Changes in the Cervical Microbiota of Women with Different High-Risk Human Papillomavirus Loads

The cervical microbiota is essential in female sexual health, and its altered states seem to have a central role in the dynamic of high-risk papillomavirus (hrHPV) infections. This study aimed to evaluate the variation in bacterial communities’ compositions according to hrHPV. We collected two samples per woman, with a difference of 12 ± 1 months between them, and performed a follow-up on 66 of these women. The viral load (VL) of the hrHPV was estimated by quantitative PCR (qPCR), then it was normalized (using the HMBS gene as reference) and transformed to the Log₁₀ scale to facilitate the interpretation. The VL was categorized as Negative, without hrHPV copies; Low, less than 10⁰ hrHPV copies; Medium, between 10⁰ to 10² hrHPV copies; and High, >10² hrHPV copies. The microbiota composition was described through the Illumina Novaseq PE250 platform. The diversity analyses revealed changes regarding the hrHPV VL, where women with low VL (<10⁰ hrHPV copies) presented high diversity. The community state type (CST) IV was the most common. However, in women with high VL, a lower association with Lactobacillus depletion was found. Lactobacillus gallinarum and L. iners were the most abundant species in women with high VL, whereas women with low VL had a 6.06 greater probability of exhibiting Lactobacillus dominance. We identified conspicuous differences in the abundance of 78 bacterial genera between women with low and high VL, where 26 were depleted (e.g., Gardnerella) and 52 increased (e.g., Mycoplasma). A multilevel mixed-effects linear regression showed changes in the diversity due to the interaction between the measurement time and the VL, with a decrease in diversity in the second follow-up in women with low VL (Coeff. = 0.47), whereas the women with medium VL displayed an increase in diversity (Coeff. = 0.58). Here, we report for the first time that the cervical microbiota is influenced by the number of copies of hrHPV, where a decrease in the abundance of Lactobacillus, greater diversity, and enrichment of bacterial taxa is relevant in women with low VL.     

Clinical Validation of the Fully Automated NeuMoDx HPV Assay for Cervical Cancer Screening

The NeuMoDx HPV assay is a novel fully automated, real-time PCR-based assay for the qualitative detection of high-risk human papillomavirus (HPV) DNA in cervical specimens. The assay specifically identifies HPV16 and HPV18 and concurrently detects 13 other high-risk HPV types at clinically relevant infection levels. Following the international guidelines, the clinical performance of the NeuMoDx HPV assay for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) against the reference standard Hybrid Capture 2, as well as intra- and inter-laboratory reproducibility were assessed on PreservCyt samples. The clinical accuracy of the assay was additionally evaluated against the clinically validated Alinity m HR HPV and COBAS 4800 HPV Test on PreservCyt samples, and against the clinically validated HPV-Risk assay on SurePath samples. The NeuMoDx HPV assay performance for CIN2+ was non-inferior to the reference methods on both sample types (all p < 0.05), and showed excellent intra- and inter-laboratory reproducibility (95.7%; 95% CI: 93.9–97.3; kappa value 0.90 (95% CI: 0.86–0.94); and 94.5%; 95% CI: 92.6–96.2; kappa value 0.87 (95% CI: 0.82–0.92), respectively). In conclusion, the NeuMoDx HPV assay meets international guideline criteria for cross-sectional accuracy and reproducibility, and performs equally well on cervical screening specimens collected in two widely used collection media. The NeuMoDx HPV assay fulfils the requirements to be used for primary cervical screening.     

Human Virome in Cervix Controlled by the Domination of Human Papillomavirus

Although other co-viral infections could also be considered influencing factors, cervical human papillomavirus (HPV) infection is the main cause of cervical cancer. Metagenomics have been employed in the NGS era to study the microbial community in each habitat. Thus, in this investigation, virome capture sequencing was used to examine the virome composition in the HPV-infected cervix. Based on the amount of HPV present in each sample, the results revealed that the cervical virome of HPV-infected individuals could be split into two categories: HPV-dominated (HD; ≥60%) and non-HPV-dominated (NHD; <60%). Cervical samples contained traces of several human viral species, including the molluscum contagiosum virus (MCV), human herpesvirus 4 (HHV4), torque teno virus (TTV), and influenza A virus. When compared to the HD group, the NHD group had a higher abundance of several viruses. Human viral diversity appears to be influenced by HPV dominance. This is the first proof that the diversity of human viruses in the cervix is impacted by HPV abundance. However, more research is required to determine whether human viral variety and the emergence of cancer are related.     

Distribution of Human Papillomavirus (HPV) Genotypes in HIV-Negative and HIV-Positive Women with Cervical Intraepithelial Lesions in the Eastern Cape Province,South Africa

South African women have a high rate of cervical cancer cases, but there are limited data on human papillomavirus (HPV) genotypes in cervical intraepithelial neoplasia (CIN) in the Eastern Cape province, South Africa. A total of 193 cervical specimens with confirmed CIN from women aged 18 years or older, recruited from a referral hospital, were tested for HPV infection. The cervical specimens, smeared onto FTA cards, were screened for 36 HPV types using an HPV direct flow kit. HPV prevalence was 93.5% (43/46) in CIN2 and 96.6% (142/147) in CIN3. HIV-positive women had a significantly higher HPV prevalence than HIV-negative women (98.0% vs. 89.1%, p = 0.012). The prevalence of multiple types was significantly higher in HIV-positive than HIV-negative women (p = 0.034). The frequently detected genotypes were HPV35 (23.9%), HPV58 (23.9%), HPV45 (19.6%), and HPV16 (17.3%) in CIN2 cases, while in CIN3, HPV35 (22.5%), HPV16 (21.8%), HPV33 (15.6%), and HPV58 (14.3%) were the most common identified HPV types, independent of HIV status. The prevalence of HPV types targeted by the nonavalent HPV vaccine was 60.9% and 68.7% among women with CIN2 and CIN3, respectively, indicating that vaccination would have an impact both in HIV-negative and HIV-positive South African women, although it will not provide full protection in preventing HPV infection and cervical cancer lesions.     

Leptomeningeal Carcinomatosis of a Poorly Differentiated Cervical Carcinoma Caused by Human Papillomavirus Type 18

Cervical cancer is caused by a persistent infection with high-risk types of Papillomaviruses (hrHPV); HPV16 and HPV18 are associated with about 70% of the cases. In the last decades the introduction of a cervical cancer screening has allowed a decrease in cervical cancer incidence and mortality; regular adhesion to the screening procedures, by pap test or HPV test, and colposcopy, according to the international guidelines, prevents cancer development and allows for diagnosis at the early stages. Nowadays, in industrialized countries, it is not common to diagnose this pathology in advanced stages, and this occurrence is frequently associated with patient’s unattendance of cervical screening programs. We describe a case of delayed diagnosis of cervical cancer, posed only after the onset of the neurological symptoms caused by leptomeningeal metastases, despite a two-year history of abnormal cytology. The endocervical mass was analyzed by immunohistochemistry, and search and typing of HPV sequences was performed by PCR in the meningeal carcinomatous cells. A poorly differentiated squamous cell carcinoma was diagnosed, and HPV18 sequences were detected. This rapidly fatal case highlights the importance of following the evidence-based recommended protocols and the preventive role of the population-based cervical cancer screening programs.     

Prevalence and Genotyping of High Risk Human Papillomavirus in Cervical Cancer Samples from Punjab,Pakistan

Cervical cancer is the third most common cause of cancer-related death in women worldwide. Infection with high-risk human papillomavirus (HPV) is established as the cause of cervical carcinoma, therefore, high risk HPV detection may have prognostic significance for the women who are at increased risk of disease progression. The paucity of data on the incidence of cervical cancer in Pakistan makes it difficult to determine disease burden. Even less information is available regarding the prevalent HPV strains in cervical specimens collected from this region. Cervical cancer is a neglected disease in Pakistan in terms of screening, prevention, and vaccination. Identification and accurate genotyping of the virus burden in cancer specimens is important to inform intervention policies for future management of HPV associated disease and to potentially stratify patients dependent on HPV status. In this study, detection and genotyping of HPV types 16 and 18 from 77 cervical specimens were carried out. Consensus primers GP5+/GP6+, which detect 44 genital HPV types, and type specific primers (TS16 and TS18) were used in conjunction with newly designed type specific primers. Using a combination of these methods of detection, a total of 94.81% (95% CI ±4.95) of cervical lesions were positive for HPV. Single infections of HPV16 were detected in 24.68% (95% CI ±9.63) of total samples and HPV18 was found in 25.97% (95% CI ±9.79) samples. Interestingly, a high proportion of samples (40.26%, 95% CI ±10.95) was positive for both HPV16 and 18, indicating a higher incidence of co-infection than previously reported for similar ethnic regions. The HPV genotype of 3.90% of HPV positive samples remained undetected, although these samples were positive with the GP5+/GP6+ primer set indicating infection with an HPV type other than 16 or 18. These data indicate that the overall incidence of high risk HPV infection in cervical cancer and intraepithelial neoplasia specimens in Punjab, Pakistan is in line with the worldwide prevalence, but that the incidence of HPV16 and 18 co-infections in our cohort is higher than that previously reported.     

High APOBEC3B mRNA Expression Is Associated with Human Papillomavirus Type 18 Infection in Cervical Cancer

The APOBEC3 (A3) proteins are cytidine deaminases that exhibit the ability to insert mutations in DNA and/or RNA sequences. APOBEC3B (A3B) has been evidenced as a DNA mutagen with consistent high expression in several cancer types. Data concerning the A3B influence on HPV infection and cervical cancer are limited and controversial. We investigated the role of A3B expression levels in cervical cancer in affected women positive for infection by different HPV types. Tumor biopsies from cancerous uterine cervix were collected from 216 women registered at Hospital do Câncer II of Instituto Nacional de Câncer, and infecting HPV was typed. A3B expression levels were quantified from RNA samples extracted from cervical biopsies using real-time quantitative PCR. Median A3B expression levels were higher among HPV18⁺ samples when compared to HPV16⁺ counterparts and were also increased compared to samples positive for other HPV types. In squamous cell carcinoma, HPV18⁺ samples also showed increased median A3B expression when compared to HPV Alpha-9 species or only to HPV16⁺ samples. Our findings suggest that A3B expression is differentially upregulated in cervical cancer samples infected with HPV18. A3B could be potentially used as a biomarker for HPV infection and as a prognostic tool for clinical outcomes in the context of cervical cancer.     

Why Do Patients of Female Physicians Have Higher Rates of Breast and Cervical Cancer Screening?

OBJECTIVE: Women are more likely to receive breast and cervical cancer screening if they see female physicians. We studied whether this is due to differences between male and female physicians, or to differences in their patients. SETTING: Large midwestern, independent practice association style of health plan. DESIGN: We surveyed male and female primary care physicians matched for age and specialty and a stratified random sample of three of each physician's women patients. Physicians reported on their practice setting, their attitudes and practices regarding prevention, and their comfort and skill with various examinations. Patients reported on their sociodemographic characteristics, their attitudes and practices regarding prevention, and their preferences for physician gender. Claims data were used to calculate mammography and Pap smear screening rates for the physicians PARTICIPANTS: We studied 154 female and 190 male internists and family physicians and 794 of their patients. MEASUREMENTS AND MAIN RESULTS: We compared the responses of male and female physicians and their patients and used multivariable analysis to identify the patient and physician factors that accounted for the differences in screening rates between male and female physicians. Female physicians were more likely to ask new patients about components of prevention, to believe in the effectiveness of mammography, to feel more personal responsibility for ensuring that their patients received screening, and to report more comfort in performing Pap smears and breast examinations. Patients of female physicians were more educated and less likely to be married, but did not differ in other sociodemographic characteristics. They had similar attitudes and practices regarding prevention, except that patients of male physicians were more likely to smoke. Significantly more patients of female physicians preferred a female for some component of care. In multivariable analyses, practice organization, patient preference for a female physician, and prevention orientation of female physicians accounted for up to 40% of screening rate differences between female and male physicians for Pap smears, and 33% for mammography. CONCLUSIONS: Differences in beliefs of male and female physicians and patient preference for a female provider contribute independently to the higher rate of breast and cervical cancer screening by female physicians.     

Preferences for Professional Assistance for Distress in a Diverse Sample of Older Adults

Older adults (N = 140; 68.6% minority) participating in community health screenings reported their use and preferences for various professionals and services to deal with distress. Race/ethnicity was recorded based on self-report. A third of participants had discussed distress with some professional within the past year. Compared with Whites, Asian and Black elders were less likely to see a mental health professional or receive counseling in the past year. Almost all participants (89.3%) were willing to discuss distress with some professional; most preferred medical (37.9%) or religious professionals (21.4%). Fewer Asians expressed willingness across most professionals and services. Findings support efforts to integrate mental health with other services, and suggest the need for additional strategies to enhance willingness to use mental health services, especially for Asian elders.     

Human Papillomavirus and Tonsillar and Base of Tongue Cancer

In 2007, human papillomavirus (HPV) type 16 was recognized as a risk factor by the International Agency for Research on Cancer, for oropharyngeal squamous cell carcinoma (OSCC), where tonsillar and base of tongue cancer (TSCC and BOTSCC) dominate. Furthermore, patients with HPV-positive TSCC and BOTSCC, had a much better clinical outcome than those with corresponding HPV-negative cancer and other head and neck cancer. More specifically, survival was around 80% for HPV-positive TSCC and BOTSCC vs. 40% five-year disease free survival, for the corresponding HPV-negative tumors with conventional radiotherapy and surgery, while this could not be observed for HPV-positive OSCC at other sites. In addition, the past 20–40 years in many Western Countries, the incidence of HPV-positive TSCC and BOTSCC has risen, and >70% are men. This has resulted in a relative increase of patients with HPV-positive TSCC and BOTSCC that may not need the intensified chemo-radiotherapy (with many more severe debilitating side effects) often given today to patients with head and neck cancer. However, before tapering therapy, one needs to enable selection of patients for such treatment, by identifying clinical and molecular markers that together with HPV-positive status will better predict patient prognosis and response to therapy. To conclude, there is a new increasing group of patients with HPV-positive TSCC and BOTSCC with good clinical outcome, where options for better-tailored therapy are needed. For prevention, it would be of benefit to vaccinate both girls and boys against HPV16 infection. For potential future screening the ways to do so need optimizing.     

Identification of the Human Papillomavirus Genotypes,According to the Human Immunodeficiency Virus Status in a Cohort of Women from Maputo,Mozambique

Background: Human papillomavirus (HPV) infection is now a well-established cause of cervical cancer and other anogenital cancers. An association between human immunodeficiency virus (HIV) infection and higher HPV incidence and prevalence are commonly reported. This study was conducted to demonstrate HPV prevalence, genotypes and its characteristics, according to the HIV status in women from Maputo in Mozambique. Methods: A total of 233 participants with ages ranging from fourteen to forty-five were included. Cervical samples were collected, DNA extracted, and HPV genotyping was performed using the HPV Direct Flow CHIP Kit. Results: In total, 177 HIV-negative and 56 HIV-positive women were included in the analysis. The overall HPV prevalence was 63% and was significantly higher among HIV-positive women (79% versus 58% among HIV-negative women; p = 0.005). The prevalence of multiple HPV type infections was 32%. High-risk HPV types 52, 68, 35, 18 and 16 were the most frequent. A higher proportion of HIV-positive women had multiple HPV types compared with HIV-negative women. Conclusions: This study demonstrated a high prevalence of HPV in the study cohort. HIV-positive women were identified as having the highest HPV prevalence and infection with multiple HPV types across all ages. High-risk genotypes were the most commonly found.     

35例维吾尔族妇女宫颈癌组织中HPV16型E7致癌基因突变分析

目的本研究旨在检测HPV16E7基因在新疆南部维吾尔妇女宫颈癌组织中的突变。方法从35份新疆南部地区维吾尔族妇女宫颈癌活检组织标本中提取组织DNA,作为模板,PCR扩增HPV16 E7全长基因,PCR产物直接测序或克隆后测序,分析新疆维吾尔族妇女宫颈癌组织HPV16E7基因的突变。结果PCR检测结果宫颈癌组织中HPV16E7阳性率为82.86%(29/35);27个E7分离片段的测序和序列分析表明,26个分离株E7基因与原型相同,1个分离株E7基因核苷酸发生2处突变,即647位(在HPV16基因组中的位置)的A→G,氨基酸由Asn变异为Ser;845位的T→C,氨基酸不变。结论新疆南部地区维吾尔妇女宫颈癌患者感染的HPV16中存在E7基因的变异株,该变异株可能是由人口流动传入。     

Human Papillomavirus and Squamous Cell Carcinoma of Unknown Primary in the Head and Neck Region: A Comprehensive Review on Clinical Implications

Squamous cell carcinoma of unknown primary (SCCUP) is a challenging diagnostic subgroup of oropharyngeal squamous cell carcinoma (OPSCC). The incidence of SCCUP is increasing in parallel with the well-documented increase in OPSCC and is likewise driven by the increase in human papillomavirus (HPV). The SCCUP patient often presents with a cystic lymph node metastasis and undergoes an aggressive diagnostic and treatment program. Detection of HPV in cytologic specimens indicates an oropharyngeal primary tumor origin and can guide the further diagnostic strategy. Advances in diagnostic modalities, e.g., transoral robotic surgery and transoral laser microsurgery, have increased the successful identification of the primary tumor site in HPV-induced SCCUP, and this harbors a potential for de-escalation treatment and increased survival. This review provides an overview of HPV-induced SCCUP, diagnostic modalities, and treatment options.     

A Retrospective Cohort Study of Young Women Spontaneously Choosing to Be Vaccinated against HPV: Outcomes from Their First Cervical Cancer Screening Test

Background: Efficacy for cervical cancer prevention of opportunistic HPV vaccination in post-pubertal girls is lower than in 11-year-olds. Methods: Women born between 1986 and 1992 vaccinated at 15–25 years of age (at least one dose of 4-valent HPV vaccine) and screened at 24–27 years of age were included. Frequency of opportunistic vaccination, overall and by birth cohort, was calculated; screening outcomes were compared between vaccinated and unvaccinated women. Results: Overall, 4718 (4.9%) HPV-vaccinated, and 91,512 unvaccinated, women were studied. The frequency of vaccination increased by birth cohort, ranging between 1.8% and 9.8%; age at vaccination decreased progressively by birth cohort (p < 0.0001). Participation in screening was 60.8% among vaccinated, and 56.6% among unvaccinated, women (p < 0.0001). Detection rates (DR) for high-grade lesions were lower in vaccinated women (2.11‰ vs. 3.85‰ in unvaccinated, for CIN3+, p = 0.24; 0.0‰ vs. 0.22‰ for cancer). The DR of CIN3+ increased with age at vaccination, scoring respectively 0.0‰, 0.83‰, and 4.68‰ for women vaccinated when they were 15–16, 17–20, and 21–25 years old (p = 0.17). Conclusions: In comparison to unvaccinated women, higher compliance with cervical cancer screening invitation and lower CIN3+ DR among vaccinated women was observed. Age at vaccination was inversely correlated to vaccination efficacy.     

Cancer Prevention and Screening for Older Adults: Part 2. Interventions to Prevent and Screen for Breast,Prostate, Cervical,Ovarian, and Endometrial Cancer

The incidence of most cancers increase with age. Cancer is the second most common cause of death in older adults after cardiovascular disease. Many common cancers in older adults can be prevented from occurring or can be identified at an early stage and treated effectively. Although cancer is feared primarily because of premature mortality, for many older adults, preventing and identifying cancer in its early stages, in an attempt to reduce discomfort and disability associated with advanced cancer and cancer treatment, is also a priority. Overscreening for cancer in older adults can lead to unnecessary diagnostic testing and unnecessary treatment. Both older adults and their healthcare providers need guidance on the appropriate use of cancer prevention and screening interventions. This is the second part of a two-part clinical review on cancer prevention and screening for adults aged 65 and older. Guidance is provided regarding the prevention and early identification of breast, prostate, cervical, ovarian, and endometrial cancer. The prevention of lung, colorectal, bladder, and kidney cancer is addressed in Part 1.     

On the Elimination of Infections Related to Oncogenic Human Papillomavirus: An Approach Using a Computational Network Model

Cervical cancer is the fourth most common malignancy in women worldwide, although it is preventable with prophylactic HPV vaccination. HPV transmission-dynamic models can predict the potential for the global elimination of cervical cancer. The random network model is a new approach that allows individuals to be followed, and to implement a given vaccination policy according to their clinical records. We developed an HPV transmission-dynamic model on a lifetime sexual partners network based on individual contacts, also accounting for the sexual behavior of men who have sex with men (MSM). We analyzed the decline in the prevalence of HPV infection in a scenario of 75% and 90% coverage for both sexes. An important herd immunity effect for men and women was observed in the heterosexual network, even with 75% coverage. However, HPV infections are persistent in the MSM population, with sustained circulation of the virus among unvaccinated individuals. Coverage around 75% of both sexes would be necessary to eliminate HPV-related conditions in women within five decades. Nevertheless, the variation in the decline in infection in the long term between a vaccination coverage of 75% and 90% is relatively small, suggesting that reaching coverage of around 70–75% in the heterosexual network may be enough to confer high protection. Nevertheless, HPV elimination may be achieved if men’s coverage is strictly controlled. This accurate representation of HPV transmission demonstrates the need to maintain high HPV vaccination coverage, especially in men, for whom the cost-effectiveness of vaccination is questioned.     

High-Risk Human Papillomavirus Targets Crossroads in Immune Signaling

Persistent infections with a high-risk type human papillomavirus (hrHPV) can progress to cancer. High-risk HPVs infect keratinocytes (KCs) and successfully suppress host immunity for up to two years despite the fact that KCs are well equipped to detect and initiate immune responses to invading pathogens. Viral persistence is achieved by active interference with KCs innate and adaptive immune mechanisms. To this end hrHPV utilizes proteins encoded by its viral genome, as well as exploits cellular proteins to interfere with signaling of innate and adaptive immune pathways. This results in impairment of interferon and pro-inflammatory cytokine production and subsequent immune cell attraction, as well as resistance to incoming signals from the immune system. Furthermore, hrHPV avoids the killing of infected cells by interfering with antigen presentation to antigen-specific cytotoxic T lymphocytes. Thus, hrHPV has evolved multiple mechanisms to avoid detection and clearance by both the innate and adaptive immune system, the molecular mechanisms of which will be dealt with in detail in this review.