Abstract With the availability of the nonavalent human papillomavirus (HPV) vaccine, vaccinees, parents and healthcare providers need guidance on how to complete an immunization course started with ...the bi- or quadrivalent vaccine and whether to revaccinate individuals who have completed a full immunization course with the bi- or quadrivalent vaccine. To answer these questions three parameters should be considered: age at the start of vaccination (9 to 14 years of age versus 15 years and older, the cut-off for 2 or 3 doses schedule), the number of doses already received and the time interval between doses. Based on a number of scenarios, we propose that the 9-valent vaccine can be used to complete an incomplete vaccination regimen or might be added to a previous completed schedule to extend protection.
Evidence regarding cancer risk after borderline ovarian tumors (BOTs) is limited. We conducted a nationwide cohort study examining the incidence of nonovarian cancers in women with serous or mucinous ...BOTs compared with the general female population with up to 41 years of follow‐up. Through the nationwide Pathology Registry, we identified nearly 5000 women with BOTs (2506 serous and 2493 mucinous) in Denmark, 1978 to 2018. We computed standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) as relative risk estimates of specific nonovarian cancers. Compared with general female population rates, women with serous BOTs had increased rates of particularly malignant melanoma (SIR = 1.9; 95% CI: 1.3‐2.6), thyroid cancer (SIR = 3.0; 95% CI: 1.4‐5.4) and myeloid leukemia (SIR = 3.2; 95% CI: 1.5‐5.8), and women with mucinous BOTs had elevated rates of lung cancer (SIR = 1.7; 95% CI: 1.3‐2.1), pancreatic cancer (SIR = 1.9; 95% CI: 1.2‐2.9) and myeloid leukemia (SIR = 2.3; 95% CI: 0.9‐4.7). We found no convincing association with neither breast nor colorectal cancer in women with BOTs. This is the first large nationwide study showing that women with specific types of BOTs have increased risks of several nonovarian cancers, likely due to some shared risk factors or genetic characteristics.
What's new?
Evidence on cancer risk following borderline ovarian tumors is limited. This study with nearly 5000 patients and up to 41 years of follow‐up found that women with serous borderline ovarian tumors had higher rates of malignant melanoma, thyroid cancer, and myeloid leukemia than expected in the general female population. Women with mucinous borderline ovarian tumors had higher rates of lung cancer, pancreas cancer, and myeloid leukemia. This is the first large nationwide study showing that women with specific types of borderline ovarian tumors have increased risks of several nonovarian cancers, likely due to some shared risk factors or genetic characteristics.
The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a ...screening trial of individuals at high risk of ovarian cancer.
The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis.
In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001).
These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.
Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with ...an improved prognosis, but the effect of BRCA1 remains unclear.
To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns.
A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998).
Five-year overall mortality.
The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio HR, 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003).
Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.
BACKGROUND
Women with fertility problems often experience higher levels of stress, anxiety and depressive symptoms associated with both the infertility diagnosis and eventual fertility treatment. The ...authors investigated whether women who do not succeed in having a child after an infertility evaluation are at a higher risk of suicide than women who succeed in having a child after an infertility evaluation.
METHODS
A cohort of 51 221 Danish women with primary or secondary infertility and referred to hospitals or private fertility clinics in Denmark during 1973–1998 was established. The cohort was linked to four Danish administrative population-based registries. Each woman was followed from the date of her initial fertility evaluation at the clinic or hospital until 2006. Cox proportional hazards regression analyses was used to calculate hazard ratios (HRs) for suicide and their corresponding 95% confidence intervals (CIs) adjusted for potential confounders.
RESULTS
Women who did not have a child after an initial fertility evaluation had a >2-fold (HR: 2.43; 95% CI: 1.38–3.71) greater risk of suicide than women who had at least one child after a fertility evaluation. Women with secondary infertility, i.e. women who had a child before a fertility evaluation but did not succeed in having one after, also had an increased risk for suicide (HR: 1.68; 95% CI, 0.82–3.41) compared with women who succeeded in having another child, although the risk estimate failed to reach significance.
CONCLUSIONS
Health-care personnel treating women with fertility problems should be aware of the emotional response of their patients in order to recognize and treat possible psychiatric morbidity after fertility problems.
Large population‐based studies are needed to examine the effect of maternal use of fertility drugs on the risk of cancer in children, while taking into account the effect of the underlying ...infertility. A cohort of 123,322 children born in Denmark between 1964 and 2006 to 68,255 women who had been evaluated for infertility was established. We used a case–cohort design and calculated hazard ratios (HRs) for cancer in childhood (0–19 years) and in young adulthood (20–29 years) associated with maternal use of six groups of fertility drugs (clomiphene, gonadotropins i.e., human menopausal gonadotropins and follicle‐stimulating hormone, gonadotropin‐releasing hormone analogs, human chorionic gonadotropins, progesterone and other fertility drugs). We found no statistically significant association between maternal use of fertility drugs and risk for overall cancer in childhood or young adulthood. However, with regard to specific cancers in childhood, our results showed that maternal use of progesterone before childbirth markedly increased the risks of their offspring for acute lymphocytic leukemia (any use: HR, 4.95; 95% CI, 1.69–14.54; ≥ three cycles of use: HR, 9.96; 95% CI, 2.63–37.77) and for sympathetic nervous system tumors (any use: HR, 5.79; 95% CI, 1.23–27.24; ≥ three cycles of use: HR, 8.51; 95% CI, 1.72–42.19). These findings show that maternal use of progesterone may increase the risk for specific cancers in the offspring. Additional large epidemiological studies are urgently needed to confirm our finding.
What's new?
The use of fertility drugs has risen dramatically in Europe since the early 1970s—and so has the incidence of childhood cancer. The authors of the present study examined the possibility for a relationship between maternal fertility drug use and cancer risk in offspring using data from the Denmark Infertility Cohort. Risks for acute lymphocytic leukemia and sympathetic nervous system tumors were markedly increased among offspring born to women who used progesterone prior to childbirth. However, maternal fertility drug use was not associated with overall cancer risk in offspring.
Exogenous sex hormones seem to play a role in colorectal carcinogenesis. Little is known about the influence of different types or durations of postmenopausal hormone therapy (HT) on colorectal ...cancer risk. A nationwide cohort of women 50-79 years old without previous cancer (n = 1,006,219) were followed 1995-2009. Information on HT exposures was from the National Prescription Register and updated daily, while information on colon (n = 8377) and rectal cancers (n = 4742) were from the National Cancer Registry. Potential confounders were obtained from other national registers. Poisson regression analyses with 5-year age bands included hormone exposures as time-dependent covariates. Use of estrogen-only therapy and combined therapy were associated with decreased risks of colon cancer (adjusted incidence rate ratio 0.77, 95 % confidence interval 0.68-0.86 and 0.88, 0.80-0.96) and rectal cancer (0.83, 0.72-0.96 and 0.89, 0.80-1.00), compared to never users. Transdermal estrogen-only therapy implied more protection than oral administration, while no significant influence was found of regimen, progestin type, nor of tibolone. The benefit of HT was stronger for long-term hormone users; and hormone users were at lower risk of advanced stage of colorectal cancer, which seems supportive for a causal association between hormone therapy and colorectal cancer.
STUDY QUESTION
Do fertility drugs increase the risk for borderline ovarian tumours, overall and according to histological subtype?
SUMMARY ANSWER
The use of any fertility drug did not increase the ...overall risk for borderline ovarian tumours, but an increased risk for serous borderline ovarian tumours was observed after the use of progesterone.
WHAT IS KNOWN ALREADY
Many epidemiological studies have addressed the connection between fertility drugs use and risk for ovarian cancer; most have found no strong association. Fewer studies have assessed the association between use of fertility drugs and risk for borderline ovarian tumours, and the results are inconsistent.
STUDY DESIGN, SIZE, DURATION
A retrospective case–cohort study was designed with data from a cohort of 96 545 Danish women with fertility problems referred to all Danish fertility clinics in the period 1963–2006. All women were followed for first occurrence of a borderline ovarian tumour from the initial date of infertility evaluation until a date of migration, date of death or 31 December 2006, whichever occurred first. The median length of follow-up was 11.3 years.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Included in the analyses were 142 women with borderline ovarian tumours (cases) and 1328 randomly selected sub-cohort members identified in the cohort during the follow-up through 2006. Cases were identified by linkage to the Danish Cancer Register and the Danish Register of Pathology by use of personal identification numbers. To obtain information on use of fertility drugs, hospital files and medical records of infertility-associated visits to all Danish fertility clinics were collected and supplemented with information from the Danish IVF register. We used case–cohort techniques to calculate rate ratios (RRs) and corresponding 95% confidence intervals (CIs) for borderline ovarian tumours, overall and according to histological subtype, associated with the use of any fertility drug or five specific groups of fertility drugs: clomiphene citrate, gonadotrophins (human menopausal gonadotrophins and follicle-stimulating hormone), gonadotrophin-releasing hormone analogues, human chorionic gonadotrophins and progesterone.
MAIN RESULTS AND THE ROLE OF CHANCE
Analyses within the cohort showed that the overall risk for borderline ovarian tumours was not associated with the use of any fertility drug (RR 1.00; 95% CI 0.67–1.51) or of gonadotrophins (RR 1.32; 95% CI 0.81–2.14), clomiphene citrate (RR 0.96; 95% CI 0.64–1.44), human chorionic gonadotrophins (RR 0.91; 95% CI 0.61–1.36) or gonadotrophin-releasing hormone analogues (RR 1.10; 95% CI 0.66–1.81). Furthermore, no associations were observed between the risk for borderline ovarian tumours and these groups of fertility drugs according to the number of cycles of use, length of follow-up or parity. In contrast, use of progesterone increased the risk for borderline ovarian tumours, particularly serous tumours, for which statistically significantly increased risks were observed with any use of progesterone (RR 1.82; 95% CI 1.03–3.24), among women treated with ≥4 cycles of progesterone (RR 2.63; 95% CI 1.04–6.64) and for all women followed up for ≥4 years after their first treatment with progesterone.
LIMITATIONS, REASONS FOR CAUTION
Although we tried to minimize the effects of the underlying infertility, the severity of infertility might have affected our risk estimates, as women with more severe fertility problems may receive more treatment. The results from the subgroup analyses, e.g. the findings of an elevated risk for borderline ovarian tumours associated with increased time since first use of progesterone and with increased number of treatment cycles, should be interpreted with caution as these analyses are based on a limited number of women with borderline ovarian tumours.
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 risk for borderline ovarian tumours, the novel observation of an increased risk for serous tumours after use of progesterone should be investigated 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 fertility problems.
STUDY FUNDING/COMPETING INTEREST(S)
No conflict of interest was reported. S.M.B. was supported by a research scholarship from the Danish Cancer Society.
Postmenopausal hormone therapy use increases the risk of ovarian cancer. In the present study, the authors examined the risks of different histologic types of ovarian cancer associated with hormone ...therapy. Using Danish national registers, the authors identified 909,946 women who were followed from 1995-2005. The women were 50-79 years of age and had no prior hormone-sensitive cancers or bilateral oophorectomy. Hormone therapy prescription data were obtained from the National Register of Medicinal Product Statistics. The National Cancer and Pathology Register provided data on ovarian cancers, including information about tumor histology. The authors performed Poisson regression analyses that included hormone exposures and confounders as time-dependent covariates. In an average of 8.0 years of follow up, 2,681 cases of epithelial ovarian cancer were detected. Compared with never users, women taking unopposed oral estrogen therapy had increased risks of both serous tumors (incidence rate ratio (IRR) = 1.7, 95% confidence interval: 1.4, 2.2) and endometrioid tumors (IRR = 1.5, 95% confidence interval: 1.0, 2.4) but decreased risk of mucinous tumors (IRR = 0.3, 95% confidence interval: 0.1, 0.8). Similar increased risks of serous and endometrioid tumors were found with estrogen/progestin therapy, whereas no association was found with mucinous tumors. Consistent with results from recent cohort studies, the authors found that ovarian cancer risk varied according to tumor histology. The types of ovarian tumors should be given attention in future studies.
Objective: The aim of the Prevention of Cervical Cancer in Tanzania (PROTECT) study is to assess the prevalence of oncogenic human papillomavirus (HPV) and to determine the type distribution among ...women in the general population according to human immunodeficiency virus (HTV) status, in preparation for a potential HPV immunization program. Methods: We included 3603 women from the general population in urban and rural areas of Tanzania. All women underwent a gynecological examination where a Pap smear was obtained and cervical cells were collected to assess the presence of high-risk (HR) HPV DNA by hybrid capture 2 test. Genotyping was performed by the LiPaExtra method. These women were also tested for HIV. Results: The prevalence of HR HPV types was 20.1%, ranging from 14.8% in women with normal cytology to 94.2% in women with high grade squamous intraepithelial lesion (HSIL) or worse (100% in 5 cancers). In women with normal cytology or low-grade lesions, the most common type was HPV52 (3.2%), followed by HPV16 (2.1%). In contrast, HPV 16 was the dominating type in HSIL or worse (32.8%). No cancers contained HPV52. The HR HPV prevalence was higher in HIV-positive women (46.7%) than in HIV-negative women (17.2%). No specific HR HPV types were significantly more common in HIV-positive women. Conclusion: The HPV type distribution is similar in HIV-positive and HIV-negative women. These results suggest that the HPV vaccines that are currently available could protect women from HPV infection independently of their HIV status.
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