Overweight and obesity as risk factors for cervical cancer and detection of precancers among screened women: A nationwide, population-based cohort study.

OBJECTIVE: Obesity is a known risk factor for many types of cancer. However, there is no clear evidence whether overweight and obesity increases the risk of cervical cancer. We investigated the association between body mass index (BMI) and detection of squamous and glandular cervical cancer and precancer. METHODS: Based on the Medical Birth Registry, we conducted a nationwide cohort study in Denmark of 384,559 women with BMI ≥18.5 kg/m2 (pre-pregnancy BMI reported at the start of the pregnancy) having a cervical cytology screening at age 23-49 years within 5 years following the date of childbirth. The cohort was followed for 10 years from the first cervical cytology screening after the childbirth. We assessed absolute risks of cervical lesions according to BMI with the Aalen-Johansen estimator. We conducted Cox proportional hazards regression analyses to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses were adjusted for age, calendar year, parity, oral contraception use, HPV vaccination, smoking, country of origin, and education. RESULTS: Overweight and obesity were associated with higher rates of cervical cancer (HR = 1.24, 95% CI 1.04-1.49 and HR = 1.14, 95% CI 0.91-1.43, respectively) and lower rates of cervical precancer detection (HR = 0.88, 95% CI 0.84-0.92 and HR = 0.67, 95% CI 0.63-0.71, respectively). CONCLUSIONS: Higher than normal BMI was associated with higher incidence rates of cervical cancer and lower rates of precancer detection, emphasizing the importance of further research in possible mechanisms behind this association.

Potential anatomical determinants of retrograde menstruation: a comprehensive narrative review.

A century ago, Sampson identified three uterine anatomical structures that may determine the amount of retrograde menstruation and the likelihood of the development of endometriosis: the cervix, the intramural portion of the fallopian tubes, and the myometrium. Critical appraisal was undertaken of data published over the last 40 years on the potential effect of the characteristics of these three anatomical variables on the risk of endometriosis. There is some evidence to support the pathogenic role of the diameter of the cervical canal, stenosis of internal or external orifices, and stiffness of cervical tissue. One study showed a significant association between the morphology of the intramural tubal tract and the frequency of endometriosis. A large body of evidence points to abnormalities of the myometrial structure as the anatomical aberration most consistently associated with endometriosis. These abnormalities have largely been interpreted as signs of early-onset adenomyosis, which may precede endometriosis and even lead to its development by increasing the amount of retrograde menstruation. Future research should aim to verify whether a positive relationship exists between the substantially increased number of ovulatory menses occurring in the decade following menarche, the development of anatomical myometrial abnormalities, changes in the amount of retrograde menstruation over time, and the risk of endometriosis.

Real-time ultrasound demonstration of uterine isthmus contractions during pregnancy.

BACKGROUND: Asymptomatic isthmic contractions are a frequent physiological phenomenon in pregnancy, sometimes triggered by bladder voiding. They can interfere with proper cervical length assessment and may lead to false images of placenta previa. However, there is limited research on the prevalence and characteristics of these contractions. OBJECTIVE: This study aimed to determine the prevalence and characteristics of isthmic contractions after bladder voiding in the second trimester of pregnancy, to evaluate their effect on cervical length assessment, and to propose a new method for the objective assessment of the presence and intensity of isthmic contractions. STUDY DESIGN: In this prospective observational study, long videos of the uterine cervix were recorded in 30 singleton pregnancies during the second trimester of pregnancy after bladder voiding. Isthmic length and cervicoisthmic length changes were assessed over time. The isthmic length was measured using a new approach, which involved calculating the distance from the base of the cervix to the internal os, including the isthmus. RESULTS: Isthmic contractions were observed in 43% of pregnant women (95% confidence interval, 26%-62%) after bladder voiding. The median time for complete isthmus relaxation was 19.7 minutes (95% confidence interval, 15.0 to not available). No substantial differences in maternal characteristics were found between individuals with and without contractions. The proposed method for measuring isthmic length provided an objective assessment of the presence and intensity of isthmic contractions. A cutoff of 18 mm in isthmic length allowed for the distinction of pregnant women presenting a contraction. In addition, the study identified a characteristic undulatory pattern in the relaxation of the isthmus in half of the cases with contractions. CONCLUSION: Isthmic contractions are a common occurrence after bladder voiding in the second trimester of pregnancy and may interfere with proper cervical length assessment. We recommend performing cervical assessment at least 20 minutes after bladder voiding to reduce the risk of bias in cervical length measurement and to avoid false images of placenta previa. The new method for measuring isthmic length provides an objective way to assess the presence and intensity of isthmic contractions. Further research is needed to understand the role of isthmic contractions in the physiology of pregnancy and birth.

Impact of CD44 genetic variants on clinicopathological characteristics of uterine cervical cancer patients.

CD44 genetic variants have been found to be related to various cancers. However, to date, no study has demonstrated the involvement of CD44 polymorphisms in uterine cervical cancer in Taiwanese women. Therefore, we conducted a retrospective study, consecutively recruiting 113 patients with invasive cancer, 92 patients with high-grade cervical intraepithelial neoplasias, and 302 control women to assess the relationships among CD44 polymorphisms, cervical carcinogenesis, and patient survival. Real-time polymerase chain reaction was used to determine the genotypic distributions of six polymorphisms: rs1425802, rs187115, rs713330, rs11821102, rs10836347, and rs13347. The results revealed that women with the mutant homozygous genotype CC exhibited a higher risk of invasive cancer compared to those with the wild homozygous genotype TT [p=0.035; hazard ratio (HR)=10.29, 95% confidence interval (95% CI)=1.18-89.40] and TT/TC [p=0.032; HR=10.66, 95% CI=1.23-92.11] in the CD44 polymorphism rs713330. No significant association was found between CD44 genetic variants and clinicopathological parameters. Among the clinicopathological parameters, only positive pelvic lymph node metastasis (p=0.002; HR=8.57, 95% CI=2.14-34.38) and the AG/GG genotype compared to AA (p=0.014; HR=3.30, 95% CI=1.28-8.49) in CD44 polymorphism rs187115 predicted a higher risk of poor five-year survival, according to multivariate analysis. In conclusion, an important and novel finding revealed that Taiwanese women with the AG/GG genotype in CD44 polymorphism rs187115 exhibited a higher risk of poor five-year survival.

Concomitant ectopic Enterobius vermicularis infection in uterine cervical cancer.

BACKGROUND: Enterobius vermicularis (E. vermicularis), also referred to as pinworm, is a widespread human intestinal parasite which predominantly occurs in young children, making their caretakers a population at risk for the transmission of this helminth. It can occasionally affect extraintestinal organs and tissues, including the female genital tract. Infestation can be asymptomatic or manifest as different kinds of gynaecological disorders, such as pelvic inflammation mimicking tumours, abnormal uterine bleeding, or vaginitis. Diagnosis is made by identifying ova in the sample collected from the perineal skin using a transparent adhesive tape or microscopic examination of resected tissue. Mebendazole is the first-line medication and should also be administered to all household members. CASE PRESENTATION: We present a case of a patient who had undergone surgery for invasive cervical cancer with an accidental finding of E. vermicularis eggs in the cervix. CONCLUSIONS: Although not very common, infestation with E. vermicularis should be considered in differential diagnoses of various gynaecological disorders accompanied by histological findings of granulomatous inflammation.

Novel predictors for identifying cervical minimal deviation adenocarcinoma patients with poor prognosis: a long-term observational study in a tertiary centre.

PURPOSE: To elucidate the clinicopathological features and prognostic factors of minimal deviation adenocarcinoma (MDA) of the uterine cervix, a clinically rare but highly invasive disease. METHODS: This was a retrospective, observational, real-world study of 43 patients with pathologically confirmed MDA at the Obstetrics and Gynaecology Hospital of Fudan University between November 2010 and November 2021. Baseline clinicopathological data were collected and reviewed. Prognostic factors for progression-free survival (PFS) and overall survival (OS) were investigated by univariate and multivariate Cox proportional hazards analyses. RESULTS: Chief complaints included irregular vaginal discharge and/or bleeding (74.4%). Preoperative diagnosis was difficult, the detection rate was low (36.8%), all cases showed endophytic lesions, and 88.4% had deep stromal invasion, with biologically aggressive characteristics. The ovarian metastasis rate was high (16.3%, 7/43). The median maximum diameter of the tumour (MDOT) was 4.3 cm (range, 0.5-8.0 cm). MDOT was significantly associated with OS (P = 0.009), and the optimal cut-off value to define bulky MDA was 5.5 cm (P < 0.0001, χ= 21.161) using X-tile software. Independent prognostic factors included MDOT (HR = 10.095, P = 0.001) and ovarian metastasis (HR = 5.888, P = 0.008) for OS and MDOT (HR = 3.944, P = 0.028), ovarian metastasis (HR = 9.285, P = 0.001), and deep infiltration (HR = 3.627, P = 0.048) for PFS. CONCLUSION: Endophytic lesion development and ovarian metastasis are likely in MDA. A bulky tumour and ovarian metastasis indicate a worse prognosis. Given the special biological features of MDA, it is more appropriate to use 5.5 cm as the threshold for defining a bulky tumour than it is to use 4 cm. Ovary removal should be given higher priority to improve prognosis.

Recommendations for strain elastography of the uterine cervix.

PURPOSE: Conventional vaginal strain ultrasound elastography, not based on shear-wave elastography imaging, can assess the biomechanical properties of the uterine cervix. This assessment may inform the risks of preterm birth and failed induction of labor. However, there is considerable variation in the approaches to strain elastography, including the placement of the region of interest (ROI). Therefore, our aim was to provide recommendations for cervical elastography. METHODS: We conducted a literature review on (1) elastography principles, and (2) the cervical anatomy. Subsequently, we performed elastography scanning using a Voluson™ E10 Expert scanner with the BT18 software of (3) polyacrylamide hydrogel simulators, and (4) pregnant women. RESULTS: Increasing the distance between the ROI and probe led to a decrease in the obtained strain value; a 53% decrease was observed at 17.5 mm. Similarly, an increased angle between the ROI and probe-centerline resulted in a 59% decrease for 40° angle. Interposition of soft tissue (e.g., cervical canal) between the ROI and the probe induced an artifact with values from the posterior lip being 54% lower than those from the anterior lip, even after adjusting for probe-ROI distance. Equipment and the recording conductance significantly influenced the results. CONCLUSION: Our findings inform recommendations for future studies on strain cervical elastography.

[A Case of Adenocarcinoma, HPV-independent, Mesonephric Type with Significant Response to Neoadjuvant Chemotherapy].

Adenocarcinoma, HPV-independent, mesonephric type (hereafter referred to as "mesonephric carcinoma") arising from the cervix is rare, its treatment has not been established, and its sensitivity to chemotherapy has not been fully investigated. Here we report on a 30-year-old female patient who presented at our hospital with a chief complaint of abnormal genital bleeding. We suspected cervical cancer. Based on examination, biopsy, and imaging, she was diagnosed with stage IIA2 adenocarcinoma of the cervix and was scheduled for surgery. Because she had a SARS-COV-2 infection, she was given two courses of paclitaxel-carboplatin (TC) therapy, based on the then-current surgical risk assessment after SARS-COV-2 infection, with a waiting period of at least 8 weeks. The patient was deemed to have a partial response and was treated with paclitaxel and carboplatin, after which she was deemed to have a partial response and underwent total hysterectomy. A diagnosis of stage IIA2 mesonephric carcinoma, ypT1b2N0M0, was made after histopathologic examination of an excised specimen. The patient was treated with 4 additional courses of TC therapy after surgery, and has had no recurrence in 13 months. We report a first case of response to neoadjuvant chemotherapy with TC regimen in a patient with mesonephric carcinoma of the cervix.

Impact of antigen retrieval protocols on the immunohistochemical detection of epigenetic DNA modifications.

This study compares three different pretreatment protocols for the immunohistochemical detection of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in nuclear DNA. The human biological samples analyzed included formalin-fixed and paraffin-embedded (FFPE) normal squamous epithelium, ethanol-fixed cultured cells, and metaphase chromosomes. The antigen retrieval methods included low pH Citrate and high pH Tris-ethylenediaminetetraacetic acid (EDTA) protocols, as well as a method using Pepsin pretreatment combined with HCl for DNA denaturation. A gradual increase in the detection levels of 5-mC and 5-hmC was observed when going from Citrate via Tris/EDTA to Pepsin/HCl retrieval. While the Citrate retrieval protocol was the least efficient for the detection of 5-mC and 5-hmC, it did preserve nuclear morphology and enabled visualization of differences in intra- and internuclear distribution patterns in tissue and cell culture samples by single- and double-fluorescence detection. Quantification of (hydroxy)methylation levels in FFPE material demonstrated a significant heterogeneity and differences in 5-mC and 5-hmC levels within and between nuclei in the different compartments of normal squamous epithelium. It was concluded that immunohistochemical detection of 5-mC and 5-hmC enables the correlation of these DNA modifications with histomorphological features in heterogeneous tissues, but this is influenced by different pretreatment protocols that must be carefully chosen to allow an appropriate interpretation of these epigenetic switches.

Relation between adenomyosis and elastographic characteristics of the cervix.

STUDY QUESTION: Is there a possible etiologic link between cervical stiffness and adenomyosis? SUMMARY ANSWER: Women with adenomyosis have a stiffer internal cervical os than those without adenomyosis. WHAT IS KNOWN ALREADY: An increased myometrial contractility during menses, leading to breaches in the endometrial basal lamina and subsequent infiltration of endometrial cells into the myometrium, has been proposed as a possible pathogenic mechanism for adenomyosis. Intense menstrual pain has already been shown to be associated with an increased stiffness, at elastography, of the internal cervical os. STUDY DESIGN, SIZE, DURATION: A cross-sectional study on 275 women was performed between 1 February and 31 July 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among the participants, 103 were and 172 women were not affected by adenomyosis as evaluated by ultrasonography. General and clinical characteristics of the patients were collected. Strain elastography was used to document tissue stiffness at different regions of interest of the cervix, i.e. the internal cervical os, the middle cervical canal, the anterior and the posterior cervical compartment. Tissue stiffness was expressed as a colour score from 0.1 = blue/violet (high stiffness) to 3.0 = red (low stiffness). Simple and multiple logistic regression analyses were used to evaluate the relation between the presence of adenomyosis, as the dependent variable, and independent factors. MAIN RESULTS AND THE ROLE OF CHANCE: Women with adenomyosis had a higher prevalence (P = 0.0001) and intensity (P = 0.0001) of pain during menses, between menses and at intercourse compared to control. The internal cervical os colour score was lower (higher stiffness) in women with adenomyosis (0.55 ± 0.29 versus 0.67 ± 0.26; P = 0.001) and the middle cervical canal/internal cervical os colour score ratio was greater (3.32 ± 4.36 versus 2.59 ± 4.99; P = 0.008), compared to controls. Upon logistic regression modelling (R2 = 0.077), the internal cervical os stiffness was an independent factor related to adenomyosis (odds ratio (OR) 0.220, 95% CI 0.077, 0.627; P = 0.005) along with age (P = 0.005) and the use of gonadal steroid therapies (P = 0.002). We obtained the same results using a different logistic regression model (R2 = 0.069), by substituting the internal cervical os stiffness with the ratio of the middle cervical canal/internal cervical os stiffness (OR 1.157, 95% CI 1.024, 1.309; P = 0.019). LIMITATIONS, REASONS FOR CAUTION: Women did not undergo surgery therefore we have no histological confirmation of the adenomyosis diagnosis. Strain elastography is a semiquantitative analysis and can be conditioned by the force applied by the operator during the analysis. The data were obtained mainly in White women in a single centre. WIDER IMPLICATIONS OF THE FINDINGS: To the best of our knowledge, this is the first study indicating that women with adenomyosis have an increased stiffness of the internal cervical os. The results indicate that a stiff internal cervical os, as determined by elastography, is a possible contributor to the development of adenomyosis. These findings may have clinical significance and should prompt further investigation. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

The role of transvaginal ultrasound in the third-trimester evaluation of patients at high risk of placenta accreta spectrum at birth.

BACKGROUND: Transvaginal ultrasound imaging has become an essential tool in the prenatal evaluation of the lower uterine segment and anatomy of the cervix, but there are only limited data on the role of transvaginal ultrasound in the management of patients at high risk of placenta accreta spectrum at birth. OBJECTIVE: This study aimed to evaluate the role of transvaginal sonography in the third trimester of pregnancy in predicting outcomes in patients with a high probability of placenta accreta spectrum at birth. STUDY DESIGN: This was a retrospective analysis of prospectively collected data of patients presenting with a singleton pregnancy and a history of at least 1 previous cesarean delivery and patients diagnosed prenatally with an anterior low-lying placenta or placenta previa delivered electively after 32 weeks of gestation. All patients had a least 1 detailed ultrasound examination, including transabdominal and transvaginal scans, within 2 weeks before delivery. Of note, 2 experienced operators, blinded to the clinical data, were asked to make a judgment on the likelihood of placenta accreta spectrum as a binary, low or high-probability of placenta accreta spectrum, and to predict the main surgical outcome (conservative vs peripartum hysterectomy). The diagnosis of accreta placentation was confirmed when one or more placental cotyledons could not be digitally separated from the uterine wall at delivery or during the gross examination of the hysterectomy or partial myometrial resection specimens. RESULTS: A total of 111 patients were included in the study. Abnormal placental tissue attachment was found in 76 patients (68.5%) at birth, and histologic examination confirmed superficial villous attachment (creta) and deep villous attachment (increta) in 11 and 65 cases, respectively. Of note, 72 patients (64.9%) had a peripartum hysterectomy, including 13 cases with no evidence of placenta accreta spectrum at birth because of failure to reconstruct the lower uterine segment and/or excessive bleeding. There was a significant difference in the distribution of placental location (X2=12.66; P=.002) between transabdominal and transvaginal ultrasound examinations, but both ultrasound techniques had similar likelihood scores in identifying accreta placentation that was confirmed at birth. On transabdominal scan, only a high lacuna score was significantly associated (P=.02) with an increased chance of hysterectomy, whereas on transvaginal scan, significant associations were found between the need for hysterectomy and the thickness of the distal part of the lower uterine segment (P=.003), changes in the cervix structure (P=.01), cervix increased vascularity (P=.001), and the presence of placental lacunae (P=.005). The odds ratio for peripartum hysterectomy were 5.01 (95% confidence interval, 1.25-20.1) for a very thin (<1-mm) distal lower uterine segment and 5.62 (95% confidence interval, 1.41-22.5) for a lacuna score of 3+. CONCLUSION: Transvaginal ultrasound examination contributes to both prenatal management and the prediction of surgical outcomes in patients with a history of previous cesarean delivery with and without ultrasound signs suggestive of placenta accreta spectrum. Transvaginal ultrasound examination of the lower uterine segment and cervix should be included in clinical protocols for the preoperative evaluation of patients at risk of complex cesarean delivery.

Performance of the Matsumiya scoring system in cervical cancer patients with bone metastasis: an external validation study.

BACKGROUND: Accurate prognostic prediction of survival in cervical cancer patients with bone metastasis is important for treatment planning. We aimed to externally validate the Matsumiya scoring system using external patient data. METHODS: We collected a retrospective cohort of patients with cervical cancer diagnosed with bone metastasis at Chiang Mai University Hospital from 1st January 2007 to 31st December 2016. The Matsumiya score was composed of 5 predictors, including the presence of extraskeletal metastasis, ECOG performance status, history of previous chemo- or radiotherapy, the presence of multiple bone metastasis, and bone metastasis-free interval < 12 months. Harrell's C-statistics and score calibration plots were used to evaluate the score performance. We also reconstructed the development study to estimate apparent performance values for comparison during external validation. RESULTS: A total of 124 cervical cancer patients with bone metastasis were included in this study. The 13-, 26-, and 52-week survival probabilities in the validation study were 70.1%, 50.5%, and 25.7%, respectively. Several differences were identified between development and validation studies regarding clinical characteristics, case-mix, and predictor-outcome associations. Harrell's C-statistics in the development and validation study were 0.714 and 0.567. The score showed poor agreement between the observed and the predicted survival probabilities in the validation study. Score reweighting and refitting showed only modest improvement in performance. CONCLUSION: A prognostic scoring system by Matsumiya et al. performed poorly in our cohort of Thai cervical cancer patients with bone metastasis. We suggested that the score should be sufficiently updated before being used.

Spindle-nucleated cells in cervical liquid-based cytology: Difficulties in distinguishing between epithelial and non-epithelial tumours based on morphology.

Uterine tumours resembling ovarian sex cord tumours of the uterine cervix are highly sporadic. Cervical liquid-based cytology revealed two cell patterns: spindle-nucleated cells and polygonal cells.

The lymphatic system of the uterine cervix: towards a more precise definition of the drainage routes.

PURPOSE: Lymph node involvement in cancer of the uterine cervix is a major independent prognostic factor for overall survival. The aim of our study was to examine the lymphatic drainage regions of the different parts of the uterine cervix. METHODS: An anatomical study of fresh cadavers was conducted by injecting patent blue in the anterior or posterior lip of the uterine cervix and dissecting drainage regions. Furthermore, a retrospective radiological and pathological studies were conducted on patients who were treated for early-stage cancer of the uterine cervix with lymph node involvement. Radiological analysis of pre-therapeutic MRIs and/or pathological analysis of surgical specimens showed the precise location of the tumour. A correlation between the anatomy of the primary lesion site and the lymphatic area involved was established. RESULTS: We administered 15 cadaveric injections: 8 in the anterior lip of the uterine cervix and 7 in the posterior one. For 100% of the anterior lip injections, lymphatic drainage was bilateral ileo-obturator (n = 8/8) combined with bilateral parametrial drainage. For the posterior injections, there was never any ileo-obturator drainage, and 6 of the 7 (75%) posterior injections drained in the posterior uterine serosa. Concerning the clinical study, we included 21 patients. We observed a non-significant tendency towards bilateral lymph node involvement when the tumour of the anterior lip. CONCLUSION: Physiological lymphatic drainage of the uterine cervix presents anatomical specificities, depending on the structure studied, anterior or posterior lip of the cervix. Better knowledge of these specificities should allow personalized surgery for each patient.

Management of Pregnancy with Cervical Shortening: Real-Life Clinical Challenges.

Background and Objectives: Preterm birth is the leading cause of neonatal mortality worldwide and may be responsible for lifelong morbidities in the survivors. Cervical shortening is one of the common pathways to preterm birth associated with its own diagnostic and management challenges. The preventive modalities that have been tested include progesterone supplementation and cervical cerclage and pessaries. The study aimed to assess the management strategies and outcomes in a group of patients with a short cervix during pregnancy or cervical insufficiency. Materials and Methods: Seventy patients from the Riga Maternity Hospital in Riga, Latvia, were included in the prospective longitudinal cohort study between 2017 and 2021. Patients were treated with progesterone, cerclage, and/or pessaries. The signs of intra-amniotic infection/inflammation were assessed, and antibacterial therapy was given when the signs were positive. Results: The rates of PTB were 43.6% (n = 17), 45.5% (n = 5), 61.1% (n = 11), and 50.0% (n = 1) in progesterone only, cerclage, pessary, and cerclage plus pesssary groups, respectively. The progesterone therapy was associated with a reduced preterm birth risk (x2(1) = 6.937, p = 0.008)), whereas positive signs of intra-amniotic infection/inflammation significantly predicted the risk of preterm birth (p = 0.005, OR = 3.82, 95% [CI 1.31-11.11]). Conclusions: A short cervix and bulging membranes, both indicators of intra-amniotic infection/inflammation, are the key risk factors in preterm birth risk predictions. Progesterone supplementation should remain at the forefront of preterm birth prevention. Among patients with a short cervix and especially complex anamnesis, the preterm rates remain high. The successful management of patients with cervical shortening lies between the consensus-based approach for screening, follow-up, and treatment on the one side and personalising medical therapy on the other.

Scientific evaluation of alleged findings in HPV vaccines: Molecular mimicry and mouse models of vaccine-induced disease.

Cervical cancer is caused by infections of the human papillomavirus (HPV), which can be prevented by vaccinations. In Japan, although about 3000 people die of cervical cancer annually, the HPV vaccination rate has remained extremely low in the eligible population since many Japanese have been concerned that "diverse symptoms," such as chronic pain, movement disorders, and cognitive impairment, may occur as adverse reactions after HPV vaccination. The concern has been raised by media coverage of the ongoing HPV vaccine lawsuits, in which the plaintiffs complained of their symptoms caused by HPV vaccination. The claims have been based on the alleged pathogenic findings in research articles on HPV vaccines, summarized in the document prepared by the plaintiffs' attorneys. We critically evaluated these articles, in which the authors proposed the following findings/hypothesis: (i) molecular mimicry between HPV L1 and human proteins leads to the production of cross-reactive antibodies; and (ii) HPV vaccine injection in mice causes damage in the brain, a mouse model for HPV vaccine associated neuro-immunopathic syndrome (HANS). We found that these hypotheses were based mainly on the findings from a few research groups and that all the articles had flaws in the method, result, or discussion sections. Our current evaluation should help better understand the validity of the findings, which have been often misunderstood as the truth by the general public. We propose to accumulate high-quality data on potential adverse events following HPV vaccination and to continue critically evaluating them.

Cervical cancer elimination in Indian context: Moving from barriers to facilitators.

It has been 46 years since the launch of cancer control programs in India and yet the recent National Family Health Survey (fifth round, 2019-2021) has reported that just 1.9% of women aged 30-49 years have ever undergone cervical cancer screening. The cost of delayed diagnosis of cervical cancer and its treatment is overwhelming, and the rural population takes the worst hit. It is the need of the hour that the Indian health system and policymakers identify the barriers and facilitators for cervical cancer early detection and provide pragmatic solutions so that the targets of cervical cancer elimination can be achieved in a timely manner.

High expression level of CXCL1/GROα is linked to advanced stage and worse survival in uterine cervical cancer and facilitates tumor cell malignant processes.

BACKGROUND: CXCL1 belongs to a member of the ELR + CXC chemokine subgroups that also known as GRO-alpha. It has been recognized that several types of human cancers constitutively express CXCL1, which may serve as a crucial mediator involved in cancer development and metastasis via an autocrine and/or paracrine fashion. However, the expression pattern and clinical significance of CXCL1 in human uterine cervix cancer (UCC), as well as its roles and mechanisms in UCC tumor biology remains entirely unclear. METHODS: The expression and clinical significance of CXCL1 in UCC tissues was explored using immunohistochemistry and bioinformatics analyses. The expression and effects of CXCL1 in HeLa UCC cells were assessed using ELISA, CCK-8 and transwell assays. Western blotting experiments were performed to evaluate the potential mechanism of CXCL1 on malignant behaviors of HeLa UCC cells. RESULTS: The current study demonstrated that CXCL1 was expressed in HeLa UCC cells, PHM1-41 human immortalized cervical stromal cells, as well as cervical tissues, with UCC tissues having an evidently high level of CXCL1. This high level of CXCL1 in cancer tissues was notably related to poor clinical stages and worse survival probability, rather than tumor infiltration and patient age. In addition, CXCL1 expression was extremely correlated with CCL20, CXCL8 and CXCL3 cancer-associated chemokines expression. In vitro, the growth and migration abilities of HeLa cells were significantly enhanced in the presence of exogenous CXCL1. Gain-function assay revealed that CXCL1 overexpression significantly promoted growth and migration response in HeLa cells in both autocrine and paracrine manners. Finally, we found that CXCL1 overexpression in HeLa cells influenced the expression of ERK signal-related genes, and HeLa cell malignant behaviors derived from CXCL1 overexpression were further interrupted in the presence of the ERK1/2 blocker. CONCLUSION: Our findings demonstrate the potential roles of CXCL1 as a promoter and a novel understanding of the functional relationship between CXCL1 and the ERK signaling pathway in UCC.

Women with obesity participate less in cervical cancer screening and are more likely to have unsatisfactory smears: Results from a nationwide Danish cohort study.

Some studies found an association between obesity and increased cervical cancer risk, but potential mechanisms are unknown. In this nationwide register-based cohort study, we investigated the association between overweight/obesity and cervical cancer screening participation and risk of unsatisfactory smears. The study population was identified in the Danish Medical Birth Registry. We included 342,526 women aged 23-49 years with pre-pregnancy body mass index (BMI) registered during 2004-2013. Screening participation and unsatisfactory smears during up to four years after child birth were identified in a nationwide pathology register. We used absolute risk regression to estimate the relative absolute risk (RAR) with 95% confidence intervals (CIs) of screening participation according to BMI, adjusted for age, calendar year, sociodemographic characteristics, parity and previous high-grade cervical intraepithelial neoplasia. Among those who were screened (n = 295,482), we used log-binomial regression to investigate the relative risk (RR) of an unsatisfactory smear according to BMI, adjusted for age, year, parity, oral contraceptive use and pathology department. A lower proportion of obese women (79.3%) than women of normal weight (85.8%) were screened, and obese women had lower adjusted probability of being screened than women of normal weight (RARadjusted = 0.94, 95% CI, 0.93-0.95). A higher proportion of obese women (2.4%) than women of normal weight (1.7%) had an unsatisfactory smear, and this association remained after adjustments (RRadjusted = 1.28, 95% CI, 1.19-1.38). In conclusion, women with obesity were less likely to participate in cervical cancer screening and more likely to have an unsatisfactory smear than women of normal weight.

Evidence of latent HPV infection in older Danish women with a previous history of cervical dysplasia.

INTRODUCTION: Understanding whether human papillomavirus (HPV) may establish latency in the uterine cervix is important. A better understanding of HPV natural history is useful for clinical counseling of women attending screening and to accurately inform health prevention strategies such as screening and HPV vaccination. We evaluated the extent of latent HPV infections in older women with a history of abnormal cytology. MATERIAL AND METHODS: We conducted a cross-sectional study in Aarhus, Denmark, from March 2013 through April 2015. Women were enrolled if they underwent cervical amputation or total hysterectomy because of benign disease. Prior to surgery, women completed a questionnaire and a cervical smear was collected for HPV testing and morphological assessment. For evaluation of latency (i.e., no evidence of active HPV infection, but HPV detected in the tissue), we selected women with a history of abnormal cervical cytology or histology, as these women were considered at increased risk of harboring a latent infection. Cervical tissue underwent extensive HPV testing using the SPF10-DEIA-LipA25 assay. RESULTS: Of 103 women enrolled, 26 were included in this analysis. Median age was 55 years (interquartile range [IQR] 52-65), and most women were postmenopausal and parous. The median number of sexual partners over the lifetime was six (IQR 3-10), and 85% reported no recent new sexual partner. Five women (19.2%) had evidence of active infection at the time of surgery, and 19 underwent latency evaluation. Of these, a latent infection was detected in 11 (57.9%), with HPV16 being the most prevalent type (50%). Nearly 80% (n = 14) of the 18 women with a history of previous low-grade or high-grade cytology with no treatment had an active or latent HPV infection, with latent infections predominating. HPV was detected in two of the six women with a history of high-grade cytology and subsequent excisional treatment, both as latent infections. CONCLUSIONS: HPV can be detected in cervical tissue specimens without any evidence of an active HPV infection, indicative of a latent, immunologically controlled infection. Modeling studies should consider including a latent state in their model when estimating the appropriate age to stop screening and when evaluating the impact of HPV vaccination.