Incidence, risk factors, outcomes, and clinical management of BK viremia in the modern era of kidney transplantation.

BK viremia is endemic among kidney transplant recipients (KTRs). Incidence, risk factors, outcomes, and clinical management of detectable versus high BK viremia have not been considered previously in KTR in the modern era. This observational study examined KTR transplanted between January 1, 2009 and December 31, 2016. Any BK viral load in the serum constituted detectable BK viremia and ≥103 copies/ml constituted high viremia. Among 1193 KTRs, the cumulative probability of developing detectable and high BK viremia within 2 years posttransplant were 27.8% and 19.6%, respectively. Significant risk factors for detectable BK viremia included recipient age (HR 1.02 [95% CI: 1.01, 1.03]) and donor age (HR 1.01 [95% CI: 1.00, 1.02]). Recipient age also predicted high BK viremia (HR 1.02 [95% CI: 1.01, 1.03]), whereas White race (HR 0.70 [95% CI: 0.52, 0.95]), nondepleting induction therapy (HR 0.61 [95% CI: 0.42, 0.89]), and delayed graft function (HR 0.61 [95% CI: 0.42, 0.88]) were protective. Mean estimated glomerular filtration rates were 4.28 ml/min/1.72 m2 (95% CI: 2.71, 5.84) lower with detectable BK viremia. Although low viral load was usually not acted upon at first presentation, antiproliferative dose reductions were the most common initial management. BK viremia remains a common early complication in a modern cohort of KTRs. These findings highlight the benefit of early BKV monitoring in addition to intensive clinical management. Clinical responses beyond first positive BK viremia tests, and their implications for graft outcomes, merit further investigation.

An assessment of bovine herpes virus 4 as a causative agent in abortions and neonatal death.

Numerous viruses, including bovine viral diarrhoea virus (BVDV), bovine herpes virus 1 (BoHV-1) and bovine herpes virus 4 (BoHV-4), and other pathogens are the most common causes of reproductive disorders and are responsible for huge economic losses in livestock production. This study investigates the aetiological role of BoHV-4 in fertility problems such as abortions, stillbirth and birth with unviable calves. Retrospective samples from 38 animals, including 17 aborting cows, 17 aborted foetuses, three stillborn calves and one unviable newborn calf were analysed. The BoHV-4 genome was detected in 25 (65.7%) animals by polymerase chain reaction. In 14 of these infected animals, we detected co-infection with BVDV, while the co-presence of BoHV-1 was also detected in one animal. In addition to the high prevalence of BoHV-4 genome in materials related to fertility problems, isolation of BoHV-4 from the brain of one stillborn calf indicated a causal link between BoHV-4 and fertility problems, such as abortion, stillbirths or birth with unviable calves.

Understanding mechanisms of cancer initiation and development supports the need for an implementation of primary and secondary cancer prevention.

The burden of cancer is increasing worldwide, with a continuous rise of the annual total cases. Although mortality rates due to cancer are declining in developed countries, the total number of cancer deaths continues to rise due to the increase in the number of aged people. Three main causes of cancer have been described, represented by environmental factors, hereditary factors and random factors related to defects originated during cell replication. The frequency of cancers is very different for the various tissues and there is great debate on the extent of the specific contribution of environmental factors and random factors (due to "bad luck") to cancer development. However, there is consensus that about 50% of all cases of cancer are related to environment and are preventable. Although a part of cancers is related to intrinsic mechanisms non preventable of genetic instability, it is evident that implementation of primary and secondary prevention measures is the only affordable strategy to meet from a medical and economic point of view the tremendous pressure created on healthcare structures by the increased cancer burden. It is time to bypass the paradox of disease prevention: celebrated in principle, resisted in practice.

Epidemiologic survey of feline leukemia virus in domestic cats on Tsushima Island, Japan: management strategy for Tsushima leopard cats.

The Tsushima leopard cat (TLC) Prionailurus bengalensis euptilurus, a subspecies of P. bengalensis, is designated a National Natural Monument of Japan, and lives only on Tsushima Island, Nagasaki Prefecture, Japan. TLCs are threatened by various infectious diseases. Feline leukemia virus (FeLV) causes a serious infectious disease with a poor prognosis in cats. Therefore, the transmission of FeLV from Tsushima domestic cats (TDCs) to TLCs may threaten the TLC population. We investigated the FeLV infection status of both TDCs and TLCs on Tsushima Island by screening blood samples for FeLV p27 antigen and using PCR to amplify the full-length FeLV env gene. The prevalence of FeLV was 6.4% in TDCs and 0% in TLCs. We also demonstrated that the virus can replicate in the cells of TLCs, suggesting its potential cross-species transmission. The viruses in TDCs were classified as genotype I/clade 3, which is prevalent on a nearby island, based on previous studies of FeLV genotypes and FeLV epidemiology. The FeLV viruses identified on Tsushima Island can be further divided into 2 lineages within genotype I/clade 3, which are geographically separated in Kamijima and Shimojima, indicating that FeLV may have been transmitted to Tsushima Island at least twice. Monitoring FeLV infection in the TDC and TLC populations is highly recommended as part of the TLC surveillance and management strategy.

Assessment and biological significance of JC polyomavirus in colorectal cancer in Tunisia.

PURPOSE: Several reports have indicated the presence of JC polyomavirus (JCV) in many human tumors, including colorectal cancers (CRCs). The presence of JCV infection in CRC patients has not been investigated in African countries. METHODS: We examined the prevalence and the biological significance of JCV in Tunisian CRC patients. The presence of JCV was assessed by polymerase chain reaction (PCR) in a series of 105 CRCs and 89 paired non-tumor colonic mucosa samples from Tunisian patients. Results were correlated with the clinicopathological features and immunohistochemical expression of ß-catenin, p53, and the proliferation marker Ki-67. RESULTS: JCV DNA was detected in 58.1% (61/105) of CRC and in only 14.6% (13/89) of paired non tumor colonic mucosa samples (p=0.03). The presence of JCV was significantly correlated with tumor differentiation (p=0.03). Moreover, JCV presence was significantly correlated with nuclear accumulation of ß-catenin (p=0.008) and p53 accumulation (p=0.0001). Multivariate logistic regression analysis showed that tumor differentiation, ß-catenin and p53 accumulation were independent parameters significantly associated with the presence of JCV in CRC (p=0.04; p=0.05; p=0.001, respectively). CONCLUSION: We support a role of JCV in colorectal carcinogenesis in Tunisian patients, especially of well differentiated morphology.

High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation.

BK virus (BKV) reactivation has been increasingly associated with the occurrence of late-onset hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT (allo-HSCT) resulting in morbidity and sometimes mortality. We investigated the incidence, risk factors and outcome of BKV-HC in 323 consecutive adult patients undergoing allo-HSCT over a 5-year period. BK viremia values for HC staging were evaluated, as well as the medico-economic impact of the complication. Forty-three patients developed BKV-HC. In univariate analysis, young age (P=0.028), unrelated donor (P=0.0178), stem cell source (P=0.0001), HLA mismatching (P=0.0022) and BU in conditioning regimen (P=0.01) were associated with a higher risk of developing BKV-HC. In multivariate analysis, patients receiving cord blood units (CBUs) (P=0.0005) and peripheral blood stem cells (P=0.011) represented high-risk subgroups for developing BKV-HC. BK viremia was directly correlated to HC severity (P=0.011) with a 3 to 6-log peak being likely associated with grades 3 or 4 HC. No correlation was found between BKV-HC and acute graft versus host disease or mortality rate. Patients with BKV-HC required a significantly longer duration of hospitalization (P<0.0001), more RBC (P=0.0003) and platelet transfusions (P<0.0001). Over the 5-year study period, the financial cost of the complication was evaluated at \[euro]2 376 076 ($3 088 899). Strategies to prevent the occurrence of late-onset BKV-HC after allo-HSCT are urgently needed, especially in CBU and peripheral blood stem cell recipients. BK viremia correlates with the severity of the disease. Prospective studies are required to test prophylactic approaches.

[Cancer incidence in Italian natives and in first-generation immigrants to Italy]. / L'incidenza dei tumori in cittadini nati in Italia e in immigrati di prima generazione.

OBJECTIVE: The aim of this study was to evaluate differences in cancer incidence in populations born in different countries in the area covered by the Tuscan Cancer Registry. SETTING: We selected cancer cases diagnosed during the period 1998-2005 in the population resident in the provinces of Firenze and Prato. Each case was classified according to the place of birth: a) born in Italy, b) born in countries with high migration (PFPM), born in other highly developed countries (PSA).To compute incidence rates we used as denominator the health regional registry. MAIN OUTCOME MEASURES: We used the European standard population in computing standardized incidence rates (restricted to the age group 20-59 years) and the standardized rate ratio (SRR) in order to compare subjects born in different countries. RESULTS: During the period 1998-2005, 14 791 invasive cancers were diagnosed (non-melanoma skin excluded) in subjects aged 20-59 years old, 4.2% in subjects born in countries outside Italy (1.2% in other PSA e 3.0% in PFPM). Incidence in subjects born in PSA did not differ significantly from incidence in subjects born in Italy. Incidence rates among subjects born in PFPM were statistically lower, both in men (151.2 per 100 000) and women (199.3 per 100 000), than in subjects born in Italy (243.5 men e 337.5 women). On the contrary, liver and cervix uteri cancer incidence showed higher rates among subjects born in PFPM (liver: SRR=2.13, p=0.007; cervix uteri: SRR=1.88, p=0.0095). CONCLUSION: Subjects born in countries with high migration showed a level of incidence lower than subjects born in Italy (healthy migration effect). Incidence was higher among subjects born in PFPM only for liver and cervix uteri, cancers with a virological aetiology. The migration phenomena open new study prospectives, but also methodological questions (definition of immigrants and of reference populations).

Assessment of human papillomavirus in lung tumor tissue.

BACKGROUND: Lung cancer kills more than 1 million people worldwide each year. Whereas several human papillomavirus (HPV)-associated cancers have been identified, the role of HPV in lung carcinogenesis remains controversial. METHODS: We selected 450 lung cancer patients from an Italian population-based case-control study, the Environment and Genetics in Lung Cancer Etiology. These patients were selected from those with an adequate number of unstained tissue sections and included all those who had never smoked and a random sample of the remaining patients. We used real-time polymerase chain reaction (PCR) to test specimens from these patients for HPV DNA, specifically for E6 gene sequences from HPV16 and E7 gene sequences from HPV18. We also tested a subset of 92 specimens from all never-smokers and a random selection of smokers for additional HPV types by a PCR-based test for at least 54 mucosal HPV genotypes. DNA was extracted from ethanol- or formalin-fixed paraffin-embedded tumor tissue under strict PCR clean conditions. The prevalence of HPV in tumor tissue was investigated. RESULTS: Specimens from 399 of 450 patients had adequate DNA for analysis. Most patients were current (220 patients or 48.9%) smokers, and 92 patients (20.4%) were women. When HPV16 and HPV18 type-specific primers were used, two specimens were positive for HPV16 at low copy number but were negative on additional type-specific HPV16 testing. Neither these specimens nor the others examined for a broad range of HPV types were positive for any HPV type. CONCLUSIONS: When DNA contamination was avoided and state-of-the-art highly sensitive HPV DNA detection assays were used, we found no evidence that HPV was associated with lung cancer in a representative Western population. Our results provide the strongest evidence to date to rule out a role for HPV in lung carcinogenesis in Western populations.

Adjunctive human papillomavirus DNA testing is a useful option in some clinical settings for disease risk assessment and triage of females with ASC-H Papanicolaou test results.

CONTEXT: Recent guidelines recommend colposcopy for women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H). objective: To determine whether adjunctive high-risk human papillomavirus (hrHPV) testing is useful for disease risk assessment in females with ASC-H Papanicolaou (Pap) test results. DESIGN: High-risk HPV prevalence and histopathologic follow-up data on 1187 females with ASC-H ThinPrep Pap test (TPPT) and hrHPV test results were analyzed. RESULTS: ASC-H was reported in 1646 (0.59%) [corrected] of 277 400 (270 338 TPPT and 7062 conventional) Pap test results. The difference in ASC-H detection rates between TPPTs and conventional Pap smears was statistically significant (0.60% vs 0.38%; P = .02). High-risk HPV was detected in 589 (49.6%) of 1187 females with ASC-H TPPT and hrHPV testing. The hrHPV DNA-positive rate in females younger than 40 years was 54.7%, significantly higher than the 36.5% in women 40 years and older. Among 505 females with histopathologic follow-up, cervical intraepithelial neoplasia 2/3 was identified in 32.7% of hrHPV-positive females compared with 1.2% in hrHPV-negative females. The sensitivity, specificity, positive predictive value, and negative predictive value of ASC-H cytology in conjunction with hrHPV DNA testing results for detection of cervical intraepithelial neoplasia 2/3 were 96.1% versus 100.0%, 54.0% versus 68.4%, 35.8% versus 20.8%, and 98.1% versus 100.0% in females younger than 40 years and women 40 years and older, respectively. CONCLUSIONS: Our data suggest that reflex hrHPV testing is a highly useful option for women with ASC-H Pap tests. Females with ASC-H and negative hrHPV testing may be more efficiently managed by follow-up with regular Pap and hrHPV testing rather than universal colposcopy, especially for women 40 years and older.

Reproductive health of adolescent girls perinatally infected with HIV.

OBJECTIVES: We sought to describe the reproductive health of adolescent girls perinatally infected with HIV. METHODS: We estimated the incidence of first pregnancy, genital infections, and abnormal cervical cytology for 638 girls aged 13 years and older in the Pediatric AIDS Clinical Trials Group protocol 219C. RESULTS: Thirty-eight girls became pregnant, for a first pregnancy rate of 18.8/1000 person-years; 7 of these girls had additional pregnancies (95% confidence interval [CI]=13.3, 25.7). Thirty-two pregnancies resulted in live births. All girls received antiretroviral therapy during pregnancy. One infant was HIV infected, 29 were uninfected, and 2 had unknown infection status, for a rate of mother-to-child transmission of HIV in infants with known infection status of 3.3% (95% CI=0.1, 18.6). Condylomata and trichomoniasis were the most frequent genital infections. Forty-eight (47.5%) of 101 girls with Papanicolaou test examinations had abnormal cervical cytology, including atypical cells of undetermined significance (n=18), low-grade squamous intraepithelial lesions (SIL; n=27), and high-grade SIL (n=3). Many abnormalities persisted despite intervention. CONCLUSIONS: Pregnancy rates were lower and cervical abnormalities were higher than among non-HIV-infected adolescents. These findings underscore the importance of Papanicolaou tests and promotion of safer sexual practices in this population.

Assessment of risk factors and human papillomavirus (HPV) related pathogenetic mechanisms of CIN in HIV-positive and HIV-negative women. Study design and baseline data of the HPV-PathogenISS study.

OBJECTIVES: In women with HIV-associated immunosuppression, HPV infections have an increased risk of progression to high-grade cervical intraepithelial neoplasia (CIN). With the HAART-induced prolonged survival and more protracted clinical course of AIDS, progression of CIN to cervical cancer (CC) has become a clinically relevant issue, and the mechanisms responsible for HIV-HPV interactions need further elucidation. The study design and analysis of the baseline data of our new project are presented. MATERIAL AND METHODS: This project is a combination of a prospective cohort study of HIV- and HIV+ women, and a retrospective analysis of CIN lesions and cervical cancer. Up to the present, 244 women have been enrolled (17 HIV+) and subjected to epidemiological interview, colposcopic examination, sampling for HPV testing and typing (PCR, InnoLiPA), and HPV serology. The retrospective series of biopsies were analysed for 13 biomarkers (monitoring key molecular events) using immunohistochemistry and tested for HPV by PCR and TaqMan. RESULTS: HIV- and HIV+ women differ in their exposure status to many of the key epidemiological risk factors of cervical cancer, the most significant ones being number of sexual partners (p = 0.0001), age at onset of sexual activity (p = 0.002), and contraception (yes-no) (p = 0.009). The differences in the baseline clinical observations are less dramatic; HIV-positive women had more frequent HSIL PAP tests (p = 0.040), CIN2 or higher in cervical biopsy (p = 0.049), and external genital warts (p = 0.019). The factors predicting intermediate endpoint markers of cervical cancer, i.e., HSIL PAP smear, ATZ2 in colposcopy, and high-grade CIN in biopsy were analysed in univariate and multivariate regression models. All factors significant in univariate analysis were entered in the multivariate model; HIV-status and Pap smear history maintained their independent predictive power of the HSIL Pap test. The most powerful predictor of ATZ2 colposcopy was HSIL in Pap test. Only the HSIL Pap test and ATZ2 colposcopy remained significant independent predictors of high-grade CIN (p = 0.0001 and p = 0.008, respectively) in the multivariate model. CONCLUSIONS: The three intermediate endpoint markers are closely interrelated, but predicted in part by different covariantes in the causal pathway to cervical cancer. To elucidate whether the increased risk of HIV-positive women to high-grade CIN is due a) to their different exposure status to the risk factors, b) to the direct effects of HIV, or c) to molecular interactions between HIV and HPV, we need to complete these analyses separately in HIV+ and HIV- women.

A comparison of single and combined visual, cytologic, and virologic tests as screening strategies in a region at high risk of cervical cancer.

Increased understanding of human papillomavirus (HPV) infection as the central cause of cervical cancer has permitted the development of improved screening techniques. To evaluate their usefulness, we evaluated the performance of multiple screening methods concurrently in a large population-based cohort of >8500 nonvirginal women without hysterectomies, whom we followed prospectively in a high-risk region of Latin America. Using Youden's index as a measure of the trade-off between sensitivity and specificity, we estimated the performances of a visual screening method (cervicography), conventional cytology, liquid-based cytology (ThinPrep), and DNA testing for 13 oncogenic HPV types. The reference standard of disease was neoplasia > or = cervical intraepithelial neoplasia grade 3 (CIN 3), defined as histologically confirmed CIN 3 detected within 2 years of enrollment (n=90) or invasive cancer detected within 7 years (n=20). We analyzed each technique alone and in paired combinations (n=112 possible strategies), and evaluated the significance of differences between strategies using a paired Z test that equally weighted sensitivity and specificity. As a single test, either liquid-based cytology or HPV DNA testing was significantly more accurate than conventional cytology or cervicography. Paired tests incorporating either liquid-based cytology or HPV DNA testing were not substantially more accurate than either of those two test strategies alone. However, a possibly useful synergy was observed between the conventional smear and cervicography. Consideration of age or behavioral risk profiles did not alter any of these conclusions. Overall, we conclude that highly accurate screening for cervical cancer and CIN 3 is now technically feasible. The remaining vital issue is to extend improved cervical cancer prevention programs to resource-poor regions.

Chapter 1: Human papillomavirus and cervical cancer--burden and assessment of causality.

Cervical cancer remains the second most common cancer in women worldwide and the most frequent in developing countries. Pre-neoplasic cervical lesions represent an additional burden in countries where screening is widespread. The human papillomavirus (HPV) prevalence and type distribution in normal smears and in cancer specimens are being described and show relatively small international variation. State-of-the-art detection techniques have unequivocally shown that HPV-DNA can be detected in 95% to 100% of adequate specimens of cervical cancer, supporting the claim that HPV is the necessary cause. The odds ratios for cervical cancer related to a cross sectional detection of HPV-DNA range from 50 to several hundred in all studies. The risk for any of 15 high-risk types is not statistically different from the risk reported for HPV16. The estimates of the attributable fraction range from 90% to 98%. Additional work should be done in providing information on incidence of cervical cancer and on HPV infection in areas where the disease is common. Theoretical work including modeling of the incidence could be of potential use in the evaluation of the existing and novel preventive strategies. Research is currently being conducted on the mechanisms of HPV carcinogenesis. These include the determinants of the systemic and cellular immune response to the viral infection, the interaction between the host and the virus and the relevance of the different strains and variants of the HPV viral types. Technology developments in this area suitable for epidemiological studies are needed.

Meta-analysis of social inequality and the risk of cervical cancer.

Previous studies of the relationship between socio-economic status and cervical cancer have been mainly based on record linkage of routine data, such as cancer registry incidence rates and regional measures of social class based on census data. These routine data are liable to substantial misclassification with respect to socio-economic status. Previous reports are also primarily from developed countries, whereas the major burden of cervical cancer is in developing countries. We have therefore pooled the data from previously reported case-control studies of cervical cancer or dysplasia, which contain individual-level information on socio-economic characteristics to investigate the relationship between cervical cancer, social class, stage of disease, geographical region, age and histological type. Based on 57 studies, we found an increased risk of approximately 100% between high and low social class categories for the development of invasive cervical cancer, and an increased risk of approximately 60% for dysplasia, including carcinoma in situ. Although the difference was observed in all countries, it was stronger in low/middle income countries and in North America than in Europe. No clear differences were observed between squamous cell carcinoma and adenocarcinoma, or between younger and older women. These results indicate that both cervical infection with human papillomavirus, which is linked to both female and male sexual behaviour, and access to adequate cervical cancer screening programmes are likely to be important in explaining the large cervical cancer incidence rates observed in different socio-economic groups, and that the importance of these factors may vary between different geographical regions.

Age-restricted cervical screening: HPV testing at age 50 identifies a high risk group for cervical disease.

Changes to the present age policy of cervical screening are currently under consideration. We conducted a retrospective matched case-control study and cost analysis study to identify risk factors for the development of an abnormal smear after age 50 and to determine the impact of age-restricted cervical screening on the annual cost of the screening program. All women (229) from an 11-year birth cohort who developed an abnormal smear at age 50 or over were age-matched for two controls with negative smears. Routine screening smears taken between age 48 and 52 were tested for human papillomavirus (HPV) subtypes 16 and 18. Epidemiologic data were collected by postal questionnaire. Changes in costs under a policy of HPV testing and age-restricted screening were assessed. We found that HPV 16 status was the only independently significant risk factor for abnormal cytology after age 50 with an odds ratio of 10.26 (95% CI 1.25-84.11). A policy of early withdrawal from screening at age 50 on the basis of HPV testing would produce net cost savings. These findings suggest that HPV testing could be a valuable means of identifying the small proportion of women still at risk after 50, and of releasing health care resources.

Cytologic screening and human papilloma virus test in women undergoing artificial fertilization.

BACKGROUND: Infertile women in Sweden are offered in vitro fertilization (IVF) within the frame of the social security system. The present investigation was undertaken to evaluate the prevalence of genital human papilloma virus (HPV) infection in relation to the results of cytologic screening and to the infertility in these women. MATERIAL AND METHODS: Two hundred and fourteen women, mean age 32 years (range 20-40), admitted to the Center for Reproduction at Uppsala University Hospital for investigation of infertility and IVF were studied. Human papilloma virus tests were performed by a sensitive polymerase chain reaction-based technique in cervical smears obtained at a medical examination or during oocyte retrieval. Cytologic screening results were obtained from medical records or at the time of investigation. The infertile women were compared with 197 healthy female controls. RESULTS: Infertility resulted from female factors in 47% and male factors in 29% of the cases, and remained unexplained in 24%. Seven percent of the infertile women were HPV-positive compared with 9.1% of the controls. Only genital and oncogenic HPV types were identified. Human papilloma virus type 16 was most prevalent, and examination of the HPV 16 E6 gene showed that this prototype predominated over variants. No correlation was found between HPV infection and cause of infertility. Abnormal cytology was observed in 2.3% of the infertile women and 4.1% of the controls. CONCLUSIONS: Human papilloma virus infections might appear somewhat less frequently in infertile women admitted for IVF than in a control population. In both groups HPV infection was more common than cytologic abnormalities, possibly indicating that present HPV tests are more sensitive in detecting HPV infections than cytologic screening.

Costs and effectiveness of alternative strategies for cervical cancer screening in military beneficiaries.

OBJECTIVE: To estimate the potential effects, on costs and outcomes, of changes in sensitivity and specificity associated with new screening methods for cervical cancer in the military. METHODS: A Markov model of the natural history of cervical cancer was created to simulate a cohort of 100,000 military beneficiaries aged 18-85. Probability estimates for various outcomes and the accuracy of screening tests were obtained from the literature. Cost estimates were obtained from military sources where available; otherwise, civilian costs were used. The outcomes and costs of conventional cytology, liquid-based cytology, and liquid-based cytology with human papillomavirus (HPV) triage were compared at 1-, 2-, and 3-year screening frequencies. RESULTS: Marginal reductions in the incidence of cervical cancer from increasing screening sensitivity are greater than reductions in cancer mortality at every screening interval. Incremental improvements in both cancer incidence and mortality are higher at less frequent screening intervals. Increases in the ratio of low- to high-grade lesions result from increasing the sensitivity of the screening test or shortening the screening interval. Both liquid-based cytology and liquid-based cytology with HPV testing are cost effective (less than $50,000 per life-year saved) when performed at 3-year screening intervals. However, neither strategy is cost-effective when performed more frequently than every 3 years. CONCLUSION: Use of a more sensitive cervical cancer screening test increases costs. However, a more sensitive test performed less frequently may be more effective and less expensive than conventional cytology done annually. In the military setting, this has significant implications for both expense reduction and readiness enhancement.

Prevalence and risk factors for anal squamous intraepithelial lesions in women.

BACKGROUND: Anal cancers are thought to arise from squamous intraepithelial lesions in the anal canal, and women infected with human immunodeficiency virus-1 (HIV) may be at higher risk of anal cancer. Our aim was to determine the prevalence of human papillomavirus (HPV)-related abnormalities of the anal canal in women and to characterize risk factors for these lesions. METHODS: We evaluated HPV-related abnormalities in 251 HIV-positive and in 68 HIV-negative women. We completed physical examinations and obtained questionnaire data on medical history and relevant sexual practices. Univariate and adjusted relative risks (RRs) and 95% confidence intervals (CIs) were computed using the Mantel-Haenszel procedure and regression techniques. All statistical tests were two-sided. RESULTS: Abnormal anal cytology, including atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesions, or high-grade squamous intraepithelial lesions (HSILs), was diagnosed in 26% of HIV-positive and in 8% of HIV-negative women. HSILs were detected by histology or cytology in 6% of HIV-positive and in 2% of HIV-negative women. HIV-positive women showed increased risk of anal disease as the CD4 count decreased (P<.0001) and as the plasma HIV RNA viral load increased (P =.02). HIV-positive women with abnormal cervical cytology had an increased risk of abnormal anal cytology at the same visit (RR = 2.2; 95% CI = 1.4 to 3.3). Abnormal anal cytology in HIV-positive women was associated with anal HPV RNA detected by the polymerase chain reaction and by a nonamplification-based test (RR = 4.3; 95% CI = 1.6 to 11). In a multivariate analysis, the history of anal intercourse and concurrent abnormal cervical cytology also were statistically significantly (P =.05) associated with abnormal anal cytology. CONCLUSIONS: HIV-positive women had a higher risk of abnormal anal cytology than did HIV-negative women with high-risk lifestyle factors. These data provide strong support for anoscopic and histologic assessment and careful follow-up of women with abnormal anal lesions.

Screening for high-grade cervical intra-epithelial neoplasia and cancer by testing for high-risk HPV, routine cytology or colposcopy.

The validity of testing for high-risk types of human papillomavirus (HPV) in cervical cancer prevention programs is undetermined. We compared the performance on primary screening of HPV DNA testing, cytology and colposcopy in detecting cervical intra-epithelial neoplasia (CIN) grade 2 or 3 or cancer. A cohort of 4,761 women, median age 35 years, was screened by routine cytology, routine colposcopy and testing for high-risk HPV by a PCR-based method. Within an 8-month period, women with abnormal findings on cytology or screening colposcopy or in whom high-risk HPV types were detected were referred for colposcopy and biopsy. Women negative on all initial screening tests were followed by a second screening examination. To correct for work-up bias, the true prevalence of CIN 2 or 3 or cancer was estimated by projection from histologically verified subgroups. Cervical biopsies were taken in 364 women (7.6%), of whom 114 (2.4%) showed CIN 2 (n = 34) or CIN 3 (n = 71) or cancer (n = 9). High-risk HPV testing achieved bias-corrected performance measures of 89.4% sensitivity, 93.9% specificity, 35.8% positive predictive value and 99.6% negative predictive value. Bias-corrected rates of true- and false-positives by high-risk HPV testing compared to cytology (colposcopy) were about 4.5 (6.7) and 19.1 (7.4) times higher, respectively. The quality of routine cytology was controlled by computer-assisted review, and the observed number of true-positives more than doubled after adding automated review results. In middle-aged women, testing for high-risk HPV types, particularly when negative, may be used to increase the screening interval in programs for secondary prevention of cervical cancer.

Effects of oral contraceptives in vaginal cytology.

Many literature studies have shown that long-term use of oral contraceptives (OC) is associated with lack of protection of the epithelium of the uterine cervix. Forty-five patients, from 18 to 35 years old, users of two contraceptive formulations, of different estrogenic concentration, took part in this study as volunteers to evaluate the predisposition of the cervix to pathologies. The results found before OC use were 11% of Chlamydia trachomatis infection and 13% of HPV infection. These pathologies were correctly treated and after 5 months of OC use we found total remission of Chlamydia trachomatis infection and 4% of persistent HPV infection. These data lead us to conclude that the OC studied here interfered very little with the presented pathologic results. The risk factors that we considered relevant were: 1) age group (the patients that presented HPV and C. trachomatis infections were young university students); 2) lifestyle (most patients certified that they did not combine the use of barrier contraceptives with the use of OC); 3) multiple sexual partners; 4) low socioeconomic condition.