Human papillomavirus (HPV) vaccination could prevent cervical and other HPV-associated cancers attributable to vaccine-associated HPV types. However, HPV vaccination coverage among women aged 9–18 years old is low in China. Common barriers include poor financial affordability, minimal public engagement, and low confidence in domestically produced HPV vaccines. Pay-it-forward offers an individual a free or subsidized service then an opportunity to voluntarily donate and/or create a postcard message to support future people. This study aims to assess the effectiveness of pay-it-forward as compared to standard-of-care self-paid vaccination to improve HPV vaccine uptake among adolescent girls aged 15–18 years, who are left out in the current pilot free HPV vaccination task force in some parts of China.This is a two-arm randomized controlled trial in Chengdu, China. Eligible adolescent girls (via caregivers) will be randomly selected and recruited through four community health centers  using the resident registration list. A total of 320 participants will be randomized into two study arms (user-paid versus pay-it-forward vaccination) in a 1:1 ratio. The intervention assignment will be blinded to recruiters and participants using envelop concealment until the research assistants open the envelop to determine which treatment to deliver to each individual. The primary outcome of the study will be HPV vaccine uptake by administrative data. Secondary outcomes include costs, vaccine hesitancy, and the completion rates of the 3-dose HPV vaccination series.This study will investigate an innovative pay-it-forward strategy’s effectiveness and economic costs to improve HPV vaccination among 15–18-year-old adolescent girls. Study findings will have implications for increasing HPV vaccine uptake in places where HPV vaccines are provided for a fee.Chinese Clinical Trial Registry (ChiCTR), ChiCTR2200055542. Registered on 11 January 2022.The online version contains supplementary material available at 10.1186/s12889-022-14947-3. Globally, about 341,831 people die from cervical cancer annually and over 15% of these deaths occurred in China in 2020 , 1312, 1We describe here a two-arm randomized controlled trial (RCT) to evaluate the effectiveness of a pay-it-forward intervention to increase HPV vaccine uptake among adolescent girls aged 15–18 against the standard-of-care user-paid approach in four clinical sites of Western China. Pay-it-forward is hypothesized to be more effective than standard-of-care in increasing HPV vaccination among 15–18-year-old adolescent girls. Study findings will have implications for filling the gaps in HPV vaccine service delivery in places where HPV vaccines are provided for a fee and may serve as a transition model to free vaccine provision.This is a two-arm randomized controlled trial among adolescent girls aged 15–18 at four study sites in Chengdu, Western China. Figure Chengdu, with a population of over 21 million residents, is the capital city of Sichuan Province located in Western China . ChengduFour community health centers  are purposively selected based on the established infrastructure to provide HPV vaccination services, including a stable HPV vaccine supply and medical personnel designated for providing HPV vaccine services. Community health centers refer to primary care facilities providing essential medical care for common health conditions and preventive health services including vaccination to residents living in the neighborhood. Community health centers are the most common pathway for local people to receive vaccination in China and these organizations work closely with residential committees to provide essential public health services to residents. The four community health centers have agreed to coordinate resources for the study implementation. All research assistants, and community health staff involved in this project have been or will be trained using the same project training material  aged 15–18 years; 2) living in the communities served by the selected community health centers; 3) with no HPV vaccination history, 4) with no prior allergies to vaccines; and 5) have a legal guardian who consents to participate the study. The exclusion criteria are females: 1) aged below 15 or above 18 years; 2) not living in the neighborhood served by the four community health centers; 3) received HPV vaccine(s); 4) ineligible to receive a vaccine based on clinical evaluation from a physician; or 5) a legal guardian refuses to consent to participate.Community engaged postcard messages) and subsidized HPV vaccination, and the opportunity to voluntarily donate money towards someone else’s vaccine dose and write postcard messages. Participants will be told that the normal price to receive one dose of domestic 2v-HPV vaccine is RMB 329(US$ 49.78), and that previous participants donated money to cover the costs of the first dose of it along with postcard messages for them.Participants assigned in this arm will receive the following 1) an educational pamphlet about cervical cancer, HPV vaccination, and differences in common types of HPV vaccines  who agree to vaccinate can receive a vaccination on the same day of recruitment (when a girl is present) or make an appointment to visit again within the next two weeks for the administration of vaccination (when a girl is absent during the recruitment stage). After receiving a vaccination, girls, with caregivers or not, need to stay at the vaccination clinic for at least half-an-hour to observe any severe adverse events. During this period, research assistants will bring postcards and offer an opportunity to participants to donate and create handwritten messages for future participants. A donation/postcard collection box will be provided on-site, and a WeChat QR code will be provided to those who prefer an online donation to the program. WeChat is a multifunctional social mobile app embedded with monetary transaction functions. The donation will be anonymous, and project staff will be unaware of the donation amount. To link donations with other participant data, a postcard is assigned the same numerical ID of a participant and participants will be asked to put an intentional donation amount on the postcard along with their handwritten messages in the event of being willing to contribute. Neither the willingness to donate nor the amount of donation will affect their receiving the HPV vaccination services. The microdonations will be used to support future users. Donations and how these are used will be publicized periodically online via WeChat public accounts.Participants assigned in this arm will be asked to pay out of pocket at the standard market price in the event of being willing to receive an HPV vaccination. The same educational pamphlet about cervical cancer, HPV vaccination, and types of HPV vaccines will be provided to participants in this arm, but they will not receive community-engaged messages or pay-it-forward information.n = 21), and interviews with healthcare workers (n = 2) involved in the pre-test to better understand parental decision-making process for their daughter to receive HPV vaccination. The pre-test helped refine problem statement, sample size calculation, types of HPV vaccines to be provided in our trial, community-engaged postcard messages addressing knowledge gaps, and random sampling and recruitment strategies. These are described in detail below.We conducted a feasibility pre-test with 100 eligible girls and field-tested the trial implementation process from January 4, 2022 to February 18, 2022 in the urban study site . We collearlier uptake of HPV vaccines that are currently available in the Chinese market among adolescent girls aged 15–18.Our pre-test suggested that, due to the shortage of 4v and 9v-HPV vaccines in the market, the overwhelming majority of caregivers (91.5%) chose to delay their daughter’s HPV vaccination to wait for the above two types of vaccines to become available. This echoed a previous study  that theOur pre-test data showed that the pay-it-forward arm had an uptake rate of 98% (49/50) compared to 82% 41/50) in the standard-of-care arm. We, therefore, estimate a difference of 16% in vaccine uptake rates between the two arms. But because the current HPV vaccination rate among this population is generally low at around 10%, for the ongoing trial, we conservatively estimate an uptake rate of 20% in the standard-of-care arm and 36% in the pay-it-forward arm rather than the uptake rates in our pre-test. To achieve an 80% power to detect a difference between the two arms, 120 participants are needed respectively in the pay-it-forward and standard-of-care arms  within the next decade in China is also unlikely. However, the supply of domestic 2v-HPV is relatively stable due to domestic pharmaceutical production lines. To ensure sufficient supply for all trial participants in the four study sites, we decided to use what is most available at the study sites . This may also help inform a cost-effective implementation strategy that complements future government-led schemes that use more accessible health products.We identified several key barriers to parental decision to vaccinate their girls against HPV. The level of awareness of HPV vaccines seemed high, but a complete understanding is lacking in terms of a) how effective of different types of HPV vaccines are in preventing cervical cancer, b) why it is optimal to vaccinate an eligible girl at an earlier age rather than later, and c) parental perception of age of sexual debut of their daughter. To integrate user perspectives in the designing process, we invited two university college students in preventive medicine to design three postcard cover messages. These cover messages were designed in response to caregiver preferences solicited during the focus group discussions, and focus on addressing the above knowledge gaps , and better educated (78% obtained university or higher-level education) compared to the local average levels. In addition, eligible participants who did not subscribe to the newsletter of the community health center do not have equal odds to be reached by our trial compared to those who subscribed.We revised the sampling strategy to a simple random sampling using the residential committee registration system. Specifically, we will obtain a de-identified contact list of adolescent girls aged 15–18 years from the residential committee via community health center staff. This list includes all girls of this age range living in the neighborhood who also registered their names and contacts at the community health center to receive relevant health services there. We will then conduct the simple random sampling of eligible girls via generating and assigning a random digit to each individual using Microsoft Excel. These individuals will then be sorted by the random digits from the smallest to the largest, and we will select individuals from the top of the list for telephone recruitment until we reach the expected sample size at each study site.The community health center will send a short text message via the patient management platform of the community health center to inform caregivers of selected participants about a follow-up telephone call from our project staff in next few days. The telephone recruitment will be conducted using landlines of the community health centers. Our project staff will introduce the general project during the telephone call and obtain verbal consent. Consented caregivers and/or participants will be invited to visit the community health center for enrollment. We aim to recruit 80 eligible participants at each study site.The research assistants will explain on-site the trial purpose, procedures, expected benefits and possible risks to participants, and obtain written consent to participate in the trial. Research assistants will then randomize participants into standard-of-care and pay-it-forward arms using a sealed envelope method. The envelope includes a random numerical ID generated using SPSS 21.0 that corresponds to the assigned arm (standard-of-care or pay-it-forward), a QR code for an online questionnaire survey, and postcard messages (pay-it-forward arm only). After receiving the allocated treatment, participants who agree to receive a vaccine will make an appointment through our trial and we will link them with a community health staff member who helps coordinate the administration of vaccination at the center.We will use an information tracking sheet to record the assigned treatment, collect information about age (verified by identification card on-site), numerical ID and contact information. Personal information will be used for arranging clinical visits only and will not be accessible to staff who are not involved in the recruitment and clinical arrangement process.Based on their assigned arm, participants will then be directed to research assistants who will deliver the allocated intervention. Participation in the study will be voluntary and anonymous. Access to other vaccination and medical services in the health center will not be affected in any way because of the participation in the study. Participants will be able to withdraw from the study at any time without giving any explanations.All participants will be asked to complete a baseline survey after the consent. The questionnaires  will be blinded to physicians who prescribe an HPV vaccine throughout the process. Finally, the outcome assessors will be blinded from the knowledge of which intervention a participant receives.Information about vaccine uptake  and types of vaccines will be ascertained by clinical administrative data. Survey data will be collected using an online questionnaire. Administrative and survey data will be linked using numerical IDs. Cost data will be collected after we complete the trial. Dependent on the need of extra data for answering the proposed project objectives, participants can be further contacted via WeChat for additional follow- ups after ethical clearance.The primary outcome of the study will be first-dose HPV vaccine uptake in each arm after the intervention as assessed by administrative records. The choice of HPV vaccines will be dependent on the availability of vaccine products at the selected community health centers, primarily 2v-HPV vaccines.Secondary study outcomes include economic evaluation and costs indicators from the provider perspective, self-reported vaccine confidence and vaccine delay, and the completion rates of 2-dose and 3-dose HPV vaccination. Vaccine confidence, defined as public trust in the vaccine safety, importance and effectiveness , will beDescriptive analyses of socio-demographic and vaccination rates by study arms will be conducted. Intention-to-treat analysis will be conducted to compare vaccine uptake between the two arms. The primary analysis will evaluate the hypothesis that the pay-it-forward arm is more effective than the standard-of-care arm in increasing HPV vaccination. The uptake rates between the pay-it-forward and standard-of-care arms will be compared using logistic regression, reported as crude odds ratios (cOR) and adjusted odds ratios (aOR), and 95% confidence intervals (95% CIs), by adjusting for demographic backgrounds .Effect modification analyses will evaluate whether the effect of the pay-it-forward intervention on HPV vaccine uptake vary in relation to the following factors: (1) family income levels; (2) level of sensitivity to vaccine costs ; (3) study sites; (4) sex of the guardian. For each factor of interest, three measures of association will be calculated: A) a crude measure of association between treatment group and vaccine uptake, B1) a measure of association between treatment group and vaccine uptake among all participants who report the factor of interest , B2) a measure of association between treatment group and vaccine uptake among all participants who deny a history of having the factor of interest . Effect modification will be deemed present when B1 and B2 are different from one another, and at least one (B1 or B2) is different from A.Markov model-based economic evaluation will be constructed to assess cost-effectiveness of pay-it-forward strategy in provider perspective. Cost for each program element will be collected, including personnel, materials, equipment and facilities, and micro-costing approach will be used to evaluate the costs of the standard-of-care and pay-it-forward arms. Pay-it-forward participant donations will be summarized and the fraction of the total cost of vaccination covered by pay-it-forward donation will be calculated. Mean donations by study site will be calculated and donation distribution by study site will be examined.2 test, regression analyses, and 95% CIs will be calculated. All statistical tests will be two-sided, and statistical significance will be defined as p < 0.05.Vaccine hesitancy and vaccine confidence will be summarized using descriptive statistics and will be compared between the two arms. The completion rates of 2-dose and 3-dose HPV vaccination will be compared between the two arms. Comparisons between the 2 arms will be assessed with χLoss-to-follow-up will be recorded during the six-month period after the enrollment of each participant. There may be missing data in self-reported secondary outcomes like vaccine hesitancy, but we do not anticipate any missing data in the primary outcome of vaccine uptake as this will be administrative data. If an outcome is missing for less than 15% of participants, analyses will use a complete-case approach. If an outcome is missing for 15% of participants or above, we will use multiple imputation to estimate the primary outcomes.China has a substantial cervical cancer burden. Women in Western China have higher HPV infection prevalence than those in Central and Eastern areas  but haveOur trial findings can have important implications for research, practice and policy. This is a rare community-engaged intervention to increase HPV vaccine uptake among underserved populations in a middle-income country. The research findings may have important implications for pro-social interventions to address vaccine hesitancy, and other common factors influencing vaccination behaviors and increasing uptake domestically and globally. Then the trial implementation process can demonstrate to some extent the adaptability of a pay-it-forward model in vaccine services and inform evidence-based practice in future vaccine programs. Third, while local governments may have limited finances for many competing health priorities and be unable to cover all priority groups for HPV vaccination at the same time, our pay-it-forward may serve as a transition model to help cover catch-up age groups and lower government pressure by mobilizing multiple players in the healthcare system . Finally, given that there is an unstable supply in the Chinese context, we will not include 4v and 9v-HPV vaccines as an option for participants to choose. This may somewhat limit our understanding of participants’ uptake of 4v and 9v-HPV vaccines, but because imported 9v-HPV vaccines are unaffordable for many, the likelihood of the imported 9v-HPV being included in government supported universal health programs is low in the next decade. Domestic 9v-HPV vaccines are still in Phase III clinical trial and production capacity for 9v-HPV vaccines in the next five to 10 years in the country is also limited. Therefore, our study focuses on HPV vaccine products that are most available in the market will have important implications for evidence-based policymaking as well as effective public messaging to improve timely HPV vaccine uptake.Additional file 1. Additional file 2.Additional file 3. Additional file 4.


The incidence of high-risk human papillomavirus (hrHPV)-driven head and neck squamous cell carcinoma, in particular oropharyngeal cancers (OPC), is increasing in high-resource countries. Patients with HPV-induced cancer respond better to treatment and consequently have lower case-fatality rates than patients with HPV-unrelated OPC. These considerations highlight the importance of reliable and accurate markers to diagnose truly HPV-induced OPC.(INK4a) immunohistochemistry (IHC) (p16), and (c) the combination of both tests (considering joint DNA and p16 positivity as positivity criterion), was analysed in tissue samples from 99 Belgian OPC patients enrolled in the HPV-AHEAD study. Presence of HPV E6*I mRNA (mRNA) was considered as the reference, indicating HPV etiology.The accuracy of three possible test strategies, i.e. (a) hrHPV DNA PCR (DNA), (b) p16Ninety-nine OPC patients were included, for which the positivity rates were 36.4%, 34.0% and 28.9% for DNA, p16 and mRNA, respectively. Ninety-five OPC patients had valid test results for all three tests . Using mRNA status as the reference, DNA testing showed 100% (28/28) sensitivity, and 92.5% (62/67) specificity for the detection of HPV-driven cancer. p16 was 96.4% (27/28) sensitive and equally specific . The sensitivity and specificity of combined p16 + DNA testing was 96.4% (27/28) and 97.0% (65/67), respectively. In this series, p16 alone and combined p16 + DNA missed 1 in 28 HPV driven cancers, but p16 alone misclassified 5 in 67 non-HPV driven as positive, whereas combined testing would misclassify only 2 in 67.(INK4a) IHC are highly sensitive but less specific than using combined testing to diagnose HPV-driven OPC patients. Disease prognostication can be encouraged based on this combined test result.Single hrHPV DNA PCR and p16The online version contains supplementary material available at 10.1186/s12879-022-07654-2. In high-resource countries, human papillomavirus (HPV)-driven head and neck squamous cell carcinoma represents an increasing health problem, particularly in cancers of the oropharyngeal region, including base of tongue and tonsils –4. An es(INK4a) expression as surrogates for HPV-induced transformation, allow a more accurate classification of HPV-driven head and neck cancers (HNC) , by pooling from multiple studies.Relative sensitivities and specificities were not significantly different from unity in our study, nor in the meta-analysis of Prigge et al. , where sFurthermore, better clinical outcomes have been reported for patients with HPV-induced compared to HPV-unrelated OPC –11. HPV-(INK4a) and hrHPV DNA detection compared to single marker analysis has been demonstrated in a large meta-analysis on tumours in the head and neck region [(INK4a) negative while actually both DNA and mRNA HPV16 positive. More than six years after diagnosis, the patient was alive without any evidence of disease.Improved prognostication by combined p16k region . In our On the other hand, disease-specific survival rates are not improved among HPV DNA-positives where HPV is not the cause of carcinogenesis. In our series of 95 Belgian OPC patients, the number of false positive cancers would be reduced from five to two with the combined p16 + DNA detection. The two HPV-unrelated cancer patients were male and diagnosed with a tonsillar cancer. The first patient, with a Tx N2 M1 tonsil NOS tumour, was a heavy drinker and current smoker who only underwent surgery and had a recurrence within 6 months. He died 2 years after being diagnosed. The other patient, with a T3 N2 tonsil NOS tumour, received surgery followed by radiotherapy and concurrent chemotherapy for 2 months. At the last follow-up date, this patient was alive, but with evidence of residual disease. Of note, these two HPV-unrelated patients clearly had a much worse disease status at diagnosis and thereby reduced survival chances compared to the above described HPV-driven tonsillar cancer patient.(INK4a) and hrHPV DNA (p16 + DNA) detection. Sequential testing algorithms (p16 → DNA and DNA → p16) resulted in equally accurate results, however, with a 60% reduction in the number of tests needed to be performed. This will cause a substantial reduction in costs and laboratory time, while providing the same clinical value. Especially the algorithm of p16(INK4a) on all samples followed by HPV DNA PCR on p16(INK4a)-positive samples only would be a practical strategy. After all, p16(INK4a) IHC can easily be combined with standard histology when a H&E-stained tissue section is prepared for examination by a pathologist. It is a routine diagnostic procedure, at a relatively low cost, available as a validated in-vitro diagnostic reagent and a fully automated protocol, which generates results within several hours after the procedure has been requested. HPV DNA PCR is also a standard laboratory procedure with high throughput and quick results, although against a higher cost. Preselection by p16(INK4a)-staining therefore reduces the workload and associated costs, and the combination of HPV DNA and p16(INK4a) testing leads to an important reduction of the number of false-positive observations versus the use of either of these assays alone.Ninety-seven percent of the OPC patients in our study would have been correctly diagnosed as patients with a HPV-driven cancer by combined p16(INK4a) immunohistochemistry in oropharyngeal squamous cell carcinomas is planned  enhances specificity up to 97%, while maintaining high sensitivity (96%), compared to single testing. The diagnostic test combination represents an accurate and accessible testing strategy in the clinical setting for diagnosis of HPV-induced OPC , allowing discriminant prognostication.In conclusion, combined testing for hrHPV DNA and p16Additional file 1: hrHPV DNA PCR versus p16INK4a and combined hrHPV DNA/p16INK4a versus p16INK4a and hrHPV DNA PCR, for RNA positive and negative oropharyngeal cancers.


To determine risk factors predicting residual lesion in a subsequent hysterectomy follow a cold knife conization (CKC) for high-grade squamous intraepithelial lesion (HSIL).Between January 2010 and December 2021, a total of 740 patients who underwent a hysterectomy within 3 months after CKC for HSIL were included in this study. We analyzed their demographic features and pathological parameters. A logistic regression model was used to analyze the relationship between parameters and residual lesion in subsequent hysterectomy specimens.P < 0.001), glandular involvement , HPV16/18 infection  and multiple HR-HPV infection  were independent risk factors for residual lesion. The AUC calculated by logistic regression model was 0.78.104 (14.1%) had residual lesion in the hysterectomy specimen, 3 patients with microinvasive carcinoma. The rate of residual lesion in patients with positive endocervical margin was 31.3%, with positive ectocervical margin was 15.3%, with positive combine margin was 38.6%. In multivariate analysis, positive margin (OR 4.015; 95% CI 2.526–6.381; Positive margin, positive glandular involvement, HPV16/18 and multiple HR-HPV infection were independent high risk factors of residual lesion in a subsequent hysterectomy following CKC for HSIL. High-grade squamous intraepithelial lesion (HSIL) was currently recognized as a precancerous lesion of cervical cancer. Without active treatment, approximately 31–50% of patients can progress to cervical cancer within 30 years, the risk of cancer can be reduced to 0.7% after routine treatment –4. ResidThe clinicopathological data of patients who underwent hysterectomy after CKC for HSIL at the department of Obstetrics and Gynecology of the First Affiliated Hospital of Yangtze University between January 2010 and December 2021 were collected. This study was approved by the Ethics Committee of the First Affiliated Hospital of Yangtze University. Informed consent was obtained for all patients or family members.740 patients were considered eligible for current study if they fulfilled the following inclusion criteria: ① preoperative colposcopy was performed to assess the nature and scope of the lesion, cervical pathological biopsy was HSIL, ② CKC was performed at the initial treatment, ③ the pathological examination after CKC was still HSIL, ④ patients who underwent further hysterectomy within 3 months after CKC, ⑤ complete clinicopathological data were available.Indications of CKC included HSIL, colposcopy suspected invasive carcinoma, colposcopy was not satisfactory, cervical cytology was inconsistent with colposcopy/histology, endocervical curettage pathological results were positive.Reference guidelines for indications of hysterectomy: 2006 edition of Chinese expert opinion include: middle-aged and elderly cervical intraepithelial neoplasia (CIN) III patients who had no fertility requirements, CIN III patients who had no fertility requirements complicated with other benign gynecological diseases, and CIN III patients who had completed fertility requirements with positive margins . 2020 edReferring to the standardised nomenclature protocol for cervical lesion jointly published in 2012 by the American Society for Pathology (CAP) and the American Society for Colposcopy and Cervical Pathology (ASCCP), cervical intraepithelial lesion was classified as follows: HSIL and LSIL. HSIL includes CIN 2 and 3 . PatientPatients with HSIL or above lesion in hysterectomy specimens were considered as residual lesion. The presence of LSIL alone was not regarded as residual lesion.Margin status of conization specimens was considered to be positive if cervical intraepithelial neoplasia 1–3 were found in the resection margin of about 1 mm or less. Including:endocervical margin, ectocervical margin and combined margin. Combined margin positive means both endocervical and ectocervical margin were positive.Lesion range: the cervix was divided into four quadrants and the lesion range was determined according to the number of quadrants involved.HPV (human papillomavirus) Test: HPV subtypes were detected in the reproductive tract shed cells by microarray technology, using microdot sampling technique, HPV type specific probe was applied to the matrix of gene chip; then PCR amplification, hybridization and coloration were performed on the DNA in samples; Finally, the HPV typing gene chip detection reading system automatically collects images and analyzes and reports the detection results. Multiple HR-HPV infection was defined as two or more HR-HPV infections.X2 test or Fisher's exact probability method. The measurement data conforming to normal distribution by normality test were expressed as mean ± standard deviation and t test was adopted. Those that do not fit the normal distribution was represented by the median (interquartile) and rank sum test was used. Logistic regression model was used to analyze the influencing factors of residual lesion in uterine specimens. The predictive value was evaluated according to the area under receiver operator characteristic (ROC) curve (AUC) calculated by Logistics regression model. AUC of 0.9–1 indicated that the predictive value of this indicator was very high. AUC of 0.7–0.9 indicates good predictive value, AUC of 0.5–0.7 indicates average predictive value, and AUC < 0.5 indicates no predictive value. P < 0.05 was considered as statistically significant.SPSS20.0 software was used for statistical analysis. The count data were expressed as absolute numbers and percentages (%) using 740 patients who underwent hysterectomy after CKC for HSIL, the average age was 47.9 years, and median age was 47 years (range 30–78), 254 patients (34.3%) was 50 years or older, and 201 patients (27.2%) was postmenopausal. There were 581 patients (78.5%) with education level below high school, and most of the patients were poorly educated. There was also a slight difference in the administrative region, the rural population accounts for 58% and urban population 42%. Only 16.9% of patients needed surgery for other gynecological diseases. HR-HPV infection was detected in the vast majority of patients, 690 (93.2%) HR-HPV infection, 408 (55.1%) HPV16/18 infection, and 191 (25.8%) multiple HR-HPV infection. 610 patients (82.4%) had abnormal Thin-cytologic test (TCT), including 113 patients (15.3%) with HSIL, 100 patients (13.5%) with ASC-H, 49 patients (6.6%) with LSIL, and 348 patients (47%) with ASCUS, which suggest that HPV/TCT plays an important role in cervical screening. According to the results of preoperative colposcopy, 409 cases (55.3%) had cervical lesion in 3 or more quadrants. According to the pathological result of CKC, glandular involvement were involved in 568 patients (76.8%), 254 patients (34.3%) had positive resection margin, including 112 endocervical margin positive, 85 ectocervical margin positive and 57 combine margin positive. 104 patients (14.1%) had residual lesions in their hysterectomy specimen, including HSIL in 101 patients and 3 patients with microinvasive carcinoma (Tables P < 0.001), glandular involvement (P < 0.001), lesion range (P = 0.014), HPV-16/18 infection (P < 0.001), and multiple HR-HPV infection (P = 0.007) were significantly associated with residual lesion. Age (P = 0.16), menopause (P = 0.108), smoking (P = 0.409), diseases of the immune system (P = 0.998), parity (P = 0.349), gravidity (P = 0.805) and lesion level (P = 0.397) were not significant statistically associated with residual lesion , glandular involvement , HPV16/18 infection  and multiple HR-HPV infection  were independent risk factors for residual lesion  , rate of residual lesion with positive endocervical margin was 31.3% (35/112), rate of residual lesion with positive ectocervical margin was 15.3% (13/85), rate of residual lesion with positive combine margin was 38.6% (22/57). There was significantly statistical difference in the residual lesions rate with positive endocervical margin, positive ectocervical margin and positive combine margin compared with negative margin . In patients positive endocervical margin with glandular involvement positive and HPV-16/18 and multiple HR-HPV infection, the rate of residual lesion was 35.3% (6/17). In patients positive ectocervical margin with glandular involvement positive and HPV-16/18 and multiple HR-HPV infection, the rate of residual lesion was 23.1% (3/13)  ⟫ and ⟪2020 Chinese expert consensus for management of HSIL⟫ had made detailed and systematic explanations: repeated cervical conization with residual lesion in HSIL was difficult, HSIL combined with other gynecological diseases had surgical indications, patients with relapse and unable to perform conization after treatment, and patients with poor compliance after cervical conization, which could consider hysterectomy . This waThere was still a risk of residual and occult cervical cancer after conization for HSIL. In the study, we found that 14.1% patients after initial CKC had residual lesion on subsequent hysterectomy specimens. This finding was similar to the reported incidence of 5.4–60% in previous studies , 9–12. IA large number of literatures had confirmed that positive margin was a predictor of residual lesion. If the cone margin was negative, the probability of residual lesion was about 2–24%, while the residual lesion rate with positive margin can be as high as 30–60% , 16. In Precancerous lesion of cervical cancer were mostly caused by persistent infection of HR-HPV. Single or multiple HR-HPV infection can increase the risk of cervical cancer, among which HPV16 and HPV18 were most closely related to cervical cancer. In this study, the infection rate of HR-HPV was as high as 93.2%, the infection rate of HPV16/18 was 55.1%, and the infection rate of multiple HR-HPV was 25.8%. It can be seen that HR-HPV infection plays an important role in the precancerous lesions of cervical cancer, and also reflects the importance of HPV screening. Other studies had shown that the sensitivity and specificity of HR-HPV in predicting CIN residual and recurrence were 91.0% and 83.8% respectively, which were independent risk factors for residual and recurrence of lesions , 12. In There were many controversies about the correlation between glandular involvement and residual lesion. Jeong-yeol Park found that among patients after CIN III conization, glandular involvement was not a risk factor for residual lesions . Chien-HAccording to the multiple analyses of risk factors for residual lesion, we found the rate of residual lesion was 66.7% in which patients positive combined margin with glandular involvement positive and HPV-16/18 and multiple HR-HPV infection. However, neither risk factors nor suspected residual lesions were indications for hysterectomy. For patients with unclear indications of hysterectomy, long-term standardized follow-up management should be recommended. Repeated cervical conization was preferred if there was evidence of residual HSIL lesions during follow-up [This study had several limitations. First, this was a single-center retrospective study, and the reliability of the reported data was reduced. Second, the small sample size makes it impossible to accurately evaluate the correlation between the status of different margin and residual lesions. Third, HPV testing is only qualitative detection, not the detection of the amount of virus vector, the correlation between HPV infection and residual lesions was less convincing.In conclusion, positive margin, positive glandular involvement, HPV16/18 and multiple HR-HPV infection were high risk factors of residual lesions for HSIL after CKC. Appropriate application of these high-risk factors, comprehensive development of standardized based on the individual treatment plan, in order to achieve accurate treatment.


Atypical atrial flutters (AAFL) are difficult-to-manage atrial arrhythmias, yet potentially amenable to effective radiofrequency catheter ablation (CA). However, data on CA feasibility are only sparingly reported in the literature in different clinical settings, such as AAFL related to surgical correction of congenital heart disease. The aim of this review was to provide an overview of the clinical settings in which AAFL may occur to help the cardiac electrophysiologist in the prediction of the tachycardia circuit location before CA. Moreover, the role and proper implementation of cutting-edge technologies in this setting were investigated as well as which procedural and clinical factors are associated with long-term failure to maintain sinus rhythm (SR) to find out which patients may, or may not, benefit from this procedure. Not only different surgical and non-surgical scenarios are associated with peculiar anatomical location of AAFL, but we also found that CA of AAFL is generally feasible. The success rate may be as low as 50% in surgically corrected congenital heart disease (CHD) patients but up to about 90% on average after pulmonary vein isolation (PVI) or in patients without structural heart disease. Over the years, the progressive implementation of three-dimensional mapping systems and high-density mapping tools has also proved helpful for ablation of these macro-reentrant circuits. However, the long-term maintenance of SR may still be suboptimal due to the progressive electroanatomic atrial remodeling occurring after cardiac surgery or other interventional procedures, thus limiting the likelihood of successful ablation in specific clinical settings. Atypical atrial flutters (AAFL) are complex cardiac arrhythmias that often involve re-entrant circuits related to atrial scarring and areas of slow conduction . They maAAFL may be observed in different clinical scenarios  spanningWhatever the underlying structural heart disease, the greater the complexity of the pathophysiological substrate, such as in case of intra-atrial reentrant tachycardias (IART) in patients with congenital heart disease (CHD), the more difficult the clinical management. In fact, by promoting slow conduction through ion channel blockade, antiarrhythmic drugs (AAD) may even paradoxically enhance the risk of arrhythmia maintenance with potentially troublesome clinical consequences in the affected patients . For thiThus, the aim of this review was to explore the wide spectrum of clinical settings in which AAFL may occur and to provide the cardiac electrophysiologist with a better understanding of common arrhythmia locations and associated arrhythmogenic substrates in all these scenarios. Further, we evaluated the methodologies  and the acute and long-term outcomes associated with CA of AAFL. The factors connected with both periprocedural and long-term failure to maintain SR were also investigated. With this review we hope to elucidate ways to improve the overall procedural efficacy in this complex clinical scenario.Macro-rentrant atrial arrhythmias or post-incisional IART represent common complications after surgical correction for congenital heart disease . IART geCardiac surgery for the correction of mitral valve (MV) disease is common and associated with the development of complex, macro-reentrant arrhythmias revolving around iatrogenic scars ,14. In tAAFL are common after non-surgical PVI . IndepenIn up to 6% of cases, AAFL occurs in patients with no evidence of structural heart disease . ReasonsWe included studies assessing the major clinical scenarios in which AAFL are commonly observed, such as surgical correction of CHD (IART), cardiac surgery for acquired valvular heart disease, and CA of AF (PVI procedure). Patients with AAFL and no history of structural heart disease were also included. To assess the role of three-dimensional electro-anatomic mapping systems, studies implementing these cutting-edge technologies were compared with those using traditional mapping or a combination of these techniques . Therefore, we performed a non-systematic bibliographic research on Medline considering manuscripts published up to and including 2021. For each clinical scenario, the identification and selection of papers was based on the two following criteria: (1) a greater sample size when multiple manuscripts were available and, in case of small sample size papers, (2) a study was included according to its clinical relevance and only after discussion among the authors. The following research MeSH terms helped in the identification of the studies included in As shown in However, despite the implementation of the latest technologic developments in experienced hands, such as high-density mapping tools ,56 or coAs for the overall peri-procedure safety, local complications may occur in up to 7% of cases , includiAs displayed in The older the publication date, the greater the incidence of arrhythmia recurrence. This would suggest that the recent implementation of dedicated mapping tools  and irrip < 0.0001) [The beneficial role of multiple CA procedures after AAFL recurrence in achieving long-lasting SR is controversial. In fact, as recently reported by a meta-analysis collecting data on patients with prior surgical correction for MV disease undergoing CA of AAFL, the overall maintenance of SR was significantly lower for repeat procedures compared with history of single CA only  . Moreove 0.0001) . In fact 0.0001) ,39,42,49 0.0001) . To supp 0.0001)  observed 0.0001) ,53,55, wisthmi anatomically [AAFL are typically sustained by critical omically  and funcomically ,38,39,46omically , slow coomically , and a tomically , which mTM system  and the EnsiteTM Omnipolar Technology (OT)  might allow for even better results [For these reasons, as already described elsewhere ,51, the  results ,63,64, pisthmi should be considered in specific settings, such as in case of roof-dependent and mitral annular AAFL [Although the implementation of these new technologies in CA procedures seems helpful in most cases, including mapping of re-entrant circuits with multiple loops ,46, CA olar AAFL .The ablation of roof-dependent circuits may be particularly challenging. The myocardial musculature surrounding the superior PV is generally thick and consistently displays adipose tissue separating the septopulmonary from the more endocardial septoatrial bundles . This coAs for mitral annular AAFL, a posterior line connecting the left inferior PV to the lateral MV annulus  represents the traditional CA strategy to manage these circuits. However, the remarkable myocardial thickness in this anatomical region; the convective cooling as the result of coronary sinus flow; the epicardial connections; and, not least, the risk of damaging the left circumflex coronary artery may all pose several challenges. To overcome these issues, epicardial ablation from the coronary sinus ; endocarRegardless of the location of the tachycardia circuit or length of the ablative lesion, bidirectional conduction block does represent the essential endpoint of every CA procedure by evidence of detouring of the electrical wavefront around an anatomical barrier or scar through dedicated pacing maneuverers and/or demonstration of double potentials along the performed ablation lines. In some particular cases, demonstration of conduction block with the abovementioned criteria can be difficult and, therefore, complete disappearance of electrical signals at the target site can be considered a surrogate endpoint.When a macro-reentrant circuit cannot be identified in the atria, a small, localized reentry can be the arrhythmia mechanism, which calls for a more accurate mapping and signal interpretation . AlternaApart from all these technical aspects, clinical considerations are also to be taken into account for proper patient management. First, the clinical history and prior cardiac surgery, particularly the Cox-Maze-IV procedure, should be reviewed in order to obtain information on all potential sites of surgical and non-surgical scars or conduction gaps in the atrial chambers. Second, symptom burden and hemodynamic tolerance of the AAFL should guide the electrophysiologist to assess how aggressive the ablation strategy should be, especially when multiple procedures are required. Third, although surface P wave morphology poorly predicts the arrhythmia origin in this setting, it is important to examine surface ECGs of all the documented episodes to evaluate the presence of multiple morphologies and possibly multiple reentrant pathways. Fourth and even more important, concomitant AF should be diagnosed in advance of CA to evaluate the need for adjunctive pulmonary vein isolation or long-term antiarrhythmic drug therapy. Fifth, pre-procedure imaging with a particular focus on atrial chamber is important to evaluate the substrate and clarify cases with complex anatomy or undiagnosed conditions.Despite all efforts, AF and other complex atrial arrhythmias refractory to medical therapy may eventually occur even after an initially successful CA procedure as an unavoidable sequela of the progressive electro-anatomic atrial remodeling occurring in diseased atrial chambers . This unThe current manuscript is affected by several limitations. First the non-systematic nature of this review. Then, study heterogeneity due to different patient populations undergoing a variety of surgical, non-surgical procedures or, in some cases, even naïve to any prior iatrogenic lesion. Finally, most papers were retrospective and observational in nature. This might have influenced our observations because of potentially uncontrolled confounders and/or other inherent biases affecting this type of study design .AAFLs are difficult-to-manage re-entrant arrhythmias that seem amenable to safe and effective CA. In experienced hands, the correct implementation of three-dimensional mapping systems, high-density mapping tools, and a clinically oriented approach could be important to clarify the arrhythmia substrate and plan a rational and effective ablation strategy. Failure to suppress the AAFL or early recurrences are possible, mainly in the presence of an arrhythmogenic substrate unsuitable for CA. Therefore, due to heavily remodeled atria, patients with a history of several surgical or interventional procedures may be prone to develop AAFL with multiple morphologies in addition to other complex atrial arrhythmias, AF included. In fact, in the long-term follow-up, the occurrence of AF could still be expected despite multiple and effective CA procedures. Therefore, a patient-oriented approach is needed for proper patient selection and peri- and post-procedure management. Differently from the setting of surgically corrected congenital heart diseases, patients with AAFL and a history of non-surgical PVI or no prior interventional procedures seem to greatly benefit from CA even at a long-term follow-up.


The present systematic review aimed to gain deeper insight into the epidemiology, clinical presentation, and histopathology of HPV-related benign and malignant lesions of the oral mucosa in pediatric patients to improve the multidisciplinary preventive and therapeutic management of oral and general healthcare. The emerging role of HPV in oral carcinogenesis in pediatric subjects, along with benign oral mucosal lesions and asymptomatic infections, brings HPV vaccination to the forefront specifically for this age group.n = 69) VV, SP, and CA, 51.37% (n = 75) FEH, and 1.37% (n = 2) OSSC, were diagnosed in 153 pediatric subjects (M:F ratio = 1:1.4) with a mean age of lesion onset of 8.46 years. The viral genotypes detected were HPV-13 (30.61%), -6 (20.41%), -11 (16.33%), HPV-2 (12.24%), -32 (10.20%), -57 (6.12%), and -16 (4.08%). No HPV vaccination was reported in any case. Further studies should be conducted to evaluate the prevalence of HPV-related benign and malignant lesions and the potential role of HPV and associated vaccination in oral carcinogenesis in pediatric subjects.The present systematic review aimed to assess the prevalence of oral HPV-related lesions, categorized as benign  and malignant , in descending order of occurrence in pediatric subjects (≤18 years of age). The secondary objectives were to evaluate the frequency and types of oral lesions described in relation to HPV genotypes and the HPV vaccine type (if any). The study protocol, compliant with the PRISMA statement, was registered at PROSPERO (CRD42022352268). Data from 60 studies, of which quality was assessed using the ROBINS-I tool, were independently extracted and synthesized. Along with seven poorly described benign HPV-related oral lesions that could not be categorized, a total of 146 HPV-related oral lesions, namely 47.26% ( Human papillomavirus (HPV) is associated with benign and malignant diseases of various locations, mainly affecting the skin and genital and oral mucosa . In detaOf the approximately 100 different HPV genotypes that have been identified, 25 are generally associated with oral lesions, including HPV-1, -2, -3, -4, -6, -7, -10, -11, -13, -16, -18, -31, -32, -33, -35, -40, -45, -52, -55, -57, -58, -59, -69, -72, and -73 [In particular, HPV-6 and HPV-11 are frequently found in squamous cell papillomas , HPV-6 aHPV is also considered an independent risk factor for benign and malignant tumors , and an However, while benign and malignant oral HPV-related lesions in adults have been extensively described in the literature, available data on the pediatric population (≤18 years of age) remain sparse, heterogeneous, and characterized by low evidence, as they are mainly case reports and series. Moreover, the emerging role of HPV in oral carcinogenesis in pediatric subjects , along wThe Centers for Disease Control and Prevention have developed new recommendations for routine HPV vaccination at ages 9 to 12 years to maximize vaccine effectiveness and increase the number of cancers prevented . In light of these considerations, the present systematic review aimed to assess the prevalence of oral HPV-related lesions in pediatric subjects (≤18 years of age), categorize them as benign and malignant, and rank them in descending order of occurrence. The secondary objectives were to evaluate the frequency and type of oral lesions described in relation to HPV genotypes and the HPV vaccine type (if any).The study protocol currently used was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement  prior toThe formulation of the search question and strategy and criteria for study selection were developed using the PECO model .P—pediatric subjects (≤18 years of age)E—human papillomavirus (HPV) infectionC—none or subjects with and without an HPV vaccine and the type O—oral lesions.The study question focused on the following: 1.Human papillomavirus OR HPVAND2.Oral lesions OR oral manifestations OR oral signsAND3.Children OR pediatric OR child OR infant OR adolescent OR teenager OR young.Case reports, case series, and observational studies in English on oral HPV-related lesions in pediatric subjects (≤18 years of age) were searched electronically in the Scopus, MED-LINE/PubMed, and BioMed Central databases, without filters, by two independent reviewers  until 11 August 2022, using the following appropriate keywords combined with Boolean operators:The collected citations were recorded, duplicates were eliminated, and the titles and abstracts obtained were independently screened by two reviewers . The full texts of potentially relevant papers and ambiguous abstracts were reviewed independently by the same authors , who resolved disagreements through discussion and consensus and, if necessary, with the involvement of a third reviewer (G.P.).An additional manual search was also performed on the reference lists of articles under consideration; relevant titles and abstracts were screened, and full texts were reviewed as described above. If full texts were missing, study authors were contacted.Inclusion criteria were as follows: case reports, case series, cross-sectional, case-control, prospective, and retrospective studies accepted and published in English between 1970 and 11 August 2022, without limitations of sample size or gender, describing HPV-related oral lesions confirmed via histopathologic analysis (with or without PCR confirmation), excluding FEH cases diagnosed clinically only.Exclusion criteria were as follows: in vitro and preclinical in vivo studies, systematic and narrative reviews, conference papers, oral communications, and books/chapters; participants ≥ 18 years of age and HIV-positive subjects; normal oral mucosal variations, likely preexisting, and self-reported oral mucosal lesions. Two reviewers  extracted data independently, and a third reviewer (G.P.) was consulted in cases of discrepancies. A standardized data extraction form was used, developed under models proposed for intervention reviews of RCTs and non-RCTs .▪First author, year, journal, funding, study quality;▪Design and number of studies reported; sample size, gender ratio, mean age, comorbidities of the population investigated; HPV vaccine ;▪Total number or prevalence of pediatric subjects with oral HPV-related lesions diagnosed through a clinical examination confirmed based on histopathologic analysis (except for FEH) with/without PCR confirmation;▪Macroscopic and microscopic features of oral lesions categorized as benign and malignant oral lesions ;▪Definitive diagnosis, diagnostic procedures, treatment, and progression of the oral lesions; ▪HPV genotypes associated with oral lesions.The following data meeting eligibility criteria were collected from each study included in this systematic review:A narrative synthesis was performed that focused on the reported characteristics of the pediatric population investigated, HPV exposure and related vaccination (if any), and oral outcomes.➢Estimating the prevalence of HPV-related lesions in pediatric subjects diagnosed via clinical examination and confirmed based on histopathologic analysis;➢Categorizing oral HPV-related lesions into benign, potentially malignant, and malignant lesions and ranking them in descending order of occurrence;➢Evaluating the frequency of oral lesions categorized as benign, potentially malignant, and malignant in pediatric subjects ➢Calculating the frequency of HPV genotype detected in oral lesions;➢Comparing the frequency and type of oral lesions in subjects with and without HPV vaccination ➢Evaluating the oral lesions in relation to the HPV vaccine type.Data from the included studies were qualitatively synthesized through descriptive statistical analysis using the Statistical Package for the Social Sciences /Microsoft Excel Software 2019, Microsoft Corporation, Redmond, WA, USA):The risk of bias in the studies included in this systematic review was assessed by three independent reviewers  using the Risk of Bias Instrument for Non-randomized Studies of Exposures , which iThe risk was classified as “low” or “moderate” if the risk of bias was low or low or moderate in all domains, respectively. A “serious” risk of bias was defined if a serious risk of bias was identified in at least one domain, but a critical risk of bias was not identified in any domain. The study was considered “critical” if the risk of bias was found to be critical in at least one area.Electronic searches retrieved a total of 83 records, 47 from MEDLINE/PubMed, 2 from Scopus, and 34 from BioMed Central databases; 3 duplicates were subsequently removed. The remaining 80 titles/abstracts were screened, and 37 were excluded because: 21 did not focus on HPV (6 focused on HIV); 5 reported oral HPV-related infection or lesions in adult women; 5 were in vitro studies; 2 did not report oral lesions ; 2 were questionnaires assessing HPV knowledge; 1 was an animal study; 1 assessed oral HPV infection without associated oral lesions.Of the 43 abstracts that were relevant to the present systematic review and met the eligibility criteria, the full texts were screened, and an additional 35 articles were excluded, specifically because: 5 studies did not report oral lesions; 15 did not involve pediatric patients, or it was not possible to extract data from them; 10 involved >18-year-old subjects; 2 described oral lesions that were not HPV-related; 3 were reviews. A total of eight studies ,23,24,25Fifty-two additional records ,73,74,75Finally, the present systematic review included 60 articles on oral HPV-related lesions in pediatric subjects (≤18 years of age) .Data from 60 studies describing oral HPV-related lesions diagnosed through clinical examination and confirmed based on histopathologic analysis in pediatric subjects were extracted and synthesized.Of the 60 included studies, 36 were case reports, 19 were case series, 3 were retrospective, and 2 were prospective studies involving a total of 153 cases diagnosed with HPV-related oral lesions in pediatric (≤18 years of age) subjects.The sources, methods, and qualitative synthesis of oral outcomes from the included studies were pooled. Only data that met eligibility criteria were extracted and analyzed; therefore, data from individuals who were >18-years-old were not detailed.A total of 76 pediatric subjects were diagnosed with oral HPV-related lesions, which were divided into 37 papillomas ,42,45,46The study population included 35 males and 33 females between the ages of 1.5 and 18 years, with a mean age of 8.9. However, the gender and age of six subjects were not reported . Country of origin or ethnicity was reported for 28 patients, as follows: 7 Black ,23; 2 LaPatients from 11 studies had no comorbidities ,43,44,45Associated treatments for comorbidities were antibiotics , aciclovHPV exposure was associated with the following: suspected abuse ,34,46; sThe mean time to the onset of oral lesions was 11.4 months and ranged from 14 days to 7 years. Only one study  reportedMacroscopic features were reported in 22 ,43,44,45HPV-related oral manifestations occurred as a single lesion in 22 cases ,43,45,46n = 8) [n = 9) [n = 13) [n = 9) [n = 6) [n = 5) [n = 6) [n = 3) [n = 2) [n = 2) [n = 2) [n = 1) [n = 1) [n = 1) [The affected sites were as follows: lower lip (n = 8) ,34,37,41 [n = 9) ,41,44; p[n = 13) ,40,42,43 [n = 9) ,42,43,44 [n = 6) ,30,39,43 [n = 5) ,28,37,43 [n = 6) ,27,29,36 [n = 3) ,33,45; t [n = 2) ; vermili [n = 1) ; vestibuThirteen patients had no extra-oral involvement on examination ,37,42,43HPV genotypes detected in oral lesions were as follows: HPV-2 in six cases ,36; HPV-n = 48) [n = 28) [n = 2) [n = 3) [n = 1) [n = 8) [n = 1) [Neisseria (N.) lactamina, N. meningitides, N. gonorrhoeae; swabs (n = 3) [n = 1) [n = 1) [n = 5) [Treponema pallidum and HBV in three cases [2 laser surgery in 2 [The diagnostic procedures performed included the following: biopsy (n = 48) ,41,42,44[n = 28) ,40,43,46 [n = 2) ; PCR ana [n = 3) ,40,41; i [n = 1) ; cytolog [n = 1)  testing  [n = 1) ; direct  [n = 1) ; serolog [n = 5) ,37,43 yi [n = 5) ,43, Trepee cases . The folee cases ,41; CO2 ery in 2 ,29,43; eery in 2 ; oral suery in 2 ; cimetidSeventy-five pediatric subjects were diagnosed with focal epithelial hyperplasia ,73,74,75Country of origin or ethnicity was reported for 52 patients, specifically as follows: 2 Hispanic ,69; 1 CaHPV exposure was associated with the following: 1 suspected abuse ; 1 horizThe median time to onset of oral lesions was 19.9 months and ranged from 1 month to 8 years. No study reported whether or not patients were vaccinated against HPV.Macroscopic and microscopic features were reported in 27 ,61,63,75Oral FEH occurred in 54 pediatric cases ,73,74,75n = 51) [n = 21) [n = 15) [n = 30) [n = 19) [n = 9) [n = 8) [n = 5) [n = 3) [n = 3) [n = 1) [n = 1) [n = 1) [The affected sites were as follows: lips n =  [51,52,5n = 51) ,72,74,75[n = 21) ,68,72,75[n = 15) ,68,72,75[n = 30) ,74,75; t[n = 19) ,71,72,73 [n = 9) ,66,68,72 [n = 8) ,63,66,72 [n = 5) ,72,75; t [n = 3) ,66,72; v [n = 3) ; vestibu [n = 1) ; anterioNine patients did not show extra-oral involvement on examination ,67,70,73The HPV genotypes detected were as follows: HPV-13 in 15 cases ,63,68,712 laser surgery [In five cases, no therapies were performed ,60,66,67 surgery ,49; shav surgery , excisio surgery ,69, cryo surgery ,75, and  surgery , oral su surgery , acitret surgery , vitaminRegarding the progression of oral FEH lesions: in 14 cases, lesions healed after an average of 15.95 months, ranging from 14 days to 3 years; in 17 cases, no recurrence occurred after an average of 11 months, with a follow-up ranging from 1.5 months to 1 year. Improvement was noted in seven cases after an average of 18.4 months, ranging from 1 month to 5 years. Recurrence occurred in two cases, after six months in 1 case, while deterioration was declared in 1 case and no improvement occurred in 9 cases with an average follow-up time of 27 months.A total of two pediatric subjects were diagnosed with oral malignant HPV-related lesions categorized as oral squamous cell carcinoma (OSCC) ,20.The study population included two males aged 5 to 8 years, with a mean age of 6.5 years, one of whom was of Caucasian origin , and botIn one case, HPV exposure through self-vaccination was suspected , which wMacroscopic and microscopic features were reported in both studies ,18, and Extra-oral involvement was described in one case  as wartsThe HPV genotype involved was not reported, but p16 positivity was noted in both cases; HPV association with pediatric OSCC was therefore reported based on the p16 status of the lesions. The diagnostic procedures performed were as follows: two biopsies ,18; one Therapies performed were as follows: one pharmacologic therapy with antibiotics ; one tooIn one case, the patient healed after 24 months  since thn = 69) verrucae vulgaris, squamous cell papillomas, and condyloma acuminata, 51.37% (n = 75) FEH, and 1.37% (n = 2) OSSC  with a mean age of 8.46 years, including 47.26% ( 2) OSSC . In addiOn average, patients visited a physician 15.65 months after the appearance of oral lesions, and in no case was HPV vaccination indicated. The most frequently affected sites were as follows, in descending order: lips (36.6%) in 74 cases (upper lip was reported in 29 and lower lip in 24 cases), followed by cheeks (17.3%) in 35 cases, tongue (13.9%) in 28 cases, palate (8.9%) in 18 cases, labial commissures (7.4%) in 15 cases, gingiva in 14 cases, vermilion (2.5%) in 5 cases, anterior faucial columns (1.5%), uvula (1.5%), and floor of mouth (1.5%) in 3 cases, tonsils (0.99%), the vestibule (0.99%) and alveolar ridge (0.99%) in 2 cases; N\D oral mucosa in 1 (0.5%).The HPV genotypes detected were as follows: HPV-13 in 15 cases (30.61%); HPV-6 in 10 cases (20.41%); HPV-11 in 8 cases (16.33%); HPV-2 in 6 cases (12.24%); HPV-32 in 5 cases (10.20%); HPV-57 in 3 cases (6.12%); HPV-16 in 2 cases (4.08%), as shown in The risk of bias of the non-randomized studies included in the present systematic review is reported in The present systematic review aimed to assess the prevalence of oral HPV-related lesions in pediatric subjects (≤18 years of age), categorize them as benign and malignant, and rank them in descending order of occurrence. The secondary objectives were to evaluate the frequency and types of oral lesions described in relation to HPV genotypes and the HPV vaccine type (if any).n = 69) VV, SP, and CA, 51.37% (n = 75) FEH, and 1.37% (n = 2) OSSC, were diagnosed in 153 pediatric subjects (M:F ratio = 1:1.4) with a mean age of lesion onset of 8.46 years. The viral genotypes detected were HPV-13 (30.61%), -6 (20.41%), -11 (16.33%), HPV-2 (12.24%), -32 (10.20%), -57 (6.12%), and -16 (4.08%). No HPV vaccination was reported in any case. Sixty studies were considered, and along with seven poorly described benign HPV-related oral lesions that could not be categorized, a total of 146 HPV-related oral lesions, namely 47.26%   and SARSThe pediatric cases diagnosed with benign oral HPV lesions had a mean age of 8.9 years, slightly lower than the mean age found for FEH (9.97 years), as described later, and lower than the range reported for the highest incidence of verruca vulgaris, between 12 and 16 years of age .In general, HPV-related oral benign lesions are more common in adults , similarThe main transmission route for HPV is skin-to-skin or skin-to-mucosa contact . Sexual n = 37). Squamous papillomas are estimated to be the most common benign oral epithelial le-sions in both pediatric and adult populations , which iSecond, in overall frequency, verrucae vulgaris is the predominant cutaneous manifestation of HPV infection, with a total incidence of 10% in children and young adults . Althougn = 13).Condyloma acuminata is more common anogenitally and is the most common manifestation of sexually transmitted infections in the United States and the United Kingdom . It is aRarely, multiple verrucae vulgaris occurs together in the oral cavity or clusters ; the samDespite the fact that CAs are the benign HPV-related oral lesions that most commonly occur as multiple lesions and tend to coalesce and although Panici et al. , examinin = 23; 31.08%), with apparently no preference for the upper or lower lip, palate , and tongue .The palate and tongue are considered the sites most commonly affected by SPs . VV, on n = 3), followed by HPV-11 (n = 2), 16 (n = 2), and 32 (n = 1); in CA, HPV-6 (n = 5) and HPV-11 (n = 4); in VV, HPV-2 (n = 6) and HPV-57 (n = 3).In the normal oral mucosa, latent infection is most commonly maintained by HPV-6 and -11 , and oraOnly one study  reportedFocal Epithelial Hyperplasia (FEH), also known as Heck’s disease, is an asymptomatic and benign condition caused by HPV-13 and/or -32 genotypes ,86 that FEH can affect children and adults  but geneThe same study  recordedn = 9) [n = 8) [n = 6) [n = 1) [n = 1) [n = 1) [n = 1) [n = 6) [In fact, there are no accurate data on the prevalence of FEH in the general population, but it is considered a rare condition . Accordin = 9) , followe [n = 8) ,64, Braz [n = 6) ,63,66. O [n = 6) . The inv [n = 1) , Libya ( [n = 1) , Algeria [n = 1) , Africa  [n = 1) ; Ghana ( [n = 6) ,64. This [n = 6)  living i [n = 6) .The mean time to the appearance of oral lesions was 19.9 months, ranging from 1 to 8 years, as on average, more than 1.5 years elapsed before patients saw a specialist for control. In two cases ,62, a spIn this regard, no study reported whether patients with manifestations of Heck’s disease received the vaccine. This may be in part because FEH is associated with low-risk HPV-13 and -32 genotypes, whereas HPV vaccines target high-risk HPV genotypes . However, although FEH is a benign condition caused by low-risk HPV genotypes, diagnosed cases may be at higher risk for infection with other viral genotypes. Of note, coinfection with multiple HPV genotypes is recognized as a risk factor for invasive cervical cancer (ICC) and high-grade squamous intraepithelial lesions (HSILs) , as is HMoreover, HPV vaccination also plays an essential role because Highly Active Antiretroviral Therapy (HAART) has been shown to be less effective for HIV–HPV coinfection-related malignancies, and to date, no vaccine against HIV is available . Furthermore, the rate of migration from areas at a higher risk of infection to high-income countries has generally increased, proportionally increasing the number of potentially underdiagnosed cases.Because oral FEH lesions often regress spontaneously  and haveThe surgical approach of excising lesions should be limited to single and limited lesions. However, in most cases, FEH occurs as multiple nodulo-papular lesions involving large and diverse mucosa and perilabial tissue areas. Coherently, in this systematic review, single lesions accounted for 5.3% of cases, while the remaining 94.7% had multiple lesions, predominantly with bilateral and asymmetric patterns. In cases with greater mucosal involvement and considering the often young age of patients (first to second decade of life), conservative and atraumatic approaches may be preferred to preserve esthetics and functions. From this perspective, a new therapeutic approach using nano-pulse stimulation (NPS) has shown promising results . This teOral squamous cell carcinoma is a malignant epithelial neoplasm of the head and neck and ranks seventh in worldwide cancer prevalence . HoweverAlthough its oncogenic role is still not well understood , HPV appThe two young subjects with HPV-related OSCC were both males, which is consistent with other studies reporting a higher prevalence of OSCC in pediatric male patients ,18 and oIn those two cases ,18, lesiIn both studies reporting HPV-related OSCC in pediatric subjects ,18, infoThe present systematic review showed that healthy pediatric patients (≤18 years of age) with HPV-related oral lesions had a mean age of 8.46 years and were most frequently diagnosed with FEH (51%), followed by squamous cell papillomas (25%), verrucae vulgaris (13%), and condyloma acuminata 9%). The HPV association with oral squamous cell carcinomas was described in two cases based on the p16 status of the tumors, and no viral genotype was reported; thus, the role of HPV in oral carcinogenesis in these cases remains unknown, and HPV-related OSCC would be extremely rare in a pediatric population [%. The HPOverall, these findings and the possible independent role of HPV in oral carcinogenesis underscore the importance of HPV vaccination. The currently available vaccines  are the primary means of protection against HPV infection. Since the COVID-19 pandemic abruptly halted the HPV vaccination campaign, it is advisable to revive and exceed the vaccination schedule in time for the first pandemic peak. Oral healthcare providers, who frequently encounter benign HPV-related lesions, should also take a leading role in this scenario, both in the early diagnosis and treatment of oral HPV-related lesions and in raising awareness of HPV vaccination among pediatric patients and their parents and caregivers.


According to the degree of HPV infection, the patients are divided into low-risk HPV type group (n = 65 cases) and high-risk HPV type group (n = 25 cases); 50 patients with cervicitis (without HPV infection) who received treatment in our hospital are selected as control group 1. Fifty healthy women who underwent physical examination are selected as the control group 2. The general data of the two groups of patients during hospitalization are collected, and HPV-DNA, IFN-γ, IL-4, and TNF-α are detected in all patients. For patients with cervicitis complicated by HPV infection, the IFN-indexes in the body are significantly decreased, IL-4 and TNF-αare significantly increased, and with the degree of HPV infection, IFN-γ, IL-4, and TNF-α have high diagnostic performance with HPV infection, and there is a significant correlation between the three, which can be used in cervicitis complicated with HPV infection. It is widely used in the early diagnosis and screening of infected patients.In order to investigate the expression levels of serum IFN- Cervical disease is a common disease in women of childbearing age, generally including acute and chronic cervicitis, cervical intraepithelial neoplasia CIN, and cervical cancer . Among tγ, IL-4, and tumor necrosis TNF-α in patients with cervicitis complicated with human papillomavirus (HPV) infection and clinical significance, this paper selects patients with cervicitis complicated by HPV infection to analyze the interferonγ (interferon gamma) in vivo. The expression levels of IFN-γ, IL-4, and TNF-α are analyzed and their correlation with HPV infection is analyzed.In order to investigate the expression levels of serum IFN-n = 65 cases) and high-risk HPV type group (n = 25 cases); 50 patients with cervicitis (without HPV infection) who received treatment in hospital are selected as control group 1. 50 healthy women served as the control group 2. Among them, the age of the patients in the study group is in the range of 23–58 years old, with an average of (42.49 ± 9.82) years old; in 1 to 4 times of pregnancy, with an average of (1.81 ± 1.03) times, the disease duration is 3 months to 55 months, with an average of (22.93 ± 11.76) months. Control group 1: aged from 23 to 59 years old, with an average of (42.86 ± 9.69) years old; in 0 to 5 times of pregnancy, with an average of (1.80 ± 0.97) times, the disease duration is 5 months to 55 months, with an average of (23.32 ± 12.74) months. Control group 2: aged 23 to 58 years, mean (41.64 ± 7.88) years old; 0 to 5 pregnancies, mean (1.82 ± 1.10) times. Comparing the general basic data such as age and course of disease among the three groups, there is no significant difference which can be compared (P > 0.05).90 patients with chronic cervicitis complicated by HPV infection who were treated in our hospital from June 2020 to June 2021 were retrospectively selected and included in the research group. According to the degree of HPV infection, the patients are divided into low-risk HPV type group (Inclusion criteria were as follows: (1) met the diagnostic criteria for cervicitis in Obstetrics and Gynecology (8th Edition) ; (2) theThe exclusion criteria include the following eight aspects: (1) cervical epithelial neoplasia grade II to III; (2) diagnosed with early cervical cancer or combined with other types of malignant tumors; (3) presence of trichomoniasis, candida, and other reproductive system infections; (4) combined with heart and brain patients with a vascular disease or dysfunction; (5) diagnosed with autoimmune or blood diseases; (6) taking hormone- related drugs or immunotherapy within the past 3 months; (7) history of pelvic radiation therapy; and (8) be pregnant or breastfeeding.The general data of the two groups of patients during hospitalization are collected, including age, course of disease, pregnancy, and other related indicators –15. In tγ and IL-4 levels are detected using an ELISA kit; it is purchased from TSZ in the United States. The standard curve is drawn and the corresponding concentrations are calculated [5 ml of cubital venous blood is drawn from all the participating research subjects on an empty stomach in the morning, 3 500 r/min, about 10 min, and the centrifugation radius is 10 cm. The serum IFN-lculated , 16–19. All data are summarized and sorted, and a database is established for all data. Using SPSS 24.0 software, normality and homogeneity of variance are tested to satisfy normal distribution. The differences tested are considered statistically significant.γ levels, the study group is the lowest and the control group 2 is the highest; IL-4 and TNF-α levels are the lowest in the study group and the highest in the control group 2(both P < 0.05). In terms of IFN-γ index, the group with high HPV infection is significantly higher, and from the level of IL-4 and TNF-α, the group with high HPV infection is significantly lower, both of which are related to the group with low HPV infection. Compared with the group, all P < 0.05.. From the level of IFN-γ ; cervicitis combined with HPV type infection is significantly positively correlated with both IL-4 and TNF-α , all P < 0.001). γ, IL-4, and TNF-α.Cervicitis combined with HPV type infection is significantly negatively correlated with IFN-γ, IL-4, and TNF-α for the assessment of high-risk HPV infection, all exceeded 0.75, which had high specificity and sensitivity. There is no statistical difference in the prediction models of the three detection methods. The area under the ROC curve of IFN-γ, IL-4, and TNF-α for the assessment of low-risk HPV infection, all exceeded 0.75, which had high specificity and sensitivity. There is no statistical difference in the prediction models of the three detection methods. The area under the ROC curve of IFN-γ is significantly negatively correlated with IL-4 and TNF-α (r = −0.803). There is a significant positive correlation with TNF-α (r = 0.870) (both P < 0.05). From the correlation of different serum indexes, there is a significant correlation among the three, and IFN-Chronic cervicitis is one of the most common diseases in clinical gynecology. According to statistics, about 60% of married women suffer from chronic cervicitis of varying degrees. In severe cases, infertility may occur, which is the main reason for patients to seek medical treatment. It not only poses a major threat to female reproductive health but also seriously affects the mental health of patients. It is well known that chronic cervical inflammation is closely related to cervical carcinoma and its mortality rate ranks first in gynecological cancer. 130,000 new cases of cervical cancer increase in my country every year, accounting for more than 1/4 of the world, and the trend of younger patients is obvious, which has caused a huge impact and damage to the body and mind of patients. For most women, it is a relatively long process from chronic cervicitis to cervical precancerous lesions to cervical cancer, and early intervention and treatment are extremely important and achievable for the prevention of cervical cancer. Therefore, the treatment of chronic cervical inflammation and the eventual eradication of cervical cancer will become the main issues for women in our country and the world to overcome serious diseases and benefit women's health. Studies have found that HPV infection has an important relationship with cervicitis. The infection of HPV in patients with cervicitis has a high carcinogenic rate, which can lead to cervical cancer and pose a serious threat to the health of patients. However, whether or not persistent HPV infection can cause the occurrence and development of cervical lesions, it is related to factors such as the autoimmune state and hormone secretion level of the infected person, and the host autoimmune regulation plays a key role in HPV-mediated carcinogenesis.γ in different groups of patients showed different differences . Tumor and immunomodulatory effects can prevent or slow the transformation of normal cells to tumor cells, and abnormal levels of IFN-γ may lead to tumorigenesis. Zhang Jing detected the expression of IFN-γ in the tissues of cancer patients and showed that the expression of IFN-γ in cancer tissues is lower than that in surrounding normal tissues and in the later tumor stage, the IFN-γ level is lower. IL-4 is a major cytokine that can inhibit the response of Th1-type cytokines and mediate the development of Th2-type cells, which is closely related to tumor malignancies. Luo et al. detected the peripheral blood mononuclear cells of breast cancer patients and the culture supernatant to detect the level of IL-4 and found that the level of IL-4 in breast cancer patients is higher than that in the normal control group, which has a markedly different significance (P < 0.05). Yu also analyzed the IL-4 concentration in the peripheral blood culture supernatant of cervical cancer patients and found that the IL-4 concentration in the peripheral blood mononuclear cell culture supernatant of cervical cancer patients is comparable to normal examination. The study detected IL-4 in patients with cervicitis complicated by HPV infection and found that with the aggravation of HPV type infection (P < 0.01). High IL-4 levels may indicate another malignant trend of the disease, suggesting that patients have more severe cervical lesions, and the more obvious the local immunosuppression, the easier it is for cancer cells to escape immune surveillance and accelerate tumor progression. In addition, statistical analysis found that IFN-γ and IL-4 concentrations are negatively correlated, suggesting that IFN-γgradually decreased, IL-4 gradually increased, and IFN-γ/IL-4 gradually increased, which can more intuitively explain the two indicators. This study also found that cervicitis combined with HPV type infection is significantly negatively and IFN-γ ; cervicitis combined with HPV type infection is significantly positively correlated with both IL-4 and TNF-α (both P < 0.001); TNF-αis a pleiotropic cytokine, which is mainly secreted by macrophages and is widely involved in the process of cellular reactions. When the human body has fever, shock, tissue damage, and tumor necrosis When the effect is equating-α can be induced by other cytokines and immunoregulatory factors, making it involved in cell proliferation, differentiation, and apoptosis. In addition, TNF-α can bind to receptors on the surface of cancer cells, and after the complexation is completed, it enters the cell and fuses with the lysosome. At this time, TNF-α plays an important role, which will promote the lysis of lysosomes and the release of proteases, and then cause cell autolysis. Although this study has achieved certain results, due to the relatively small number of cases included in the study, it may cause a certain bias to the results. Therefore, the sample size needs to be further expanded in future studies to further analyze the serum levels of IFN-γ and IL-4 in patients with cervicitis complicated by HPV infection.This study found that the levels of IFN-γ (interferon gamma) in vivo. The expression levels of IFN-γ, IL-4, and TNF-α are analyzed, and their correlation with HPV infection is analyzed. The IFN-γ indexes in patients with cervicitis complicated with HPV infection are significantly decreased and those of IL-4 and TNF-α are significantly increased. IL-4 and TNF-α have a high diagnostic performance with HPV infection, and there is a significant correlation between the three, which can be widely used in the early diagnosis and screening of patients with cervicitis complicated with HPV infection.This paper selects patients with cervicitis complicated by HPV infection to analyze the interferon