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Human germ cell tumours (GCTs) are derived from stem cells of the early embryo and the germ line. They occur in the gonads (ovaries and testes) and also in extragonadal sites, where migrating primordial germ cells are located during embryogenesis. This group of heterogeneous neoplasms is unique in that their developmental potential is in effect determined by the latent potency state of their cells of origin, which are reprogrammed to omnipotent, totipotent or pluripotent stem cells. Seven GCT types, defined according to their developmental potential, have been identified, each with distinct epidemiological and (epi)genomic features. Heritable predisposition factors affecting the cells of origin and their niches likely explain bilateral, multiple and familial occurrences of the different types of GCTs. Unlike most other tumour types, GCTs are rarely caused by somatic driver mutations, but arise through failure to control the latent developmental potential of their cells of origin, resulting in their reprogramming. Consistent with their non-mutational origin, even the malignant tumours of the group are characterized by wild-type TP53 and high sensitivity for DNA damage. However, tumour progression and the rare occurrence of treatment resistance are driven by embryonic epigenetic state, specific (sub)chromosomal imbalances and somatic mutations. Thus, recent progress in understanding GCT biology supports a comprehensive developmental pathogenetic model for the origin of all GCTs, and provides new biomarkers, as well as potential targets for treatment of resistant disease.

Although the autopsy still is a valuable tool in health statistics, health care quality control, medical education, and biomedical research, autopsy rates have been declining worldwide. The aim of this study was to examine trends of overall, clinical and forensic autopsy rates among adults in the Netherlands over the last four decades, and trends per sex, age (groups), and hospital type. We performed a retrospective study covering 35 years of Dutch national death counts (1977-2011), the number of in-hospital deceased patients, the number of deaths due to external causes, and the proportion of autopsies performed in these populations. The effects of sex, age and hospital category were analysed by linear and logistic regression and differences were evaluated by chi-square tests. Overall autopsy rates declined by 0.3% per calendar year, clinical autopsy rates by 0.7% per calendar year (from 31.4% to 7.7%), and forensic autopsy rates did not decline. Per calendar year the fraction of in-hospital deceased patients decreased by 0.2%. Autopsy rates were highest among men and younger patients; clinical autopsy rates were highest for patients dying in academic hospitals. In the Netherlands clinical autopsy rates have rapidly declined while at the same time the fraction of in-hospital deaths decreased, both contributing to the overall reduced absolute number of autopsies performed. It is important to improve awareness among both clinicians and general practitioners of the significance of the clinical autopsy.

Key Points Germ-cell tumours (GCTs) of all anatomical sites can be classified into five groups, characterized by their chromosomal complement and developmental potential. The most significant recurrent chromosomal aberrations in type I yolk-sac tumours are loss of 1p, 4 and 6q, and gain of 1q, 12(p13) and 20q. In type II seminomas and non-seminomatous GCTs, the most significant recurrent chromosomal aberrations are gain of 7, 8, 12p, 21 and X, and loss of chromosomes 1p, 11, 13 and 18. Aberrations of 12p are the only recurrent structural abnormalities in type II GCTs. In type III spermatocytic seminomas, gain of chromosome 9 is most common. The originating cell is most probably a primitive germ cell of which the developmental potential differs according to its stage of maturation and pattern of genomic imprinting. Animal models are available for the different groups of GCTs, except for the type II seminomas and non-seminomatous GCTs. An activating KIT mutation in codon 816 is an early pathogenetic event in bilateral testicular seminomas and non-seminomatous GCTs. The transcription factor OCT3/4, a characteristic of primordial germ cells and pluripotent stem cells, is a new and robust diagnostic marker for type II seminomas and non-seminomatous GCTs, including their intratubular precursor. Treatment sensitivity and resistance of GCTs probably correlates with retention and loss of embryonic characteristics (in particular, DNA-repair deficiency), respectively. The germ-cell tumours are a fascinating group of neoplasms because of their unusual biology and the spectacular therapeutic results that have been obtained in these tumours. Traditionally, this group of neoplasms is presented in an organ-oriented approach. However, recent clinical and experimental data convincingly demonstrate that these neoplasms are one disease with separate entities that can manifest themselves in different anatomical sites. We propose five entities, in which the developmental potential is determined by the maturation stage and imprinting status of the originating germ cell. Recent progress begins to explain the apparent unpredictable development of germ-cell tumours and offers a basis for understanding their exquisite sensitivity to therapy.

Objectives Autopsies are used for healthcare quality control and improving medical knowledge. Because autopsy rates are declining worldwide, various non-invasive or minimally invasive autopsy methods are now being developed. To investigate whether these might replace the invasive autopsies conventionally performed in naturally deceased adults, we systematically reviewed original prospective validation studies. Materials and methods We searched six databases. Two reviewers independently selected articles and extracted data. Methods and patient groups were too heterogeneous for meaningful meta-analysis of outcomes. Results Sixteen of 1538 articles met our inclusion criteria. Eight studies used a blinded comparison; ten included less than 30 appropriate cases. Thirteen studies used radiological imaging (seven dealt solely with non-invasive procedures), two thoracoscopy and laparoscopy, and one sampling without imaging. Combining CT and MR was the best non-invasive method (agreement for cause of death: 70 %, 95%CI: 62.6; 76.4), but minimally invasive methods surpassed non-invasive methods. The highest sensitivity for cause of death (90.9 %, 95%CI: 74.5; 97.6, suspected duplicates excluded) was achieved in recent studies combining CT, CT-angiography and biopsies. Conclusion Minimally invasive autopsies including biopsies performed best. To establish a feasible alternative to conventional autopsy and to increase consent to post-mortem investigations, further research in larger study groups is needed. Key points • Health care quality control benefits from clinical feedback provided by ( alternative ) autopsies . • So far , sixteen studies investigated alternative autopsy methods for naturally deceased adults . • Thirteen studies used radiological imaging modalities , eight tissue biopsies , and three CT - angiography . • Combined CT , CT - angiography and biopsies were most sensitive diagnosing cause of death .

Some germ cell tumors (GCTs) in men develop into hematologic malignancies; however, the clonal origins of such malignancies remain unknown. In this issue of the JCI, Taylor, Donoghue, et al. unravel the clonal relationship between primary mediastinal nonseminomas (PMNs) and hematologic somatic-type malignancies (HSTMs). Whole-exome sequencing was used to construct phylogenetic trees of the PMNs and the ensuing HSTM clones. HSTMs were derived from multiple distinct clones not detected within the PMNs. Clones from PMNs and HSTMs shared a common precursor, arguably an embryonal carcinoma cell resulting from a reprogrammed primordial germ cell from the thymus. Mutational and copy number variation analysis of a large cohort of patients with PMNs also demonstrated a high prevalence of TP53 mutations not found in testicular nonseminomas. These data likely explain why patients with PMNs are frequently resistant to platinum-based chemotherapy and provide TP53 mutations as potential targets.

Background Testicular germ cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an embryonic germ cell. This study determines intratumour heterogeneity to unravel tumour progression from initiation until metastasis. Methods In total, 42 purified samples of four treatment-resistant nonseminomatous (NS) TGCC were investigated, including the precursor germ cell neoplasia in situ (GCNIS) and metastatic specimens, using whole-genome and targeted sequencing. Their evolution was reconstructed. Results Intratumour molecular heterogeneity did not correspond to the supposed primary tumour histological evolution. Metastases after systemic treatment could be derived from cancer stem cells not identified in the primary cancer. GCNIS mostly lacked the molecular marks of the primary NS and comprised dominant clones that failed to progress. A BRCA-like mutational signature was observed without evidence for direct involvement of BRCA1 and BRCA2 genes. Conclusions Our data strongly support the hypothesis that NS is initiated by whole-genome duplication, followed by chromosome copy number alterations in the cancer stem cell population, and accumulation of low numbers of somatic mutations, even in therapy-resistant cases. These observations of heterogeneity at all stages of tumourigenesis should be considered when treating patients with GCNIS-only disease, or with clinically overt NS.

To evaluate the frequency of total-body CT and MR features of postmortem change in in-hospital deaths. In this prospective blinded cross-sectional study, in-hospital deceased adult patients underwent total-body postmortem CT and MR followed by image-guided biopsies. The presence of PMCT and PMMR features related to postmortem change was scored retrospectively and correlated with postmortem time interval, post-resuscitation status and intensive care unit (ICU) admittance. Intravascular air, pleural effusion, periportal edema, and distended intestines occurred more frequently in patients who were resuscitated compared to those who were not. Postmortem clotting was seen less often in resuscitated patients (p = 0.002). Distended intestines and loss of grey-white matter differentiation in the brain showed a significant correlation with postmortem time interval (p = 0.001, p<0.001). Hyperdense cerebral vessels, intravenous clotting, subcutaneous edema, fluid in the abdomen and internal livores of the liver were seen more in ICU patients. Longer postmortem time interval led to a significant increase in decomposition related changes (p = 0.026). There is a wide variety of imaging features of postmortem change in in-hospital deaths. These imaging features vary among clinical conditions, increase with longer postmortem time interval and must be distinguished from pathologic changes.

Autopsy rates worldwide have dropped significantly over the last decades and imaging-based autopsies are increasingly used as an alternative to conventional autopsy. Our aim was to evaluate the clinical performance and cost of minimally invasive autopsy. This study was part of a prospective cohort study evaluating a newly implemented minimally invasive autopsy consisting of MRI, CT, and biopsies. We calculated diagnostic yield and clinical utility-defined as the percentage successfully answered clinical questions-of minimally invasive autopsy. We performed minimally invasive autopsy in 46 deceased (30 men, 16 women; mean age 62.9±17.5, min-max: 18-91). Ninety-six major diagnoses were found with the minimally invasive autopsy of which 47/96 (49.0%) were new diagnoses. CT found 65/96 (67.7%) major diagnoses and MRI found 82/96 (85.4%) major diagnoses. Eighty-four clinical questions were asked in all cases. Seventy-one (84.5%) of these questions could be answered with minimally invasive autopsy. CT successfully answered 34/84 (40.5%) clinical questions; in 23/84 (27.4%) without the need for biopsies, and in 11/84 (13.0%) a biopsy was required. MRI successfully answered 60/84 (71.4%) clinical questions, in 27/84 (32.1%) without the need for biopsies, and in 33/84 (39.8%) a biopsy was required. The mean cost of a minimally invasive autopsy was €1296 including brain biopsies and €1087 without brain biopsies. Mean cost of CT was €187 and of MRI €284. A minimally invasive autopsy, consisting of CT, MRI and CT-guided biopsies, performs well in answering clinical questions and detecting major diagnoses. However, the diagnostic yield and clinical utility were quite low for postmortem CT and MRI as standalone modalities.

Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0–24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers. Genomic landscape studies of malignant germ cell tumors (GCTs) that occur in children, adolescents and young adults are limited. Here the authors perform multi-omics profiling of different types of GCTs across the age spectrum from 0–24 years and show that WNT signalling pathway is activated in GCTs and is associated with poor clinical outcomes.