This meta-analysis aimed to explore penile cancer survival based on p53 and Ki-67 status.A systematic literature search identified studies assessing overall and cancer-specific survival after penile cancer with p53 or Ki-67 expression. Pooled hazard ratios (HRs) and restricted mean survival time differences (RMSTD) were calculated using a random-effects model. The analysis included 930 and 391 men for p53 expression in overall survival (OS) and cancer-specific survival (CSS), respectively. Those with the p53 mutant pattern exhibited significantly worse OS and CSS compared to the p53 wild-type pattern (HROS=2.42, 95%CI: 1.75-3.34. HRCSS=4.18, 95%CI: 1.87-9.35). The 5-year RMSTD for OS, according to p53 status, was -10.62 months (95%CI: -16.20– -5.03). We included 202 men with penile cancer tested for Ki-67 expression and found a HR of CSS of 1.96 (95%CI: 1.15–3.32).In conclusion, men with the p53 mutant pattern penile cancer have worse OS and CSS than men with p53 wild-type pattern penile cancer. Evidence regarding Ki-67 status was sparse, but the pooled estimate indicated that penile cancers with high Ki-67 expression may have a slightly worse CSS than those with low Ki-67 expression. These findings may inform clinicians when planning the best management and follow-up strategy for penile cancer patients.

BACKGROUND:Human papillomavirus (HPV) testing is increasingly used as the primary cervical cancer screening test. In a large pilot implementation, we compared participation, referrals and detection of high-grade cervical intraepithelial neoplasia (CIN) in HPV- versus cytology-based cervical cancer screening.METHODS:The implementation was embedded into the routine screening program at Lillebaelt Hospital, Department of Pathology, Vejle, Denmark. Based on the area of residence, women aged 30-59 years were screened by either HPV testing (with HPV16/18 genotyping and cytology triage) or cytology (with HPV triage for minor abnormalities). Our analysis includes women invited or screened during May 2017-May 2018 (invited: n=35,081; screened: n=28,352) with 6 months of follow-up. Information on screening results and sociodemographic characteristics were obtained from registers. Using logistic regression, we estimated odds ratios (ORs) with 95% confidence intervals (CIs) of participation, referral and CIN3+-detection in HPV- versus cytology-based screening, adjusting for sociodemographic characteristics.RESULTS:Participation was virtually identical in the HPV- and cytology group (58.4% vs 58.8%; ORadjusted=0.97, 95% CI, 0.93-1.01). Referral to colposcopy was more common in the HPV- than cytology group (3.8% vs 2.1%; ORadjusted=1.88, 95% CI, 1.63-2.17). More cases of CIN3+ were detected in the HPV- than cytology group (1.0% vs 0.7%, ORadjusted=1.47; 95% CI, 1.13-1.91).CONCLUSION:Participation did not differ between HPV- and cytology-based screening. HPV-based screening detected more cases of CIN3+, but in this initial screening round also led to more colposcopies than cytology-based screening.

Objective: This systematic review and meta -analysis aims to investigate the prevalence of cervical high -risk human papillomavirus (hrHPV) among kidney transplant recipients (KTRs) and, furthermore to compare it to that in immunocompetent controls. Methods: A systematic literature search was conducted in PubMed, EMBASE, and Cochrane Library databases from January 2000 to February 2023, to identify studies investigating the prevalence of cervical hrHPV in KTRs. Pooled cervical hrHPV prevalences, odds ratios (ORs) comparing KTRs to controls and corresponding confidence intervals (CIs) were estimated using random effects logistic regression models. Heterogeneity between studies was assessed through the I 2 statistic, and the significance was evaluated by the Cochrane's Q test. Results: Altogether, 16 studies covering >1200 KTRs were included. The prevalence of cervical hrHPV in KTRs was 27.7% (95% CI 21.3-35.1) with substantial interstudy heterogeneity. Stratification indicated a higher prevalence in recent years (2019-2023) and in Asia (39% (95% CI 11.2-61.4)). The prevalence of HPV16 and HPV18 in KTRs was 8.0% (95% CI 3.9-15.9) and 1.7% (95% CI 0.8-3.7), respectively. Comparing hrHPV prevalence in KTRs and controls based on six studies including >500 KTRs and 1000 controls, the OR for hrHPV was 2.0 (95% CI 1.1-3.6). Conclusions: This meta -analysis establishes an increased cervical hrHPV prevalence in KTRs compared to controls. The increased risk may be associated with immunosuppressive therapy post -transplantation. Further research is needed to explore the potential benefits of HPV vaccination, including potential revaccination strategies in KTRs.

OBJECTIVES:We present incidence trends of cancer and precancer at human papillomavirus(HPV)-associated sites, and genital warts, including the current burden of HPV-associated disease in Denmark, a country with multi-cohort HPV vaccination. METHOD:Cases were identified from high-quality nationwide registries (2000-2022). The age-specific incidence rate, age-standardized incidence rate (ASR) and estimated annual percentage change (EAPC) were calculated according to sex and calendar year. The current burden (2020-2022) of HPV-associated disease was estimated as the average annual number of each lesion multiplied by the disease-specific HPV-attributable fraction. RESULTS:ASRs of cervical precancer and genital warts declined markedly in the post-HPV vaccination period - for genital warts corresponding to an EAPC of -13.7 % (-15.0;-12.4)(women) and -8.8 % (-9.4;-8.2)(men), respectively. ASRs of HPV-associated cancer sites increased continuously in men (EAPC: 2.8 % (2.2;3.5)), and the same was observed for non-cervical HPV-associated cancer sites in women (EAPC: 2.5 % (2.0;3.0)). Cervical cancer, however, decreased in the post-HPV vaccination period (EAPC: -2.7 % (-3.8;-1.5)). Age-specific incidence rates of HPV-associated cancer sites decreased slightly in younger women and were stable in younger men, while incidence rates in older men approached or even surpassed that of older women. Data on the current burden showed that cervical precancer and genital warts are still the major contributors to HPV-associated disease, and oropharyngeal cancer now accounts for more annual cases on a population level than cervical cancer. CONCLUSION:Danish data show decreased incidence of cervical lesions and genital warts in the post-vaccine era. Despite population impact of HPV vaccination, HPV-associated disease remains a public health issue and increasingly among men.

High-risk human papillomavirus (hrHPV) is the cause of virtually all cervical cancers, most vaginal and anal cancers, and some vulvar cancer cases. With HPV testing becoming the primary screening method for cervical cancer, understanding the link between cervical hrHPV infection and the risk of other anogenital cancers is crucial. We assessed the risk of vulvar, vaginal and anal cancer and precancer (VIN2+, VaIN2+ and AIN2+) in a prospective cohort study including 455,349 women who underwent cervical hrHPV testing in Denmark from 2005 to 2020. We employed Cox proportional hazard models, adjusting for age, calendar year and HPV vaccination status, and estimated hazard ratios (HRs) and 95% confidence intervals (CI). We used the Aalen Johansen estimator to calculate the absolute risks of VIN2+, VaIN2+ and AIN2+. In total, 15% of the women were hrHPV positive at baseline. A positive cervical hrHPV test was associated with increased incidence of vulvar, vaginal and anal squamous cell carcinoma (SCC). Five-year risk estimates of VIN2+, VaIN2+ and AIN2+ among hrHPV-positive women (0.45%, 0.14% and 0.12%) were higher than among hrHPV-negative women (0.14%, 0.01% and 0.05%). Particularly high risk was observed among the hrHPV-positive women of the oldest age, with a history of anogenital precancer and those not HPV vaccinated. In conclusion, our study confirms the association between cervical hrHPV infection and non-cervical anogenital precancers and cancers. Currently, no established risk threshold or guidelines for follow-up. As HPV testing becomes the primary method for cervical cancer screening, future data will help define high-risk groups and acceptable risk thresholds.

OBJECTIVE:Human papillomavirus (HPV) testing is the recommended primary screening method against cervical cancer. Denmark started implementing HPV testing as a primary screening method in 2021, but no national data are yet available. We report the results of the first and second screening rounds in a large Danish pilot implementation study. The objective was to compare colposcopy referrals, identify high-grade cervical intraepithelial neoplasia (CIN) and cancer, and positive predictive value (PPV) between HPV-based and cytology-based screening. METHOD:In the HPV SCREEN DENMARK cohort (established May 2017-December 2019), participants were assigned to HPV-based (n = 28,677) or cytology-based screening (n = 43,622) based on the municipality of residence. RESULTS:The first round of screening showed higher colposcopy referrals in the HPV group (6.4 %) compared to cytology (2.3 %), with HPV screening detecting more CIN3+ (n = 306/28,677 (1.1 %)) than cytology (n = 241/43,622 (0.6 %)) (RR = 1.9 (95 %CI 1.6-2.3). In absolute terms, 41 additional colposcopy referrals resulted in the detection of 10 more cases of CIN2+ and five extra CIN3+ cases per 1000 women screened. The PPV for CIN3+ of a colposcopy initiated by routine screening was similar in the HPV group (24.1 %) and cytology group (25.7 %). Within the initial years of screening, the cumulative incidence of CIN3+ and cervical cancer showed a more rapid increase in the HPV group compared to the cytology group. CONCLUSION:HPV-based cervical screening detects almost twice as many CIN3+ cases but at the expense of a more than two-fold increase in colposcopy referrals. Furthermore, we found that HPV-based screening detects cervical cancer earlier than cytology-based screening.

Background: In the general population, human papillomavirus (HPV) prevalence is reportedly increased during pregnancy, and emerging evidence suggests that it may be associated with adverse pregnancy outcomes. Women living with HIV (WLWH) experience higher rates of both HPV infection and certain adverse pregnancy outcomes, yet there are no prior reviews of HPV infection during pregnancy in WLWH. Methods: We conducted a systematic review and meta-analysis of pooled and type-specific HPV prevalence and associated pregnancy outcomes among pregnant WLWH and, if available, within-study comparators of women without HIV. Subgroup analyses were performed according to polymerase chain reaction primers used and geographic location. Results: Ten studies describing HPV prevalence in 1594 pregnant WLWH were included. The pooled HPV prevalence in pregnant WLWH was 75.5% (95% confidence interval: 50.2 to 90.4) but ranged widely (23%-98%) between individual studies. Among studies that also assessed HPV prevalence in pregnant women without HIV, the pooled prevalence was lower at 48.1% (95% confidence interval: 27.1 to 69.8). Pregnant WLWH had 54% higher odds of being HPV positive compared with pregnant women without HIV. The most common HPV type detected in pregnant WLWH was HPV16. No studies reported pregnancy outcomes by the HPV status. Conclusions: High prevalence of HPV was documented in pregnant WLWH, exceeding the prevalence among pregnant women without HIV. The limited research on this topic must be addressed with further studies to inform the use of HPV testing as a screening modality for this population as well as the role of HPV in adverse pregnancy outcomes.

Objective: To study the association between use of fertility drugs and colorectal cancer among women with infertility.Design: Population-based cohort study.Setting: Not applicable.Patient(s): The study cohort was obtained from the Danish Infertility Cohort and consisted of all women with infertility aged 20-45 years living in Denmark during 1995-2017.Intervention(s): Information on the use of specific types of fertility drugs, colorectal cancer diagnoses, covariates, and vital status were obtained from the Danish Infertility Cohort and Danish national registers.Main Outcome Measure(s): Cox proportional hazard models adjusted for potential confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer overall and rectal and colon cancer separately.Results(s): Among 148,036 women in the final study cohort, 205 women were diagnosed with colorectal cancer. Ever use of clomi-phene citrate (CC) was associated with a lower rate of colorectal cancer (unadjusted HR, 0.67; 95% CI, 0.51-0.89; adjusted HR, 0.68; 95% CI, 0.50-0.93). However, the lower rate was only seen among women who first used CC >8 years ago (unadjusted HR, 0.56; 95% CI, 0.41-0.76; adjusted HR, 0.52; 95% CI, 0.36-0.75). No marked associations were found between the use of any of other types of fertility drugs and colorectal cancer. The results for colon and rectal cancer analyzed separately were similar, except for a suggestion of a decreased risk of rectal cancer associated with the use of gonadotropins (adjusted HR, 0.46; 95% CI, 0.20-1.08).Conclusion(s): Among women with infertility, the use of most types of fertility drugs was not associated with colorectal cancer. How-ever, CC may decrease the risk of colorectal cancer and gonadotropins might decrease the risk of rectal cancer, but we cannot rule out that these findings may be more related to the underlying conditions in these women or are chance findings. Consequently, the results from this study should be investigated further in large epidemiological studies. (Fertil Sterile 2022;118:738-47. (c) 2022 by American Society for Reproductive Medicine.)

To investigate the association between fertility drugs and tumors of the central nervous system (CNS). This cohort study was based on The Danish Infertility Cohort and included 148,016 infertile women living in Denmark (1995–2017). The study cohort was linked to national registers to obtain information on use of specific fertility drugs, cancer diagnoses, covariates, emigration, and vital status. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all CNS tumors and separately for gliomas, meningiomas and diverse benign tumors of the brain and other parts of the CNS. During a median 11.3 years of follow-up, 328 women were diagnosed with CNS tumors. No marked associations were observed between use of the fertility drugs clomiphene citrate, gonadotropins, gonadotropin-releasing hormone receptor modulators and progesterone and CNS tumors. However, use of human chorionic gonadotropin was associated with a decreased rate of meningiomas (HR 0.49 95% CI 0.28–0.87). No clear associations with CNS tumors were observed according to time since first use or cumulative dose for any of the fertility drugs. No associations between use of most types of fertility drugs and CNS tumors were observed. However, our findings only apply to premenopausal women and additional studies with longer follow-up time are necessary.

STUDY QUESTION:Do fertility drugs increase the risk of thyroid cancer among infertile women?SUMMARY ANSWER:The use of most types of fertility drugs was not associated with an increased risk of thyroid cancer.WHAT IS KNOWN ALREADY:The incidence of thyroid cancer is higher for women than men, especially during reproductive years, indicating that reproductive hormones may be involved in the development of thyroid cancer. Only a few previous studies have examined the association between the use of fertility drugs and incidence of thyroid cancer and the results are inconclusive.STUDY DESIGN, SIZE, DURATION:A retrospective, population-based cohort study including all 146 024 infertile women aged 20-45 years and living in Denmark in the period 1995-2017. The women were followed from the date of entry in the cohort (i.e. date of first infertility diagnosis) until the occurrence of thyroid cancer or any other cancer (except non-melanoma skin cancer), death, emigration, total thyroidectomy or the end of follow-up (31 December 2018), whichever occurred first. The median length of follow-up was 11.3 years.PARTICIPANTS/MATERIALS, SETTING, METHODS:In total, 167 women were diagnosed with thyroid cancer during the follow-up period. Information on the use of specific fertility drugs (clomiphene citrate, gonadotropins, hCGs, GnRH receptor modulators and progesterone), thyroid cancer, covariates and vital status was obtained from the Danish Infertility Cohort and various Danish national registers. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% CIs for thyroid cancer overall and for papillary thyroid cancer.MAIN RESULTS AND THE ROLE OF CHANCE:After adjustment for the calendar year of infertility diagnosis, the highest obtained level of education, parity status, obesity or thyroid disease and mutual adjustment for other registered fertility drugs, no marked associations were observed between the use of clomiphene citrate, hCG, gonadotropins or GnRH receptor modulators and risk of overall or papillary thyroid cancer. However, ever use of progesterone was associated with an increased rate of both overall (HR 1.63; 95% CI 1.07-2.48) and papillary (HR 1.66, 95% CI 1.04-2.65) thyroid cancer after mutual adjustment for other specific fertility drugs. For most specific fertility drugs, we observed a tendency toward higher associations with thyroid cancer within the first 5 years after the start of drug use than after 5 years from the start of use. No marked associations were detected according to the cumulative dose for any of the specific fertility drugs.LIMITATIONS, REASONS FOR CAUTION:Despite a large study population, the statistical precision in some subgroup analyses may be affected due to the low number of thyroid cancer cases. Although we were able to adjust for a number of potential confounders, residual and unmeasured confounding may potentially have affected the observed associations, as we could not adjust for some factors that may influence the association between fertility drugs and thyroid cancer, including age at menarche and BMI.WIDER IMPLICATIONS OF THE FINDINGS:Although this study, which is the largest to date, provides reassuring evidence that there is no strong link between the use of fertility drugs and thyroid cancer incidence, we observed a modest increased thyroid cancer incidence after the use of progesterone. However, we cannot rule out that this is a chance finding and the potential association between the use of progesterone and thyroid cancer should therefore be investigated further in large epidemiological studies. The results of the present study provide valuable knowledge for clinicians and other health care personnel involved in the diagnosis and treatment of infertility.STUDY FUNDING/COMPETING INTEREST(S):The study was supported by research grants from the Jascha Foundation and the Aase and Ejner Danielsens Foundation. B.N. received honoraria and/or non-financial support by Gedeon Richter Nordics AB, IBSA Nordic APS and Merck KGAA. The remaining authors have no competing interests.TRIAL REGISTRATION NUMBER:N/A.

Importance In recent decades, the global rates of cesarean delivery have rapidly increased. Nonetheless, the influence of cesarean deliveries on surgical complications later in life has been understudied. Objective To investigate whether previous cesarean delivery increases the risk of reoperation, perioperative and postoperative complications, and blood transfusion when undergoing a hysterectomy later in life. Design, Setting, and Participants This registry-based cohort study used data from Danish nationwide registers on all women who gave birth for the first time between January 1, 1993, and December 31, 2012, and underwent a benign, nongravid hysterectomy between January 1, 1996, and December 31, 2012. The dates of this analysis were February 1 to June 30, 2016. Exposure Cesarean delivery. Main Outcomes and Measures Reoperation, perioperative and postoperative complications, and blood transfusion within 30 days of a hysterectomy. Results Of the 7685 women (mean [SD] age, 40.0 [5.3] years) who met the inclusion criteria, 5267 (68.5%) had no previous cesarean delivery, 1694 (22.0%) had 1 cesarean delivery, and 724 (9.4%) had 2 or more cesarean deliveries. Among the 7685 included women, 3714 (48.3%) had an abdominal hysterectomy, 2513 (32.7%) had a vaginal hysterectomy, and 1458 (19.0%) had a laparoscopic hysterectomy. In total, 388 women (5.0%) had a reoperation within 30 days after a hysterectomy. Compared with women having vaginal deliveries, fully adjusted multivariable analysis showed that the adjusted odds ratio of reoperation for women having 1 previous cesarean delivery was 1.31 (95% CI, 1.03-1.68), and the adjusted odds ratio was 1.35 (95% CI, 0.96-1.91) for women having 2 or more cesarean deliveries. Perioperative and postoperative complications were reported in 934 women (12.2%) and were more frequent in women with previous cesarean deliveries, with adjusted odds ratios of 1.16 (95% CI, 0.98-1.37) for 1 cesarean delivery and 1.30 (95% CI, 1.02-1.65) for 2 or more cesarean deliveries. Blood transfusion was administered to 195 women (2.5%). Women having 2 or more cesarean deliveries had an adjusted odds ratio for receiving blood transfusion of 1.93 (95% CI, 1.21-3.07) compared with women having no previous cesarean delivery. Conclusions and Relevance Women with at least 1 previous cesarean delivery face an increased risk of complications when undergoing a hysterectomy later in life. The results support policies and clinical efforts to prevent cesarean deliveries that are not medically indicated.