HPV16 genetic variation and the development of cervical cancer worldwide.

BACKGROUND: Factors that favour a small proportion of HPV16 infections to progress to cancer are still poorly understood, but several studies have implicated a role of HPV16 genetic variation. METHODS: To evaluate the association between HPV16 genetic variants and cervical cancer risk, we designed a multicentre case-control study based on HPV16-positive cervical samples (1121 cervical cancer cases and 400 controls) from the International Agency for Research on Cancer biobank. By sequencing the E6 gene, HPV16 isolates were classified into variant lineages and the European (EUR)-lineage isolates were subclassified by the common polymorphism T350G. RESULTS: Incidence of variant lineages differed between cases and controls in Europe/Central Asia (P=0.006, driven by an underrepresentation of African lineages in cases), and South/Central America (P=0.056, driven by an overrepresentation of Asian American/North American lineages in cases). EUR-350G isolates were significantly underrepresented in cervical cancer in East Asia (odds ratio (OR)=0.02 vs EUR-350T; 95% confidence interval (CI)=0.00-0.37) and Europe/Central Asia (OR=0.42; 95% CI=0.27-0.64), whereas the opposite was true in South/Central America (OR=4.69; 95% CI=2.07-10.66). CONCLUSION: We observed that the distribution of HPV16 variants worldwide, and their relative risks for cervical cancer appear to be population-dependent.

Lung cancer in the Swiss HIV Cohort Study: role of smoking, immunodeficiency and pulmonary infection.

BACKGROUND: Immunodeficiency and AIDS-related pulmonary infections have been suggested as independent causes of lung cancer among HIV-infected persons, in addition to smoking. METHODS: A total of 68 lung cancers were identified in the Swiss HIV Cohort Study (SHCS) or through linkage with Swiss Cancer Registries (1985-2010), and were individually matched to 337 controls by centre, gender, HIV-transmission category, age and calendar period. Odds ratios (ORs) were estimated by conditional logistic regression. RESULTS: Overall, 96.2% of lung cancers and 72.9% of controls were ever smokers, confirming the high prevalence of smoking and its strong association with lung cancer (OR for current vs never=14.4, 95% confidence interval (95% CI): 3.36-62.1). No significant associations were observed between CD4+ cell count and lung cancer, neither when measured within 1 year (OR for <200 vs ≥500=1.21, 95% CI: 0.49-2.96) nor further back in time, before lung cancer diagnosis. Combined antiretroviral therapy was not significantly associated with lung cancer (OR for ever vs never=0.67, 95% CI: 0.29-1.52), and nor was a history of AIDS with (OR=0.49, 95% CI: 0.19-1.28) or without (OR=0.53, 95% CI: 0.24-1.18) pulmonary involvement. CONCLUSION: Lung cancer in the SHCS does not seem to be clearly associated with immunodeficiency or AIDS-related pulmonary disease, but seems to be attributable to heavy smoking.

Bowel cancer screening is safe, detects earlier stage cancer and adenomas in 50% of cases: experience of the prevalent round of screening from two first wave centres in the North East of England.

OBJECTIVE: The NHS Bowel Cancer Screening Programme (BCSP) began roll-out in 2006 aiming to reduce cancer mortality through detection at an earlier stage. We report results from the prevalent round of screening at two first wave centres and compare with the UK pilot study. DESIGN: This is a service evaluation study. Data were collected prospectively for all individuals undergoing faecal occult blood testing (FOBt) and colonoscopy including: uptake and outcomes of FOBt, colonoscopic performance, findings, histological data and complications. Continuous data were compared using a two-tailed test of two proportions. SETTING: The South of Tyne and Tees Bowel Cancer Screening centres. PATIENTS: Participants of the BCSP. MAIN OUTCOME MEASURES: 1) Colonoscopy Quality Assurance and 2) Cancer stage shift. RESULTS: 195,772 individuals were invited to participate. Uptake was 54% and FOBt positivity 1.7%. 1524 underwent colonoscopy with caecal intubation in 1485 (97%). 180 (12%) cancers were detected. Dukes stages were: 76 (42%) A; 47 (26%) B; 47 (26%) C; 8 (4%) D and 2 (1%) unknown. This demonstrates a significantly earlier stage at diagnosis compared with data from 2867 non-screening detected cancers (p<0.001). Adenomas were detected in 758 (50%). One perforation occurred (0.07%) and two intermediate bleeds requiring transfusion only (0.12%). Both caecal intubation and adenoma detection were significantly higher than in the UK pilot study (p<0.001). CONCLUSIONS: The prevalent round of screening demonstrates a high adenoma and cancer detection rate and significantly earlier stage at diagnosis. Complications were few providing reassurance regarding safety. Efforts are required to improve uptake.

Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study.

BACKGROUND: The advent of highly active antiretroviral therapy (HAART) in 1996 led to a decrease in the incidence of Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL), but not of other cancers, among people with HIV or AIDS (PWHA). It also led to marked increases in their life expectancy. METHODS: We conducted a record-linkage study between the Swiss HIV Cohort Study and nine Swiss cantonal cancer registries. In total, 9429 PWHA provided 20,615, 17,690, and 15,410 person-years in the pre-, early-, and late-HAART periods, respectively. Standardised incidence ratios in PWHA vs the general population, as well as age-standardised, and age-specific incidence rates were computed for different periods. RESULTS: Incidence of KS and NHL decreased by several fold between the pre- and early-HAART periods, and additionally declined from the early- to the late-HAART period. Incidence of cancers of the anus, liver, non-melanomatous skin, and Hodgkin's lymphoma increased in the early- compared with the pre-HAART period, but not during the late-HAART period. The incidence of all non-AIDS-defining cancers (NADCs) combined was similar in all periods, and approximately double that in the general population. CONCLUSIONS: Increases in the incidence of selected NADCs after the introduction of HAART were largely accounted for by the ageing of PWHA.

Human papillomavirus infection in women with and without cervical cancer in Karachi, Pakistan.

BACKGROUND: No data exist on the population prevalence of, or risk factors for, human papillomavirus (HPV) infection in predominantly Muslim countries in Asia. METHODS: Cervical specimens were obtained from 899 married women aged 15-59 years from the general population of Karachi, Pakistan and from 91 locally diagnosed invasive cervical cancers (ICCs). HPV was detected using a GP5+/6+ PCR-based assay. RESULTS: The prevalence of HPV in the general population was 2.8%, with no evidence of higher HPV prevalence in young women. The positivity of HPV was associated with women's lifetime number of sexual partners, but particularly with the age difference between spouses and other husbands' characteristics, such as extramarital sexual relationships and regular absence from home. The HPV16/18 accounted for 24 and 88% of HPV-positive women in the general population and ICC, respectively. CONCLUSION: Cervical cancer prevention policies should take into account the low HPV prevalence and low acceptability of gynaecological examination in this population.

HPV infection in women with and without cervical cancer in Conakry, Guinea.

BACKGROUND: Cervical cancer incidence in western Africa is among the highest in the world. METHODS: To investigate human papillomavirus (HPV) infection in Guinea, we obtained cervical specimens from 831 women aged 18-64 years from the general population of the capital Conakry and from 77 locally diagnosed invasive cervical cancers (ICC). Human papillomavirus was detected using a GP5+/6+ PCR-based assay. RESULTS: Among the general population, the prevalence of cervical abnormalities was 2.6% by visual inspection and 9.5% by liquid-based cytology. Fourteen of 15 high-grade squamous intraepithelial lesions were visual inspection-negative. Human papillomavirus prevalence was 50.8% (32.1% for high-risk types) and relatively constant across all age groups. Being single or reporting > or =3 sexual partners was significantly associated with HPV positivity. HPV16 was the most common type, both among the general population (7.3%) and, notably in ICC (48.6%). HPV45 (18.6%) and HPV18 (14.3%), the next most common types in ICC, were also more common in ICC than in HPV-positive women with normal cytology from the general population. CONCLUSION: The heavy burden of HPV infection and severe cervical lesions in Guinean women calls for new effective interventions. Sixty-three per cent of cervical cancers are theoretically preventable by HPV16/18 vaccines in Guinea; perhaps more if some cross-protection exists with HPV45.

Kaposi sarcoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy.

Between 1984 and 2006, 12 959 people with HIV/AIDS (PWHA) in the Swiss HIV Cohort Study contributed a total of 73 412 person-years (py) of follow-up, 35 551 of which derived from PWHA treated with highly active antiretroviral therapy (HAART). Five hundred and ninety-seven incident Kaposi sarcoma (KS) cases were identified of whom 52 were among HAART users. Cox regression was used to estimate hazard ratios (HR) and corresponding 95% confidence intervals (CI). Kaposi sarcoma incidence fell abruptly in 1996-1998 to reach a plateau at 1.4 per 1000 py afterwards. Men having sex with men and birth in Africa or the Middle East were associated with KS in both non-users and users of HAART but the risk pattern by CD4 cell count differed. Only very low CD4 cell count (<50 cells microl(-1)) at enrollment or at HAART initiation were significantly associated with KS among HAART users. The HR for KS declined steeply in the first months after HAART initiation and continued to be low 7-10 years afterwards (HR, 0.06; 95% CI, 0.02-0.17). Thirty-three out of 52 (63.5%) KS cases among HAART users arose among PWHA who had stopped treatment or used HAART for less than 6 months.

Human papillomavirus infection in women with and without cervical cancer in Warsaw, Poland.

Cervical cancer incidence and mortality in Poland is among the highest in Europe. To investigate infection with different human papillomaviruses (HPV) in Warsaw, Poland, we obtained cervical cell specimens from 834 women aged 18-59 years from the general population, and 88 cervical cancers. DNA of 44 HPV types was detected using a GP5+/6+-based PCR assay. HPV prevalence was 16.6% in the general female population, being highest (24.2%) in women aged 25-34 years, notably among unmarried women (37.3%). HPV prevalence fell to 8.6% at ages 55-59. High-risk HPV prevalence was 11.3%, with HPV16 being the most common type (3.7%). All but one cervical cancer were high-risk HPV-positive, although the importance of HPV16 (73%) was much greater, and multiple infections fewer (1%), than among HPV-positive women in the general female population. In summary, we report a relatively high burden of HPV infection in Warsaw, Poland, where 79% of cervical cancers are theoretically preventable by HPV16/18 vaccines.

Worldwide variation in the relative importance of hepatitis B and hepatitis C viruses in hepatocellular carcinoma: a systematic review.

We combined information published worldwide on the seroprevalence of hepatitis B surface antigen (HbsAg) and antibodies against hepatitis C virus (anti-HCV) in 27 881 hepatocellular carcinomas (HCCs) from 90 studies. A predominance of HBsAg was found in HCCs from most Asian, African and Latin American countries, but anti-HCV predominated in Japan, Pakistan, Mongolia and Egypt. Anti-HCV was found more often than HBsAg in Europe and the United States.

Hepatitis C virus and non-Hodgkin's lymphoma: Findings from the Swiss HIV Cohort Study.

Infections with hepatitis C virus (HCV) and, possibly, hepatitis B virus (HBV) are associated with an increased risk of non-Hodgkin's lymphoma (NHL) in the general population, but little information is available on the relationship between hepatitis viruses and NHL among people with HIV (PHIV). We conducted a matched case-control study nested in the Swiss HIV Cohort Study (SHCS). Two hundred and ninety-eight NHL cases and 889 control subjects were matched by SHCS centre, gender, age group, CD4+ count at enrollment, and length of follow-up. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were computed using logistic regression to evaluate the association between NHL and seropositivity for antibodies against HCV (anti-HCV) and hepatitis B core antigen (anti-HBc), and for hepatitis B surface antigen (HBsAg). Anti-HCV was not associated with increased NHL risk overall (OR = 1.05; 95% CI: 0.63-1.75), or in different strata of CD4+ count, age or gender. Only among men having sex with men was an association with anti-HCV found (OR = 2.37; 95% CI: 1.03-5.43). No relationships between NHL risk and anti-HBc or HBsAg emerged. Coinfection with HIV and HCV or HBV did not increase NHL risk compared to HIV alone in the SHCS.

Human papillomavirus infection in Shenyang City, People's Republic of China: A population-based study.

To investigate the prevalence of, and risk factors for, cervical infection with human papillomavirus (HPV) in Shenyang City, People's Republic of China, we interviewed and obtained cervical cell samples from 685 women aged 15-59 years enumerated from local population lists. Human papillomavirus DNA was detected in cervical cell samples using a GP5+/6+-based PCR assay for 44 HPV types. Human papillomavirus prevalence was 16.8% overall and 13.6% among women without cervical abnormalities (16.6% and 12.4%, respectively, age-standardised to the world standard population), with no significant trends in HPV prevalence by age group. Of the 32 types identified, high-risk HPV types predominated in all age groups, HPV16 being the most common (3.4% of all women), followed by HPV52 (2.5%) and 58 (1.9%). Multiple-type infections accounted for 31.3% of all infected women. Not being married, reporting multiple sexual partners and husband's extramarital sexual relationships were all significantly associated with being HPV-positive. The disclosure of a relatively high HPV prevalence in Shenyang, in comparison with other worldwide populations, raises important questions concerning the prevention of cervical cancer in China, especially given the promising efficacy of prophylactic HPV vaccines.

Human papillomavirus infection in Shanxi Province, People's Republic of China: a population-based study.

To investigate the prevalence of, and risk factors for, cervical infection with human papillomavirus (HPV) in the rural province of Shanxi, People's Republic of China, which has relatively high cervical cancer mortality rates, we interviewed and obtained cervical cell samples from 662 women aged 15-59 years. A total of 24 different HPV types were identified using a GP5+/6+-based PCR assay able to detect 44 different HPV types. Human papillomavirus prevalence was 14.8% overall and 9.6% among women without cervical abnormalities (14.2 and 8.9%, respectively, age standardised to the world standard population). Multiple-type infections accounted for 30.6% of all infections. By far the most commonly found type was HPV16 (5.7% of all women and 38.8% of HPV-positive women), followed by HPV 58, 52, 33 and 18. Unlike most previous studies published, HPV prevalence was lower among women younger than 35 years (8.7%) than those older than 35 years (17.8%). High-risk HPV types predominated in all age groups. Although low-risk HPV types were rare in young women, they became more common with increasing age. 92.3% of women with cervical intraepithelial neoplasia grade 3 were infected with high-risk HPV types, but none with low-risk types only. No significant difference in HPV positivity was observed by educational level, sexual habits, reproductive history or use of contraceptive methods in this rural low-income Chinese population.

Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis.

BACKGROUND: The proportion of women infected with human papillomavirus (HPV) varies greatly across populations, as might the distribution of HPV types. We aimed to compare HPV-type distribution in representative samples of women from different world regions. METHODS: Women were randomly selected from the general population of 13 areas from 11 countries (Nigeria, India, Vietnam, Thailand, Korea, Colombia, Argentina, Chile, the Netherlands, Italy, and Spain). A standardised protocol was used for cervical specimen collection. All HPV testing was by GP5+/6+ PCR-based EIA. The proportion of HPV-positive women infected with different HPV types was compared by study area and between pooled regions with age-adjusted odds ratios (ORs) with corresponding 95% floating CIs. FINDINGS: 15 613 women aged 15-74 years without cytological abnormalities were included in a pooled analysis. Age-standardised HPV prevalence varied nearly 20 times between populations, from 1.4% (95% CI 0.5-2.2) in Spain to 25.6% (22.4-28.8) in Nigeria. Although both overall HPV prevalence and HPV16 prevalence were highest in sub-Saharan Africa, HPV-positive women in Europe were significantly more likely to be infected with HPV16 than were those in sub-Saharan Africa (OR 2.64, p=0.0002), and were significantly less likely to be infected with high-risk HPV types other than HPV16 (OR 0.57, p=0.004) and/or low-risk HPV types (OR 0.44. p=0.0002). Women from South America had HPV-type distribution in between those from sub-Saharan Africa and Europe. Heterogeneity between areas of Asia was significant. INTERPRETATION: Heterogeneity in HPV type distribution among women from different populations should be taken into account when developing screening tests for the virus and predicting the effect of vaccines on the incidence of infection.

Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: a meta-analysis.

Particular types of human papillomavirus (HPV) infection may preferentially progress from high-grade squamous intraepithelial lesions (HSIL) to squamous cell carcinoma of the cervix (SCC). We performed a meta-analysis of published data to compare HPV type distribution in HSIL and SCC. HPV16, 18 and 45 were each more prevalent in SCC than HSIL, whereas the reverse was true for other oncogenic types including HPV31, 33, 52 and 58. These data suggest that HSILs infected with HPV16, 18 and 45 preferentially progress to SCC. This may have implications for follow-up protocols of future HPV-based cervical cancer screening programmes and for HPV vaccine trials.

Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis.

This study investigated regional variations in the contribution made by different human papilloma (HPV) types to invasive cervical cancer (ICC). A total of 85 studies using polymerase chain reaction to estimate HPV prevalence in ICC were identified. Data on HPV prevalence were extracted separately for squamous cell carcinoma (SCC) and for adeno- and adenosquamous-carcinoma (ADC). A total of 10 058 cases (8550 SCC, 1508 ADC) were included in pooled analyses. The most common HPV types in ICC were, in order of decreasing prevalence, HPV16, 18, 45, 31, 33, 58, 52, 35, 59, 56, 6, 51, 68, 39, 82, 73, 66 and 70. In SCC, HPV16 was the predominant type (46-63%) followed by HPV18 (10-14%), 45 (2-8%), 31 (2-7%) and 33 (3-5%) in all regions except Asia, where HPV types 58 (6%) and 52 (4%) were more frequently identified. In ADC, HPV prevalence was significantly lower (76.4%) than in SCC (87.3%), and HPV18 was the predominant type in every region (37-41%), followed by 16 (26-36%) and 45 (5-7%). The overall detection of HPV DNA was similar in different regions (83-89%). A majority of ICC was associated with HPV16 or 18 in all regions, but approximately a quarter of all ICC cases were associated with one of 16 other HPV types, their distribution varying by region.

Translocation of hormone-sensitive lipase and perilipin upon lipolytic stimulation during the lactation cycle of the rat.

The removal of the litter from lactating rats results in a decrease in the lipolytic response to catecholamines in maternal adipocytes; this effect can be prevented by concomitant treatment of the rats with growth hormone. The decrease in response to catecholamines following litter removal was not due to a change in the amount of either hormone-sensitive lipase (HSL) or perilipin per adipocyte or in the proportion of either of these proteins associated with the fat droplet. Incubation in vitro with isoproterenol did not cause any apparent net translocation of HSL to the fat droplet in adipocytes from the mature female rats in any state used in this study, but isoproterenol did cause a movement of perlipin away from the fat droplet. This translocation of perilipin was not altered by litter removal. Thus, the decrease in response to catecholamines found on litter removal from lactating rats appears to be due to a diminished ability to activate HSL associated with fat droplet.

Lower urinary tract symptoms suggestive of benign prostatic obstruction--Triumph: the role of general practice databases.

The Triumph project aims to document the current management of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) in general practice and to assess the effectiveness of the initial treatment options used. The first phase of the project will consider existing data sources in primary care. A patient's medical record will contain most, if not all, clinically relevant information, and databases combining the records from a network of computerised general practices can provide longitudinal data for complete populations, linking prescribing records to clinical information on disease progression and outcomes for individual patients. Database research can provide rapid information and offers the ability to conduct studies on a scale that would previously have been prohibited by both time and expense. Within the Triumph project, the THALES, General Practice Research Database (GPRD) and Integrated Primary Care Information (IPCI) databases are, or will be, used to examine the current management of LUTS/BPH in France, the UK and the Netherlands respectively. Preliminary results from the UK General Practice Research Database (GPRD) showed that LUTS/BPH incidence increased linearly from the ages of 45 to 85 years (r(2) = 0.992) and prevalence increased from 3.5% to 35% for men in their late 40s and 80s respectively. With treatment failure defined as a change to another medical therapy, catheterisation or prostatic surgery, and accounting for age and year variation, patients receiving the older alpha(1)-blockers (indoramin and prazosin) appeared to fail significantly earlier than those receiving finasteride. There was no significant difference between finasteride and the newer alpha(1)-blockers (tamsulosin, alfuzosin, terazosin and doxazosin). Patterns of changes between products from the THALES database in France were broadly similar to those seen in the UK.

How do symptoms indicative of BPH progress in real life practice? The UK experience.

OBJECTIVE: Lower urinary tract symptoms (LUTS) are usually, but not exclusively associated with benign prostatic hyperplasia (BPH). Using a population identified from the UK General Practice Research Database (GPRD), we describe the changes in the management of LUTS/BPH and assess the effectiveness of medical therapy between 1992 and 1998. METHODS: 61,364 men with LUTS/BPH and without a record of prostatic cancer were identified on the database. 14,195 were treated with an alpha1-blocker or finasteride. Treatment failure was defined as prostatic surgery, catheterisation or a switch in medical therapy. RESULTS: LUTS/BPH incidence increased linearly from the age of 45 to 85 years (r2 = 0.992) and prevalence increased from 3.5% to 35% for men in their late 40s and 80s respectively. Prostatectomy rates increased linearly from the age of 50 to 80 years (r2 = 0.984). Between 1992 and 1998, total treated-patient time had increased 3-fold, patients have been medically treated earlier and have increasingly been prescribed the LUTS/BPH-specific treatments finasteride, tamsulosin and alfuzosin in comparison to older treatments (indoramin, prazosin). In parallel, there has been a progressive increase in the interval between first diagnosis and prostatic surgery, and this interval is significantly longer for medically treated patients than those receiving no medical therapy. The intervals between the start and failure of medical therapy were significantly shorter for patients receiving indoramin and prazosin than for those receiving specific LUTS/BPH treatments. CONCLUSIONS: Between 1992 and 1998 there has been a significant lengthening of the period between first diagnosis of LUTS/BPH and surgery. This postponement of surgery is associated with earlier treatment and the increased use of specific LUTS/BPH treatments that appear more effective than older products in delaying treatment failure.

Medical therapy for benign prostatic hyperplasia: a review of the literature.

OBJECTIVE: To review the existing evidence regarding the efficacy and safety of medical therapy for lower urinary tract symptoms (LUTS) indicative of benign prostatic hyperplasia (BPH). To assess randomised controlled trials investigating the six alpha-adrenergic receptor antagonists (alpha-blockers), prazosin, alfuzosin, indoramin, terazosin, doxazosin, and tamsulosin, that benefit patients by relaxing prostatic smooth muscle, and the anti-androgen, finasteride, that mediates its more long-term benefits by reducing prostate size. RESULTS: This review suggests that both classes of drug offer significant improvement in criteria used to evaluate symptomatic BPH and can be effective whilst being acceptably safe. Furthermore, the therapeutic efficacy of all contemporary alpha-blockers appear similar, both in terms of symptom relief and urodynamic improvements. Randomised controlled trials have additionally demonstrated that finasteride therapy can provide improvement in terms of quality of life indices, prostate volume, and risks of progressing to acute urinary retention or prostatic surgery. While alpha-blockers have a rapid onset of action, likely to produce a therapeutic result within weeks, regardless of whether prostatic enlargement or bladder outlet obstruction is present, finasteride appears to be effective for more long-term therapy for up to 4 years, but only in alleviating symptoms when they are associated with a significantly large prostate. Neither finasteride nor the alpha(1a)-receptor-selective blocker, tamsulosin, are associated with the lowering of blood pressure and incidence of cardiovascular side effects that are apparent with other less selective alpha-blocker therapies such as dizziness and postural hypertension. They are, however, both associated with an increased risk of sexual dysfunction, albeit less than those associated with surgical intervention. Whereas tamsulosin is associated only with ejaculatory dysfunction, finasteride is additionally linked to decreased libido and impotence.