Joakim Dillner

Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck

BACKGROUND Oncogenic human papillomaviruses (HPVs), especially HPV type 16 (HPV-16), cause anogenital epithelial cancers and are suspected of causing epithelial cancers of the head and neck. METHODS To examine the relation between head and neck cancers and HPVs, we performed a nested case-control study within a joint Nordic cohort in which serum samples were collected from almost 900,000 subjects. Samples collected at enrollment from 292 persons in whom squamous-cell carcinoma of the head and neck developed, on average, 9.4 years after enrollment and from 1568 matched controls were analyzed for antibodies against HPV-16, HPV-18, HPV-33, and HPV-73 and for cotinine levels as a marker of smoking habits. Polymerase-chain-reaction (PCR) analyses for HPV DNA were performed in tumor tissue from 160 of the study patients with cancer. RESULTS After adjustment for cotinine levels, the odds ratio for squamous-cell carcinoma of the head and neck in subjects who were seropositive for HPV-16 was 2.2 (95 percent confidence interval, 1.4 to 3.4). No increased risk was observed for other HPV types. Fifty percent of oropharyngeal and 14 percent of tongue cancers contained HPV-16 DNA, according to PCR analysis. CONCLUSIONS HPV-16 infection may be a risk factor for squamous-cell carcinoma of the head and neck.

Type-Specific Persistence of Human Papillomavirus DNA before the Development of Invasive Cervical Cancer

BACKGROUND Infection with the human papillomavirus (HPV) has been established as a cause of cervical cancer, but the association between a positive test for HPV DNA and the risk of the subsequent development of invasive cervical cancer is unknown. METHODS In a study of women who participated in a population-based screening program for cancer of the cervix in Sweden from 1969 to 1995, we compared the proportion of normal cervical smears (Pap smears) that were positive for HPV DNA among 118 women in whom invasive cervical cancer developed an average of 5.6 years later (range, 0.5 month to 26.2 years) with the proportion of HPV DNA-positive smears from 118 women who remained healthy during a similar length of follow-up (controls). The control women were matched for age to the women with cancer, and they had had two normal Pap smears obtained at time points that were similar to the times of the baseline smear and the diagnosis of cancer confirmed by biopsy in the women with cancer. RESULTS At baseline, 35 of the women with cancer (30 percent) and 3 of the control women (3 percent) were positive for HPV DNA (odds ratio, 16.4; 95 percent confidence interval, 4.4 to 75.1). At the time of diagnosis, 80 of the 104 women with cancer for whom tissue samples were available (77 percent) and 4 of the 104 matched control women (4 percent) were positive for HPV DNA. The HPV DNA type was the same in the base-line smear and the biopsy specimen in all of the women with cancer in whom HPV DNA was detected at base line. None of the control women had the same type of HPV in both smears. CONCLUSIONS A single positive finding of HPV DNA in a Pap smear confers an increased risk of future invasive cervical cancer that is positive for the same type of virus as identified earlier.

Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study.

Objective To obtain large scale and generalisable data on the long term predictive value of cytology and human papillomavirus (HPV) testing for development of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+). Design Multinational cohort study with joint database analysis. Setting Seven primary HPV screening studies in six European countries. Participants 24 295 women attending cervical screening enrolled into HPV screening trials who had at least one cervical cytology or histopathology examination during follow-up. Main outcome measure Long term cumulative incidence of CIN3+. Results The cumulative incidence rate of CIN3+ after six years was considerably lower among women negative for HPV at baseline (0.27%, 95% confidence interval 0.12% to 0.45%) than among women with negative results on cytology (0.97%, 0.53% to 1.34%)). By comparison, the cumulative incidence rate for women with negative cytology results at the most commonly recommended screening interval in Europe (three years) was 0.51% (0.23% to 0.77%). The cumulative incidence rate among women with negative cytology results who were positive for HPV increased continuously over time, reaching 10% at six years, whereas the rate among women with positive cytology results who were negative for HPV remained below 3%. Conclusions A consistently low six year cumulative incidence rate of CIN3+ among women negative for HPV suggests that cervical screening strategies in which women are screened for HPV every six years are safe and effective.

Guidelines for human papillomavirus DNA test requirements for primary cervical cancer screening in women 30 years and older

Given the strong etiologic link between high‐risk HPV infection and cervical cancer high‐risk HPV testing is now being considered as an alternative for cytology‐based cervical cancer screening. Many test systems have been developed that can detect the broad spectrum of hrHPV types in one assay. However, for screening purposes the detection of high‐risk HPV is not inherently useful unless it is informative for the presence of high‐grade cervical intraepithelial neoplasia (CIN 2/3) or cancer. Candidate high‐risk HPV tests to be used for screening should reach an optimal balance between clinical sensitivity and specificity for detection of high‐grade CIN and cervical cancer to minimize redundant or excessive follow‐up procedures for high‐risk HPV positive women without cervical lesions. Data from various large screening studies have shown that high‐risk HPV testing by hybrid capture 2 and GP5+/6+‐PCR yields considerably better results in the detection of CIN 2/3 than cytology. The data from these studies can be used to guide the translation of high‐risk HPV testing into clinical practice by setting standards of test performance and characteristics. On the basis of these data we have developed guidelines for high‐risk HPV test requirements for primary cervical screening and validation guidelines for candidate HPV assays.

Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: A longitudinal, nested case-control study in the Nordic countries

Vitamin D inhibits the development and growth of prostate cancer cells. Epidemiologic results on serum vitamin D levels and prostate cancer risk have, however, been inconsistent. We conducted a longitudinal nested case‐control study on Nordic men (Norway, Finland and Sweden) using serum banks of 200,000 samples. We studied serum 25(OH)‐vitamin D levels of 622 prostate cancer cases and 1,451 matched controls and found that both low (≤19 nmol/l) and high (≥80 nmol/l) 25(OH)‐vitamin D serum concentrations are associated with higher prostate cancer risk. The normal average serum concentration of 25(OH)‐vitamin D (40–60 nmol/l) comprises the lowest risk of prostate cancer. The U‐shaped risk of prostate cancer might be due to similar 1,25‐dihydroxyvitamin D3 availability within the prostate: low vitamin D serum concentration apparently leads to a low tissue concentration and to weakened mitotic control of target cells, whereas a high vitamin D level might lead to vitamin D resistance through increased inactivation by enhanced expression of 24‐hydroxylase. It is recommended that vitamin D deficiency be supplemented, but too high vitamin D serum level might also enhance cancer development.

Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial.

Objectives To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). Design Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months’ follow-up. Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. Participants 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy. Intervention Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6. Main outcome measures Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. Results In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. Conclusions Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up. Trial registrations NCT00092521 and NCT00092534.

Should donors be allowed to give broad consent to future biobank research

Large international biobank studies can make substantial contributions to scientific research by validation of the biological importance of previous research and by identification of previously unknown causes of disease. However, regulations for patient consent that are too strict and discrepancies in national policies on informed consent might hinder progress. Therefore, establishment of common ground for ethical review of biobank research is essential. In this essay, broad consent is defined on a scale between strictly specified (eg, for a specific study) and blanket consent (ie, with no restrictions regarding the purpose of the research). Future research includes that which might not be planned or even conceptualised when consent is obtained. In conclusion, broad consent and consent for future research are valid ethically and should be recommended for biobank research provided that: personal information related to research is handled safely; donors of biological samples are granted the right to withdraw consent; and new research studies or changes to the legal or ethical authority of a biobank are approved by an ethics-review board.

Smoking, diet, pregnancy and oral contraceptive use as risk factors for cervical intra-epithelial neoplasia in relation to human papillomavirus infection

Smoking, nutrition, parity and oral contraceptive use have been reported as major environmental risk factors for cervical cancer. After the discovery of the very strong link between human papillomavirus (HPV) infection and cervical cancer, it is unclear whether the association of these environmental factors with cervical cancer reflect secondary associations attributable to confounding by HPV, if they are independent risk factors or whether they may act as cofactors to HPV infection in cervical carcinogenesis. To investigate this issue, we performed a population-based case–control study in the Västerbotten county of Northern Sweden of 137 women with high-grade cervical intra-epithelial neoplasia (CIN 2–3) and 253 healthy age-matched women. The women answered a 94-item questionnaire on diet, smoking, oral contraceptive use and sexual history and donated specimens for diagnosis of present HPV infection (nested polymerase chain reaction on cervical brush samples) and for past or present HPV infections (HPV seropositivity). The previously described protective effects of dietary micronutrients were not detected. Pregnancy appeared to be a risk factor in the multivariate analysis (P< 0.0001). Prolonged oral contraceptive use and sexual history were associated with CIN 2–3 in univariate analysis, but these associations lost significance after taking HPV into account. Smoking was associated with CIN 2–3 (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.7–4.0), the effect was dose-dependent (P = 0.002) and the smoking-associated risk was not affected by adjusting for HPV, neither when adjusting for HPV DNA (OR 2.5, CI 1.3–4.9) nor when adjusting for HPV seropositivity (OR 3.0, CI 1.9–4.7). In conclusion, after taking HPV into account, smoking appeared to be the most significant environmental risk factor for cervical neoplasia.

Efficacy of HPV DNA Testing With Cytology Triage and/or Repeat HPV DNA Testing in Primary Cervical Cancer Screening

BACKGROUND Primary cervical screening with both human papillomavirus (HPV) DNA testing and cytological examination of cervical cells with a Pap test (cytology) has been evaluated in randomized clinical trials. Because the vast majority of women with positive cytology are also HPV DNA positive, screening strategies that use HPV DNA testing as the primary screening test may be more effective. METHODS We used the database from the intervention arm (n = 6,257 women) of a population-based randomized trial of double screening with cytology and HPV DNA testing to evaluate the efficacy of 11 possible cervical screening strategies that are based on HPV DNA testing alone, cytology alone, and HPV DNA testing combined with cytology among women aged 32-38 years. The main outcome measures were sensitivity for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) within 6 months of enrollment or at colposcopy for women with a persistent type-specific HPV infection and the number of screening tests and positive predictive value (PPV) for each screening strategy. All statistical tests were two-sided. RESULTS Compared with screening by cytology alone, double testing with cytology and for type-specific HPV persistence resulted in a 35% (95% confidence interval [CI] = 15% to 60%) increase in sensitivity to detect CIN3+, without a statistically significant reduction in the PPV (relative PPV = 0.76, 95% CI = 0.52 to 1.10), but with more than twice as many screening tests needed. Several strategies that incorporated screening for high-risk HPV subtypes were explored, but they resulted in reduced PPV compared with cytology. Compared with cytology, primary screening with HPV DNA testing followed by cytological triage and repeat HPV DNA testing of HPV DNA-positive women with normal cytology increased the CIN3+ sensitivity by 30% (95% CI = 9% to 54%), maintained a high PPV (relative PPV = 0.87, 95% CI = 0.60 to 1.26), and resulted in a mere 12% increase in the number of screening tests (from 6,257 to 7,019 tests). CONCLUSIONS Primary HPV DNA-based screening with cytology triage and repeat HPV DNA testing of cytology-negative women appears to be the most feasible cervical screening strategy.

Screening-Preventable Cervical Cancer Risks : Evidence From a Nationwide Audit in Sweden

BACKGROUND The effectiveness of cervical cancer screening programs differs widely in different populations. The reasons for these differences are unclear. Routine and comprehensive audits have been proposed as an ethically required component of screening. We performed a nationwide audit of the effectiveness of the Swedish cervical cancer screening program. METHODS We identified all invasive cervical cancer cases that were diagnosed in Sweden from January 1, 1999, through December 31, 2001, and had been reported to the Swedish Cancer Registry (n = 1230 cases). We verified the diagnoses by histopathologic rereview and matched each case subject to five (population-based) age-matched control subjects who were identified from the National Population Register. The Pap smear screening histories for case and control subjects were reviewed for a 6-year period using the National Cervical Cancer Screening Register, which contains data on essentially all relevant cytological and histological diagnoses in Sweden. Odds ratios (ORs), and their 95% confidence intervals (CIs), of cervical cancer according to screening history were calculated in conditional logistic regression models. All statistical tests were two-sided. RESULTS Women who had not had a Pap smear within the recommended screening interval had higher risk of cervical cancer than women who had been screened (OR = 2.52, 95% CI = 2.19 to 2.91). This risk was similarly increased for all age groups (P(homogeneity) = .96). The risk for non-squamous cell cervical cancers (OR = 1.59, 95% CI = 1.20 to 2.11) was also increased. Women who had not had a Pap smear within the recommended screening interval had a particularly high risk of advanced cancers (OR = 4.82, 95% CI = 3.61 to 6.44). Among women who had been screened within the recommended interval, those with abnormal Pap smears had a higher risk of cervical cancer than those with normal smears (OR = 7.55, 95% CI = 5.88 to 9.69) and constituted 11.5% of all women with cervical cancer. CONCLUSIONS Nonadherence to screening intervals was the major reason for cervical cancer morbidity. The screening program was equally effective for women of all ages and was also effective against non-squamous cancers.