Polygenic liability, stressful life events and risk for secondary-treated depression in early life: a nationwide register-based case-cohort study.

BACKGROUND: In this study, we examined the relationship between polygenic liability for depression and number of stressful life events (SLEs) as risk factors for early-onset depression treated in inpatient, outpatient or emergency room settings at psychiatric hospitals in Denmark. METHODS: Data were drawn from the iPSYCH2012 case-cohort sample, a population-based sample of individuals born in Denmark between 1981 and 2005. The sample included 18 532 individuals who were diagnosed with depression by a psychiatrist by age 31 years, and a comparison group of 20 184 individuals. Information on SLEs was obtained from nationwide registers and operationalized as a time-varying count variable. Hazard ratios and cumulative incidence rates were estimated using Cox regressions. RESULTS: Risk for depression increased by 35% with each standard deviation increase in polygenic liability (p < 0.0001), and 36% (p < 0.0001) with each additional SLE. There was a small interaction between polygenic liability and SLEs (ß = -0.04, p = 0.0009). The probability of being diagnosed with depression in a hospital-based setting between ages 15 and 31 years ranged from 1.5% among males in the lowest quartile of polygenic liability with 0 events by age 15, to 18.8% among females in the highest quartile of polygenic liability with 4+ events by age 15. CONCLUSIONS: These findings suggest that although there is minimal interaction between polygenic liability and SLEs as risk factors for hospital-treated depression, combining information on these two important risk factors could potentially be useful for identifying high-risk individuals.

The influence of marital status and partner concordance on participation in colorectal cancer screening.

BACKGROUND: Colorectal cancer screening program using a fecal immunochemical test aims to reduce morbidity and mortality through early detection. Although screening participation is free-of-charge, almost 40% of the invited individuals choose not to participate. To bring new insight into how non-participation can be identified and targeted, we examined the association between marital status and screening participation; with a focus on partner concordance in participation and sex differences. METHODS: This nationwide cross-sectional study included all Danish citizens aged 50-74 years, who were invited to colorectal cancer screening between 2014 and 2017. Logistic regression analysis was used to estimate odds ratio (OR) of participation while adjusting for sociodemographic variables. RESULTS: A total of 1 909 662 individuals were included in the analysis of which 62.7% participated in the screening program. Participation was highest among women. Stratified by marital status, screening participation was markedly lower in widowed (61.5%), divorced (54.8%) and single (47.3%), while participation reached 68.4% in married individuals. This corresponded to ORs of 0.59 (95% CI 0.58-0.59) for widowed, 0.56 (95% CI 0.55-0.56) for divorced and 0.47 (95% CI 0.47-0.48) for single, compared to married individuals. Individuals married to a participating partner were five times more likely to participate than married individuals with a non-participating partner, regardless of gender. CONCLUSIONS: Marital status was strongly associated with participation in colorectal cancer screening, and participation was even higher in married individuals with a participating partner. Future efforts to increase participation in colorectal cancer screening could potentially benefit from considering the role of partner concordance.

Modeling the cumulative incidence function of multivariate competing risks data allowing for within-cluster dependence of risk and timing.

We propose to model the cause-specific cumulative incidence function of multivariate competing risks data using a random effects model that allows for within-cluster dependence of both risk and timing. The model contains parameters that makes it possible to assess how the two are connected, e.g. if high-risk is related to early onset. Under the proposed model, the cumulative incidences of all failure causes are modeled and all cause-specific and cross-cause associations specified. Consequently, left-truncation and right-censoring are easily dealt with. The proposed model is assessed using simulation studies and applied in analysis of Danish register-based family data on breast cancer.

Excess cumulative incidence estimation for matched cohort survival studies.

We suggest a regression approach to estimate the excess cumulative incidence function (CIF) when matched data are available. In a competing risk setting, we define the excess risk as the difference between the CIF in the exposed group and the background CIF observed in the unexposed group. We show that the excess risk can be estimated through an extended binomial regression model that actively uses the matched structure of the data, avoiding further estimation of both the exposed and the unexposed CIFs. The method naturally deals with two time scales, age and time since exposure and simplifies how to deal with the left truncation on the age time-scale. The model makes it easy to predict individual excess risk scenarios and allows for a direct interpretation of the covariate effects on the cumulative incidence scale. After introducing the model and some theory to justify the approach, we show via simulations that our model works well in practice. We conclude by applying the excess risk model to data from the ALiCCS study to investigate the excess risk of late events in childhood cancer survivors.

Maternal use of hormonal contraception and risk of childhood leukaemia: a nationwide, population-based cohort study.

BACKGROUND: Maternal hormonal contraception has been suspected of being linked to an increased risk of childhood cancer. The aim of this study was to assess the association between maternal use of hormonal contraception and diagnosis of leukaemia in their children. METHODS: In this cohort study, we followed a nationwide cohort of 1 185 157 liveborn children between 1996 and 2014 listed in the Danish Medical Birth Registry and identified those diagnosed with leukaemia in the Danish Cancer Registry. Redeemed prescriptions from the Danish National Prescription Registry provided information about maternal hormonal contraceptive use, categorised as: no use (never used contraception before birth; reference category), previous use (>3 months before start of pregnancy), and recent use (≤3 months before and during pregnancy). We also calculated risk estimates separately for maternal hormonal contraceptive use during pregnancy. The primary outcome of interest was a diagnosis of any leukaemia in the children. Secondary outcomes were diagnoses of lymphoid leukaemia and non-lymphoid leukaemia. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% CIs for risk of leukaemia in children. The Data Protection Agency registration number for this study is 2017-41-5221. FINDINGS: Between Jan 1, 1996, and Dec 31, 2014, the 1 185 157 liveborn children accumulated 11 114 290 person-years of follow-up (median 9·3 years, IQR 4·6-14·2), during which 606 children were diagnosed with leukaemia (465 with lymphoid leukaemia and 141 with non-lymphoid leukaemia). Children born to women with recent use of any type of hormonal contraception were at higher risk for any leukaemia than children of women who never used contraception (HR 1·46, 95% CI 1·09-1·96; p=0·011); and for exposure during pregancy the risk was 1·78 (0·95-3·31; p=0·070). No association was found between timing of use and risk for lymphoid leukaemia (HR 1·23, 95% CI 0·97-1·57, p=0·089, for previous use and 1·27, 0·90-1·80, p=0·167, for recent use); however, the HRs for non-lymphoid leukaemia were 2·17 (1·22-3·87; p=0·008) for recent use and 3·87 (1·48-10·15; p=0·006) for use during pregnancy. Hormonal contraception use close to or during pregnancy might have resulted in one additional case of leukaemia per about 50 000 exposed children, or 25 cases during the 9-year study period. INTERPRETATION: Our findings suggest the maternal hormonal use affects non-lymphoid leukaemia development in children. Since almost no risk factors have been established for childhood leukaemia, these findings suggest an important direction for future research into its causes and prevention. FUNDING: The Danish Cancer Research Foundation, the Arvid Nilssons Foundation, the Gangsted Foundation, the Harboe Foundation, and the Johannes Clemmesens Foundation.

Liver diseases in Adult Life after Childhood Cancer in Scandinavia (ALiCCS): A population-based cohort study of 32,839 one-year survivors.

Information on late onset liver complications after childhood cancer is scarce. To ensure an appropriate follow-up of childhood cancer survivors and reducing late liver complications, the need for comprehensive and accurate information is presented. We evaluate the risk of liver diseases in a large childhood cancer survivor cohort. We included all 1-year survivors of childhood cancer treated in the five Nordic countries. A Cox proportional hazards model was used to estimate hospitalisation rate (hazard) ratios (HRs) for each liver outcome according to type of cancer. We used the risk among survivors of central nervous system tumour as internal reference. With a median follow-up time of 10 years, 659 (2%) survivors had been hospitalised at least once for a liver disease. The risk for hospitalisation for any liver disease was high after hepatic tumour (HR = 6.9) and leukaemia (HR = 1.7). The Danish sub-cohort of leukaemia treated with haematopoietic stem cell transplantation had a substantially higher risk for hospitalisation for all liver diseases combined (HR = 3.8). Viral hepatitis accounted for 286 of 659 hospitalisations corresponding to 43% of all survivors hospitalised for liver disease. The 20-year cumulative risk of viral hepatitis was 1.8% for survivors diagnosed with cancer before 1990 but only 0.3% for those diagnosed after 1990. The risk of liver disease was low but significantly increased among survivors of hepatic tumours and leukaemia. Further studies with focus on the different treatment modalities are needed to further strengthen the prevention of treatment-induced late liver complications.

Long-Term Metastatic Risk after Biopsy of Posterior Uveal Melanoma.

PURPOSE: Biopsy of posterior uveal melanoma continues to be intensely debated in terms of the clinical benefits and safety profile. Although several studies have reported a low frequency of ocular complications after tumor biopsy, the potential long-term risk of iatrogenic dissemination remains unresolved. The purpose of this study was to assess the risk of metastatic disease after biopsy of posterior uveal melanoma. DESIGN: Retrospective nationwide cohort study linking clinical and histopathologic records to pathology, cancer, and mortality registries. PARTICIPANTS: All patients with posterior uveal melanoma treated in Denmark between January 1985 and December 2016. METHODS: For each patient, we recorded detailed information on age, gender, tumor characteristics, and diagnostic and therapeutic measures, including tumor biopsy, if any, and the primary treating hospital. Absolute risk of melanoma-specific death was presented by cumulative incidence curves that accounted for competing risks. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and melanoma-specific mortality of patients who underwent biopsy during primary treatment compared with nonbiopsied patients through November 1, 2017. Fine and Gray risk regression was used as a sensitivity analysis to evaluate the impact of competing risks. MAIN OUTCOME MEASURES: All-cause and melanoma-specific mortality. RESULTS: Among 1637 patients, 567 (35%) underwent biopsy during primary treatment. At diagnosis, biopsied patients exhibited better prognostic characteristics, including smaller tumor size (P < 0.001) and younger age (P < 0.001), than nonbiopsied patients. In the adjusted analyses, we observed no apparent differences in all-cause mortality (HR, 1.07; 95% CI, 0.89-1.26; P = 0.47) or melanoma-specific mortality (HR, 1.11; 95% CI, 0.89-1.39; P = 0.35) among biopsied patients compared with nonbiopsied patients. CONCLUSIONS: All-cause and melanoma-specific mortality after primary treatment were similar among biopsied and nonbiopsied patients with posterior uveal melanoma. Our findings do not support an increased metastatic risk after intraocular tumor biopsy.

The distress thermometer in survivors of gynaecological cancer: accuracy in screening and association with the need for person-centred support.

PURPOSE: Unrecognised psychological distress among cancer survivors may be identified using short screening tools. We validated the accuracy of the distress thermometer (DT) to detect psychological distress on the Hospital Anxiety and Depression Scale (HADS) among early stage gynaecological cancer survivors and whether the women's DT and HADS scores were associated with the need of an individualised supportive intervention. METHODS: One hundred sixty-five gynaecological cancer survivors answered DT and HADS before randomisation in a trial testing a nurse-led, person-centred intervention using supportive conversations. The number of conversations was decided in the woman-nurse dyad based on the woman's perceived need. Nurses were unaware of the women's DT and HADS scores. We validated DT's accuracy for screening using HADS as gold standard and receiver operating characteristic curves. Associations between DT and HADS scores and the number of conversations received were investigated. RESULTS: For screening of distress (HADS ≥ 15), a DT score ≥ 2, had a sensitivity of 93% (95% CI 82-98%), a specificity of 40% (32-49%), and positive and negative predictive values of 36% (28-45%), and 94% (84-98%), respectively; area under curve was 0.73 (0.64-0.81). Higher DT and HADS scores were associated with more interventional conversations. CONCLUSIONS: In gynaecological cancer survivors, DT may perform fairly well as a first stage screening tool for distress, but a second stage is likely needed due to a high number of false positives. DT and HADS scores may predict the number of supportive conversations needed in an individualised intervention in gynaecological cancer survivors.

Incorporation of the time aspect into the liability-threshold model for case-control-family data.

Familial aggregation and the role of genetic and environmental factors can be investigated through family studies analysed using the liability-threshold model. The liability-threshold model ignores the timing of events including the age of disease onset and right censoring, which can lead to estimates that are difficult to interpret and are potentially biased. We incorporate the time aspect into the liability-threshold model for case-control-family data following the same approach that has been applied in the twin setting. Thus, the data are considered as arising from a competing risks setting and inverse probability of censoring weights are used to adjust for right censoring. In the case-control-family setting, recognising the existence of competing events is highly relevant to the sampling of control probands. Because of the presence of multiple family members who may be censored at different ages, the estimation of inverse probability of censoring weights is not as straightforward as in the twin setting but requires consideration. We propose to employ a composite likelihood conditioning on proband status that markedly simplifies adjustment for right censoring. We assess the proposed approach using simulation studies and apply it in the analysis of two Danish register-based case-control-family studies: one on cancer diagnosed in childhood and adolescence, and one on early-onset breast cancer. Copyright © 2017 John Wiley & Sons, Ltd.

The potential diagnostic value of serum microRNA signature in patients with pancreatic cancer.

Biomarkers for early diagnosis of patients with pancreatic cancer (PC) are needed. Our aim was to identify panels of miRNAs in serum in combination with CA 19-9 for use in the diagnosis of PC. Four hundred seventeen patients with PC were included prospectively from Denmark (n = 306) and Germany (n = 111). Controls included 59 patients with chronic pancreatitis (CP) and 248 healthy subjects (HS). MiRNAs were analyzed in pretreatment serum samples from 3 cohorts: discovery cohort (754 human miRNAs, TaqMan(®) Human MicroRNA assay, Applied Biosystem; PC n = 133, controls n = 72); training cohort (34 miRNAs, real-time qPCR using the Fluidigm BioMark™ System; PC n = 198, controls n = 184); validation cohort (13 miRNAs, real-time qPCR using the Fluidigm BioMark™ System; PC n = 86, controls n = 51). We found that 34 miRNAs in serum from PC patients in the discovery cohort were expressed differently than in controls. These miRNAs were tested in the training cohort, and four diagnostic panels were constructed that included 5 or 12 miRNAs (miR-16, -18a, -20a, -24, -25, -27a, -29c, -30a.5p, -191, -323.3p, -345 and -483.5p). Diagnostic accuracy of detecting PC in the training cohort was AUC (Index I 0.85; II 0.87; III 0.85; IV 0.95; CA 19-9 0.93); specificity (I 0.71; II 0.76; III 0.66; IV 0.90 (fixed sensitivity at 0.85); CA 19-9 0.93). Combining serum CA 19-9 and Index II best discriminated Stages I and II PC from HS [AUC 0.93 (0.90-0.96), sensitivity 0.77 (0.69-0.84), specificity 0.94 (0.90-0.96) and accuracy 0.88 (0.84-0.91)]. In conclusion, we identified four diagnostic panels based on 5 or 12 miRNAs in serum that could distinguish patients with PC from HS and CP.

Increased risk of borderline ovarian tumors in women with a history of pelvic inflammatory disease: A nationwide population-based cohort study.

OBJECTIVE: Some studies suggest that pelvic inflammatory disease (PID) is a potential risk factor for ovarian cancer. However, only few studies have investigated the association between PID and risk of borderline ovarian tumors. We conducted a population-based cohort study to investigate the association between PID and risk of borderline ovarian tumors. METHODS: Using various nationwide Danish registries we identified all women in Denmark during 1978-2012, who were born during 1940-1970 (n=1,318,925). Of these, 81,263 women were diagnosed with PID in the study period, and 2736 women had a borderline ovarian tumor (1290 serous and 1344 mucinous). Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between PID and risk of borderline tumors were estimated using Cox regression models with adjustment for potential confounders. RESULTS: A history of PID was associated with an increased risk of borderline ovarian tumors (HR=1.39; 95% CI: 1.19-1.61). However, histotype-specific analyses revealed significant variation in risk as PID was only associated with an increased risk of serous borderline tumors (HR=1.85; 95% CI: 1.52-2.24), but not with mucinous borderline tumors (HR=1.06; 95% CI: 0.83-1.35). CONCLUSIONS: PID is associated with an increased risk of serous borderline tumors. Further research on the potential underlying biological mechanisms and on the identification of the subset of women with PID who are at increased risk of serous borderline tumors is warranted.

Effect of socioeconomic position on survival after childhood cancer in Denmark.

Background One fifth of all deaths among children in Europe are accounted for by cancer. If this is to be reduced there is a need for studies on not only biology and treatment approaches but also on how social factors influence cure rates. We investigated how various socioeconomic characteristics were associated with survival after childhood cancer. Material and methods In a nationwide cohort of 3797 children diagnosed with cancer [hematological cancer, central nervous system (CNS) tumors, non-CNS solid tumors] before age 20 between 1990 and 2009 we identified parents and siblings and obtained individual level parental socioeconomic variables and vital status through 2012 by linkage to population-based registries. Hazard ratios (HR) and 95% confidence intervals (CI) for dying were estimated using multivariate Cox proportional hazard models. Results For all children with cancer combined, survival was slightly but not statistically significantly better the higher the education of the mother or the father, and with maternal income. Significantly better survival was observed when parents were living together compared to living alone and worse survival when the child had siblings compared to none. Young (<20) or older (≥40) maternal age showed non-significant associations, but based on small numbers. For hematological cancers, no significant associations were observed. For CNS tumors, better survival was seen with parents living together (HR 0.70, CI 0.51-0.97). For non-CNS solid tumors, survival was better with high education of the mother (HR 0.66, CI 0.44-0.99) compared to basic and worse for children with one (HR 1.45, CI 1.11-1.89) or two or more siblings (HR 1.29, CI 0.93-1.79) (p for trend 0.02) compared to none. Conclusion The impact of socioeconomic characteristics on childhood cancer survival, despite equal access to protocolled and free-of-charge treatment, warrants further and more direct studies of underlying mechanisms in order to target these as a means to improve survival rates.

Long-term follow-up of the risk for cervical intraepithelial neoplasia grade 2 or worse in HPV-negative women after conization.

Little research has been conducted on the long-term value of human papillomavirus (HPV) testing after conization. We investigated whether cytology adds to the value of a negative HPV test for long-term prediction of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). In addition, we compared risk of CIN2+ following a negative HPV test in women after conization with that in women from the general population. During 2002-2005, 667 women treated for CIN2+ were tested for HPV and cytology 46 months after conization. Only HPV-negative women were included. Women participating in routine screening were age-matched with post-conization HPV-negative women, leaving 13,230 and 477 women, respectively, for analysis. By linkage to the Pathology Data Bank, we identified all cases of CIN2+ by December 2013. The 3-, 5-, 8- and 10-year risks for CIN2+ were 0.7, 0.9, 2.8 and 5.7% after a negative HPV test and 0.5, 0.8, 2.9 and 6.1% in HPV and cytology-negative women. HPV-negative women in the general population had similar 3-year and 5-year risks of 0.4 and 1.0%; thereafter, they had lower risks of 1.9% at 8 years and 2.7% at 10 years. Our results indicate that HPV testing may be used as a test of cure after conization. In the first 5 years after testing, the risk for CIN2+ of women who were HPV-negative at 34 months after conization was similar to that of HPV-negative women in the general population. After 67 years, however, women who have undergone conization may be at higher risk for CIN2+.

Lifestyle, family history, and risk of idiopathic Parkinson disease: a large Danish case-control study.

The relationship between Parkinson disease (PD) and smoking has been examined in several studies, but little is known about smoking in conjunction with other behaviors and a family history of PD. Using unconditional logistic regression analysis, we studied individual and joint associations of these factors with idiopathic PD among 1,808 Danish patients who were diagnosed in 1996-2009 and matched to 1,876 randomly selected population controls. Although there was a downward trend in duration of smoking, this was not observed for daily tobacco consumption. A moderate intake of caffeine (3.1-5 cups/day) was associated with a lower odds ratio for PD (0.45, 95% confidence interval: 0.34, 0.62), as was a moderate intake of alcohol (3.1-7 units/week) (odds ratio = 0.60, 95% confidence interval: 0.58, 0.84); a higher daily intake did not reduce the odds further. When these behaviors were studied in combination with smoking, the odds ratios were lower than those for each one alone. Compared with never smokers with no family history of PD, never smokers who did have a family history had an odds ratio of 2.81 (95% confidence interval: 1.91, 4.13); for smokers with a family history, the odds ratio was 1.60 (95% confidence interval: 1.15, 2.23). In conclusion, duration of smoking seems to be more important than intensity in the relationship between smoking and idiopathic PD. The finding of lower risk estimates for smoking in combination with caffeine or alcohol requires further confirmation.

Distress after a psychosocial cancer rehabilitation course. Main effects and effect modification in a randomised trial at 12 months of follow-up.

BACKGROUND: In 2002, the Danish Cancer Society opened a rehabilitation centre in which cancer patients were offered a free, six-day, multidimensional residential course. Our previous studies of the effects of this course at one and six months of follow-up showed no positive effect on distress. We investigated long-term effects at 12 months of follow-up and whether subgroups with fewer psychosocial resources received more benefit from the intervention than patients with better resources. MATERIAL AND METHODS: In two Danish counties, 507 patients with breast, prostate, colon or rectum cancer diagnosed within the past two years who had completed primary treatment were randomised to a six-day, multidimensional residential rehabilitation course or to standard care. Of these, 208 patients received the allocated intervention and 244 received the allocated control condition and were included in the analyses. Patients in both groups completed questionnaires at baseline and at one, six and 12 months of follow-up, including the 'Profile of Mood States short form', the 'General Self-efficacy' scale and a question on emotional support. At 12 months of follow-up, 179 participants in the intervention group and 195 in the control group provided data. RESULTS: No effect of the intervention was found on distress at 12 months of follow-up, even in subgroups with fewer psychosocial resources at baseline, i.e. greater baseline distress, poorer self-efficacy and less emotional support. CONCLUSION: Multidimensional rehabilitation programmes may not be effective in the treatment of distress. During the past few decades, studies of psychotherapy or psycho-education in cancer patients have shown small to moderate effects. More focused rehabilitation programmes may be more effective.

Social position and referral to rehabilitation among cancer patients.

OBJECTIVES: In Denmark, most healthcare services, including cancer treatment and rehabilitation, are offered free of charge by referral from a treating physician; thus, social equality should be expected. In a population-based cohort study of registry-based data, we examined the association between socioeconomic position, measured as educational level, and referral to rehabilitation services among cancer patients. MATERIAL AND METHODS: Through the Danish Cancer Registry, we identified all people resident in the Municipality of Copenhagen with cancer diagnosed in 2007-2012. Information on all rehabilitation referrals was retrieved from the Municipal Centre for Cancer Rehabilitation for 2009-2012. Information on demographic and socioeconomic characteristics was obtained from national Danish registers. The Cox proportional hazards model was used to investigate associations between educational level and referral to rehabilitation with adjustment for sex, age, diagnosis, disposable income, cohabitation status and number of children living at home at the time of diagnosis. RESULTS: A primary cancer was diagnosed in 13 840 people, of whom 2148 (16%) were referred to rehabilitation services during follow-up. In the fully adjusted model, we found education to be a predictor of referral, with a hazard ratio of 1.33 (95% CI 1.19-1.49) for patients with long education and a hazard ratio of 1.15 (95% CI 1.03-1.29) for patients with medium education as compared with patients with short education. CONCLUSIONS: Our findings suggest that, even after differences in demographics and cancer characteristics are accounted for, referral to rehabilitation services is not equally distributed by social group. Higher educational level is associated with a higher probability of referral to rehabilitation services.

Role of human papillomavirus testing and cytology in follow-up after conization.

OBJECTIVE: Adequate follow-up of women who have undergone conization for high-grade cervical lesions is crucial in cervical cancer screening programs. We evaluated the performance of testing for high-risk human papillomavirus (HPV) types, cytology alone, and combined testing in predicting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) after conization. DESIGN: Prospective cohort study. SETTING: Denmark. POPULATION: 667 women attending for conization. METHODS: Cervical specimens were collected during 2002-2006 at first visit after conization for cytological examination and Hybrid Capture 2 detection of high-risk HPV. The women were passively followed until 2 years after first follow-up visit by linkage to the nationwide Pathology Data Bank. RESULTS: At first visit after conization (median time, 3.4 months), 20.4% were HPV-positive and 17.2% had atypical squamous intraepithelial lesions or more severe cytology (ASCUS+). The 2-year incidence of CIN2+ after conization was 3.6%. Sensitivity for detection of CIN2+ after conization was 81.0% [95% confidence interval (CI) 58.1-94.6] for positive cytology (ASCUS+ threshold) and 95.2% (95% CI 76.2-99.9) for HPV testing and for combined testing. Specificity of ASCUS+ cytology (85.2%; 95% CI 82.0-88.0) was higher than that of HPV testing (82.4%; 95% CI 79.0-85.4) and markedly higher than that of combined testing (73.2%; 95% CI 69.3-76.8). The margin status had no significant added value. CONCLUSIONS: Testing for high-risk HPV three to four months after conization is more sensitive than ASCUS+ cytology for identifying women at risk for relapse of CIN2+ within 2 years. Further studies are needed to evaluate whether HPV testing could be a stand-alone test in follow up after conization.

MicroRNA biomarkers in whole blood for detection of pancreatic cancer.

IMPORTANCE: Biomarkers for the early diagnosis of patients with pancreatic cancer are needed to improve prognosis. OBJECTIVES: To describe differences in microRNA expression in whole blood between patients with pancreatic cancer, chronic pancreatitis, and healthy participants and to identify panels of microRNAs for use in diagnosis of pancreatic cancer compared with the cancer antigen 19-9 (CA19-9). DESIGN, SETTING, AND PARTICIPANTS: A case-control study that included 409 patients with pancreatic cancer and 25 with chronic pancreatitis who had been included prospectively in the Danish BIOPAC (Biomarkers in Patients with Pancreatic Cancer) study (July 2008-October 2012) plus 312 blood donors as healthy participants. The microRNA expressions in pretreatment whole blood RNA samples were collected and analyzed in 3 randomly determined subcohorts: discovery cohort (143 patients with pancreatic cancer, 18 patients with chronic pancreatitis, and 69 healthy participants), training cohort (180 patients with pancreatic cancer, 1 patient with chronic pancreatitis, and 199 healthy participants), and validation cohort (86 patients with pancreatic cancer, 7 patients with chronic pancreatitis, and 44 healthy participants); 754 microRNAs were screened in the discovery cohort and 38 microRNAs in the training cohort and 13 microRNAs in the validation cohort. MAIN OUTCOMES AND MEASURES: Identification of microRNA panels (classifiers) for diagnosing pancreatic cancer. RESULTS: The discovery cohort demonstrated that 38 microRNAs in whole blood were significantly dysregulated in patients with pancreatic cancer compared with controls. These microRNAs were tested in the training cohort and 2 diagnostic panels were constructed comprising 4 microRNAs in index I (miR-145, miR-150, miR-223, miR-636) and 10 in index II (miR-26b, miR-34a, miR-122, miR-126*, miR-145, miR-150, miR-223, miR-505, miR-636, miR-885.5p). The test characteristics for the training cohort were index I area under the curve (AUC) of 0.86 (95% CI, 0.82-0.90), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.64 (95% CI, 0.57-0.71); index II AUC of 0.93 (95% CI, 0.90-0.96), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.85 (95% CI, 0.80-0.85); and CA19-9 AUC of 0.90 (95% CI, 0.87-0.94), sensitivity of 0.86 (95% CI, 0.80-0.90), and specificity of 0.99 (95% CI, 0.96-1.00). Performances were strengthened in the validation cohort by combining panels and CA19-9 (index I AUC of 0.94 [95% CI, 0.90-0.98] and index II AUC of 0.93 [95% CI, 0.89-0.97]). Compared with CA19-9 alone, the AUC for the combination of index I and CA19-9 was significantly higher (P = .01). The performance of the panels in patients with stage IA-IIB pancreatic cancer was index I AUC of 0.80 (95% CI, 0.73-0.87); index I and CA19-9 AUC of 0.83 (95% CI, 0.76-0.90); index II AUC of 0.91 (95% CI, 0.87-0.94); and index II and CA19-9 AUC of 0.91 (95% CI, 0.86-0.95). CONCLUSIONS AND RELEVANCE: This study identified 2 diagnostic panels based on microRNA expression in whole blood with the potential to distinguish patients with pancreatic cancer from healthy controls. Further research is necessary to understand whether these have clinical implications for early detection of pancreatic cancer and how much this information adds to serum CA19-9.

Hospital contact for mental disorders in survivors of childhood cancer and their siblings in Denmark: a population-based cohort study.

BACKGROUND: Survivors of childhood cancer are known to be at risk for long-term physical and mental effects. However, little is known about how cancers can affect mental health in the siblings of these patients. We aimed to assess the long-term risks of mental disorders in survivors of childhood cancer and their siblings. METHODS: Hospital contact for mental disorders was assessed in a population-based cohort of 7085 Danish children treated for cancer by contemporary protocols between 1975 and 2010 and in their 13 105 siblings by use of data from the Danish Psychiatric Central Research Registry. Hazard ratios (HRs) for first hospital contact were calculated using a Cox proportional hazards model. We compared these sibling and survivor cohorts with two population-based cohorts who were not childhood cancer survivors or siblings of survivors. FINDINGS: Survivors of childhood cancer were at increased risk of hospital contact for mental disorders, with HRs of 1·50 (95% CI 1·32-1·69) for males and 1·26 (1·10-1·44) for females. Children younger than 10 years at diagnosis had the highest risk, and increased risks were seen in survivors of CNS tumours, haematological malignancies, and solid tumours. Survivors had higher risk of neurodevelopmental, emotional, and behavioural disorders than population-based comparisons and siblings, and male survivors had higher risk for unipolar depression. Overall, siblings had no excess risk for mental disorders. However, our data suggest that siblings who were young at the time of cancer diagnosis of the survivor were at increased risk for mental disorders, whereas those older than 15 years at diagnosis were at a lower risk than the general population. INTERPRETATION: Childhood cancer survivors should be followed up for mental late effects, especially those diagnosed in young age. Further, clinicians should also be aware that siblings who were young at the time of cancer diagnosis might be at increased risk for mental health disorders.