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Background A nine-valent human papilloma virus (9vHPV) vaccine has been developed to prevent infections and diseases related to HPV 6/11/16/18 (as per the licensed quadrivalent HPV (qHPV) vaccine) as well as to five additional oncogenic HPV types (HPV 31/33/45/52/58). The 9vHPV vaccine has the potential to prevent 90% of cervical cancers, HPV-related anal, vaginal and vulval cancers and anogenital warts. We compared the immunogenicity and safety of the 9vHPV vaccine versus the qHPV vaccine in 16–26-year-old men. Methods Participants ( N = 500) were randomised to receive 9vHPV or qHPV vaccines on day 1, month 2 and month 6. Serology testing was performed on day 1 and month 7. HPV type-specific antibody titres (anti-HPV 6/11/16/18/31/33/45/52/58) were determined by competitive Luminex immunoassay and expressed as geometric mean titres and seroconversion rates. Vaccine safety was also assessed. Results The HPV 6/11/16/18 immune responses elicited by the 9vHPV vaccine were comparable with those elicited by the qHPV vaccine. All participants receiving the 9vHPV vaccine seroconverted for HPV 31/33/45/52/58. The 9vHPV and qHPV vaccines showed comparable safety profiles. Conclusions In addition to immune responses to HPV 31/33/45/52/58, a three-dose regimen of the 9vHPV vaccine elicited a similar immune response to HPV 6/11/16/18 when compared with the qHPV vaccine in men aged 16–26 years. The safety profile was also similar for the two vaccines. The results from this study support extending the efficacy findings with qHPV vaccine to 9vHPV vaccine in men aged 16–26 years. NCT02114385 [ABSTRACT FROM AUTHOR]

Summary Background The European Medicines Agency (EMA) recently approved two-dose immunization schedules for bivalent (HPV 16/18) and quadrivalent (HPV 6/11/16/18) human papillomavirus (HPV) vaccines in nine to fourteen and thirteen year-old-girls, respectively. Registration was based on trials comparing immunogenicity of two-dose schedules in girls 9–14 years to three-dose schedules in young women 15–26 years. We evaluate comparability of antibody levels between and within age groups and discuss potential implications for monitoring the effectiveness of HPV vaccination. Methods A systematic literature search was performed for studies comparing immunogenicity of two- to three-dose schedules of HPV vaccination. We compared geometric mean concentrations (GMCs) of vaccine-type antibodies between different dosing schedules across different age groups. Meta-analysis was used to estimate pooled GMC ratios (bivalent vaccine) of two- compared with three-dose schedules within girls. Findings For both vaccines, two-dose immunization of girls yielded non-inferior GMCs relative to a three-dose schedule in young women up to respectively 36 and 48 months follow-up. Pooled GMC ratios for the bivalent vaccine within girls showed the two-dose schedule becoming inferior to the three-dose schedule in girls for HPV 16 at approximately two years after the first dose. For the quadrivalent vaccine, antibody responses for HPV-18 became inferior from 18 months follow-up onwards when comparing the two-dose schedule with the three-dose schedule within girls. Implications Two-dose immunization of girls has non-inferior immunogenicity compared to a three-dose schedule among young women. However, non-inferior immunogenicity of two- compared with three-dose schedules within girls has not been shown at all time points. Due to this inconclusive evidence, implementation of two-dose HPV vaccination needs to be monitored closely. [ABSTRACT FROM AUTHOR]

Summary Objectives To assess whether HPV serum antibodies detected after natural infection protect against subsequent anal or penile infection with the same HPV type in HIV-negative and HIV-infected men who have sex with men (MSM). Methods MSM aged ≥18 years were recruited in Amsterdam, the Netherlands (2010–2011), and followed-up semi-annually. Antibodies against 7 high-risk HPV types in baseline serum samples were tested using a multiplex immunoassay; baseline, 6-, and 12-month anal and penile samples were tested for HPV DNA and genotyped using the SPF 10 -PCR DEIA/LiPA 25 system (version 1). Statistical analyses were performed using the Wei–Lin–Weissfeld method. Results 719 MSM (median age 40 years; IQR 35–48) with baseline and follow-up data were included in these analyses; 287 (40%) were HIV-infected. HPV seropositivity at baseline was not significantly associated with subsequent type-specific HPV infection at 6 or 12 months in multivariable analyses (for anal infection adjusted hazard ratio (aHR) 1.2; 95% CI 0.9–1.6; for penile infection aHR 0.8; 95% CI 0.6–1.2). High antibody concentrations showed no protective effect against subsequent infection either. Conclusions In a population of highly sexually active, adult MSM, naturally induced HPV antibodies may not protect MSM against subsequent anal or penile HPV infection within one year. [ABSTRACT FROM AUTHOR]

Enteropathy Associated T-cell Lymphoma (EATL) is an intestinal tumour of intra-epithelial lymphocytes. Based on morphology, immunohistochemistry and genetic profile EATL can be divided into two groups. EATL type I is a large cell lymphoma which is highly associated with Coeliac Disease (CD) and mostly presents with malabsorption, weight loss and CD-related symptoms. EATL type II consists of small to medium-sized cells and presents often with obstruction or perforation of the small bowel. This type of EATL has no known association with CD. When EATL has been diagnosed a thorough diagnostic work-up is needed. This work-up preferably includes video capsule enteroscopy (VCE), double-balloon enteroscopy (DBE), computed tomography (CT) combined with 18F-fluorodeoxyglucose positron emission tomography scan (18F-FDG-PET scan) if possible and magnetic resonance enteroclysis (MRE). Nowadays, most EATL patients are treated with chemotherapy mostly preceded by resection of the tumour and followed by stem cell transplantation. Despite these therapies outcome of EATL remains very poor with a 5-year survival of 8–20%. In order to improve survival prospective multicentre trials, studying new therapies are needed. The combination of chemotherapy, monoclonal antibodies and/or apoptosis inducing small molecules might be a potential treatment for EATL in the (nearby) future. [Copyright &y& Elsevier]

Abstract: Cross-protection against non-HPV16/18 types and the emergence of broad spectrum vaccines protecting against multiple HPV types will influence the cost-effectiveness of future screening. To assess this influence we used an individual-based simulation model describing the relation between 14 HPV types and cervical disease, allowing the occurrence of multiple type infections. Screening scenarios for vaccinated women were evaluated, firstly for HPV16/18 vaccination with partial cross-protection against HPV 31, 33, 45 and 58 and secondly, for broad spectrum vaccination against 5–13 HPV types. The vaccine-induced incidence reduction of type-specific infection was varied from 0 to 95% in the cross-protection setting and set at 100% in the setting of broad spectrum vaccines. Scenarios of either cytology or HPV DNA screening were considered under varying lifetime number of screening rounds. At a cost-effectiveness threshold of €20,000/QALY, four times HPV DNA screening between 30 and 60 years was the selected scenario in addition to HPV16/18 vaccination, whether or not cross-protection was conferred (€6707 and €9994/QALY, respectively). In the absence of cross-protection, a fifth screening round might be considered (ICER €22,967/QALY). In addition to broad spectrum vaccination, one screen during lifetime was cost-effective up to an 11-valent vaccine. If the vaccine-induced type-specific incidence reduction was lowered to 99%, one screen during lifetime was cost-effective even in addition to 13-valent vaccination. In conclusion, in a cohort of HPV16/18 vaccinated women, four rounds of HPV DNA screening is cost-effective. One screen during lifetime remains cost-effective in addition to broad spectrum vaccination offering protection against many high-risk HPV types. [Copyright &y& Elsevier]

Abstract: Background: The use of human papillomavirus (HPV) vaccines has been universally approved for women from age 12 to 25 years, but those older than 16 years receive no reimbursement for the cost of the vaccine in the Netherlands. Reductions in the vaccine price as well as new insights in the efficacy of HPV vaccines offer renewed arguments to consider HPV vaccination in adult women. We calculated the clinical benefit and cost-effectiveness of vaccinating women aged 17–25 years in 2010. Methods: The calculations were based on an individual-based simulation model for cervical carcinogenesis, with HPV infection risks obtained from a type-specific HPV transmission model. The indirect protective effect from vaccinating 12 to 16 year-old girls was adjusted for. Cervical screening in the model was incorporated according Dutch screening guidelines, i.e. 7 cytology-based rounds at 5-year intervals from the age of 30. As base-case, we assumed the vaccine to offer full protection against HPV16/18 only if no prior exposure to that type had occurred before vaccination. In sensitivity analyses, we considered partial cross-protection against types 31/33/45/58 and efficacy against all future infections, irrespective of previous or current infection status. Results: In base-case analyses, vaccinating 17 year-olds reduced their lifetime risk of treatment for precancerous lesions from 7.77% to 3.48% and their lifetime cervical cancer risk from 0.52% to 0.24%. These risks were 6.12% and 0.45%, respectively, for a 25 year-old vaccinee. The incremental cost-effectiveness ratio (ICER) for vaccinating 17–25 year-olds was €22,526 per quality-adjusted life-year (QALY) at a vaccine price of €65 per dose, a 50% reduction of the 2010 pharmacy price in the Netherlands. If cross-protection against types 31/33/45/58 was included, the ICER decreased to €14,734 per QALY. Results were robust to efficacy assumptions with respect to previous or current infection status. Conclusion: The clinical benefit of HPV vaccination of women up to 25 years moderately depends on cross-protection to non-vaccine types. Refunding the cost of the vaccine to 17–25 year-old women in the Netherlands can be considered cost-effective at anticipated price reductions. [Copyright &y& Elsevier]

Abstract: Recent studies have revealed an important and intriguing role for human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC). There are indications that the prevalence of HPV-positive HNSCC has recently increased, and genetic analyses point to a completely distinct class of HNSCCs. Most studies suggest that patients with this type of tumour have a better prognosis and some argue that an adjusted therapeutic approach is needed. One crucial point in the research of HNSCC–HPV involvement has often been neglected, which is the lack of a standardised assay to detect HPV. This has resulted in a considerable variation in the frequency of HPV-positive tumours between studies reported thus far. Especially for PCR-based tests, the risk exists that the assay is too sensitive and detects virus without implying a causal involvement in HNSCC. A reliable algorithm to detect a clinically relevant HPV infection in formalin-fixed paraffin embedded tissue has recently become available. Here, we address important biological and analytical aspects of HPV involved in the development of HNSCC and it is emphasised that a standardised HPV assay is a prerequisite for assessing the clinical importance of a HPV infection in HNSCC. [Copyright &y& Elsevier]

Only clinically validated HPV assays can be accepted in cervical cancer screening. To update the list of high-risk HPV assays that fulfil the 2009 international validation criteria (Meijer-2009). PubMed/Medline, Embase, Scopus, references from selected studies; published in January 2014 to August 2020. HPV test validation studies and primary screening studies, involving testing with an index HPV test and a comparator HPV test with reporting of disease outcome (occurrence of histologically confirmed cervical precancer; CIN2+). Women participating in cervical cancer screening. Testing with an index and a comparator HPV test of clinician-collected cervical specimens and assessment of disease outcome (

With the availability of the nonavalent human papillomavirus (HPV) vaccine, vaccinees, parents and healthcare providers need guidance on how to complete an immunization course started with the bi- or quadrivalent vaccine and whether to revaccinate individuals who have completed a full immunization course with the bi- or quadrivalent vaccine. To answer these questions three parameters should be considered: age at the start of vaccination (9 to 14 years of age versus 15 years and older, the cut-off for 2 or 3 doses schedule), the number of doses already received and the time interval between doses. Based on a number of scenarios, we propose that the 9-valent vaccine can be used to complete an incomplete vaccination regimen or might be added to a previous completed schedule to extend protection. [ABSTRACT FROM AUTHOR]

Introduction Because of the long interval between infection with high-risk human papillomavirus (hrHPV) and development of cervical cancer surrogate markers for cancer incidence are necessary to monitor vaccine effectiveness (VE). The aim of this study was to calculate VE of HPV16/18 vaccination by annually assessing incident and persistent infections among (un)vaccinated girls from the general Dutch population up to 3 years after vaccination. Methods In 2009, 1668 girls (54% vaccinated) aged 14–16 years were enrolled in a prospective cohort study. Annually, questionnaire data were obtained, and a vaginal swab was tested for type-specific HPV DNA with SPF 10 -LiPA. VE was estimated by a Poisson model comparing type-specific infection rates in (un)vaccinated girls. Results The adjusted VE (95% CI) was 73% (49–86%) against incident infections with HPV16/18 and 72% (52–84%) against HPV16/18/31/45. VE against persistent HPV16/18 was 100% and 76% (−17 to 95%) against HPV16/18/31/45. This number was lower (36%) when girls who were positive for HPV16 and 18 at baseline were included in the analysis. The overall VE for hrHPV types combined was small. Although 96% of girls were HPV-naïve at baseline, the cumulative 36-month incidence for any HPV was 20%, indicating high sexual activity. Discussion Vaccination is effective against incident and persistent infections with HPV16/18 and HPV16/18/31/45. Low VE against persistent HPV16/18 infection in girls positive at baseline indicates importance of vaccination before sexual debut. [ABSTRACT FROM AUTHOR]

Abstract: Background: We assessed age- and type-specific HPV prevalence, incidence and persistence and their associated risk factors in young women prior to vaccination, to enable monitoring of the impact of introduction of HPV vaccination in the years before participation in the cervical screening program. Methods: The HPV status was assessed in 3282 women aged 16–29 who participated in a Chlamydia trachomatis screening implementation program, of which 2014 women (61%) participated in two rounds (one year apart). Self-collected vaginal swab were analyzed by SPF10 LiPA on the presence of HPV DNA. Risk factors for prevalent, incident and persistent HPV infections were calculated using generalized estimating equation. Results: The prevalence of any HPV in the first round amounted to 54%, while 34% of the women who participated in the second round had a persistent infection and 45% an incident infection. The five most common HPV types found in this study were HPV16, −51, −52, −31 and −53. HPV16 and/or HPV18 prevalence, incidence and persistence in the second round were 15%, 8% and 9%, respectively and for HPV6 and/or HPV11 6%, 4% and 2%, respectively. Relatively to other HPV genotypes, hrHPV types were found more often as a persistent infection than as an incident infection. Furthermore, there is an age-dependent increase within this age range for persistent infections but not for incident infections. Conclusion: The HPV prevalence (54%), incidence (45%) and persistence (34%) is high among sexually active young women in the Netherlands. The different HPV type distribution and risk factors for prevalent, incident and persistent infections, as well as the observed age-trends should be taken into account in interpreting data obtained after vaccine introduction. Repeating measurements post-immunization are particularly relevant until the age when screening starts (i.e. 30 years in the Netherlands). [Copyright &y& Elsevier]

Abstract: Background: To obtain insight into the age-specific seroprevalence for seven high-risk human papillomavirus (hr-HPV) serotypes (HPV16, 18, 31, 33, 45, 52, and 58) among the general population in the pre-vaccination era in The Netherlands. Methods: From a cross-sectional population-based study (ISRCTN 20164309) performed in 2006/2007 6384 sera of men, women and children were tested for seven hr-HPV specific antibodies using a fluorescent bead-based multiplex immunoassay with virus-like particles of the seven HPV serotypes. Results: An increase in seroprevalence was observed in adolescents, especially for the most prevalent HPV type 16 (up to 11.3%). The increase was most pronounced in women, but was less clear for the other six HPV serotypes. Relatively stable seroprevalences were found in the middle aged cohorts and a slight decrease in the elderly. For the age cohorts >14 years, the seroprevalence among women (25.2%) was higher compared with men (20.3%) (p =0.0002). We found that 10.1% of the population was seropositive for multiple HPV serotypes. Conclusions: The HPV vaccination program is targeted at preadolescents as is justified by the results in this study in which a step-up in HPV seroprevalence is observed at ages of sexual debut. Although direct interpretation of seroprevalence data are hampered by cross-reactivity and seroconversion rate, these data are useful as baseline to evaluate long-term population effects of the HPV16/18 vaccination program. [Copyright &y& Elsevier]

Abstract: Background: Self-sampling for high-risk human papillomavirus (hrHPV) testing is accepted by up to 30% of non-attendees to the regular cervical screening programme. Here, the yield of cervical intraepithelial neoplasia (CIN)2 or worse (⩾CIN2) and CIN3 or worse (⩾CIN3) of 15, 274 HPV self-sampling responders amongst non-attendees were compared to that of 176, 027 women participating in regular screening in the same period and in the same region. We also analysed which subpopulations amongst non-attendees are targeted by HPV self-sampling, and which characteristics relate to hrHPV prevalence and yield of ⩾CIN2/⩾CIN3. Method: Data from two consecutive self-sampling studies were pooled. ⩾CIN2/⩾CIN3 yields, screening history, age and ethnic status were retrieved from centralised pathology and screening databases, respectively. A logistic regression model was fitted to analyse method of invitation, ethnicity, age group, and screening history as predictors for response rate, hrHPV presence and ⩾CIN2/⩾CIN3 in non-attendees. For screening history analyses, women <34years were excluded since it was the first screening round in their life. Findings: ⩾CIN2/⩾CIN3 yields of HPV self-sampling responders were higher than those of screening participants (⩾CIN2: relative risk (RR)=1.6, 95% confidence interval=1.4–1.9; ⩾CIN3: RR=1.8, 95%CI=1.5–2.1 with relative risk values increasing with age (test of homogeneity: ⩾CIN2: p =0.04; ⩾CIN3: p =0.03). Native Dutch non-attendees responded better than immigrants (32% versus 22%, p <0·001) and those screened in the previous round revealed a higher response than underscreened (i.e. previous smear taken >7years ago) or never screened (34% versus 25%, p <0·001) women. Strikingly, amongst under- and never screened women aged ⩾39years, never screened women responded better (25% versus 23%, p <0·001). ⩾CIN2 rates were higher amongst responding native Dutch women than immigrants (p <0·01), and higher in under-/never screened women than in women screened in the previous round (p <0·01). Interpretation: Offering hrHPV self-sampling increases the efficacy of the screening programme by targeting a substantial portion of non-attendees of all ethnic groups who have not regularly been screened and are at highest risk of ⩾CIN2. [Copyright &y& Elsevier]

Abstract: Background: No accurate estimates of cervical cancer incidence or mortality currently exist in Georgia. Nor are there any data on the population-based prevalence of high-risk (HR) human papillomavirus (HPV) infection, which, in the absence of good-quality screening, is known to correlate with cervical cancer incidence. Methods: We obtained cervical cell specimens from 1309 women aged 18–59 years from the general population of Tbilisi, and also from 91 locally diagnosed invasive cervical cancers (ICC). DNA of 44 HPV types was tested for using a GP5+/6+-based PCR assay. Results: In the general population (of whom 2% reported a previous Pap smear) HPV prevalence was 13.5% (95% CI: 11.6–15.9), being highest in women aged 25–34 years (18.7%) and falling to between 8.6% and 9.5% for all age groups above 34 years. HR HPV prevalence was 8.6% overall, being 6.8% and 38.9% among women with normal and abnormal cytology, respectively. HPV45 (1.6%) was the most common type in women with normal cytology, whereas HPV16 predominated among women with cervical abnormalities (including 7 of 10 histologically confirmed cervical intraepithelial neoplasia 2/3) and among ICC (57.6%). The next most common types in ICC in Georgia were HPV45 and 18 (13.2 and 11.0%, respectively). Conclusions: We report a relatively high burden of HPV infection in Tbilisi, Georgia. Improving cervical cancer prevention, through screening and/or HPV vaccination, is an important public health issue in Georgia, where 70% of ICC are theoretically preventable by HPV16/18 vaccines. [Copyright &y& Elsevier]

Abstract: Methylation-mediated silencing of the tumour suppressor CADM1 has been functionally linked to lung cancer development. We aimed to determine whether CADM1 promoter methylation is a candidate early detection marker for lung cancer. To this end frozen tissue samples of 36 non-small cell lung cancers, 26 corresponding tumour distant normal tissue samples as well as 6 samples of normal lung from non-lung cancer patients were tested for DNA methylation at three different regions within the CADM1 promoter (M1, M5 and M9) using methylation specific PCR followed by methylation specific reverse line blot analysis. Sixty-four percentage of tumour samples tested positive at the M1 region, 47% at M5 and 74% at the M9 region, compared with 65% (M1), 23% (M5) and 46% (M9) of paired normal tissue samples. Methylation of each of these promoter regions was also detected in the majority of non-lung cancer control samples. Dense methylation, defined as methylation at ≥2 promoter regions, was detected in 66% of tumour samples compared with 38% of paired normal tissues and 67% of non-lung cancer control samples. Within the small subgroup of female patients dense methylation was found in all tumour samples but only 22% of paired normal samples. Neither methylation of individual sites nor dense methylation was correlated with disease free survival. In conclusion, CADM1 promoter methylation is a frequent event in NSCLC as well as normal lung, both of lung cancer and non-lung cancer patients. Hence, CADM1 methylation analysis is unlikely to have diagnostic value for the early detection of lung cancer in an unselected population. However, a diagnostic value for selected subjects, such as females, cannot be excluded. [Copyright &y& Elsevier]

Abstract: Background: More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods. Material and methods: A summary is given from recently published meta-analyses on three possible clinical applications of human papillomavirus (HPV)-DNA testing: triage of women with equivocal or low-grade cytological abnormalities; prediction of the therapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN) lesions, and last not but not least, primary screening for cervical cancer and pre-cancer. Results: Consistent evidence is available indicating that HPV-triage with the Hybrid Capture-2 assay (HC2) is more accurate (significantly higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results. When triaging women with low-grade squamous intraepithelial lesions (LSIL), a reflex HC2 test does not show a significantly higher sensitivity, but a significantly lower specificity compared to a repeat Pap smear. After treatment of cervical lesions, HPV testing easily detects (with higher sensitivity and not lower specificity) residual or recurrent CIN than follow-up cytology. Primary screening with HC2 generally detects 23% (95% confidence interval, CI: 13–23%) more CIN-2, CIN-3, or cancer compared to cytology at cut-off atypical squamous cells of undetermined significance (ASCUS) or LSIL, but is 6% (95% CI: 4–8%) less specific. By combined HPV and cytology screening, a further 4% (95% CI: 3–5%) more CIN-3 lesions can be identified but at the expense of a 7% (95% CI: 5–9%) loss in specificity, in comparison with isolated HC2 screening. Conclusions: Sufficient evidence exists to recommend HPV testing in triage of women with atypical cytology and in surveillance after treatment of CIN lesions. In the United States, recently reviewed knowledge has resulted in the approval of combined cytology and HC2 primary screening in women older than 30 years. However, in Europe, cytology-based screening still remains the standard screening method. The European screening policy will be reviewed based on the longitudinal results of randomised population trials which are currently underway. [Copyright &y& Elsevier]

Abstract: In The Netherlands, vaccination against HPV16/18 has been recommended for all 12-year-old girls. Because screening of vaccinated women remains important, we evaluated the model-based cost-effectiveness of cervical cancer screening strategies. We considered cytology and the HPV DNA test as primary screening instrument, varied the number of screening rounds from 7 to 4, and set the screening starting age at 30 and 35 years. Our model predicted reductions in cervical cancer mortality between 60 and 81% (from 199 deaths to 37–79) when adding screening to vaccination (assumptions for vaccination: 95% efficacy, 100% compliance, lifelong protection). Screening 5 times with HPV DNA (€11,133/QALY) or 7 times with cytology (€17,627/QALY) were scenarios with comparable costs and effects and incremental cost-effectiveness ratios below the threshold in The Netherlands (€20,000 per QALY). [Copyright &y& Elsevier]

Abstract: A persistent infection with human papillomavirus (HPV) is a prerequisite for the development of cervical cancer. Clinical trials with HPV-vaccines have been very successful in preventing persistent HPV16/18 infections, the two most oncogenic HPV-genotypes. We assessed the introduction of universal HPV-vaccination for preadolescent girls in the Dutch National Immunization Programme. Long-term vaccine efficacy, the need and extent of a catch-up programme for young women, and the impact of vaccination on the cervical cancer screening programme are major unresolved issues. Preliminary conservative estimates (80% vaccine efficacy and no effects on the screening programme, transmission rate, non-cervical cancer incidence, and cross protection) predict an acceptable cost-effectiveness ratio for universal vaccination of preadolescent girls. [Copyright &y& Elsevier]

Abstract: Rationale in the development of novel treatment strategies for HPV-associated cancers is targeting on the basis of the presence of HPV in (pre)malignant cells. Here, we designed a new conditionally replicating adenovirus (CRAd) for selective and effective oncolytic replication in HPV-containing cells. As the backbone, we used the CRAd AdCB016, which replicates selectively in cells expressing HPV E6 and E7 proteins. To enhance its oncolytic potency, we armed AdCB016 with p53 variant mp53(268N), which is resistant to HPV E6-mediated degradation. The new CRAd AdCB016-mp53(268N) was analyzed for its lytic replication properties in cervical carcinoma cell lines, HPV-immortalized keratinocyte cell lines representing dysplastic cells, and primary human keratinocytes. AdCB016-mp53(268N) exhibited 10- to 1000-fold greater efficacy than AdCB016 on high-risk HPV-positive cervical carcinoma cells and HPV-immortalized keratinocytes. Importantly, infection with AdCB016-mp53(268N) did not affect primary nonmalignant human keratinocytes. This favorable efficacy and safety profile was confirmed in organotypic raft cultures. Our findings suggest that AdCB016-mp53(268N) is a promising new agent for treatment of HPV-associated human cancers. [Copyright &y& Elsevier]

Abstract: Cytotoxic T lymphocytes (CTLs) play an important role in the defense against viral infections and malignant diseases. Interleukin (IL)-12 plays a crucial role in induction of antigen-specific primary CTL responses and enhances proliferation, interferon-γ (IFN-γ) production, and cytolytic activity of mitogen-stimulated T cells. However, the effects of IL-12 on proliferation and effector functions of previously in vitro or in vivo primed antigen-specific CTLs are less clear. Our results show that IL-12 induces an increase in proliferation of and IFN-γ production by influenza peptide-specific CTLs, but no increase in cytolytic activity on a per cell basis was observed in bulk cultures. Stimulation of a CTL clone confirmed these results; IL-12 supported an increase in IFN-γ production, but did not increase cytolytic activity. The extent of the effect of IL-12 on IFN-γ production differs per CTL clone and depends on the avidity of the clone and the peptide concentration on its target. Our data suggest that IL-12 is a good adjuvant for boosting CTL responses, in terms of proliferation and IFN-γ production, the latter particularly for CTLs with low to intermediate avidity, such as tumor-associated self-antigen-specific CTLs. [Copyright &y& Elsevier]

Abstract: One of the few and most extensively studied human papilloma virus (HPV) type 16 oncoprotein E7-derived cytotoxic T lymphocyte (CTL) epitopes is YMLDLQPETT, presented to CTL by HLA-A2.1. We previously identified an altered peptide ligand (APL) of this epitope with increased binding affinity for HLA-A2.1, YMLDLQPETV. Herein, the in vivo immunogenicity of this APL was investigated in HLA-A2.1 transgenic HHD mice. Both in vitro and direct ex vivo analysis, performed using newly generated HHD tetramers, showed a significant increase in the number of specific CD8+ T cells upon vaccination with the APL as compared to its unmodified counterpart. Improved immunogenicity of the APL was also observed in functional analyses, including antigen-specific lytic activity and cytokine production of primed CD8+ T cells. Consequently, the YMLDLQPETV peptide may prove useful when included in vaccination strategies against HPV16-induced cervical carcinoma. [Copyright &y& Elsevier]

Abstract: Human papillomavirus (HPV) is recognised as necessary for the development of cervical cancer. An age-stratified random sample of 1013 women, aged 25–70 years, participating in the organised cervical screening programme in Turin, Italy was tested for 36 HPV types using polymerase chain reaction (PCR) with the general primers GP5+/GP6+. The overall HPV prevalence was 8.8%. High-risk types were found in 7.1% of women and multiple infections in 1.1%. HPV-16 was the most common type (32.6% of HPV-positive women). HPV prevalence (any type) was 13–14% at ages 25–39 years, 11.5% at age 40–44 years, and approximately 5% among older women. After age-adjustment, HPV prevalence was significantly increased in single vs married, (Odds Ratio (OR)=2.23; 95% Confidence Interval (CI): 1.28–3.89) and decreased in parous vs nulliparous women (OR=0.49; 95% CI: 0.31–0.78). However, the association with marital status and parity was restricted to women less than 45 years of age. In conclusion, overall, the female population of Turin showed an HPV prevalence that is intermediate compared with worldwide levels. [Copyright &y& Elsevier]

Recent studies indicate a role of atherosclerosis-like changes involved in the pathogenesis of aortic valve stenosis. Interestingly, one of the major advanced glycation end products (AGEs), N#x03B5;-(carboxymethyl)lysine (CML) has been related to the process of atherosclerosis in blood vessels. In the present study, we have analyzed the presence of CML in degenerative altered aortic valves with atherosclerosis-like changes, and in degenerated mitral valves without atherosclerosis-like changes, derived from patients suffering from acute rheumatism during childhood. Degenerated and non-degenerated valves were derived from autopsy or obtained during cardiac surgery. The presence of CML was examined by immunohistochemistry. CML was found on the endothelium and fibroblasts in control aortic and mitral valves. Minor differences in CML staining were observed between control and degeneratively affected mitral valves. In contrast, in degenerated aortic valves, CML accumulation was found in macrophages and on calcification sites, comparable to that in atherosclerotic arteries, while the presence of CML staining on the endothelium and fibroblasts was significantly less as compared with control aortic valves. Our data support the hypothesis that the process of degeneration of aortic valves resembles that of atherosclerosis in blood vessels. They suggest that CML also plays a role in the process of atherosclerosis in aortic valves. [Copyright &y& Elsevier]

Endobronchial carcinoma develops through a continuum of morphologically recognizable pre-neoplastic changes. At present, no marker has been identified that can reliably predict the biological behavior of these lesions. Endobronchial lesions (n=39) sampled from patients (n=20) without clinically overt lung cancer, were analyzed by immunohistochemistry (IHC) for abnormal expression regarding the p53 protein, i.e. suprabasal p53 expression. Clear suprabasal p53 immunostaining was found in two (12%) of the hyperplastic or squamous metaplastic lesions, in one (10%) of the mildly or moderately dysplastic lesions and in nine (75%) of the severely dysplastic or carcinoma in situ (CIS) lesions. Suprabasal p53 immunostaining was found significantly more frequent in severe dysplasia or CIS (P<0.01). Of 17 patients follow-up data were available. After a median follow up of 7 months (range 2–37 months), six patients presented with bronchial carcinoma within the same lobe or bronchial spur where biopsies had been taken. Four of these patients revealed suprabasal p53 immunostaining in the biopsies obtained from the sites of future cancer. In three patients biopsies were obtained from future cancer sites as well as from distant sites in the ipsilateral lung. Suprabasal p53 immunostaining was found exclusively at future cancer sites of these patients (P=0.02). Suprabasal p53 immunostaining in addition to histology improved the specificity and the positive predictive value for bronchial carcinoma development in the same lobe or bronchial spur, compared with histology alone. These results suggest that suprabasal p53 immunostaining is associated with bronchial cancer and might have additive value to predict the biological behavior of pre-neoplastic endobronchial lesions in the population at risk of bronchial cancer. [Copyright &y& Elsevier]

Epstein–Barr virus (EBV) is associated with a still growing spectrum of clinical disorders, ranging from acute and chronic inflammatory diseases to lymphoid and epithelial malignancies. Based on a combination of in vitro and in vivo findings, EBV is thought to contribute in the pathogenesis of these diseases. The different EBV gene expression patterns in the various disorders, suggest different EBV-mediated pathogenic mechanisms. In the following pages, an overview of the biology of EBV-infection is given and functional aspects of EBV-proteins are discussed and their putative role in the various EBV-associated disorders is described. EBV gene expression patterns and possible pathogenic mechanisms are discussed. In addition, expression of the cellular genes upregulated by EBV in vitro is discussed, and a comparison with the in vivo situation is made. [Copyright &y& Elsevier]

Objective: To study the source of human papillomavirus (HPV) in semen.Design: Observational study (CCMO-NL3248800010).Setting: Academic hospital-based laboratory.Patient(s): Healthy male volunteers (n = 213).Intervention(s): One penile scrape and three semen samples were obtained per participant for HPV-DNA testing by both GP5+/6+ polymerase chain reaction (PCR) and SPF10-PCR to detect moderate/high and low viral loads, respectively; flat penile lesions (FPL) were detected by penoscopy.Main Outcome Measure(s): HPV-DNA presence in semen and penile scrapes, and the presence of FPL.Result(s): HPV-DNA at moderate/high viral loads (i.e., GP5+/6+ PCR-positive) was detected in ≥1 semen sample(s) in 27% of participants. Most men with moderate/high viral loads in the penile scrape also had moderate/high viral loads in semen (85%). Men with a HPV-negative penile scrape were very unlikely to have moderate/high viral loads in semen (3%). The presence of HPV in semen was associated with the presence of HPV in the penile scrape also on a genotype-specific level. Having FPL was a risk factor for HPV presence in semen.Conclusion(s): HPV-DNA presence in semen of healthy men is common and associated with HPV infections of the penile epithelium. HPV-DNA presence in semen may result from desquamation of HPV-infected penile cells. [ABSTRACT FROM AUTHOR]