COVID-19 and Gynecologic Oncology: What Have We Learned?

OPINION STATEMENT: COVID-19 has transformed the care we provide to gynecologic oncology patients. In addition to directly impacting the diagnosis and treatment of women with gynecologic cancer, it has affected our patient's ability to undergo recommended surveillance and has made an impact on every caregiver providing care during this time. Herein we review the current literature on the impact of COVID-19 on gynecologic oncology and highlight new approaches and innovations that have resulted in gynecologic cancer care as a result of the pandemic. The impact of COVID-19 on the field of gynecologic oncology has been profound. In addition to directly impacting the diagnosis and treatment of women with cancer, it has also challenged the very ethics with which we practice medicine. The equitable distribution of resources is paramount to upholding the Hippocratic Oath which we all invoke. The COVID-19 pandemic has stripped this oath down to its very core, forcing all medical practitioners to scrutinize who gets what resources and when. As the pandemic continues to unfold, the question remains - in the setting of a strained and overburdened healthcare system, how do we maximize beneficence to one group of patients, while maintaining non-maleficence to others? As gynecologic oncologists, we are responsible for advocating for our patients to ensure that the quality of their cancer care is not compromised, while also not overutilizing resources that are sorely needed for the care of COVID-19 victims, and not making them more likely to succumb to COVID-19 by the very nature of the treatment we provide. The effects of the pandemic are far-reaching and broad, and many of these are yet to be determined. Future studies are needed to analyze how the above-utilized strategies in GYN cancer care during the pandemic will impact the long-term outcomes of our patients.

Human papillomavirus genotypes and the risk factors associated with multicentric intraepithelial lesions of the lower genital tract: a retrospective study.

BACKGROUND: Multicentric intraepithelial lesions of the lower genital tract (multicentric lesions) were defined as intraepithelial lesions of two or three sites within cervix, vagina, and vulva occurring synchronously or sequentially. The characteristics of multicentric lesions has been poorly understood. This study aimed to evaluate the risk factors for multicentric lesions, including specific HPV genotypes. METHODS: A retrospective case-control study was performed involving patients histologically diagnosed with multicentric lesions between January 2018 and October 2019. Controls were patients histologically diagnosed with single cervical intraepithelial neoplasia (CIN) and admitted during the same period. Univariable and multivariable analyses were used to assess the risk factors for multicentric lesions. RESULTS: Of 307 patients with multicentric lesions, the median age was 50 years (interquartile range: 43-55.5), and they were older than patients with single CIN (median age: 43 years, interquartile range: 36-50). In the multicentric lesion group, the proportions of cytologic abnormalities, HPV positivity, and multiple HPV infections were 68.9, 97.0, and 36.5%, respectively. In the multivariable analysis, menopause, a history of malignant tumors beyond the lower genital tract and multiple HPV infections were associated with the incidence of multicentric lesions (Odd ratio (OR) = 3.14, 95% confidence interval (CI) 2.24-4.41; OR = 9.58, 95% CI 1.02-89.84; OR = 1.47, 95% CI 1.03-2.10). The common HPV genotypes were HPV16, HPV53, HPV58, HPV52, HPV51, HPV56 and HPV18 in patients with multicentric lesions. The proportion of HPV16 infection was higher in high-grade lesions group than that in low-grade lesions group (OR = 2.54, 95% CI 1.34-4.83). The OR for multicentric lesions, adjusted for menopause, smoking, gravidity, parity, a history of malignant tumor beyond the lower genital tract and multiple HPV infection, was 1.97 (95% CI 1.04-3.75) in patients with HPV51 infection. CONCLUSIONS: Multicentric lesions were associated with menopause, a history of malignant tumors and multiple HPV infections. HPV16 was the most common genotype, especially in high grade multicentric lesions and HPV51 infection was found to be a risk factor for detecting multicentric lesions.

Molecular and Phylogenetic Characterization of Novel Papillomaviruses Isolated from Oral and Anogenital Neoplasms of Japanese Macaques (Macaca fuscata).

Papillomaviruses (PVs) are a diverse group of host species-specific DNA viruses, etiologically linked with various benign and malignant neoplasms of cutaneous and mucosal epithelia. Here, we describe the detection and characterization of the first two PVs naturally infecting Japanese macaques (Macaca fuscata), including the determination of their etiological association(s) with the development of original neoplasms. The molecular and phylogenetic analyses were performed on complete genome sequences of Macaca fuscata PV types 1 (MfuPV1) and 2 (MfuPV2), which were completely sequenced in samples of a malignant oral tumor and benign anogenital neoplasm of Japanese macaques, respectively. Subsequently, two type-specific quantitative real-time PCRs were developed to estimate viral loads of MfuPV1 and MfuPV2 and to evaluate their etiological roles. The in silico molecular analyses revealed that both viral genomes encode characteristic PV proteins with conserved functional domains and have a non-coding genomic region with regulatory sequences to regulate and complete the viral life cycle. However, additional experimental evidence is needed to finally confirm the presence and biological functionality of the molecular features of both novel PVs. While MfuPV1, together with PVs identified in other macaques, is classified into the Alphapapillomavirus (Alpha-PV) species 12, MfuPV2 is most likely a representative of the novel viral species within the Alpha-PV genus. Their relatively high viral loads suggest that both PVs are etiologically linked with the development of the original neoplasms.

Multizonal anogenital neoplasia in women: a cohort analysis.

BACKGROUND: There is currently a lack of information on full anogenital evaluation of women with a previous history of anogenital neoplasia. METHODS: Retrospective analysis of the Homerton Anogenital Neoplasia Service records from January 2012 to March 2017, to identify all new referrals of women with previous anogenital neoplasia, who had had at least one complete examination of all anogenital sites. Multizonal anogenital disease (MZD) was defined as the presence of high-grade squamous intraepithelial lesions (HSIL)/carcinoma concurrently at two or more of the following sites/zones: perianus, anal canal, vulva, vagina or cervix. RESULTS: 253 women were included, mean age was 47 (SD=15) years and median duration of follow-up was 12 (IQR=21) months. Fifty-six women (22%) were diagnosed with MZD at first assessment and/or during follow-up. Current smokers (RR=1.84, 95% CI 1.21-2.79, p=0.004) and women on immunodulators/immunosuppressive drugs (RR=2.57, 95% CI 1.72-3.86, p<0.001) had an increased risk for MZD. The risk was lower for women without a previous history of anogenital high-grade lesions/cancer compared to those with this history (RR=0.06, 95% CI 0.01-0.45, p=0.006). CONCLUSIONS: Multizonal assessment was important to diagnose occult areas of disease and should be especially considered in current smokers, pharmacologically immunocompromised and those with a previous history of anogenital HSIL/cancer.

Case Report: Intra-Tumoral Vaccinations of Quadrivalent HPV-L1 Peptide Vaccine With Topical TLR-7 Agonist Following Recurrence: Complete Resolution of HPV-HR-Associated Gynecologic Squamous Cell Carcinomas in Two Patients.

The human papilloma virus (HPV) high-risk variants (HPV-HR) such as HPV16 and HPV18 are responsible for most HPV related cancers, including anogenital and head and neck cancers. Here, we present two patients with HPV-HR-associated gynecological malignancies who, after failing radiation therapy, were treated with experimental salvage immunotherapy regimen resulting in complete, durable responses in both patients. Each patient was diagnosed with recurrent, radiation-refractory, HPV-HR positive, squamous cell carcinoma of the lower genital tract. Patient A was a 90-year-old, African American, with metastatic vulvar cancer to the right inguinal-femoral triangle and pulmonary metastases. Patient B was a 41-year-old, Caucasian, with a central-recurrence of cervix cancer. Each patient received at least two intratumoral quadrivalent HPV-L1 vaccine (Gardasil™) injections and daily topical TLR-7 agonist (imiquimod) to the tumor surface 2 weeks apart. This combination of intratumoral vaccinations and topical TLR-7 agonist produced unexpected complete resolution of disease in both patients. The importance of radiation therapy, despite being considered a treatment failure by current definitions, cannot be understated. Radiation therapy appears to have offered a therapeutic immune advantage by modifying the tumor microenvironment. This immune protocol has potential to help patients with advanced HPV-HR-related malignancies previously considered incurable.

A meta-analysis of anal cancer incidence by risk group: Toward a unified anal cancer risk scale.

Certain population groups are known to have higher than average anal cancer risk, namely persons living with HIV (PLHIV), men who have sex with men (MSM), women diagnosed with human papillomavirus (HPV)-related gynecological precancerous lesions or cancer, solid organ transplant recipients (SOTRs) and patients with autoimmune diseases. Our aim was to provide robust and comparable estimates of anal cancer burden across these groups. Summary incidence rates (IRs), as cases per 100 000 person-years (py), were calculated by fixed-effects meta-analysis. IRs were 85 (95% confidence interval [CI] = 82-89) for HIV-positive MSM (n = 7 studies; 2 229 234 py), 32 (95% CI = 30-35) for non-MSM male PLHIV (n = 5; 1626 448 py) and 22 (95% CI = 19-24) for female PLHIV (n = 6; 1 472 123 py), with strong variation by age (eg, from 16.8 < 30 years to 107.5 ≥ 60 years for HIV-positive MSM). IR was 19 (95% CI = 10-36) in HIV-negative MSM (n = 2; 48 135 py). Anal cancer IRs were much higher after diagnosis of vulvar (IR = 48 [95% CI = 38-61]; n = 4; 145 147 py) than cervical (9 [95% CI = 8-12]; n = 4; 779 098 py) or vaginal (IR = 10 [95% CI = 3-30]; n = 4; 32 671) cancer, with equivalent disparity after respective precancerous lesions. IR was 13 (95% CI = 12-15) in SOTRs (n = 5; 1 946 206 py), reaching 24.5 and 49.6 for males and females >10 years after transplant. Anal cancer IRs were 10 (95% CI = 5-19), 6 (95% CI = 3-11) and 3 (95% CI = 2-4) for systemic lupus erythematosus, ulcerative colitis and Crohn's disease, respectively. In conclusion, a unifying anal cancer risk scale, based upon comprehensive meta-analysis, can improve prioritization and standardization in anal cancer prevention/research initiatives, which are in their public health infancy.

Targeting HPV in gynaecological cancers - Current status, ongoing challenges and future directions.

Despite the success of preventive vaccination, the Human Papilloma Virus still accounts for 266,000 deaths annually, as the main causative factor of cervical, vaginal, anal, penile and oropharyngeal cancers. Human Papilloma Virus infects epithelial cells, driving tumourigenesis primarily from incorporation of DNA into the host cellular genome. Translation of two particular Human Papilloma Virus-specific oncoproteins, E6 and E7, are the key drivers of malignancy. If diagnosed early cervical, vaginal and vulval cancers have good prognosis and are treated with curative intent. However, metastatic disease carries a poor prognosis, with first-line systemic treatment providing only modest increase in outcome. Having shown promise in other solid malignancies, immune checkpoint inhibition and therapeutic cancer vaccines have been directed towards Human Papilloma Virus-associated gynaecological cancers, mindful that persistent Human Papilloma Virus infection drives malignancy and is associated with immunosuppression and lack of T-cell immunity. In this review, we discuss novel therapeutic approaches for targeting Human Papilloma Virus-driven gynaecological malignancies including vaccination strategies, use of immunomodulation, immune checkpoint inhibitors and agents targeting Human Papilloma Virus-specific oncoproteins. We also highlight the evolving focus on exciting new treatments including adoptive T-cell therapies.

Gynaecologic cancer care during COVID-19 pandemic in India: a social media survey.

BACKGROUND: Health care services across the globe are undergoing a major transformation to combat the coronavirus disease 2019 (COVID-19) pandemic. Regardless of the strength of health care infrastructure across different economies, all countries are diverting their resources toward care for COVID-19 patients. AIM: The aim of this survey was to evaluate the pattern of care of gynaecologic cancers in a developing country during the COVID-19 pandemic. METHODS: An anonymous survey consisting of 20 questions intended for the gynaecologic cancer care providers with emphasis on their current practice and approach to their patients was distributed online via social media from April 30 to May 31, 2020. Basic descriptive statistics were applied. RESULTS: Among a total of 61 respondents, 63.9% were gynaecologic oncologists, 18.0% were radiation oncologists and 18.0% were medical oncologists. Majority, that is, 95.1% health care professionals felt that COVID-19 pandemic has had a significant change on their practice pattern and 56.2% practitioners had stopped registering new cases of cancer. In 75.4% centers surgery was being done for gynaecologic cancer cases and among them 60.8% were doing surgery only for cases requiring immediate intervention. Among the centers providing chemotherapy, 39.1% had switched to oral drugs. Among the centers providing radiation, 40.9% were providing radiation to cases based on their type and urgency and 9.0% had implemented hypofractionation. In early stage low risk cases, majority, that is, 34.0% centers were managing as before. In early stage high-risk cases, 32.6% centers were managing as before. In advanced stage endometrial cancer cases, 28.8% had postponed any treatment and 28.8% administered chemotherapy. In early stage, epithelial ovarian cancer 65.9% centers were performing complete staging of the disease. In advanced stage epithelial ovarian cancer, 65.9% centers preferred biopsy followed by neoadjuvant chemotherapy and 11.3% centers performed primary debulking surgery. In cases of interval debulking surgery, 73.3% centers deferred surgery till all six cycles of chemotherapy was completed. In cases of recurrent ovarian cancer amenable for secondary debulking surgery, 38.6% preferred chemotherapy. In early stage cervical cancer, surgical treatment was provided in 46.5% centers. In locally advanced cervical cancer, chemoradiation was given in 65.9% centers. In cases of metastatic cervical cancer, 46.6% centers were performing palliative radiation. CONCLUSION: COVID-19 has affected the treatment of gynecologic cancers patients and health care professionals are trying to mitigate the damage by incorporating new elements which are suited to the current scenario.

Human Papillomavirus Vaccination: ACOG Committee Opinion, Number 809.

Human papillomavirus (HPV) causes significant morbidity and mortality in women and men. The HPV vaccine significantly reduces the incidence of anogenital cancer and genital warts in women and in men. Human papillomavirus vaccines are among the most effective vaccines available worldwide, with unequivocal data demonstrating greater than 99% efficacy when administered to women who have not been exposed to that particular type of HPV. Obstetrician-gynecologists and other health care professionals should strongly recommend HPV vaccination to eligible patients and stress the benefits and safety of the HPV vaccine. Further, obstetrician-gynecologists are encouraged to stock and administer HPV vaccines in their offices when feasible. Ideally, the HPV vaccine should be given in early adolescence because vaccination is most effective before exposure to HPV through sexual activity. Unvaccinated women age 26 years and younger should receive the HPV vaccine series regardless of sexual activity, prior exposure to HPV, or sexual orientation. The HPV vaccine is now licensed in the United States for women and men through age 45 years. For some women aged 27-45 years who are previously unvaccinated, obstetrician-gynecologists and other health care professionals may use shared clinical decision making regarding HPV vaccination, considering the patient's risk for acquisition of a new HPV infection and whether the HPV vaccine may provide benefit.

Adjusting to the new reality: Evaluation of early practice pattern adaptations to the COVID-19 pandemic.

OBJECTIVE: We aim to define national practice patterns to assess current clinical practice, anticipated delays and areas of concern that potentially could lead to deviations from the normal standard of care. METHODS: Anonymous surveys were emailed to members of the Society of Gynecologic Oncology (SGO). The spread of COVID-19 and its impact on gynecologic oncology care in terms of alterations to normal treatment patterns and anticipated challenges were assessed. The Wilcoxon rank sum test was performed to determine risk factors for COVID-19 infection. RESULTS: We analyzed the responses of 331 gynecologic oncology providers. COVID-19 is present in 99.1% of surveyed communities with 99.7% reporting mitigation efforts in effect. The infection rate differs significantly between regions (p≪0.001) with the Northeast reporting the highest number of COVID-19 cases. Practice volume has dropped by 61.6% since the start of the pandemic with most cancellations being provider initiated. A majority of responders (52.8%) believed that ovarian cancer will be the most affected cancer by COVID-19. >94% of responders are proceeding with gynecologic cancer surgeries with exception of grade 1, endometrioid endometrial adenocarcinoma (36.3%). Surgical backlog (58.6%), delayed cancer diagnosis (43.2%) and re-establishing normal care with delayed patient (37.8%) were identified as the top 3 challenges after COVID-19 has abated. CONCLUSIONS: COVID-19 is widespread and has radically altered normal practice patterns. Despite COVID-19 related concerns, most gynecologic oncology care is proceeding. However, the steep decline in clinical volume shows there is a large group of patients who are not being diagnosed or are deferring care.

When to Operate, Hesitate and Reintegrate: Society of Gynecologic Oncology Surgical Considerations during the COVID-19 Pandemic.

The COVID-19 pandemic has challenged our ability to provide timely surgical care for our patients. In response, the U.S. Surgeon General, the American College of Srugeons, and other surgical professional societies recommended postponing elective surgical procedures and proceeding cautiously with cancer procedures that may require significant hospital resources and expose vulnerable patients to the virus. These challenges have particularly distressing for women with a gynecologic cancer diagnosis and their providers. Currently, circumstances vary greatly by region and by hospital, depending on COVID-19 prevalence, case mix, hospital type, and available resources. Therefore, COVID-19-related modifications to surgical practice guidelines must be individualized. Special consideration is necessary to evaluate the appropriateness of procedural interventions, recognizing the significant resources and personnel they require. Additionally, the pandemic may occur in waves, with patient demand for surgery ebbing and flowing accordingly. Hospitals, cancer centers and providers must prepare themselves to meet this demand. The purpose of this white paper is to highlight all phases of gynecologic cancer surgical care during the COVID-19 pandemic and to illustrate when it is best to operate, to hestitate, and reintegrate surgery. Triage and prioritization of surgical cases, preoperative COVID-19 testing, peri-operative safety principles, and preparations for the post-COVID-19 peak and surgical reintegration are reviewed.

Cancer patients affected by COVID-19: Experience from Milan, Lombardy.

OBJECTIVE: SARS-CoV-2 pandemic is continuing to spread. There are growing concerns on the impact of COVID-19 in cancer patients. Several papers reporting recommendations and guidelines are published. But few data on cancer patients affected by COVID-19 are available. METHODS: This is a retrospective study including all consecutive patients affected by gynecological cancer who developed COVID-19. All patients were treated in an academic setting (in Milan, Lombardy, Italy) between February and March 2020. RESULTS: Overall, 355 patients had active treatment during the study period due to newly diagnosed or recurrent gynecological disease. Among those, 19 (5.3%) patients affected developed COVID-19. All patients were asymptomatic at the time of COVID-19 detection. Six patients were diagnosed before starting planned treatments; while the remaining 13 were diagnosed for COVID-19 after their started their treatments. Considering the first group of six patients, one patient died due to COVID-19 3 days after the diagnosis; while the other patients recovered from COVID-19 after a median of three weeks. The latter group of 13 patients (treatments started) included five patients who underwent surgery and eight patients who underwent chemotherapy. Focusing on five patients who were diagnosed after surgery, we observed that two patients died during postoperative course, while in other two cases prolonged hospitalization was needed. One patient had no issues. Chemotherapy was delayed for the remaining patents without sequelae. CONCLUSIONS: Our report highlights that COVID-19 impacts the quality of treatments for cancer patients. Mortality rate is high, especially after surgery. More important, patients under active treatment for cancer are at high risk of developing severe evolution of COVID-19. Prioritizing patients journey during COVID-19 is of paramount importance.

Radiation therapy for gynecologic malignancies during the COVID-19 pandemic: International expert consensus recommendations.

OBJECTIVE: To develop expert consensus recommendations regarding radiation therapy for gynecologic malignancies during the COVID-19 pandemic. METHODS: An international committee of ten experts in gynecologic radiation oncology convened to provide consensus recommendations for patients with gynecologic malignancies referred for radiation therapy. Treatment priority groups were established. A review of the relevant literature was performed and different clinical scenarios were categorized into three priority groups. For each stage and clinical scenario in cervical, endometrial, vulvar, vaginal and ovarian cancer, specific recommendations regarding dose, technique, and timing were provided by the panel. RESULTS: Expert review and discussion generated consensus recommendations to guide radiation oncologists treating gynecologic malignancies during the COVID-19 pandemic. Priority scales for cervical, endometrial, vulvar, vaginal, and ovarian cancers are presented. Both radical and palliative treatments are discussed. Management of COVID-19 positive patients is considered. Hypofractionated radiation therapy should be used when feasible and recommendations regarding radiation dose, timing, and technique have been provided for external beam and brachytherapy treatments. Concurrent chemotherapy may be limited in some countries, and consideration of radiation alone is recommended. CONCLUSIONS: The expert consensus recommendations provide guidance for delivering radiation therapy during the COVID-19 pandemic. Specific recommendations have been provided for common clinical scenarios encountered in gynecologic radiation oncology with a focus on strategies to reduce patient and staff exposure to COVID-19.

Could the human papillomavirus vaccine prevent recurrence of ano-genital warts?: a systematic review and meta-analysis.

Human papillomavirus (HPV) is the most prevalent sexually transmitted infection worldwide and ano-genital warts (AGWs) are highly infectious. This virus is transmitted through sexual, anal, or oral contact as well as skin-to-skin contacts. Treatment for this condition has significant morbidity and it can be frustrating in certain cases. The HPV vaccination has been demonstrated as a promising strategy of secondary prevention in HPV-related diseases such as head and neck cancers, cervical diseases, and recurrent respiratory papillomatosis. Regarding AGWs, it is unclear whether vaccination can provide analogous clinical benefit. The aim of this work is to systematically review the literature regarding HPV vaccination for secondary disease prevention after treatment of AGWs. From October to December 2018, a systematic search for clinical trials was conducted in five databases: PubMed, MEDLINE, EMBASE, Cochrane, and clinicaltrials.gov using a combination of the following descriptors: 'gardasil' OR 'cervarix' OR 'nine-valent' OR '9-valent' OR 'vaccine' AND 'recurrence' OR 'relapse' AND 'hpv' OR 'papillomavirus' AND 'warts' OR 'condyloma.' Data were synthetized and entered in the Review Manager software (RevMan 5.3.5) to perform the meta-analysis. The search yielded 824 potentially relevant studies. Two studies fulfilled the eligibility criteria involving 656 participants. The meta-analysis estimated the rate of recurrence of AGWs was similar between the vaccine group and the control group. The overall effect estimate was 1.02 (0.75-1.38). This is the first meta-analysis exploring the effect of HPV vaccine in preventing the relapse of AGWs. These results suggest that HPV vaccination does not provide secondary benefit in patients with previous AGWs. However, these results cannot be generalized due to the scarce number of RCTs currently available in the literature. The outcomes from future randomized controlled trials (RCTs) are warranted to further clarify the precise effect of the vaccine.

Anti-cancer therapy and clinical trial considerations for gynecologic oncology patients during the COVID-19 pandemic crisis.

OBJECTIVES: The COVID-19 pandemic has consumed considerable resources and has impacted the delivery of cancer care. Patients with cancer may have factors which place them at high risk for COVID 19 morbidity or mortality. Highly immunosuppressive chemotherapy regimens and possible exposure to COVID-19 during treatment may put patients at additional risk. The Society of Gynecologic Oncology convened an expert panel to address recommendations for best practices during this crisis to minimize risk to patients from deviations in cancer care and from COVID-19 morbidity. METHODS: An expert panel convened to develop initial consensus guidelines regarding anti-neoplastic therapy during the COVID-19 pandemic with respect to gynecologic cancer care and clinical trials. RESULTS: COVID-19 poses special risks to patients who are older, have medical co-morbidities, and cancer. In addition, this pandemic will likely strain resources, making delivery of cancer care or conduct of clinical trials unpredictable. Recommendations are to limit visits and contact with health care facilities by using telemedicine when appropriate, and choosing regimens which require less frequent visits and which are less immunosuppressive. Deviations will occur in clinical trials as a result of limited resources, and it is important to understand regulatory obligations to trial sponsors as well as to the IRB to ensure that clinical trial and patient safety oversight are maintained. CONCLUSIONS: The ongoing crisis will strain resources needed to deliver cancer care. When alterations to the delivery of care are mandated, efforts should be taken to minimize risks and maximize safety while approximating standard practice.

Increased risk of dementia in patients with genital warts: A nationwide cohort study in Taiwan.

Genital warts are a common sexually transmitted disease caused by human papillomavirus (HPV) infections. The prevalence of dementia is 4-8% in those aged 65 years or older in Taiwanese community studies, with a high social and economic burden for patients, family caregivers, the community and society. Previous studies have shown that viral infections such as herpes simplex and herpes zoster were associated with dementia. This study aimed to investigate the association between dementia and HPV infections. A population-based cohort study using data from Taiwan's National Health Insurance Research Database was conducted. Fine and Grays's survival analysis was employed to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association between genital warts and dementia. From all of the potential participants aged 50 years or more, a total of 16 116 patients were enrolled, including 4029 genital warts-infected patients, with 12 087 sex-, age- and indexed date-matched controls (1:3). The cumulative incidences of dementia were 10.72 per 103  person-years and 6.43 per 103  person-years in the genital warts and control group, respectively. There were 475 dementia cases from the genital warts cohort during the follow-up period of 15 years. The adjusted HR for dementia was 1.485 (95% CI, 1.321-1.668; P < 0.001) for genital warts patients after adjusting for all of the covariates. Our study indicates that genital warts infection may increase the risk of dementia.

Human papillomavirus genotypes in cervical and other HPV-related anogenital cancer in Rwanda, according to HIV status.

The study aim was to describe human papillomavirus (HPV)-attributable cancer burden in Rwanda, according to anogenital cancer site, HPV type, age and HIV status. Tissue specimens of cervical, vulvar, vaginal, penile and anal cancer diagnosed in 2012-2018 were retrieved from three cancer referral hospitals and tested for high-risk (HR) HPV DNA. Cervical cancer represented the majority of cases (598 of 738), of which 96.0% were HR-HPV positive. HPV-attributable fractions in other cancer sites varied from 53.1% in 81 penile, through 76.7% in 30 vulvar, 83.3% in 24 vaginal, up to 100% in 5 anal cases. HPV16 was the predominant HR-HPV type in cervical cancer (55.0%), followed by HPV18 (16.6%) and HPV45 (13.4%). HPV16 also predominated in other cancer sites (60-80% of HR-HPV-attributable fraction). For cervical cancer, type-specific prevalence varied significantly by histology (higher alpha-9 type prevalence in 509 squamous cell carcinoma vs. higher alpha-7 type prevalence in 80 adenocarcinoma), but not between 501 HIV-negative and 97 HIV-positive cases. With respect to types targeted, and/or cross-protected, by HPV vaccines, HPV16/18 accounted for 73%, HPV31/33/45/52/58 for an additional 22% and other HR-HPV types for 5%, of HPV-attributable cancer burden, with no significant difference by HIV status nor age. These data highlight the preventive potential of the ongoing national HPV vaccination program in Rwanda, and in sub-Saharan Africa as a whole. Importantly for this region, the impact of HIV on the distribution of causal HPV types was relatively minor, confirming type-specific relevance of HPV vaccines, irrespective of HIV status.