Objective: To systematically summarize and analyze the clinical research progress of therapeutic vaccines for cervical cancer or precancerous lesions. Methods: English databases (PubMed, Embase, Web of Science, Cochrane library, Proquest, and ClinicalTrails.gov) and Chinese databases (SinoMed, CNKI, WanFang, and VIP Database) were systematically searched to collect literature on therapeutic vaccines for cervical cancer or precancerous lesions from inception to February 18, 2021. After screening, we evaluated the risk of bias of included studies, and combed the basic information of the literature, research designs, information of vaccines, study patients, outcome indicators and so on, qualitatively summarized the clinical research progress. Results: A total of 71 studies were included in this systematic review, including 14 random controlled trials, 15 quasi-random controlled trials, 4 cohort studies, 1 case-control study, 34 case series studies and 3 case reports. The study patients included women aged 15~79 with cervical cancer or precancerous lesions in 18 countries from 1989 to 2021. On the one hand, there were 40 studies on therapeutic vaccines for cervical precancerous lesions (22 867 participants), involving 21 kinds of vaccines in 6 categories. Results showed 3 marketed vaccines (Cervarix, Gardasil, Gardasil 9) as adjuvant immunotherapies were significant effective in preventing the recurrence of precancerous lesions compared with the conization only. In addition, MVA E2 vaccine had been in phase Ⅲ clinical trials as a specific therapeutic vaccine, with relative literature showing it could eliminate most high-grade precancerous lesions. Therapeutic vaccines for precancerous lesions all showed good safety. On the other hand, there were 31 studies on therapeutic vaccines for cervical cancer (781 participants), involving 19 kinds of vaccines in 7categories, with none had been marketed. 25 studies were with no control group, showing the vaccines could effectively eliminate solid tumors, prevent recurrence, and prolong the median survival time. However, the vaccines effectiveness couldn't be statistically calculated due to the lack of a control group. As for the safety of therapeutic vaccines for cervical cancer, 9 studies showed that patients experienced serious adverse events after treatments, where 7 studies reported that serious adverse events occurred in patients couldn't be ruled out as the results of therapeutic vaccines. Conclusions: The literature review shows that the literature evidence for the therapeutic vaccines for cervical precancerous lesions is relatively mature compared with the therapeutic vaccines for cervical cancer. The four kinds of vaccines on the market are all therapeutic vaccines for precancerous lesions, but they are generally used as vaginal infection treatments or adjuvant immunotherapies for cervical precancerous lesions, not used for the specific treatments of cervical precancerous lesions. Other specific therapeutic vaccines are in the early stage of clinical trials, mainly phase Ⅰ/Ⅱ clinical trials with small sample size. The effectiveness and safety data are limited, and further research is still needed.
Cancer Vaccines/therapeutic use* ; Cervical Intraepithelial Neoplasia/prevention & control* ; Female ; Humans ; Papillomavirus Infections/prevention & control* ; Papillomavirus Vaccines/therapeutic use* ; Precancerous Conditions/therapy* ; Uterine Cervical Neoplasms/prevention & control*

Objective: To evaluate the performance of point-of-care testing for cervical cancer and precancerous lesions screening. Methods: In September 2020, 197 and 273 women were selected by using simple random sampling method from "self-sampling" cohort and "physician-sampling" cohort established in Xiangyuan county, Shanxi Province, China, respectively. Cervical exfoliated cells were collected by women themselves or gynecologists. All samples were detected by POCT and women with positive result were directly referred for colposcopy. Subsequently, all the samples were detected by careHPV and PCR test. Colposcopy and punch biopsy were performed for women with POCT negative but careHPV or PCR test positive at another visit. Using histopathological diagnosis as the gold standard, we calculated sensitivity, specificity and drew the receiver operating characteristic (ROC) curves. The accuracy of POCT was analyzed and compared to that of careHPV and conventional PCR test in cervical cancer and precancerous lesions screening. Results: The median (Q₁ , Q₃) age of 470 women was 51 (45, 57) years old. Based on self-sampling, the sensitivity and specificity of POCT for CIN2+ were 100.00% (95%CI: 56.56%-100.00%) and 28.95% (95%CI: 22.97%-35.76%), respectively. Compared with POCT, POCT HPV16/18 test had similar sensitivity and higher specificity of 89.47% (95%CI: 84.30%-93.08%). Self-sampling POCT HPV16/18 test had an AUC of 0.947 (95%CI:0.910-0.985), which was higher than that of careHPV and PCR test. Physician-sampling POCT test had 100.00% sensitivity (95%CI: 64.57%-100.00%) and 55.85% specificity (95%CI: 49.83%-61.70%) for detecting CIN2+. POCT HPV16/18 test had lower sensitivity (71.43%, 95%CI: 35.90%-91.76%) and higher specificity (92.45%, 95%CI: 88.63%-95.06%). POCT HPV16/18 test generally showed similar AUC on both self-collected samples and clinician-collected samples (0.947 vs 0.819, P=0.217). Conclusion: POCT HPV16/18 test is an effective method with relatively high sensitivity and specificity for cervical cancer screening.
Cervical Intraepithelial Neoplasia/diagnosis* ; Colposcopy ; Early Detection of Cancer/methods* ; Female ; Human papillomavirus 16/genetics* ; Human papillomavirus 18 ; Humans ; Mass Screening/methods* ; Papillomaviridae ; Papillomavirus Infections/diagnosis* ; Point-of-Care Testing ; Pregnancy ; Sensitivity and Specificity ; Uterine Cervical Neoplasms

Objective: To evaluate the relationship between red blood cell folate (RBC folate) and the prognosis of low-grade cervical intraepithelial neoplasia (CIN 1). Methods: In the married women cohort established in 2014, 564 women with CIN 1 diagnosed by pathology were recruited. The demographic characteristics and factors of cervical intraepithelial neoplasia were collected. Meanwhile, the infection status of human papillomavirus (HPV) was detected by molecular diversion hybridization, and the level of RBC folate was measured by chemical photoimmunoassay. After 24 months of follow-up, pathological examination was performed again to observe the prognosis of participants. The women with reversal were taken as the control group,and those with continuous and progressive CIN 1 were taken as the case group respectively. The relationship between RBC folate and CIN 1 outcome was evaluated by logistic regression model. Results: 453 women completed the follow-up, aged (49.72±6.84) years old. CIN 1 was reversed in 342 women, continued in 58 cases and progressed in 53 cases. The RBC folate level M (Q_1,Q₃) were 399.01 (307.10, 538.97) ng/ml, 316.98 (184.74, 428.49) ng/ml and 247.14 (170.54, 348.97) ng/ml, respectively. With the decrease of RBC folate, the risk of continuous and progressive CIN 1 increased (all P<0.001), while the risk of reversal CIN 1 decreased gradually (P<0.001). Combined with high-risk human papillomavirus (HR-HPV) infection status, low level of RBC folate could increase the risk of CIN 1 progression regardless of HR-HPV infection (HR-HPV infection: OR=21.34, 95%CI: 3.98-114.54; HR-HPV uninfection: OR=11.15, 95%CI: 2.34-53.13). Conclusion: Low level of RBC folate could increase the risk of CIN 1 persistence and progression regardless of HR-HPV infection.
Adult ; Alphapapillomavirus ; Case-Control Studies ; Cervical Intraepithelial Neoplasia ; Erythrocytes ; Female ; Folic Acid ; Humans ; Male ; Middle Aged ; Papillomaviridae ; Papillomavirus Infections ; Uterine Cervical Neoplasms

No abstract available.
Cervical Intraepithelial Neoplasia

OBJECTIVE: To investigate pathologic discrepancies between colposcopy-directed biopsy (CDB) of the cervix and loop electrosurgical excision procedure (LEEP) in women with cytologic high-grade squamous intraepithelial lesions (HSILs).METHODS: We retrospectively identified 297 patients who underwent both CDB and LEEP for HSILs in cervical cytology between 2015 and 2018, and compared their pathologic results. Considering the LEEP to be the gold standard, we evaluated the diagnostic performance of CDB for identifying cervical intraepithelial neoplasia (CIN) grades 2 and 3, adenocarcinoma in situ, and cancer (HSIL+). We also performed age subgroup analyses.RESULTS: Among the study population, 90.9% (270/297) had pathologic HSIL+ using the LEEP. The diagnostic performance of CDB for identifying HSIL+ was as follows: sensitivity, 87.8%; specificity, 59.3%; balanced accuracy, 73.6%; positive predictive value, 95.6%; and negative predictive value, 32.7%. Thirty-three false negative cases of CDB included CIN2,3 (n=29) and cervical cancer (n=4). The pathologic HSIL+ rate in patients with HSIL− by CDB was 67.3% (33/49). CDB exhibited a significant difference in the diagnosis of HSIL+ compared to LEEP in all patients (p<0.001). In age subgroup analyses, age groups <35 years and 35–50 years showed good agreement with the entire data set (p=0.496 and p=0.406, respectively), while age group ≥50 years did not (p=0.036).CONCLUSION: A significant pathologic discrepancy was observed between CDB and LEEP results in women with cytologic HSILs. The diagnostic inaccuracy of CDB increased in those ≥50 years of age.
Adenocarcinoma in Situ ; Biopsy ; Cervical Intraepithelial Neoplasia ; Cervix Uteri ; Colposcopy ; Conization ; Dataset ; Diagnosis ; Early Detection of Cancer ; Female ; Humans ; Papanicolaou Test ; Retrospective Studies ; Sensitivity and Specificity ; Squamous Intraepithelial Lesions of the Cervix ; Uterine Cervical Neoplasms

cervical cancer, the Korean Society of Obstetrics and Gynecology and the Korean Society of Gynecologic Oncology support the following scientific facts:• Compared to cytology, hrHPV screening has higher sensitivity and detects more cases of high-grade cervical intraepithelial neoplasia.• Qualified hrHPV testing can be considered as an alternative primary screening for cervical cancer to the current cytology method.• The starting age of primary hrHPV screening should not be before 25 years because of possible overtreatment in this age, which has a high human papillomavirus (HPV) prevalence but rarely progresses to cancer. The screening interval should be no sooner than every 3 years and no longer than every 5 years.• Before the introduction of hrHPV screening in Korea, research into comparative effectiveness of primary hrHPV screening for cervical cancer should be conducted to determine the appropriate HPV assay, starting age, and screening interval.]]>
Cervical Intraepithelial Neoplasia ; Early Detection of Cancer ; Gynecology ; Human Papillomavirus DNA Tests ; Humans ; Korea ; Mass Screening ; Medical Overuse ; Methods ; Obstetrics ; Prevalence ; Uterine Cervical Neoplasms

OBJECTIVE: To screen potential plasma protein biomarkers for the progression of cervical precancerous lesions into cervical carcinoma and analyze their functions. METHODS: Plasma samples obtained from healthy control subjects, patients with low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), cervical cancer (CC), and patients with CC after treatment were enriched for low-abundance proteins for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The MS data of the samples were analyzed using Discoverer 2.2 software, and the differential proteins (peptide coverage ≥20%, unique peptides≥2) were screened by comparison of LSIL, HSIL and CC groups against the control group followed by verification using target proteomics technology. Protein function enrichment and coexpression analyses were carried out to explore the role of the differentially expressed proteins as potential biomarkers and their pathological mechanisms. RESULTS: Compared with the control group, both LSIL group and HSIL group showed 9 differential proteins; 5 differentially expressed proteins were identified in CC group. The proteins ORM2 and HPR showed obvious differential expressions in LSIL and HSIL groups compared with the control group, and could serve as potential biomarkers for the progression of cervical carcinoma. The expression of F9 increased consistently with the lesion progression from LSIL to HSIL and CC, suggesting its value as a potential biomarker for the progression of cervical cancer. CFI and AFM protein levels were obviously decreased in treated patients with CC compared with the patients before treatment, indicating their predictive value for the therapeutic efficacy. Protein function enrichment analysis showed that all these differentially expressed proteins were associated with the complement system and the coagulation cascades pathway. CONCLUSIONS We identified 5 new protein biomarkers (F9, CFI, AFM, HPR, and ORM2) for cervical precancerous lesions and for prognostic evaluation of CC, and combined detection of these biomarkers may help in the evaluation of the development and progression of CC and also in improving the diagnostic sensitivity and specificity of cervical lesions.
Antigens, Neoplasm ; blood ; Biomarkers, Tumor ; blood ; Carrier Proteins ; blood ; Case-Control Studies ; Cervical Intraepithelial Neoplasia ; blood ; diagnosis ; Chromatography, Liquid ; Complement Factor I ; analysis ; Early Detection of Cancer ; Female ; Glycoproteins ; blood ; Haptoglobins ; Humans ; Neoplasm Proteins ; blood ; Orosomucoid ; analysis ; Precancerous Conditions ; blood ; diagnosis ; Serum Albumin, Human ; Tandem Mass Spectrometry ; Uterine Cervical Neoplasms ; blood ; diagnosis

OBJECTIVE: To show noninferiority of a limited-excision (resection of the dysplastic lesion only) vs. classical Large Loop Excision of the Transformation Zone (LLETZ). METHODS: In this prospective, randomized, multicenter trial, women with human papillomavirus (HPV) positive cervical intraepithelial neoplasia grade 3 were randomized into two groups (1:1). Primary outcome was the rate of negative HPV tests after 6 months, secondary outcomes included cone size, complete resection rates as well as cytological and histological results after 6 and 12 months. A sample size of 1,000 was calculated to show noninferiority of the limited-excision compared to the LLETZ group using a noninferiority margin of 5%. Enrollment was stopped after 100 patients due to slow accrual. RESULTS: Patients in the limited-excision group did not show a lower number of negative HPV tests (78% [LLETZ]−80% [limited-excision]=−2%; 90% confidence interval=−15%, 12%). The limited-excision resulted in a substantially lower cone size (LLETZ: 1.97 mL vs. limited-excision: 1.02 mL; p < 0.001) but higher numbers of involved margins (LLETZ: 8% vs. limited-excision: 20%). Although postoperative cytological results slightly differed, histological results were similar in both groups. One limited-excision patient received immediate re-conisation, whereas one patient in each group was scheduled for re-conisation after 6 months. CONCLUSION: The limited-excision could represent a promising option to reduce the surgical extent of conisations while maintaining oncological safety. The trial was not sufficiently powered to reach statistical significance due to early termination. Nevertheless, the study provides important insights in the feasibility of a limited-excision and could serve as a pilot study for future trials. TRIAL REGISTRATION: German Clinical Trials Register Identifier: DRKS00006169
Cervical Intraepithelial Neoplasia ; Conization ; Female ; Humans ; Multicenter Studies as Topic ; Pilot Projects ; Premature Birth ; Prospective Studies ; Sample Size

Loop electrosurgical excision procedure (LEEP) is commonly performed for the management of cervical intraepithelial neoplasia. Although LEEP is considered to be a relatively simple procedure, several unexpected complications have been reported in the literature. Herein, we report a case of hemoperitoneum caused by uterine perforation following LEEP. Blood collection in pelvic cavity and two small defects of the uterus were confirmed by diagnostic laparoscopy. The defects were sutured and the patient recovered well after the operation.
Cervical Intraepithelial Neoplasia ; Conization ; Hemoperitoneum ; Humans ; Laparoscopy ; Uterine Perforation ; Uterus

OBJECTIVE: To evaluate the risk of genotype-specific human papillomavirus (HPV) infections for the spectrum of cervical carcinogenesis and the distribution of HPV types according to age and different cervical lesions METHODS: This study included HPV-positive women who underwent cervical biopsy at the Cheil General Hospital & Women's Healthcare Center between July 1, 2011 and December 31, 2017. HPV genotyping was conducted using a Cheil HPV DNA chip kit. RESULTS: The study sample consisted of 400 normal, 399 cervical intraepithelial neoplasia (CIN) 1, 400 CIN 2, 400 CIN 3, and 389 cervical cancer cases. HPV 16 was the most common type found with a prevalence of 9.5% in normal, 6.8% in CIN 1, 15.0% in CIN 2, 44.5% in CIN 3, and 64.3% in cervical cancer. The most common HPV types were 16, 52, 58, 53, 51, 56, 68, and 18 in all study samples. HPV 16, 31, 33, and 58 were more common in CIN 2/3 and cancer, and HPV 39, 51, 53, 56, 66, and 68 were more common in CIN 1 and normal cases (p<0.001). In CIN 3 and cervical cancer, HPV 16 was the most common type in all age groups. HPV 52 was the most common type in CIN 2 (all age groups) and in CIN 1/normal (age ≤30 years) cases. Among the high-risk HPV types, 16, 31, 33, 52, and 58 showed significant risk for high-grade disease. CONCLUSIONS: HPV 16, 31, 33, 52, and 58 showed the significant risk of high-grade disease for cervical carcinogenesis.
Biopsy ; Carcinogenesis ; Cervical Intraepithelial Neoplasia ; Delivery of Health Care ; Female ; Genotype ; Hospitals, General ; Human papillomavirus 16 ; Humans ; Oligonucleotide Array Sequence Analysis ; Papillomaviridae ; Prevalence ; Uterine Cervical Neoplasms