Karolina Louvanto

COVID‐19 pandemic impact on gynecologic cancer treatment pathways in a Finnish tertiary center

AbstractIntroductionCOVID‐19 and new guidelines during the pandemic affected the gynecologic cancer treatment pathways, resulting in recorded delays and modifications in the treatment protocols. The aim of this study was to determine the impact of the COVID‐19 pandemic in one of the major gynecologic cancer care centers in Finland, Tampere University Hospital.Material and MethodsOur retrospective register study included 909 patients that were new gynecologic cancer cases (uterine, cervical, vulvar, vaginal, or ovarian) referred to the Tampere University Hospital Gynecologic Oncology Outpatient Clinic between March 17th, 2018, and March 15th, 2022. The patients were divided into two separate groups depending on their time of referral: time before COVID (March 17th, 2018, to March 15th, 2020), and during COVID (March 16th, 2020, to March 15th, 2022). These groups were compared in terms of patient characteristics, different cancer types and stages, symptoms, and treatment methods.ResultsDuring the COVID‐19 pandemic, patients generally suffered from cancer symptoms longer (p < 0.003) and were more likely to be overweight (p = 0.035). The improved multidisciplinary team meeting gave the patients a faster route to their first intervention during COVID (p < 0.05). An insignificant shift toward nonsurgical first interventions and non‐curative intent was seen during COVID, but the multidisciplinary team treatment plans were mostly implemented accordingly on both eras. No decrease was seen in the number of new gynecologic cancer cases, and the one‐year overall survival remained the same in both groups.ConclusionsOverall, the COVID‐19 pandemic did not significantly alter treatment pathways in gynecologic cancer care at Tampere University Hospital. The number of new patients and given treatments remained relatively stable. During COVID, access from referral to cancer treatment was significantly accelerated, which is likely confounded by changes to the multidisciplinary team protocol made in early 2021.

Human papillomavirus vaccinations’ impact on preterm birth rates

Abstract Removal of human papillomavirus (HPV) infection associated precancerous cervical lesions by conization is one of the most important causes of preterm birth. Prophylactic HPV-vaccinations can prevent these lesions and reduce the need of their ablative treatment, thereby preventing preterm births. We evaluated whether preterm birth rates vary between HPV-vaccinated and unvaccinated women. Study subjects comprised 6200 cluster-randomized cohorts of HPV-vaccinated and 1667 hepatitis B-virus vaccinated women born in 1992–1993, and age- and community-aligned reference cohort of 19 473 unvaccinated women born in 1990–1991. Age-aligned registry linkage data from the nationwide Finnish Medical Birth Registry were retrieved up to 2018 (older age cohorts) and 2020 (younger age cohorts). Preterm births were categorized as early (gestational age of 22 + 0–33 + 6 weeks) and late preterm births (gestational age 34 + 0–36 + 6 weeks). Logistic regression was used to evaluate the association of HPV-vaccination and preterm births. By the age 28, 23.9% (n = 1484) of HPV-vaccinees and 28.4% (n = 6006) of the unvaccinated women had at least one childbirth recorded. Precisely, 4.1% (n = 61) of HPV-vaccinated and 5.2% (n = 310) of unvaccinated primiparas had a preterm birth. The association of preterm birth with HPV-vaccination was protective with a borderline significant odds ratio of 0.79 (95% CI 0.59–1.04). Most preterm births were at late preterm among both HPV-vaccinees (3.1%) and unvaccinated women (3.4%). Prophylactic HPV-vaccination is likely to reduce the incidence of preterm births. The decrease of preterm births is crucial to reduce the need for extensive and costly postnatal care and life-long morbidity.

Human papillomavirus vaccinations’ association to childbirth rates

Prophylactic HPV vaccines are effective against cervical cancer and its precursors, but data on their impact on fertility and pregnancy are limited. This registry-based study examined the association between HPV vaccination and childbirth rates. Study population comprised 6200 HPV- and 1667 hepatitis B-virus (HBV) vaccinated women born in 1992-1993 and an age- and community-aligned cohort of 19,473 unvaccinated women born in 1990-1991. Nearly half of the HPV-vaccinated women participated in a cervical screening trial between ages 22 and 28. Childbirth numbers and rates per 10,000 person-years with 95% confidence interval (CI) were compared across the groups. The mean age at first childbirth ranged between 22.9 and 23.4 years among the vaccinated and unvaccinated women. At the age of 28, the cumulative proportion of all childbirths among HPV-vaccinated and screened cohorts was 2277 (36.7%), among HBV-vaccinated 781 (46.9%) and among unvaccinated reference cohorts 8997 (46.2%). Childbirth rates per 10,000 person years were 306 (95% CI 294-319), 390 (95% CI 364-419) and 385 (95% CI 377-393), respectively. HPV-vaccinated and screened women had lower childbirth rates compared to unvaccinated women at young age, possibly due to sexual counseling that HPV-vaccinated participants got in an overlapping cervical screening trial conducted between ages 22 and 28. This may have postponed their family planning to later ages.

Predictors for regression and progression of actively surveilled cervical intraepithelial neoplasia grade 2: A prospective cohort study

AbstractIntroductionTo evaluate predicting clinical factors for regression and progression of cervical intraepithelial neoplasia (CIN) grade 2 (CIN2) in young women during two years of active surveillance.Material and MethodsThis was a single‐center prospective observational cohort study. Women under 31 years of age giving written informed consent with histologically confirmed CIN2 were followed with colposcopy, cytology, and biopsies every 6 months up to 24 months. At baseline, HPV genotyping was performed on cervical samples. The rates of regression and progression were recorded for every timepoint and at the end of study overall and stratified according to clinical factors and HPV genotypes at baseline. Risk ratio (RR) was used to estimate the relative risks for regression and progression. The study was registered in the ISRCTN registry (ISRCTN91953024).ResultsIn total, 205/243 (84.4%) women completed the study. Complete regression (normal histology and/or normal or atypical squamous cells of undetermined significance (ASC‐US) cytology) was detected in 64.4.% (n = 132) while 16.1% (n = 33) of the lesions progressed to CIN grade 3 (CIN3) or worse including 31 CIN3 cases, one adenocarcinoma in situ and one cervical cancer case. Factors associated with progression were initial large (>50% of the transformation zone) lesion size, risk ratio (RR) 3.06 (95% confidence interval (CI) 1.40–6.69), and high‐grade referral cytology RR 4.73 (95% CI 1.18–19.03). Compared with baseline HPV negativity or having only low‐risk HPV genotypes present, high‐risk HPV (hrHPV) positivity was associated with lower likelihood of regression RR 0.74 (95% CI 0.60–0.91). Age, cigarette smoking, use of combined oral contraceptives or baseline high‐risk HPV genotype, including HPV16, were not associated with the outcomes.ConclusionsThe majority of CIN2 lesions regress in young women. Women with large lesions and/or high‐grade referral cytology should perhaps more often be treated instead of active surveillance. Initial hrHPV genotype does not appear to predict outcomes while not harboring hrHPV favors regression.

Low methylation marker levels among human papillomavirus‐vaccinated women with cervical high‐grade squamous intraepithelial lesions

AbstractCervical cancer screening programs, including triage tests, need redesigning as human papillomavirus (HPV)‐vaccinated women are entering the programs. Methylation markers offer a potential solution to reduce false‐positive rates by identifying clinically relevant cervical lesions with progressive potential. In a nested case–control study, 9242 women who received the three‐dose HPV16/18‐vaccine at ages 12–15 or 18 in a community‐randomized trial were included. Subsequently, they were re‐randomized for either frequent or infrequent cervical cancer screening trials. Over a 15‐year post‐vaccination follow‐up until 2022, 17 high‐grade squamous intraepithelial lesion (HSIL) and 15 low‐grade (LSIL) cases were identified at the 25‐year screening round, alongside 371 age and community‐matched HPV16/18‐vaccinated controls. Methylation analyses were performed on cervical samples collected at age 25, preceding histologically confirmed LSIL or HSIL diagnoses. DNA methylation of viral (HPV16/18/31/33) and host‐cell genes (EPB41L3, FAM19A4, and miR124‐2) was measured, along with HPV‐genotyping. No HPV16/18 HSIL cases were observed. The predominant HPV‐genotypes were HPV52 (29.4%), HPV59/HPV51/HPV58 (each 23.5%), and HPV33 (17.7%). Methylation levels were generally low, with no significant differences in mean methylation levels of viral or host‐cell genes between the LSIL/HSIL and controls. However, a significant difference in methylation levels was found between HSIL cases and controls when considering a combination of viral genes and EPB41L3 (p value = .0001). HPV‐vaccinated women with HSIL had HPV infections with uncommon HPV types that very rarely cause cancer and displayed low methylation levels. Further investigation is warranted to understand the likely regressive nature of HSIL among HPV‐vaccinated women and its implications for management.

Baseline findings and safety of infrequent vs. frequent screening of human papillomavirus vaccinated women

Less frequent cervical cancer screening in human papillomavirus (HPV) vaccinated birth cohorts could produce considerable savings without increasing cervical cancer incidence and loss of life‐years. We report here the baseline findings and interim results of safety and accuracy of infrequent screening among HPV16/18 vaccinated females. The entire 1992–1994 birth‐cohorts (30,139 females) were invited to a community‐randomized HPV16/18‐vaccination trial. A total of 9,482 female trial participants received HPV16/18‐vaccination in 2007–2009 at age of 13–15. At age 22, 4,273 (45%) of these females consented to attend a randomized trial on frequent (ages 22/25/28; Arm 1: 2,073 females) vs. infrequent screening (age 28; Arm 2: 2,200 females) in 2014–2017. Females (1,329), who had got HPV16/18 vaccination at age 18 comprised the safety Arm 3. Baseline prevalence and incidence of HPV16/18 and other high‐risk HPV types were: 0.5% (53/1,000 follow‐up years, 104) and 25% (2,530/104) in the frequently screened Arm 1; 0.2% (23/104) and 24% (2,413/104) in the infrequently screened Arm 2; and 3.1% (304/104) and 23% (2,284/104) in the safety Arm 3. Corresponding prevalence of HSIL/ASC‐H and of any abnormal cytological findings were: 0.3 and 4.2% (Arm 1), 0.4 and 5.3% (Arm 2) and 0.3 and 4.7% (Arm 3). Equally rare HSIL/CIN3 findings in the infrequently screened safety Arm A3 (0.4%) and in the frequently screened Arm 1 (0.4%) indicate no safety concerns on infrequent screening despite the up to 10 times higher HPV16/18 baseline prevalence and incidence in the former.

Methylation in Predicting Progression of Untreated High-grade Cervical Intraepithelial Neoplasia

Abstract Background There is no prognostic test to ascertain whether cervical intraepithelial neoplasias (CINs) regress or progress. The majority of CINs regress in young women, and treatments increase the risk of adverse pregnancy outcomes. We investigated the ability of a DNA methylation panel (the S5 classifier) to discriminate between outcomes among young women with untreated CIN grade 2 (CIN2). Methods Baseline pyrosequencing methylation and human papillomavirus (HPV) genotyping assays were performed on cervical cells from 149 women with CIN2 in a 2-year cohort study of active surveillance. Results Twenty-five lesions progressed to CIN grade 3 or worse, 88 regressed to less than CIN grade 1, and 36 persisted as CIN1/2. When cytology, HPV16/18 and HPV16/18/31/33 genotyping, and the S5 classifier were compared to outcomes, the S5 classifier was the strongest biomarker associated with regression vs progression. The S5 classifier alone or in combination with HPV16/18/31/33 genotyping also showed significantly increased sensitivity vs cytology when comparing regression vs persistence/progression. With both the S5 classifier and cytology set at a specificity of 38.6% (95% confidence interval [CI], 28.4–49.6), the sensitivity of the S5 classifier was significantly higher (83.6%; 95% CI, 71.9–91.8) than of cytology (62.3%; 95% CI, 49.0–74.4; P = 0.005). The highest area under the curve was 0.735 (95% CI, 0.621–0.849) in comparing regression vs progression with a combination of the S5 classifier and cytology, whereas HPV genotyping did not provide additional information. Conclusions The S5 classifier shows high potential as a prognostic biomarker to identify progressive CIN2.

The quality of life of frequently vs. infrequently screened HPV vaccinated women

Abstract Purpose Cervical lesions caused by human papillomavirus (HPV) are related to decreased quality of life (QoL) of women. Also, cervical cancer (CC) screening can cause psychological adverse effects. It has been assumed that by decreasing the HPV-related disease burden, HPV vaccinations would increase the QoL. This study compares the effect of CC screening on QoL of HPV vaccinated women in two different screening protocols. Methods A total of 753 HPV16/18 vaccinated women were randomized to frequent (22/25/28 years of age) and infrequent (28 years of age) CC screening arms. QoL questionnaires (EQ VAS, RAND 36, amended CECA 10) were sent at the age of 28. Results Median EQ VAS scores were 80 (Q1–Q3 75–90) in both screening arms. Mean RAND 36 scores of frequently and infrequently screened women were 78.13/81.64 in Physical role functioning domain and, respectively, 77.93/80.18 in Pain, 69.10/69.12 in General Health, 54.67/53.61 in Energy, 83.72/85.11 in Social functioning, 69.53/69.68 in Emotional role functioning, and 68.16/69.29 in Emotional well-being domain. Among women with a self-reported history of Pap cytology abnormalities, overall mean scores of amended CECA 10 were 69.52/72.07, and among women with a self-reported history of genital warts, 60.09/66.73, respectively. Conclusion There was no significant difference in the QoL of HPV vaccinated women between the two CC screening arms. Women were mostly satisfied with the screening experience despite the screening frequency. This information is important for the future screening program planning as we need to reach the best possible balance with screening benefits and harms. Trial registration number NCT02149030, date of registration 29/5/2014.