Factors associated with loss to follow up after abnormal cervical cancer screening in pregnancy.

OBJECTIVE: To assess risk factors associated with loss to follow up in patients referred for colposcopy after abnormal cervical cytology during pregnancy in a Southern safety net hospital population. METHODS: An urban colposcopy center was queried for patients referred for follow up of abnormal cervical cytology during pregnancy and the postpartum period. Patients were identified through a standardized referral code in the electronic medical record. Multivariable logistic regression was used to compare patient characteristics between those who followed up for colposcopy and those lost to follow up. Independent risk factors assessed included age, parity, race, insurance, HIV status, history of mental illness, BMI, gestational age and trimester at screening, cytology at colposcopy referral, interval days until colposcopy, and biopsy histology. RESULTS: 1063 patients were identified, with 40.8% of patients who completed referred colposcopy. Patient characteristics predictive for colposcopy follow up included: maternal age at referral cervical cytology >30 years (1.67; 1.27-2.20; < 0.003), gestational age < 18 weeks at abnormal cervical cytology (1.57; 1.23-2.01; <0.0002), maternal race non-African American (2.20; 1.32-3.65; <0.0024) and with high grade cervical cytology (2.42; 1.81-3.24; <0.0001). CONCLUSION: In this population, inadequate follow up for abnormal cervical cytology during pregnancy is prominent, especially among those with younger maternal age, African American (AA) race, cervical cytology completed at later gestational ages of pregnancy, and low-grade initial cytology. Higher no-show rate among AA patients supports well-documented health disparities and need for further investigation and protocols to identify those at risk for loss to follow up.

An Alternative to Cytology in Triaging Cisgender Men and Transgender Women With HIV for High-Resolution Anoscopy.

OBJECTIVES: To evaluate high-risk human papillomavirus testing (hrHPV) as an alternative for anal cytology in screening for high-grade anal neoplasia (AIN2-3) among males with HIV. To identify predictive risk factors for AIN2-3 and develop a clinical tool to triage males with HIV for high-resolution anoscopy (HRA) without cytology. DESIGN: Retrospective cohort study of 199 adult cisgender men and transgender women with HIV referred to an anal neoplasia clinic in the Southeastern United States between January 2018 and March 2021. METHODS: Each subject underwent cytology, hrHPV, and HRA. Clinical and sociodemographic risk factors were collected for each subject. Significant risk factors for AIN2-3 were identified using logistic regression, and a triage tool incorporating these factors was developed. Screening test characteristics were calculated for cytology with and without adjunct hrHPV, hrHPV alone, and the triage tool. RESULTS: In multivariate analysis, significant predictors of AIN2-3 were hrHPV positivity (odds ratio [OR] = 11.98, CI = 5.58-25.69) and low CD4 count (OR = 2.70, CI = 1.20-6.11). There was no significant difference in positive or negative predictive values among the tool, stand-alone hrHPV, and anal cytology with adjunct hrHPV. Sensitivity and specificity were not significantly different for stand-alone or adjunctive hrHPV testing. Compared with cytology, stand-alone hrHPV and the novel triage tool reduced unnecessary HRA referrals by 65% and 30%, respectively. CONCLUSIONS: Stand-alone hrHPV would have missed 11 of 74 AIN2-3 and generated 74 fewer unnecessary HRAs than current cytology-based screening patterns, which led to 115 unnecessary HRAs in our cohort. We propose triaging those with low CD4 count, hrHPV positivity, and/or smoking history for HRA.

Promoting COVID-19 vaccine acceptance: recommendations from the Lancet Commission on Vaccine Refusal, Acceptance, and Demand in the USA.

Since the first case of COVID-19 was identified in the USA in January, 2020, over 46 million people in the country have tested positive for SARS-CoV-2 infection. Several COVID-19 vaccines have received emergency use authorisations from the US Food and Drug Administration, with the Pfizer-BioNTech vaccine receiving full approval on Aug 23, 2021. When paired with masking, physical distancing, and ventilation, COVID-19 vaccines are the best intervention to sustainably control the pandemic. However, surveys have consistently found that a sizeable minority of US residents do not plan to get a COVID-19 vaccine. The most severe consequence of an inadequate uptake of COVID-19 vaccines has been sustained community transmission (including of the delta [B.1.617.2] variant, a surge of which began in July, 2021). Exacerbating the direct impact of the virus, a low uptake of COVID-19 vaccines will prolong the social and economic repercussions of the pandemic on families and communities, especially low-income and minority ethnic groups, into 2022, or even longer. The scale and challenges of the COVID-19 vaccination campaign are unprecedented. Therefore, through a series of recommendations, we present a coordinated, evidence-based education, communication, and behavioural intervention strategy that is likely to improve the success of COVID-19 vaccine programmes across the USA.

Prevalence of Anal Squamous Intraepithelial Lesions in HIV-1-Infected Young Men Who Have Sex With Men and Transwomen.

OBJECTIVE: Anal cancer rates are increasing among HIV-infected persons. Although an efficacious human papillomavirus (HPV) vaccine is available, HPV vaccination rates remain low. Therefore, providers perform anal cancer screening, but there is no consensus on the optimal methods or timing of screening. This study was performed to determine the prevalence of and factors associated with anal squamous intraepithelial lesions in sexually active HIV-infected young men who have sex with men and transgender women. MATERIALS AND METHODS: We performed a single-center, retrospective study of sexually active HIV-infected young men who have sex with men and transgender women aged 13 to 24 years at an HIV clinic in Atlanta GA from 2009 to 2016. We used analysis of variance and χ tests of independence to evaluate bivariate associations and identify demographic, behavioral, and clinical risk factors. RESULTS: Of 314 subjects with a mean (SD) age of 20.4 (2.1) years at initial anal cytology testing, 5% had completed the HPV vaccine series at or before the time that cytology was obtained. Ninety-five percent of the anal cytology tests obtained were abnormal, and 72 (29%) of those subjects returned for diagnostic testing either by intraoperative biopsy or high-resolution anoscopy. Fifty-seven percent of those who underwent biopsy had histologic high-grade squamous intraepithelial lesions including 2 cases of carcinoma in situ. A history of greater than 20 lifetime sexual partners was associated with abnormal histology (probability < 0.001, p = .017). CONCLUSIONS: Our study highlights the value of early, standardized screening to avoid missing anal dysplasia or cancer, particularly in unvaccinated persons with high numbers of sexual partners.

Multimodal hyperspectroscopy as a triage test for cervical neoplasia: pivotal clinical trial results.

OBJECTIVE: To prospectively evaluate a new non invasive device that combines fluorescence and reflectance spectroscopy in a population in women at risk for cervical dysplasia. METHODS: A total of 1607 women were evaluated with multimodal hyperspectroscopy (MHS), a painless test with extremely high spectral resolution. Subjects who were referred to colposcopy based on abnormal screening tests or other referral criteria underwent the MHS test and also had a sample taken for additional cytology and presence of high risk human papilloma virus (HPV) prior to undergoing biopsy. RESULTS: Sensitivity of MHS for cervical intraepithelial neoplasia (CIN) 2+ was 91.3% (252/276). Specificity, or the potential reduction in referrals to colposcopy and biopsy, was 38.9% (222/570) for women with normal or benign histology and 30.3% (182/601) for women with CIN1 histology. Two year follow-up data, collected for a subgroup of 804 women, revealed 67 interval CIN2+ that originally were diagnosed at enrollment as normal or CIN1. MHS identified 60 of these (89.6%) as positive for CIN2+ prior to their discovery during the two year follow-up period. CONCLUSIONS: MHS provides an immediate result at the point of care. Recently, the limitations of cytology have become more obvious and as a consequence greater emphasis is being placed on HPV testing for cervical cancer screening, creating a need for an inexpensive, convenient and accurate test to reduce false positive referrals to colposcopy and increase the yield of CIN2+ at biopsy. MHS appears to have many of the attributes necessary for such an application.

Treating cervical cancer: Breast and Cervical Cancer Prevention and Treatment Act patients.

OBJECTIVE: To investigate cervical cancer treatment of patients enrolled under the Breast and Cervical Cancer Prevention and Treatment Act in Georgia. STUDY DESIGN: Georgia Comprehensive Cancer Registry and Medicaid enrollment/claims were used to identify enrollees with preinvasive disease (n = 1149) and invasive cervical cancer (n = 444). Logistic regressions were used to estimate factors associated with the odds of receiving: (1) cancer workup, (2) precancerous procedure, (3) surgery, (4) radiation, and (5) chemotherapy. RESULTS: Preinvasive disease cases with cervical intraepithelial neoplasia 3, in situ, a comorbidity or without a Commission on Cancer approved hospital nearby were more likely to receive surgery. Among invasive cases, later stage was associated with higher odds of receiving radiation or chemotherapy. Black patients were less likely to have surgery than white patients regardless of preinvasive (P < .01) or invasive status (P = .05). CONCLUSION: Treatment patterns among Georgia Medicaid cases appear appropriate to stage but 18% with invasive cervical cancer received no cancer treatment, although Medicaid enrolled.

Elevated expression of the oncogene c-fms and its ligand, the macrophage colony-stimulating factor-1, in cervical cancer and the role of transforming growth factor-beta1 in inducing c-fms expression.

Cervical cancer is the third most common gynecologic cancer in the United States. The presence and possible involvement of several cytokines have been studied in cervical cancer; however, very little data, if any, are available on whether cervical tumors are responsive to stimulation by the macrophage colony-stimulating factor-1 (CSF-1). Given the involvement of c-fms and its ligand CSF-1 in gynecologic cancers, such as that of the uterus and the ovaries, we have examined the expression of c-fms and CSF-1 in cervical tumor (n = 17) and normal cervix (n = 8) samples. The data show that c-fms and its ligand are significantly higher in cervical carcinomas compared with normal samples. Immunohistochemistry not only showed that tumor cells expressed significantly higher levels of c-fms but also c-fms levels were markedly higher in tumor cells than tumor-associated stromal cells. Blocking c-fms activity in cervical cancer cells, which express CSF-1 and c-fms, resulted in increased apoptosis and decreased motility compared with control, suggesting that CSF-1/c-fms signaling may be involved in enhanced survival and possibly invasion by cervical cancer cells via an autocrine mechanism. Combined, the data show for the first time the induction of CSF-1 and c-fms in cervical carcinomas and suggest that c-fms activation may play a role in cervical carcinogenesis. Additionally, our data suggest that transforming growth factor-beta1 may be a factor in inducing the expression of c-fms in cervical cancer cells. The data suggest that c-fms may be a valuable therapeutic target in cervical cancer.

Methylation of High-Risk Human Papillomavirus Genomes Are Associated with Cervical Precancer in HIV-Positive Women.

BACKGROUND: HIV-positive women are at substantial risk of HPV-associated cervical neoplasia caused by high-risk (HR) HPVs. Methylation of the HPV genome is associated with cervical intraepithelial neoplasia grade 3 (CIN3) in HIV-negative women, yet it is unknown whether this holds true for HIV-positive women. METHODS: We designed a case-control study within the Women's Interagency HIV Study (WIHS) cohort comparing HIV-positive CIN3 cases (N = 72) to HIV-positive controls without detectable CIN2+. The unit of analysis and matching was HPV-type infection. Cases with ≥2 HR-HPV types (N = 23; 32%) had a separate control for each HR-HPV type. We developed and utilized next-generation sequencing (NGS) methylation assays for 12 different HR-HPVs, focusing on CpG sites in the L1/L2 regions. RESULTS: Significant case-control differences in individual CpG site methylation levels were observed for multiple alpha-9 (HPV16/31/35/58) and alpha-7 HPV (HPV18/39/45) types, based on dichotomization of tertile levels (T3 vs. T1 and T2). Analyses combining homologous CpG sites [e.g., HPV16-L1-5608/HPV31-L1-5521/HPV35-L2L1-5570; OR = 7.28; 95% confidence interval (CI): 2.75-19.3], and (e.g., HPV18-L1-7062/HPV45-L1-7066; OR = 6.94; 95% CI: 1.23-39.3) were significant in separate case-control comparisons. In cases with multiple HR-HPVs, we tested and confirmed the hypothesis that one HR-HPV type would have higher methylation than other types detected, consistent with there being a single HR-HPV causally related to a lesion. CONCLUSIONS: CIN3 is associated with elevated L1/L2 CpG methylation levels in HIV-positive women. IMPACT: HPV DNA CpG methylation is a promising triage option in HIV-positive women testing positive for HR-HPV types and provides risk attribution in women with multiple HPV type infections.

Evaluation of RNA markers for early detection of cervical neoplasia in exfoliated cervical cells.

Numerous molecular biomarkers have been suggested for early detection of cervical cancer, but their usefulness in routinely collected exfoliated cells remains uncertain. We used quantitative reverse transcription-PCR to evaluate expression of 40 candidate genes as markers for high-grade cervical intraepithelial neoplasia (CIN) in exfoliated cervical cells collected at the time of colposcopy. Samples from the 93 women with CIN3 or cancer were compared with those from 186 women without disease matched (1:2) for age, race, and high-risk human papillomavirus status. Normalized threshold cycles (C(t)) for each gene were analyzed by receiver operating characteristics to determine their diagnostic performance in a split sample validation approach. Six markers were confirmed by an area under the curve >0.6 in both sample sets: claudin 1 (0.75), minichromosome maintenance deficient 5 (0.71) and 7 (0.64), cell division cycle 6 homologue (0.71), antigen identified by monoclonal antibody Ki-67 (0.66), and SHC SH2-domain binding protein 1 (0.61). The sensitivity for individual markers was relatively low and a combination of five genes to a panel resulted in 60% sensitivity with 76% specificity, not positively increasing this performance. Although the results did not indicate superiority of RNA markers for cervical cancer screening, their performance in detecting disease in women referred for colposcopy suggests that the genes and pathways they highlight could be useful in alternative detection formats or in combination with other screening indicators.

Vulvo-vaginal cancers: risks, evaluation, prevention and early detection.

Vulvar and vaginal cancers are rare and account for approximately 7% of cancers of the female reproductive tract. Vulvar and vaginal neoplasia share similar risk factors: human papillomavirus infection, previous cervical intraepithelial neoplasia or cervical cancer, current smoking, sexual factors, and immunosuppression. Several treatment options are available for patients with documented histologic high-grade intraepithelial vulvar or vaginal neoplasia, including excision, laser vaporization, and 5-fluorouracil. After treatment, lifetime follow-up with cytology and colposcopy is recommended. With the widespread use of the human papillomavirus vaccine, one half to two thirds of vulvar and vaginal cancers may be prevented. Patient education regarding reduction of risk factors for progression and close surveillance of at-risk individuals may prevent the progression to invasive disease.

Control of COX-2 gene expression through peroxisome proliferator-activated receptor gamma in human cervical cancer cells.

PURPOSE: The peroxisome proliferator-activated receptor-gamma (PPARgamma), a ligand-dependent transcription factor belonging to the family of nuclear receptors, has been implicated in the control of cyclooxygenase (COX) 2 expression in some tissue, although the exact mechanism(s) of this activity has not been elucidated. In this study we explored the possible mechanism(s) of control of COX-2 gene expression through PPARgamma signaling in human cervical cancer. EXPERIMENTAL DESIGN: Using primary human cervical tissues and the CaSki human cervical cancer cell line, we assayed for PPARgamma and COX-2 mRNA expression by reverse transcription-PCR. Nuclear protein binding activities to three response elements located in the COX-2 promoter [nuclear factor kappaB (NFkappaB), cyclic AMP response element, and activator protein (AP)-2] were measured by gel mobility shift assays. We used transient transfection assays with COX-2 promoter reporter gene constructs to determine the regulatory sites in this promoter, which mediates PPARgamma regulation of COX-2 activity. RESULTS: We showed, for the first time, that primary human cervical cancer tissues express PPARgamma. Using CaSki cells, we demonstrated that COX-2 and PPARgamma mRNA levels were inversely regulated by PPARgamma ligands in that these compounds up-regulated PPARgamma but down-regulated COX-2. In contrast, epidermal growth factor (EGF), a potent activator of COX-2, decreased PPARgamma mRNA levels. This down-regulation of PPARgamma mRNA by EGF was blocked in the presence of NS-398, a selective COX-2 inhibitor. PPARgamma ligands suppressed the binding activities of AP-1 (binding to CRE) and NFkappaB but not AP-2. Transient transfection results indicated that EGF stimulated whereas PPARgamma ligands inhibited COX-2 promoter (-327/+59) activity. This effect by PPARgamma ligands on the COX-2 promoter was blocked when the CRE, but not the NFkappaB, binding site was mutagenized. CONCLUSION: Cervical cancer cells express readily detectable levels of PPARgamma. There is reciprocal negative regulation between COX-2 and PPARgamma signaling in human cervical cancer cells. The ability of PPARgamma ligands to inhibit COX-2 appears to be mediated predominantly through inhibition of AP-1 protein binding to the CRE site in the COX-2 promoter.

Factors Associated with Intention to Receive Influenza and Tetanus, Diphtheria, and Acellular Pertussis (Tdap) Vaccines during Pregnancy: A Focus on Vaccine Hesitancy and Perceptions of Disease Severity and Vaccine Safety.

BACKGROUND: Improving influenza and tetanus, diphtheria and acellular pertussis (Tdap) vaccine coverage among pregnant women is needed. PURPOSE: To assess factors associated with intention to receive influenza and/or Tdap vaccinations during pregnancy with a focus on perceptions of influenza and pertussis disease severity and influenza vaccine safety. METHODS: Participants were 325 pregnant women in Georgia recruited from December 2012 - April 2013 who had not yet received a 2012/2013 influenza vaccine or a Tdap vaccine while pregnant. Women completed a survey assessing influenza vaccination history, likelihood of receiving antenatal influenza and/or Tdap vaccines, and knowledge, attitudes and beliefs about influenza, pertussis, and their associated vaccines. RESULTS: Seventy-three percent and 81% of women believed influenza and pertussis, respectively, would be serious during pregnancy while 87% and 92% believed influenza and pertussis, respectively, would be serious to their infants. Perception of pertussis severity for their infant was strongly associated with an intention to receive a Tdap vaccine before delivery (p=0.004). Despite perceptions of disease severity for themselves and their infants, only 34% and 44% intended to receive antenatal influenza and Tdap vaccines, respectively. Forty-six percent had low perceptions of safety regarding the influenza vaccine during pregnancy, and compared to women who perceived the influenza vaccine as safe, women who perceived the vaccine as unsafe were less likely to intend to receive antenatal influenza (48% vs. 20%; p < 0.001) or Tdap (53% vs. 33%; p < 0.001) vaccinations. CONCLUSIONS: Results from this baseline survey suggest that while pregnant women who remain unvaccinated against influenza within the first three months of the putative influenza season may be aware of the risks influenza and pertussis pose to themselves and their infants, many remain reluctant to receive influenza and Tdap vaccines antenatally. To improve vaccine uptake in the obstetric setting, our findings support development of evidence-based vaccine promotion interventions which emphasize vaccine safety during pregnancy and mention disease severity in infancy.

Improved survival in p16-positive vaginal cancers across all tumor stages but no correlation with MIB-1.

OBJECTIVES: Survival as it relates to p16 overexpression and MIB-1 (Ki-67) proliferation in primary squamous cell vaginal carcinoma was studied. METHODS: Retrospective chart review from 1997 to 2006 revealed 43 patients who were treated for primary vaginal cancer at Emory University hospitals. Tissue was evaluated by immunohistochemical staining for the presence of p16 and MIB-1 markers, and survival data were examined. RESULTS: Patients who had primary squamous cell vaginal cancers (n = 31) with a positive diffuse staining of p16 had significantly (P = .003) improved survival (~49.5 months) compared with p16-negative patients (~25.3 months). Stage-specific analysis with 30 additional reported cases showed a significant survival benefit for p16-positive vaginal cancers compared with p16-negative cancers for stages I and II (P = .017; hazard ratio [HR] 0.400; 95% confidence interval [CI], 0.189-0.850) and stages III and IV (P = .001; HR, 0.176; 95% CI, 0.066-0.479). No difference was observed in survival for MIB-1-positive tumors (P = .984; HR, 1.008; 95% CI, 0.483-2.104). CONCLUSIONS: The p16 marker has a significant prognostic impact in primary squamous cell vaginal cancers across all tumor stages.

Age-group differences in human papillomavirus types and cofactors for cervical intraepithelial neoplasia 3 among women referred to colposcopy.

BACKGROUND: Recommendations for high-risk human papillomavirus (HR-HPV) testing as an adjunct to cytology for cervical cancer screening differ by age group, because HR-HPV tests lack adequate specificity in women aged <30. Here, we assess age-group differences in HPV types and other risk factors for cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) versus CIN0-2 in women from four colposcopy clinics. METHODS: Women ages 18 to 69 (n = 1,658) were enrolled and completed structured interviews to elicit data on behavioral risk factors prior to their examinations. HPV genotyping was done on exfoliated cervical cell samples. We estimated relative risks (RR) for HPV types and cofactors for CIN3+, overall and stratified by age group. RESULTS: After 2 years of follow-up, we identified 178 CIN3+, 1,305 CIN0-2, and 175 indeterminate outcomes. Nonvaccine HR-HPV types were only associated with CIN3+ among women ≥ 30 (RR = 2.3, 95% CI: 1.5-3.4; <30: RR = 0.9). Among all HR-HPV-positive women, adjusting for age, significant cofactors for CIN3+ included current smoking (RR = 1.5), former smoking (RR = 1.8), regular Pap screening (RR = 0.7), current regular condom use (RR = 0.5), and parity ≥ 5 (RR = 1.6, P(trend) for increasing parity = 0.07). However, the parity association differed by age group (≥ 30: RR = 1.8, P(trend) = 0.008; <30: RR = 0.9; P(trend) =.55). CONCLUSION: Subgroup variation by age in the risk of CIN3+ points to the importance of the timing of exposures in relation to CIN3+ detection. IMPACT: Future screening strategies need to consider natural history and secular trends in cofactor prevalence in the pursuit of appropriately sensitive and specific screening tools applied to appropriate age groups.

Lack of HPV 16 and 18 detection in serum of colposcopy clinic patients.

BACKGROUND: Persistent infection with high-risk human papillomavirus (HPV) types is necessary for the development of high-grade cervical dysplasia and cervical carcinoma. The presence of HPV DNA in the blood of cervical cancer patients has been reported; however, whether HPV DNA is detectable in the blood of patients with pre-invasive cervical disease is unclear. OBJECTIVES: The objectives of this study were to determine if HPV 16 and HPV 18 DNA could be detected in the serum of colposcopy clinic patients, and if serum HPV detection was associated with grade of cervical disease and HPV cofactors. STUDY DESIGN: Samples were selected from a biorepository collected from non-pregnant, HIV-negative women ages 18-69 attending colposcopy clinics at two urban public hospitals. Cervical disease status was based on review of colposcopy, biopsy and cytology findings. Serum HPV DNA detection was conducted using a novel PCR and mass spectroscopy-based assay. RESULTS: Of the 116 adequate serum samples, all (100%) were negative for HPV 16 and HPV 18. Over half (51.7%) of participants had cervical HPV 16 and/or HPV 18 infection. Nearly one-third (31.1%) had high grade, 10.3% had low grade, and 50.9% had no cervical disease. Nearly one-third (28.5%) had ever regularly smoked cigarettes, 70.7% had early onset of sexual intercourse, and 75% had ever used oral contraceptives. CONCLUSIONS: In this colposcopy clinic population with a range of clinical characteristics and established HPV cofactors, HPV DNA was undetectable in their serum. Our findings suggest that serum HPV DNA detection is not a cervical cancer screening tool.