Birgitte G. Toft

Dysregulation of the mitosis–meiosis switch in testicular carcinoma in situ

Testicular germ cell tumours (TGCT) of young adults arise from the intratubular precursor, carcinoma in situ (CIS). CIS cells are thought to be developmentally arrested and transformed fetal germ cells that survive through childhood and gain invasive capacity after puberty. Given that germ cell neoplasms arise frequently in undervirilized and dysgenetic gonads and the striking physiological difference between meiotic entry in ovaries (fetal life) versus testes (at puberty), this study aimed to investigate whether errors in regulation of meiosis may be implicated in the pathogenesis of CIS or its invasive progression to TGCT. The main focus was on a key sex differentiation and meiosis regulator, DMRT1, which has also been linked to TGCT risk in recent genetic association studies. Expression patterns of DMRT1 and other meiosis regulators (SCP3, DMC1, STRA8, CYP26B1, NANOS2, NANOS3) were investigated in pre‐ and post‐pubertal CIS samples and TGCT by quantitative RT–PCR and immunohistochemistry. The results demonstrated that meiosis markers and meiosis inhibitors were simultaneously expressed in CIS cells, in both pre‐ and post‐pubertal testis samples. DMRT1 was present in a restricted subset of CIS cells, which was relatively greater in pre‐pubertal (27%) compared to adult (2.6%) samples. In contrast to the majority of CIS cells, DMRT1‐positive CIS cells in adult testes were not proliferating. DMRT1 and most of the other meiosis regulators were absent or expressed at low levels in invasive TGCT, except in spermatocytic seminoma (not derived from CIS). In conclusion, this study indicates that meiosis signalling is dysregulated in CIS cells and that a key regulator of the mitosis–meiosis switch, DMRT1, is expressed in early‐stage CIS cells but is down‐regulated with further invasive transformation. Whether this mixed meiosis signalling in CIS cells is caused by insufficient virilization of the fetal somatic niche or a partial post-pubertal maturation remains uncertain and requires further study.

Risk of prostate cancer diagnosis and mortality in men with a benign initial transrectal ultrasound-guided biopsy set: a population-based study

BACKGROUNDnThe risk of missing prostate cancer in the transrectal ultrasound-guided systematic biopsies of the prostate in men with suspected prostate cancer is a key problem in urological oncology. Repeat biopsy or MRI-guided biopsies have been suggested to increase sensitivity for diagnosis of prostate cancer, but the risk of disease-specific mortality in men who present with raised prostate-specific antigen (PSA) concentration and a benign initial biopsy result remains unknown. We investigated the risk of overall and prostate cancer-specific mortality in men with a benign initial biopsy set.nnnMETHODSnData were extracted from the Danish Prostate Cancer Registry-a population-based registry including all men undergoing histopathological assessment of prostate tissue. All men who were referred for transrectal ultrasound-guided biopsy for assessment of suspected prostate cancer between Jan 1, 1995, and Dec 31, 2011, in Denmark were eligible for inclusion. Follow-up data were obtained on April 28, 2015. The primary endpoint was the cumulative incidence of prostate cancer-specific mortality, analysed in a competing risk setting, with death from other causes as the competing event.nnnFINDINGSnBetween Jan 1, 1995, and Dec 31, 2011, 64u2008430 men were referred for transrectal ultrasound-guided biopsy, of whom 63u2008454 were eligible for inclusion. Median follow-up was 5·9 years (IQR 3·8-8·5) and the total follow-up time, from the enrolment of the first patient on Jan 1, 1995, until the extraction of causes of death on April 28, 2015, was 20 years. 10u2008407 (30%) of 35u2008159 men with malignant initial biopsy sets died from prostate cancer, compared with 541 (2%) of 27u2008181 men with benign initial biopsy sets. Estimated overall 20-year mortality was 76·1% (95% CI 73·0-79·2). In all men referred for transrectal ultrasound-guided biopsy, the cumulative incidence of prostate cancer-specific mortality after 20 years was 25·6% (24·7-26·5) versus 50·5% (47·5-53·5) for mortality from other causes. In men with benign initial biopsy sets, the cumulative incidence of prostate cancer-specific mortality was 5·2% (3·9-6·5) versus 59·9% (55·2-64·6) for mortality from other causes. In men with PSA concentrations 10 μg/L or lower and benign initial biopsy sets (2779 men), the cumulative incidence of prostate cancer-specific mortality was 0·7% (0·2-1·3). Cumulative incidence of prostate cancer specific mortality in men with benign initial biopsy sets was 3·6% (95% CI 0·1-7·2) for men with a PSA higher than 10 ng/mL but 20 ng/mL or less (855 men) and 17·6% (12·7-22·4) and for men with a PSA higher than 20 ng/mL (454 men).nnnINTERPRETATIONnThe first systematic transrectal ultrasound-guided biopsy set holds important prognostic information. The 20-year risk of prostate cancer-specific mortality in men with benign initial results is low. Our findings question whether men with low PSA concentration and a benign initial biopsy set should undergo further diagnostic assessment in view of the high risk of mortality from other causes.nnnFUNDINGnCapital Region of Denmarks Fund for Health Research, Danish Cancer Society, Danish Association for Cancer Research, and Krista and Viggo Petersens Foundation.

DaPeCa-3: promising results of sentinel node biopsy combined with 18F-fluorodeoxyglucose positron emission tomography/computed tomography in clinically lymph node-negative patients with penile cancer – a national study from Denmark

To estimate the diagnostic accuracy of sentinel node biopsy (SNB) combined with preoperative 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) for inguinal lymph node (LN) evaluation in patients with invasive penile squamous cell carcinoma (PSCC) with no clinical evidence of inguinal metastases (cN0) at two tertiary centres with complete clinical follow‐up.

Diagnostic characteristics of lethal prostate cancer

BACKGROUNDnThe diagnostic characteristics of men who eventually die from prostate cancer (PCa) and the extent to which early diagnostic strategies have affected these characteristics are unclear. We aimed to investigate trends in survival and clinical presentation at diagnosis in men who eventually died from PCa.nnnPATIENTS AND METHODSnBased on the national database, the Danish Prostate Cancer Registry, a nationwide population-based study of all 19,487 men who died from PCa in Denmark between 1995 and 2013 was conducted. Trends in median survival and trends in age, prostate-specific antigen (PSA), clinical stage, and Gleason score (GS) at diagnosis were analysed.nnnRESULTSnA total of 46.9%, 16.8%, and 36.3% had metastatic (M+), locally advanced/lymph node positive (LaN+), and localised disease, respectively, at diagnosis. Only 0.15% had localised disease, GSxa0≤xa06 and PSA<10. Over time, the proportion of men with M+ disease at diagnosis decreased from 54.0-38.3% (pxa0<xa00.0001), whereas the proportion LaNxa0+xa0disease increased from 8.6-27.3% (pxa0<xa00.0001). The proportion of localised disease remained stable at 33.2-41.9%. Median survival increased 2.11 years from 1.88 (95% CI: 1.68-2.08) in 1995 to 3.99 (95% CI: 3.71-4.28) years in 2013, pxa0<xa00.0001.nnnCONCLUSIONSnIn a large population-based study, the results confirmed concurrent literature that the majority of men who eventually died from PCa had LaN+ or M+ disease at diagnosis. The proportion of men with M+ disease at diagnosis decreased significantly over time, parallelled by an increase in median survival. Taken together, this indicates a lead-time effect on survival, which presently, however, is not substantial enough to result in a reduced PCa-specific mortality.

Trends in incidence and 5-year mortality in men with newly diagnosed, metastatic prostate cancer-A population-based analysis of 2 national cohorts: Incidence & Mortality in de Novo M+ PCa

Early detection has increased prostate cancer (PCa) incidence. Randomized trials have demonstrated that early detection reduces the incidence of de novo metastatic PCa. Concurrently, life‐prolonging treatments have been introduced for patients with advanced PCa. On a populations‐based level, the authors analyzed whether early detection and improved treatments changed the incidence and 5‐year mortality of men with de novo metastatic PCa.

The use of transrectal ultrasound-guided biopsy following the introduction of prostate-specific antigen testing in Denmark: a population-based analysis

Abstract Objective: Incidence rates of prostate cancer in Denmark resemble those of countries that endorse prostate-specific antigen (PSA) screening. So far, no studies have described the consequences of PSA testing on diagnostic activity on a population level. The aim of this study was to describe the frequency of systematic transrectal ultrasound-guided biopsy (TRUS-gb) activity, including rebiopsy rates, in Denmark between 1995 and 2011. Materials and methods: All men who underwent TRUS-gb during the period were identified in the Danish Prostate Cancer Registry. In total, 83,041 biopsy sets from 64,430 individuals were identified. The diagnostic rate and the frequency of rebiopsy were analyzed. Age, histology and PSA were compared at the time of biopsy. Results: The number of TRUS-gb per 100,000 men per year increased 4.6-fold. The mean number of TRUS-gb procedures per individual increased from 1.08 in 1995 to 1.46 in 2011 (pu2009=u2009.0001), and the proportion of men with negative initial biopsy sets who underwent rebiopsy increased from 22% in 1995 to 41% in 2004, later decreasing to 31% in 2009. Conclusions: The diagnostic activity in Denmark and the rebiopsy rates in men with initial negative TRUS-gb have increased substantially, and guidelines for the management of men with a negative initial biopsy are highly warranted.