Vaccination against HPV: indications for women and the impact on the cervical screening programme

A novel approach for primary prevention of cervical cancer has become available by the discovery of efficient prophylactic human papillomavirus (HPV) vaccines based on virus-like particles. This review elaborates on the progress in the field of prophylactic HPV vaccination achieved in the past decade, provides indications for prophylactic HPV vaccination, and discusses the impact on public health and the current secondary prevention system. In summary, with current vaccines, effective prevention and control of cervical cancer within the next decades requires an integrated vaccination-screening approach, including routine prophylactic vaccination to young women and adapted cervical screening for older women ( ‡30 years)

Low methylation marker levels among human papillomavirus-vaccinated women with cervical high-grade squamous intraepithelial lesions.

Cervical cancer screening programs, including triage tests, need redesigning as human papillomavirus (HPV)-vaccinated women are entering the programs. Methylation markers offer a potential solution to reduce false-positive rates by identifying clinically relevant cervical lesions with progressive potential. In a nested case-control study, 9242 women who received the three-dose HPV16/18-vaccine at ages 12-15 or 18 in a community-randomized trial were included. Subsequently, they were re-randomized for either frequent or infrequent cervical cancer screening trials. Over a 15-year post-vaccination follow-up until 2022, 17 high-grade squamous intraepithelial lesion (HSIL) and 15 low-grade (LSIL) cases were identified at the 25-year screening round, alongside 371 age and community-matched HPV16/18-vaccinated controls. Methylation analyses were performed on cervical samples collected at age 25, preceding histologically confirmed LSIL or HSIL diagnoses. DNA methylation of viral (HPV16/18/31/33) and host-cell genes (EPB41L3, FAM19A4, and miR124-2) was measured, along with HPV-genotyping. No HPV16/18 HSIL cases were observed. The predominant HPV-genotypes were HPV52 (29.4%), HPV59/HPV51/HPV58 (each 23.5%), and HPV33 (17.7%). Methylation levels were generally low, with no significant differences in mean methylation levels of viral or host-cell genes between the LSIL/HSIL and controls. However, a significant difference in methylation levels was found between HSIL cases and controls when considering a combination of viral genes and EPB41L3 (p value = .0001). HPV-vaccinated women with HSIL had HPV infections with uncommon HPV types that very rarely cause cancer and displayed low methylation levels. Further investigation is warranted to understand the likely regressive nature of HSIL among HPV-vaccinated women and its implications for management

An analysis of temporal and generational trends in the incidence of anal and other HPV-related cancers in Southeast England

Patients diagnosed in 1960–2004 with cancer of the cervix, anus, vulva, vagina or penis were identified from the Thames Cancer Registry database, and age-standardised period (temporal) incidence rates calculated by direct standardisation. Age-cohort modelling techniques were used to estimate age-specific incidence rates in the earlier and later cohorts, enabling the calculation of age-standardised cohort (generational) rates. Incidence of anal cancer increased for both men and women over the period studied, mainly in those born from 1940 onwards. Similar generational patterns were seen for cancers of the vulva and vagina, but those for penile cancer were different. For cervix cancer, the steep downward trend in cohort rates due to screening levelled off in women born from 1940 onwards. Our findings are compatible with the hypothesis that changes in sexual practices were a major contributor to the increases of these cancers. Programmes of vaccination against HPV, aimed at reducing the burden of cervical cancer, may also help to reduce the incidence of cancer at other anogenital sites

Hepatic stellate cells:central modulators of hepatic carcinogenesis

Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related death worldwide, and is increasing in incidence. Currently, our therapeutic repertoire for the treatment of HCC is severely limited, and therefore effective new therapies are urgently required. Recently, there has been increasing interest focusing on the cellular and molecular interactions between cancer cells and their microenvironment. HCC represents a unique opportunity to study the relationship between a diseased stroma and promotion of carcinogenesis, as 90 % of HCCs arise in a cirrhotic liver. Hepatic stellate cells (HSC) are the major source of extracellular proteins during fibrogenesis, and may directly, or via secreted products, contribute to tumour initiation and progression. In this review we explore the complex cellular and molecular interplay between HSC biology and hepatocarcinogenesis. We focus on the molecular mechanisms by which HSC modulate HCC growth, immune cell evasion and angiogenesis. This is followed by a discussion of recent progress in the field in understanding the mechanistic crosstalk between HSC and HCC, and the pathways that are potentially amenable to therapeutic intervention. Furthermore, we summarise the exciting recent developments in strategies to target HSC specifically, and novel techniques to deliver pharmaceutical agents directly to HSC, potentially allowing tailored, cell-specific therapy for HCC

The use of host cell DNA methylation analysis in the detection and management of women with advanced cervical intraepithelial neoplasia: a review

This paper briefly reviews the role of hypermethylation of host cell genes in cervical carcinogenesis and discusses potential clinical applications of methylation analysis in the management of high-risk HPV (hrHPV) -positive women. We argue that methylation assays can be used: 1. for primary triage of hrHPV-positive women to detect cervical cancer and advanced cervical intraepithelial neoplasia (CIN); 2. as secondary triage for women with minor cytological abnormalities to identify those with the highest risk of CIN3 or worse; 3. as exit test for women leaving the screening programme to identify cervical cancer and advanced CIN; and 4. to support management of CIN. Tweetable abstract: This paper discusses potential clinical applications of DNA methylation analysis in the management of women with a high-risk HPV infection