study these cofactors were investigated in a longitudinal setting.
A cohort of 329 women (mean age 25.5 y) were enrolled in the Finnish Family HPV Study, and followed-up for 6 y with serial cervical samples for HPV genotyping, virus integration status, and HPV serology. Hospital records were reviewed until March 2010 and linked with HPV detection data. All incident CIN lesions were subjected to HPV genotyping. HPV covariates were studied in an age- and HPV-matched nested case-control (1:4) setting.
Twelve of the 329 women developed an incident CIN: 2 CIN1, 3 CIN2, and 7 CIN3. HPV16 was detected most frequently (7/12), followed by HPV58 (2/12), HPV18, HPV31, and HPV42. HPV integration was present in 4/12 cases. Long-lasting persistence of HPV31 and HPV16 preceded incident CIN2 and CIN3. In multivariate conditional logistic regression, the risk for incident CIN increased up to 4-fold with increasing number of deliveries (p = 0.024) and decreased with history of genital warts (p = 0.036).
Baseline HR-HPV infections and their persistence precede incident CIN by several years. The 2 independent covariates of HR-HPV were (1) number of deliveries (increasing the risk), and (2) history of genital warts (protective effect).
[Show abstract][Hide abstract] ABSTRACT: Securin is an oncogene with functions in cell proliferation, tumour initiation and progression. Its prognostic value in rectal cancer is somewhat unknown. Accordingly, we studied securin expression together with Ki-67 in rectal cancer in relation to preoperative (chemo)radiotherapy (RT) and disease outcome.
Biopsies (n = 65 for securin; n = 57 for Ki-67) and operative specimens (n = 207) from 211 patients treated with short-course RT (n = 87), long-course RT (n = 54) or surgery only (n = 70) were studied with immunohistochemistry (IHC) for securin and Ki-67 expression. In the long-course RT group, 45 patients received chemotherapy (5-fluorouracil or capecitabine) concomitantly with RT. The results of IHC were related to clinicopathological variables, disease outcome and tumour regression grade (TRG) after long-course RT.
Both markers showed significant reduction after RT (p < 0.001). No differences in expression was seen in the long-course RT group between the patients with or without concomitant chemotherapy (p = 0.23 for securin; p = 0.31 for Ki-67). Low Ki-67 expression, but not that of securin, in operative specimens was significantly related to excellent TRG (p = 0.02 for Ki-67; p = 0.21 for securin). In univariate survival analysis, excellent TRG predicted longer disease-specific survival (DSS; p = 0.03). In multivariate Cox analysis, high securin expression after long-course (chemo)RT was an independent predictor of shorter DSS (p = 0.036) together with patient age (p = 0.043) and disease recurrence (local or distant; p = 0.009), whereas no similar appearance was seen in other treatment groups.
Securin expression in rectal cancer is significantly reduced after RT. High securin expression and poor TRG after long-course (chemo)RT are indicators of unfavourable disease outcome.
[Show abstract][Hide abstract] ABSTRACT: The knowledge on type specificity and factors that increase or decrease the risk of incident HPV-infections is important to better understand the dynamics of HPV-infections.
A series of 329 pregnant women were enrolled in Finnish Family HPV Study at 3rd trimester of pregnancy and followed-up for 6 years, during which 203 baseline HPV-negative women acquired incident HPV infection. Incidence times and incidence rates (IR) were calculated for 24 low-and high-risk HPV-types detected by Multiplex-HPV-genotyping at each visit. Poison regression was used to estimate predictors of incident HPV infections of species 7 and 9 HPV-genotypes.
HPV16 was the most frequent (47.8%) incident genotype followed by multiple-type infections (25.1%), and single infection with HPV18, 70, 6 and 45. Actuarial mean times to incident event were longest for HPV31 (34.5 months) and HPV45 (32.8 months), while crude mean times were longest for HPV56 (42.4 months) and HPV16 (23.1 months). Actuarial IR was highest for HPV16 and multiple-type infections. Independent protective factors against incident infections were 1) > 2 life-time sexual partners (p = 0.014), 2) later initiation of oral contraceptives (age > 20 years) (p = 0.017) and 3) pregnancy at FU visit (p = 0.0001).
Among newly delivered mothers, higher number of life-time sexual partners, initiation of OC use after age 20 and becoming pregnant during FU decreased the risk for incident species 7/9 HPV infections.
[Show abstract][Hide abstract] ABSTRACT: To study the incidence times and rates for cervical intraepithelial neoplasia (CIN) and its predictors.
This is a prospective follow-up study at Turku University Hospital, Finland. The Finnish Family human papillomavirus (HPV) study comprised 329 pregnant women followed up for 3 years. In an extension of the follow-up period, 171 women participated in an additional 3 years follow-up. Cervical scrapings for HPV testing and cervical smears were collected at each follow-up visit (2, 12, 24 and 36 months and 6 years). Following two abnormal cervical smears, colposcopy with biopsies was done. The main outcome measures were actuarial and crude incidence times, incidence rates and predictors of incident CIN.
During the follow-up period, 10 women (3.2%) developed biopsy-confirmed CIN, and four presented with incident atypical squamous cells suggesting high-grade squamous intraepithelial lesion cytology. The CIN/squamous intraepithelial lesion developed in 74.5 and 66.3 months, with crude incidence rates of 13.4/1,000 and 15.1/1,000 women months at risk, respectively. In multivariate Poisson regression, independent predictors of incident CIN were as follows: high-risk HPV positive at baseline (incidence rate ratio = 5.54; 95% confidence interval 1.02-30.14, p= 0.048); type-specific high-risk HPV persistence during follow-up (incidence rate ratio = 5.84; 95% confidence interval 2.28-17.93, p= 0.0001); cervical smear cytologically diagnosed for atypical squamous cells of undetermined significance or worse at any follow-up visit (incidence rate ratio = 4.56; 95% confidence interval 2.37-8.78, p= 0.0001); and new sexual partner during follow-up (incidence rate ratio = 9.45; 95% confidence interval 1.90-46.97, p= 0.006).
The results indicate that combined use of cervical smear and HPV testing, with prompt referral to colposcopy, enables accurate detection of incident CIN well before progression to invasive cancer. In addition to baseline and persistent high-risk HPV, abnormal cervical smear and new sexual partner are key predictors of incident CIN.
[Show abstract][Hide abstract] ABSTRACT: Persistent human papillomavirus (HPV) infection is the most important risk factor for cervical cancer, and understanding genotype-specific HPV persistence is essential for elucidating the natural history of HPV infections.
In the Finnish Family HPV Study, 329 pregnant women (mean age, 25.5 years) were recruited during the third trimester of pregnancy and were followed up for 6 years. Multiplex HPV genotyping for 27 low- and high-risk HPV types was used to define genotype-specific prevalence at each visit. Generalized estimating equation models were constructed to estimate predictors of type-specific persistence (positive results at 2 consecutive visits) of species 7 and 9 HPV genotypes.
HPV16 was the most common type, followed by HPV types 18, 31, 35, 45, 58, 70, and 6. Prevalence of multiple infections ranged from 21% to 45%. Persistence was most prolonged for HPV types 35, 58, and 52, with durations of 38.7, 32.1, and 24.2 months, respectively, and was equal for multiple-type infections and HPV16, with durations of 21 and 24 months, respectively. Independent predictors of type-specific persistence of species 7 and 9 HPV genotypes were age (odds ratio, 1.13 [95% confidence interval, 1.02-1.25]; P=.017), oral sex (odds ratio, 0.37 [95% confidence interval, 0.17-0.81]; P=.013), and young age (<13 years) at initiation of smoking (odds ratio, 0.51 [95% confidence interval, 0.27-0.98]; P=.046).
HPV16 was the most frequent persisting HPV genotype followed by multiple infections. Early initiation of smoking, practicing oral sex and older age increase the risk for persistence of species 7 and 9 HPV genotypes.
The Journal of Infectious Diseases 08/2010; 202(3):436-44. · 5.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The majority of cervical human papillomavirus (HPV) infections in young women are transient, but whether the clearance differs among different HPV genotypes and the different factors predicting genotype-specific clearance are partly unknown. In the Finnish Family HPV Study, 131 of 252 women (mean age, 25.5 years) cleared their infection during the prospective follow-up of 6 years (median, 62.4 months; range, 1.6 to 94.5 months). Cervical scrapings collected at each visit were tested for 24 low-risk and high-risk (HR) HPV types with multiplex HPV genotyping. Poison regression (panel data) was used to estimate predictors for the clearance of species 7 and 9 HPV genotypes. Of all HPV genotypes detected in these women, multiple-type and HPV type 16 (HPV16) infections showed clearance least frequently (46.1% and 50.5%, respectively). The actuarial and crude mean times to first clearance were variable among different genotypes. The actuarial clearance rate (events/person-time at risk) was highest for HPV16 and multiple-type infections, while HPV66 and -82 had the highest crude clearance rate. Independent predictors increasing type-specific clearance of species 7/9 HPV genotypes were older age (incidence rate ratio [IRR] = 1.1; 95% confidence interval [95% CI], 1.03 to 1.18; P = 0.002) and baseline oral HR HPV DNA-negative status (IRR = 2.94; 95% CI, 1.03 to 8.36; P = 0.042), while a higher number of sexual partners during the follow-up decreased the probability of clearance (IIR = 0.35; 95% CI, 0.15 to 0.83; P = 0.018). To conclude, HPV16 and multiple-type infections showed the lowest clearance among young mothers. Increasing age and negative oral HR HPV DNA status at baseline were associated with increased clearance, whereas a higher number of current sexual partners decreased the probability of species 7/9 HPV genotype clearance.
Journal of clinical microbiology 08/2010; 48(8):2665-71. · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare two management strategies for cervical intraepithelial neoplasia (CIN) 2, and evaluate reproducibility of the diagnosis.
Ninety (90) women with biopsy-proven CIN2 diagnosed through the Brazilian public health service were randomly allocated into two groups: 45 in prospective follow-up without treatment, and 45 for radical loop electrosurgical excision procedure (LLETZ). As in the real-life situation, pathology-reviewed diagnoses and HPV genotypes were not available.
Excision of the lesion proved to be more effective than prospective follow-up in reaching clearance of CIN2 (hazard ratio=3.66; 95% confidence interval 2.02-6.64). However, 44.1% of the lesions regressed without treatment during the 12-month follow-up.
CIN2 lesions regress without treatment in one year, although an ablative procedure is more effective. However, excision of CIN2 may lead to additional morbidity and costs, and tailoring the management on an individual basis may result in better outcome. Misclassification of CIN2 is not a negligible problem.
Anticancer research 06/2010; 30(6):2319-23. · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Finland is a country with a dual role in the human papillomavirus (HPV) field. Finnish scientists have pioneered in HPV research and participated in international HPV vaccine trials, but officially Finland is reluctant to implement HPV vaccines into its national vaccination program owing to the reasons discussed in this article. In contrast to other European countries, Finnish authorities were reluctant to initiate the evaluation process for HPV vaccines after licensure. Instead of prompt implementation, it was decided that a long-term prospective (Phase IV effectiveness) study to evaluate the bivalent HPV vaccine in a randomized community trial should be started. In addition, the Finnish authorities refuse to accept the compelling scientific evidence on the efficacy and safety of HPV vaccines. They report that cervical cancer (CC) is effectively controlled by the national screening program, despite the fact that CC in Finland has increased very rapidly since 1992. The Finnish perspective on HPV vaccines appears to postpone all critical decisions until the second half of the 2010s. This will have two direct consequences: 1) every year of delay means that an entire birth cohort (>60,000 girls and boys) will lose the opportunity of being offered the state-of-art cancer prevention provided by prophylactic HPV vaccines; and 2) given the declining trends of CC elsewhere, within a few years Finland will fall among the countries with a high incidence of CC. It is the personal conviction of this author that there are no sustainable arguments remaining that advocate continuing this Finnish perspective on HPV vaccines any further.
Expert Review of Vaccines 01/2010; 9(1):45-57. · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to determine the prevalence of concurrent oral and anogenital human papillomavirus (HPV) infection in male patients using polymerase chain reaction and reverse hybridization.
Thirty consecutive men were recruited among those attending the Clinic for Sexually Transmitted Diseases of the Outpatient Department of Dermatology and Sexually Transmitted Diseases, Santa Casa Hospital, São Paulo. The criteria for enrollment in the study were: age between 15 and 60 years, negative human immunodeficiency virus (HIV) status, and the presence of HPV anogenital lesion(s) confirmed by polymerase chain reaction and reverse hybridization. As a part of their management, all patients were subjected to punch biopsy of the anogenital lesions to confirm HPV and an HIV blood test to ensure that they were HIV negative. All patients had their oral mucosa examined with an artificial light. All oral lesions were sampled by biopsy, and subjects with no detectable lesions were sampled by oral mucosal scraping for HPV testing by polymerase chain reaction and reverse hybridization. All patients also completed a questionnaire that recorded their sexual preferences (heterosexual or homosexual, monogamous or polygamous), frequency of sexual activity, practice of oral and/or anal sex, and the use of condoms.
Only 3 patients presented with a clinically detectable oral lesion. Among them, just 1 was HPV positive by the molecular assay. In all of the other patients (27 out of 30), oral clinical lesions were not detected and scrapings were all negative for HPV infection.
The prevalence of concurrent oral and anogenital HPV infection was very low in this study (1 out of 30).
[Show abstract][Hide abstract] ABSTRACT: Objective. To analyze human papillomavirus (HPV) DNA in umbilical cord blood and in placenta, including its cellular localization. Design. Longitudinal prospective study. Setting. Maternity Unit of Turku University Hospital, and MediCity, University of Turku. Samples. Placental and cord blood samples obtained at delivery from 315 mothers and 311 neonates included in the Finnish HPV Family Study. Methods. HPV testing by nested PCR and sequencing. Tyramide amplified in situ hybridization (ISH) for viral DNA localization in placenta. Correlation to mother's and neonate's oral and genital HPV status and maternal demographic data. Main outcome measures. Detection and cellular localization of HPV DNA. Results. HPV DNA was detected in 4.2 and 3.5% of placenta and cord blood samples, respectively, including HPV types 16, 6, 83 and 39. In placenta, HPV6 and 16 DNA was localized in syncytiotrophoblasts. Abnormal cytology increased the risk of HPV+ placenta and cord blood. History of genital warts was the only independent predictor of cord blood HPV in multivariate analysis (adjusted OR=4.0, 95% CI: 1.09–14.54, p=0.036). HPV DNA in cord blood increased the risk of genital (OR=4.0, 95% CI: 1.08–14.83, p=0.048) and oral (OR=4.4, 95% CI: 1.17–16.14, p=0.039) HPV DNA carriage of the neonate. HPV+ placenta increased the risk of oral HPV of the neonate (OR=8.6, 95% CI: 2.73–27.13, p=0.0001). Delivery mode did not predict HPV status of the neonate. Conclusions. HPV DNA is detected in placental trophoblasts and umbilical cord blood. The presence of HPV DNA at these sites increases the risk of a neonate testing HPV-positive at birth.
[Show abstract][Hide abstract] ABSTRACT: In addition to cancer of the lower female genital tract, human papillomaviruses (HPV) are associated with a large number of benign, precancer and cancer lesions at different anatomic sites in both genders. Malignant tumours and their precursors are usually attributed to the oncogenic (high-risk, HR) HPV types, whereas benign lesions (papillomas) are associated with the low-risk (LR) HPV types, most notably with HPV6 and HPV11. Until recently, the main interest in HPV research has been focused on HR-HPV types and their associated pathology, and much less attention has been paid to the lesions caused by the LR-HPV types. With the recent licensing of an effective prophylactic vaccine against the 2 most important LR-HPV types (HPV6 and HPV11), it has become timely to make a systematic survey on the annual disease burden due to these 2 HPV genotypes in our country. These types of data should form the foundation for all calculations of the annual costs needed to treat these diseases by conventional means. Accurate estimates of disease burden are also mandatory for all modelling of the cost-effectiveness of prophylactic HPV6 and HPV11 vaccines. If proven useful for any of these purposes, this document will have fulfilled its purpose. In the first step, published HPV literature was used to create a list of benign, premalignant and malignant lesions associated with this virus at different anatomic sites. GLOBOCAN 2004 (IARC) database was used to derive the global numbers of incident cases for each of these malignancies in 2002, and the Finnish Cancer Registry (FCR) website for obtaining these (y 2005) numbers in Finland. The evidence linking HPV to each individual tumour category was classified as: 1) established, 2) emerging, and 3) controversial. All published evidence was weighted for each individual malignant, premalignant and benign lesion, anatomic region by region, while assessing the attributable fraction of HPV6/11 genotypes in each lesion. Because benign and most of the precancer lesions are not registered by FCR or GLOBOCAN, different approaches had to be used to derive the best estimates for their incidence, based on published literature or other registries (e.g. genital wart registry of the UK and Wales, and mass screening registry of FCR). With a lack of reasonable consensus, a lower and an upper limit was set for the range of estimates. In cases with different age-specific incidence (e.g. genital warts), the population pyramid of Finland was used to calculate the incident cases. Where well established, the different incidence rates among males and females were used to calculate the numbers of incident cases by gender. The malignant neoplasms with established or emerging evidence on the causal role of HPV are listed by their ICD-10 codes in Table I. Included in this list are also 2 controversial malignancies (colorectal cancer and endometrial cancer), of which the contradictory HPV data are critically discussed. The third major cancer in this same category (prostate cancer) was not included in the list, because the data are clearly insufficient to categorize this entity even among the emerging HPV associated malignancies. Estimated disease burden due to HPV6/11 in Finland, calculated as numbers of annual new cases by anatomic region and tumour type is given in Table II, and summarized in Figure 1. The present analysis implicates that a minimum of 12,666 to 13,066 new cases of HPV6- or HPV11-associated clinical lesions would be detected each y in Finland, if all were registered. Notably, these numbers represent the disease burden due to these 2 HPV types. However, these clinical lesions only represent a small minority of the total viral burden due to the infections by these 2 HPV genotypes. This is because the vast majority of all infections by these ubiquitous viruses are latent, being transient in nature and spontaneously resolving within a few months (up to 1 y), without ever developing a clinically detectable disease. This spontaneous clearance does not make these latent infections less important, however, because as long as the virus reservoir exists, it serves as the source of viral transmission to susceptible individuals, with a multitude of HPV6/11 associated pathologies as a potential outcome, as described in this document. The implications of these data in the era of effective prophylactic HPV vaccination against HPV6 and HPV11 should be clear.
Scandinavian journal of infectious diseases. Supplementum 01/2009; 107:3-32.
[Show abstract][Hide abstract] ABSTRACT: Apart from cancers of the lower female genital tract, human papillomaviruses (HPV) are associated with a large number of benign, premalignant and malignant lesions at different anatomic sites in both genders. Malignant tumours and their precursors are usually attributed to the oncogenic (high-risk, HR) HPV types, whereas benign lesions (mostly papillomas) are ascribed to the low-risk (LR) HPV types, most notably HPV6 and HPV11. To date, the main interest has been focused on HR-HPV types and their associated pathology, and much less attention has been paid to the lesions caused by the LR-HPV types. The recent licensing of an effective prophylactic vaccine against the 2 most important LR-HPV types (HPV6 and HPV11) has resulted in considerably increased interest in these LR-HPV types as well. This author recently conducted a systematic survey of the annual disease burden due to HPV6/11 infections in Finland. As a rational continuation, the present survey was conducted to estimate the annual disease burden due to HPV16 and HPV18 infections in our country. Together, these 2 documents form the foundation for calculations of the annual costs needed to treat the diseases caused by these 2 most common LR and HR HPV types. Similar to HPV6/11, accurate estimates of disease burden are also mandatory for all modelling of the cost-effectiveness of prophylactic HPV16/18 vaccines. In the first step, the published HPV literature was used to create a list of benign, premalignant and malignant lesions associated with this virus at different anatomic sites. The GLOBOCAN 2004 (IARC; International Agency for Research on Cancer) database was used to derive the global numbers of incident cases for each of these malignancies in 2002, and the Finnish Cancer Registry (FCR) website was used to obtain these numbers for Finland (y 2005). The evidence linking HPV to each individual tumour category was classified as: (1) established, (2) emerging, and (3) controversial. All published evidence was weighted for each individual malignant, premalignant and benign lesion, anatomic region-by-region, while assessing the attributable fraction of HPV16/18 genotypes in each lesion. Because benign and most of the precancer lesions are not registered by the FCR or GLOBOCAN, different approaches had to be used to derive the estimates for their incidence, based on published literature or other registries. In cases with no reasonable consensus, a lower and an upper boundary was set for the range of these estimates. Where well established, the different incidence rates among males and females were used to calculate the numbers of incident cases by gender. The present survey implicates that a minimum of 7859 to 8316 new cases of HPV16- or HPV18-associated clinical lesions would be detected each y in Finland, if all were registered. In other words, these numbers represent the annual disease burden due to these 2 most common HR-HPV genotypes. In the Finnish population, these lower and upper limits translate to the crude annual incidence rates of 147/100,000 and 156/100,000, respectively. When adjusted for the European Standard Population, the respective age-adjusted incidence rates are 137/100,000 and 145/100,000. As compared with the annual disease burden of HPV6/11 in this country (12,666-13,066 new cases), these numbers for HPV16/18 are significantly smaller. Another major difference between HPV6/11 and HPV16/18 is that the disease burden due to the former is much more evenly distributed among the genders, with only a slight female preponderance (approximately 7500 vs 5500 cases). This is in sharp contrast to HPV16/18 disease burden, of which by far the major proportion is contributed by females (approximately 7000 vs 1300 cases). Of note, these clinical lesions counted in this report for HPV16/18 only represent a small minority of the total viral burden due to the infections by these 2 HR-HPV genotypes. This is because the vast majority of these HR-HPV infections are transient and spontaneously resolve within a few months, without ever developing a clinical disease. However, this spontaneous clearance does not make these latent infections less important, because as long as the virus reservoir exists, it serves as the source of viral transmission to susceptible individuals, with a multitude of HPV16/18-associated pathologies as a potential outcome. The implications of these data in the era of effective prophylactic HPV vaccination should be straightforward. However, the 2 impending challenges for designers of future HPV vaccines and vaccination programmes are: (1) the marked imbalance of HPV16/18 disease burden between the genders, and (2) the fact that HPV6/11 annual disease burden far exceeds that of HPV16/18 and it is also more evenly contributed by both genders.
Scandinavian journal of infectious diseases. Supplementum 01/2009; 108:2-32.
[Show abstract][Hide abstract] ABSTRACT: The sensitivity (Se) and the specificity (Sp) are the two most common measures of the performance of a diagnostic test, where Se is the probability of a diseased individual to be correctly identified by the test while Sp is the probability of a healthy individual to be correctly identified by the same test. A problem appears when all individuals cannot be verified by a gold standard. This occurs when there is not a definitive test for detection of the disease or the verification by a gold standard is an impracticable procedure according to its cost, accessibility or risks. In this paper we develop a Bayesian analysis to estimate the disease prevalence, the sensitivity and specificity of screening tests in the presence of a covariate and in the absence of a gold standard. We use the Metropolis–Hastings algorithm to obtain the posterior summaries of interest. We have as motivation for the investigation the LAMS (Latin American Screening) Study, an extensive project designed for comparing screening tools for cervical cancer in Brazil and Argentina. When applied to the analysis of data from LAMS Study, the proposed Bayesian method shows to be a useful alternative to estimate measures of performance of screening tests in the presence of covariates and when a gold standard is not available. An advantage of the method is the fact that the number of parameters to be estimated is not limited by the number of observations, as it happens with several frequentist approaches. However, it is important to point out that the Bayesian analysis requires informative priors in order for the parameters to be identifiable. The method can be easily extended for the analysis of other medical data sets.
Brazilian Journal of Probability and Statistics 01/2009; 23(2009). · 0.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ObjectivesTo describe the expression of vascular endothelial growth factor (VEGF), proto-oncogene macrophage colony-stimulating factor receptor (c-fms) and cyclooxygenase-2 (COX-2) in cervical carcinogenesis and to analyze the correlation of VEGF with c-fms and COX-2 expression.MethodsIn this study, 26 cases of benign cervix, 28 low-grade cervical intraepithelial neoplasia (CIN; CIN 1), 30 high-grade CIN (CIN 2/3) and 28 squamous cervical carcinomas (SCC) were examined by immunohistochemistry (IHC) and analysis was performed separately for epithelium and stroma.ResultsPositive epithelial expressions in normal cervix, low-grade CIN, high-grade CIN and SCC were, respectively: VEGF — 11.5%, 39.3%, 53.3% and 75% (P < 0.001); c-fms — 0%, 10.7%, 40% and 67.9% (P < 0.001); COX-2 — 7.7%, 39.3%, 80% and 100% (P < 0.001). Stromal VEGF expression was higher than epithelial expression in all CIN grades and was also associated with the lesion grade, while c-fms and COX-2 stromal expression was weak. VEGF expression was statistically correlated to c-fms and COX-2 expression in high-grade CIN (P = 0.020 and P = 0.027, respectively) and SCC (P = 0.015 and P = 0.005, respectively).ConclusionsOn the basis of our findings, these factors may participate in the development and progression of CIN lesions, with possible interaction of c-fms and COX-2 on VEGF expression, and may be potential molecular targets for studies of cervical cancer prevention and treatment.
[Show abstract][Hide abstract] ABSTRACT: In this paper we develop a Bayesian analysis to estimate the disease prevalence, the sensitivity and specificity of three cervical cancer screening tests (cervical cytology, visual inspection with acetic acid and Hybrid Capture II) in the presence of a covariate and in the absence of a gold standard. We use Metropolis-Hastings algorithm to obtain the posterior summaries of interest. The estimated prevalence of cervical lesions was 6.4% (a 95% credible interval [95% CI] was 3.9, 9.3). The sensitivity of cervical cytology (with a result of >or= ASC-US) was 53.6% (95% CI: 42.1, 65.0) compared with 52.9% (95% CI: 43.5, 62.5) for visual inspection with acetic acid and 90.3% (95% CI: 76.2, 98.7) for Hybrid Capture II (with result of >1 relative light units). The specificity of cervical cytology was 97.0% (95% CI: 95.5, 98.4) and the specificities for visual inspection with acetic acid and Hybrid Capture II were 93.0% (95% CI: 91.0, 94.7) and 88.7% (95% CI: 85.9, 91.4), respectively. The Bayesian model with covariates suggests that the sensitivity and the specificity of the visual inspection with acetic acid tend to increase as the age of the women increases. The Bayesian method proposed here is an useful alternative to estimate measures of performance of diagnostic tests in the presence of covariates and when a gold standard is not available. An advantage of the method is the fact that the number of parameters to be estimated is not limited by the number of observations, as it happens with several frequentist approaches. However, it is important to point out that the Bayesian analysis requires informative priors in order for the parameters to be identifiable. The method can be easily extended for the analysis of other medical data sets.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: to investigate womens age at their first sexual intercourse and its correlation with their present age, human papillomavirus (HPV) infection and cytological abnormalities at Pap smear. METHODS: women from the general population were invited to be screened for cervical cancer and pre-malignant lesions. After answering a behavior questionnaire, they were submitted to screening with cervical cytology and high-risk HPV testing with Hybrid Capture 2 (HC2). This report is part of the Latin American Screening (LAMS) study, that comprises centers from Brazil and Argentina, and the data presented herein refer to the Brazilian women evaluated at the cities of Porto Alegre, São Paulo and Campinas. RESULTS: from 8,649 women that answered the questionnaire, 8,641 reported previous sexual activity and were included in this analysis. The mean age at the interview was 38.1±11.0 years and the mean age at the first sexual intercourse was 18.5±4.0 years. The age at the first sexual intercourse increased along with the age at the interview, i.e., younger women reported they had begun their sexual life earlier than older women (p<0.001). From the total of women who had already begun having sexual intercourse, 3,643 patients were tested for high-risk HPV infection and 17.3% of them had positive results. In all the centers, it became clear that the women with the first sexual intercourse at ages below the mean age of all the population interviewed presented higher rates of HPV infection (20.2%) than the women with the first sexual intercourse at ages above the mean (12.5%) Odds Ratio (OR) 1.8 (IC95% 1.5-2.2;p<0,001). According to the cytology, the women with first sexual intercourse at ages under the mean, presented higher percentage of abnormal cytology ³ ASC-US (6.7%) than the women with the first sexual intercourse at ages above the mean (4.3%) OR 1.6 (IC95% 1.3-2.;p<0.001). CONCLUSIONS: the high-risk HPV infection and cytological abnormalities identified during the asymptomatic population screening were significantly associated to the womens age at the first sexual intercourse. Additionally, we have also identified that the womens age at the first sexual intercourse has decreased during the last decades, suggesting an important contribution to the increase of HPV infection and the subsequent cervical lesions.
Revista Brasileira de Ginecologia e Obstetrícia 11/2007; 29(11):580-587.