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The pathogenesis of testicular germ cell tumours (GCTs) is still incompletely understood. Any progress in its understanding must derive from observational studies. Recently, it has been suggested that the incidence of GCTs may follow a seasonal pattern based on circannual changes in the Vitamin D serum levels, with maximum incidence rates in winter months. To examine this promising hypothesis, we studied monthly incidence rates of testicular GCTs in Germany by analysing 30,988 GCT cases aged 15–69 years, diagnosed during 2009–2019. Monthly incident case numbers with data regarding histology and patient age were obtained from the Robert Koch Institut, Berlin, along with annual male population counts. We used precision weighting for deriving pooled monthly incidence rates for GCTs of the period 2009–2019. We stratified pooled rates by histology (seminoma and nonseminoma) and age (15–39 and 40–69 years). By assuming a cyclical effect, we used an estimator of the intensity of seasonal occurrence and report seasonal relative risks (RR). The mean monthly incidence rate was 11.93/105 person-months. The seasonal RR for testicular cancer over-all is 1.022 (95% CI 1.000–1.054). The highest seasonal RR was found in the subgroup of nonseminoma aged 15–39 years, with a RR 1.044 (95% CI 1.000–1.112). The comparison of the pooled monthly rates of the winter months (October—March) with the summer months (April-September) revealed a maximum relative difference of 5% (95% CI 1–10%) for nonseminoma, aged 15–39 years. We conclude that there is no evidence of a seasonal variation of incidence rates of testicular cancer. Our results are at odds with an Austrian study, but the present data appear sound because the results were obtained with precision weighted monthly incidence rates in a large population of GCT cases. [ABSTRACT FROM AUTHOR]

Data on robotic retroperitoneal lymph node dissection (R-RPLND) for metastatic testicular germ cell tumours (mTGCTs) are scarce and the use of R-RPLND itself is still under debate. The aim of our study was to evaluate the indications, feasibility and outcomes of R-RPLND, with special emphasis on differences between primary R-RPLND (pR-RPLND) and post-chemotherapeutic R-RPLND (pcR-RPLND) in mTGCTs. We retrospectively analysed the data of patients who underwent R-RPLND for mTGCT between November 2013 and September 2019 in two centres in Germany. Indications, operative technique, intra- and postoperative complications and oncologic outcome were analysed. Twenty-three mTGCT patients underwent R-RPLND (7 pR-RPLND, 16 pcR-RPLND). For pR-RPLND versus pcR-RPLND, median time of surgery was 243 min [interquartile range (IQR) 123–303] versus 359 min (IQR 202–440, p = 0.154) and median blood loss 100 mL (IQR 50–200) versus 275 mL (IQR 100–775, p = 0.018). Intra- and postoperative complications were more frequent in pcR-RPLND (pcR-RPLND: intra/post: 44%/44%; pR-RPLND: intra/post: 0%/29%). However, these were only statistically significant in the case of intraoperative complications (intra: p = 0.036, post: p = 0.579). Intraoperative complications (n = 7), conversions (n = 4) and transfusions (n = 4) occurred in pcR-RPLND patients only. After a median follow-up of 16.3 months (IQR 7.5–35.0) there were no recurrences or deaths. R-RPLND displays a valuable, minimally invasive treatment option in mTGCT. However, R-RPLND is challenging and pcR-RPLND especially bears a considerable risk of complications. This operation should be limited to patients with an easily accessible residual tumour mass and to surgeons experienced in robotic surgery and TGCT treatment. [ABSTRACT FROM AUTHOR]

Study Question: Which Y genes mapped to the 'Gonadoblastoma Y (GBY)' locus on human Y chromosome are expressed in germ cells of individuals with some Differences of Sexual Development (DSD) and a Y chromosome in their karyotype (DSD-XY groups)?Summary Answer: The GBY candidate genes DDX3Y and TSPY are expressed in the germ cells of DSD-XY patients from distinct etiologies: patients with mixed gonadal dysgenesis (MGD) and sex chromosome mosaics (45,X0/46,XY; 46,XX/46,XY); patients with complete androgen insensitivity (CAIS), patients with complete gonadal dysgenesis (CGD; e.g. Swyer syndrome).What Is Known Already: A GBY locus was proposed to be present on the human Y chromosome because only DSD patients with a Y chromosome in their karyotype have a high-although variable-risk (up to 55%) for germ cell tumour development. GBY was mapped to the proximal part of the short and long Y arm. TSPY located in the proximal part of the short Y arm (Yp11.1) was found to be a strong GBY candidate gene. It is expressed in the germ cells of DSD-XY patients with distinct etiologies but also in foetal and pre-meiotic male spermatogonia. However, the GBY region extends to proximal Yq11 and therefore includes probably more than one candidate gene.Study Design, Size, Duration: Protein expression of the putative GBY candidate gene in proximal Yq11, DDX3Y, is compared with that of TSPY in serial gonadal tissue sections of 40 DSD-XY individuals from the three DSD patient groups (MGD, Complete Androgen Insensitivity Syndrome [CAIS], CGD) with and without displaying malignancy. Expression of OCT3/4 in the same tissue samples marks the rate of pluripotent germ cells.Participants/materials, Setting, Method: A total of 145 DSD individuals were analysed for the Y chromosome to select the DSD-XY subgroup. PCR multiplex assays with Y gene specific marker set score for putative microdeletions in GBY Locus. Immunohistochemical experiments with specific antisera mark expression of the GBY candidate proteins, DDX3Y, TSPY, in serial sections of the gonadal tissue samples; OCT3/4 expression analyses in parallel reveal the pluripotent germ cell fraction.Main Results and the Role Of Chance: Similar DDX3Y and TSPY protein expression patterns were found in the germ cells of DSD-XY patients from each subgroup, independent of age. In CAIS patients OCT3/4 expression was often found only in a fraction of these germ cells. This suggest that GBY candidate proteins are also expressed in the non-malignant germ cells of DSD-XY individuals like in male spermatogonia.Limitations, Reasons For Caution: Variation of the expression profiles of GBY candidate genes in the germ cells of some DSD-XY individuals suggests distinct transcriptional and translational control mechanisms which are functioning during expression of these Y genes in the DSD-XY germ cells. Their proposed GBY tumour susceptibility function to transform these germ cells to pre-malignant GB/Germ Cell Neoplasia in Situ (GB/GCNIS) cells seems therefore to be limited and depending on their state of pluripotency.Wider Implications Of the Findings: These experimental findings are of general importance for each individual identified in the clinic with DSD and a Y chromosome in the karyotype. To judge their risk of germ cell tumour development, OCT3/4 expression analyses on their gonadal tissue section is mandatory to reveal the fraction of germ cells still being pluripotent. Comparative expression analysis of the GBY candidate genes can be helpful to reveal the fraction of germ cells with genetically still activated Y chromosomes contributing to further development of malignancy if at high expression level.Study Funding/competing Interest(s): This research project was supported by a grant (01GM0627) from the BMBF (Bundesministerium für Bildung und Forschung), Germany to P.H.V. and B.B. The authors have no competing interests. [ABSTRACT FROM AUTHOR]

Abstract: Recent results from studies on animals suggest that functional germ cells may be generated from human pluripotent stem cells, giving rise to three possibilities: research with these so‐called artificial gametes, including fertilization experiments in vitro; their use in vivo for therapy for the treatment of human infertility; and their use in assisted reproductive technologies in vitro. While the legal, philosophical, and ethical questions associated with these possibilities have been already discussed intensively in other countries, the debate in Germany is still at its beginning. A systematic and detailed analysis of the legal framework in Germany is provided with regard to the three possibilities, including the applicable statutory laws as well as the constitutional law. The question emerges as to whether the statutory laws as well as the constitution justify a distinction to be made between embryos of artificial and natural origin. This question is subject to philosophical analysis, discussing the distinction between person and thing, dignity and price, personality and property, and nature and technique. As a result, the criterion of naturalness alone may not be sufficient to differentiate between embryos of natural and artificial origin, and other criteria need to be identified. [ABSTRACT FROM AUTHOR]

Background and objectives The objective of this study was to elucidate the effects of different growth factors on the migration of dental follicle cells ( DFCs). DFCs are ectomesenchymally derived easily accessible multipotent stem cells. Cell migration is a crucial step in many biological processes but also for tissue engineering. Growth factors such as epidermal growth factor ( EGF), bone morphogenetic protein-2 ( BMP2) or transforming growth factor β1 ( TGF-β1) can be used to modify the behavior of cells. Material and Methods We used different migration assays (gel spot assay, scratch assay, transwell assay) to evaluate the influence of EGF, BMP2 and TGF-β1 on the migration of DFCs. We investigated the expression of migration-related genes after growth factor stimulation using the PCR array human cell motility. Results DFCs treated with BMP2 or TGF-β1 migrated faster than DFCs treated with EGF. Additionally, more migration-related genes are regulated after treatment with BMP2 or TGF-β1 than with EGF. TGF-β1 additionally functions as a chemoattractant for DFCs. Osteogenic differentiation markers were regulated after BMP2 treatment only. Conclusion Whereas the strong migration induced by BMP2 was accompanied by beginning osteogenic differentiation the strong migration induced by TGF-β1 was directional. EGF exhibited not only the weakest migration stimulation but also the weakest induction of differentiation into mineralizing cells. [ABSTRACT FROM AUTHOR]

Building a family using donated gametes (semen, oocytes or embryos) is associated with specific issues which differ from building a family with gametes from both intended parents, the resulting family comprising separated biological and social parenthood. To respect the welfare of all parties involved, the 'Beratungsnetzwerk Kinderwunsch Deutschland e.V.' (Infertility Counselling Network Germany) has developed guidelines for psychosocial counselling in this area. The following article summarizes international developments and introduces the German guidelines. [ABSTRACT FROM AUTHOR]

New assisted reproduction technologies provide access to, and require the handling of, genetic material. Such material includes gametes or early-stage embryos. After a selective appraisal of some of the most relevant developments facilitated by the access to germ cells and embryos, this paper identifies some major ethical challenges created by the assisted reproduction technologies, with a special focus on Germany. The rapid progress in medical technology makes it difficult to prohibit or allow assisted reproduction technologies on the basis of such traditional criteria as the protection of human life, medical indications or a preference to adhere to natural processes. Instead, a more open discussion and a flexible application of ethical principles may be more helpful, such as: (i) considering DNA as a biological data file which allows potential access to a person's biography or identity; (ii) reconciling the protection of the early embryo with patients' needs; and (iii) placing both the mother and her embryo at the centre of bioethical and legal considerations, instead of exclusively relying on ethical principles and expert opinions with regard to the embryo alone. To continue the success of assisted reproduction, more attention should be given to the 'lifeworld' philosophy, as some authors have put it. [ABSTRACT FROM AUTHOR]

Despite generally high cure rates in patients with metastatic germ cell cancer, patients with progressive disease on first-line cisplatin-based chemotherapy or with relapsed disease following high-dose salvage therapy exhibit a very poor prognosis. Irinotecan has shown antitumour activity in human testicular tumour xenografts in nude mice. We have performed a phase II study examining the single agent activity of irinotecan in patients with metastatic relapsed or cisplatin-refractory germ cell cancer. Refractory disease was defined as progression or relapse within 4 weeks after cisplatin-based chemotherapy or relapse after salvage high-dose chemotherapy with autologous stem cell support. Irinotecan was administered at a dose of 300 (-350) mg m(-2) every 3 weeks. Response was evaluated every 4 weeks. Fifteen patients have been enrolled. Median age was 35 (19-53) years. Primary tumour localisation was gonadal/mediastinal in 12/3 patients. Patients had been pretreated with a median of six (4-12) cisplatin-containing cycles and 13 out of 15 patients had previously failed high-dose chemotherapy with blood stem cell support. Median number of irinotecan applications was two (1-3). Fourteen patients are assessable for response and all for toxicity. In one patient, no adequate response evaluation was performed. Toxicity was generally acceptable and consisted mainly of haematological side effects with common toxicity criteria 3 degrees anaemia (two patients), common toxicity criteria 3 degrees leukocytopenia (one patient) and common toxicity criteria 3 degrees thrombocytopenia (three patients). Common toxicity criteria 3/4 degrees non-haematological toxicity occurred in five patients (33%): 1 x diarrhoea, 2 x alopecia, 1 x fever and in one patient worsening of pre-existing peripheral polyneuropathy from 1 degrees to 4 degrees. No response was observed to irinotecan therapy. Currently, 13 patients have died of the disease and two patients are alive with the disease. The patients included in our study exhibit similar prognostic characteristics as patients treated in previous trials evaluating new drugs in this setting. Irinotecan at a dose of 300-350 mg m(-2) every 3 weeks appears to have no antitumour activity in patients with cisplatin-refractory germ cell cancer and, thus, further investigation in this disease is not justified. [ABSTRACT FROM AUTHOR]

The German Embryo Protection Act prohibits any kind of intervention in a human embryo that is not conducive to the embryo's own survival. However, recent advances in human embryonic stem (ES)-cell research have stoked a debate about whether research that uses human ES cells can be justified in Germany. Because the derivation of ES cells requires the destruction of the embryo, it is prohibited in Germany. [ABSTRACT FROM AUTHOR]

Bark and leaves of Ailanthus altissima (Mill.) Swingle are widely used in European folk medicine to treat intestinal worm infections. The study aimed to rationalize a potential anthelmintic effect of A. altissima extract against the model organism Caenorhabditis elegans. A methanol-water (7:3, v /v) extract of the primary stem bark was tested on L4 larvae of C. elegans for induction of mortality and influence on reproduction. Bioactivity-guided fractionation was performed by chromatography on MCI-gel, preparative HPLC on RP18 stationary phase and fast-centrifugal-partition-chromatography. Structural elucidation of isolated quassinoids was performed by NMR and HR-ESI-MS. The sterilizing effect on C. elegans was investigated by light microscopy and atomic force microscopy of ultra-sections. Different GFP-tagged reporter strains were used to identify involved signaling pathways. A. altissima extract (1 mg/mL) irreversibly inhibited the reproduction of C. elegans L4 larvae. This effect was dependent on the larval stage since L3 larvae and adults were less affected. Bioactivity-guided fractionation revealed the quassinoid ailanthone 1 as the major active compound (IC 50 2.47 μM). The extract caused severe damages to germ cells and rachis, which led to none or only poorly developed oocytes. These damages led to activation of the transcription factor DAF-16, which plays a major role in the nematode's response to stress. A regulation via the respective DAF-2/insulin-like signaling pathway was not observed. The current findings support the traditional use of A. altissma in phytotherapy to treat helminth infections and provide a base for standardization of the herbal material. Unlabelled Image [ABSTRACT FROM AUTHOR]

PURPOSE: Testicular intraepithelial neoplasia (TIN), also called intratubular germ cell neoplasia, is thought to be the precursor of testicular germ cell tumors (GCTs). Evidence for this theory stems from clinicopathological studies because to our knowledge experimental models are lacking. While GCT clinical risk groups have been studied extensively for TIN, only 1 small study to date has assessed the presence of TIN in the general population. In the current study we analyzed the prevalence of TIN in a large group of healthy men. MATERIALS AND METHODS: Bilateral testicular specimens were obtained from 1,388 presumably healthy men who died unexpectedly and underwent autopsy at forensic institutes in Germany. Median age in this patient sample was 33 years. Specimens were fixed in Stieve′s solution and all specimens were examined immunohistologically with placental alkaline phosphatase staining. RESULTS: TIN was found in 6 cases (0.43%, 95% CI 0.16 to 0.94). Two cases also showed microinvasive seminoma. TIN was bilateral in 1 case. The right testicle was afflicted in 4 cases and the left was affected in 1. Median age of the individuals with TIN was 33 years. CONCLUSIONS: As found in the current study, the prevalence of TIN is consistent with the lifetime risk of GCT in Germany. Data in the current study are in accordance with those in a previous study from Denmark. In all these data represent fundamental support of the role of TIN as the precursor of GCT. [ABSTRACT FROM AUTHOR]

This brief paper summarizes a series of postal investigations on the acceptance of selection for X or Y spermatozoa. These were conducted mainly in Germany but also in the UK, the Netherlands and the US. Selected families were approached with a series of questions about their wish to use sperm selection, and their choice of boys or girls. In general, large majorities opposed this approach for family balancing or sex selection on the basis of cost and inconvenience of the treatment. The view was expressed that its use in medicine was more acceptable. Care was taken to compose a series of open questions to particular sections of the population, e.g. men versus women, differing ages, and families with imbalanced sex ratios. More favourable responses arose, for example in pregnant women. Overall, all four nations had large majorities against the use of sex selection. [ABSTRACT FROM AUTHOR]

All patients with medullary thyroid cancer (MTC) are routinely screened for germline mutations in the rearranged during transfection (RET) proto-oncogene. In this Practice Point commentary, we discuss a cross-sectional study by Machens and Dralle, who performed germline RET protooncogene mutation analysis in patients with MTC at a tertiary referral centre in Germany to reveal patterns of familial disease presentation over the generations. The study identified a typical distribution of germline RET mutations (subclassified into three accepted risk categories) in the study population, consistent with the reported literature. The investigators also attempted to obtain data on the time of appearance of RET germline mutations in previous generations of the families. The natural history of MTC and penetrance of specific RET mutations could not be clearly identified in each family because of the cross-sectional nature of the study. Nevertheless, the study re-establishes the importance of routine screening for germline RET mutations in all new cases of MTC. [ABSTRACT FROM AUTHOR]

Focuses on the result of the study regarding the use of irinotecan in patients with cisplatin-refractory germ cell cancer in Germany. Role of topoisomerase 1 inhibitor; Effectiveness of topotecan in treating patients in relapsed cell cancer; Survival period of patients given with the drug.

Since the identification of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, a large number of different germline mutations in both genes have been found by conventional PCR‐based mutation detection methods. Complex germline rearrangements such as those reported in the BRCA1 gene are often not detectable by these standard diagnostic techniques. To detect large deletions or duplications encompassing one or more exons of the BRCA1 gene and in order to estimate the frequency of BRCA1 rearrangements in German breast or ovarian cancer families, a semi‐quantitative multiplex PCR method was developed and applied to DNA samples of patients from families negatively tested for disease causing mutations in the BRCA1 and BRCA2 coding regions by direct sequencing. Out of 59 families analysed, one family was found to carry a rearrangement in the BRCA1 gene (duplication of exon 13). The results indicate that the semi‐quantitative multiplex PCR method is useful for the detection of large rearrangements in the BRCA1 gene and therefore represents an additional valuable tool for mutation analysis of BRCA1 and BRCA2. © 2003 Wiley‐Liss, Inc. [ABSTRACT FROM AUTHOR]

The article comments on the commitment of the German government to address the challenges of reproductive medicine. According to the author, a study on the germ cell potential is the most important contributions to research in reproductive biology in the country. The author adds that there are no private foundations with a focus on reproduction, reflecting the importance that research in reproductive bio medicine has in Germany's public opinion.

The article focuses on the ability of CXCR7 chemokine receptor to soak up SDF-1 cytokine in zebrafish embryos based on a study conducted by Bijan Boldajipour, Harsha Mahabaleshwar and Erez Raz of the Center for Molecular Biology of Inflammation in Münster, Germany. The researchers found the receptor surrounding somatic cells where it soaked SDF-1. Migrating germ cells were found to have avoided the regions where CXCR7 sopped up SDF-1. According to Raz, the mechanism will inhibit the expression of SDF-1.

Objective: This article mainly attempts to review the recent human literature on the adverse effects of occupational factors on fertility, developmental effects and genetic changes in the germ line, which lead to genetic malformations or to genetic disease. The secondary study aim is to answer whether occupational exposures are quantitative momentously for 15% involuntarily childless couples, 10-20% spontaneous abortions and 3% birth defects., Methods: A literature survey was conducted for publications on these subjects focusing on the latest publications. PubMed (Medline. 2005) was used for this literature search., Results: Publication bias and a large amount of confounding factors, which have to be controlled, make the design of human fertility studies difficult. Epidemiologic studies using time to conception techniques have been useful in identifying substances and exposure scenarios with proven toxic effect on fertility. The collected studies suggest that the exposure to the following substances or occupational settings may affect fertility function: lead, organic mercury compounds, manganese, carbon disulfide, 2-bromopropane and dibromochloropropane, welding, professional driving and working with heat. Concerning developmental effects even for methyl mercury, which was in group A of the German MAK list, to date no reliable evidence of the damaging effect on the human fetus under actual work conditions has been obtained. It is also difficult to classify substances according to their mutagenic potential for the germ cell, since no direct evidence of an association between exposure against a physical or chemical pollutant and the occurrence of a hereditary disorder has been found yet., Conclusion: In conclusion there are only a few substances which may affect reproductive function in the workplace without a doubt. The decreasing fertility of women in Western countries can be explained by the increasing female reproduction age, rather than by occupational exposures. Also the rates for spontaneous abortions and birth defects cannot be explained by industrial exposures at the workplace.

In the debate regarding the different possibilities for gene therapy, it is presupposed that the manipulations are limited to the nuclear genome (nDNA). Given recent advances in genetics, mitochondrial genome (mtDNA) and diseases must be considered as well. In this paper, we propose a three dimensional framework for the ethical debate of gene therapy where we add the genomic type (nDNA vs. mtDNA) as a third dimension to be considered beside the paradigmatic dimensions of target cell (somatic vs. germ-line) and purpose (therapeutic vs. enhancement). Somatic gene therapy can be viewed today as generally accepted, and we review the contemporary arguments surrounding it on the basis of bioethical-pragmatic, socio-political and deontological classifications. Many of the supposed ethical questions of somatic gene therapy today are not new; they are well-known issues of research ethics. We also critically summarize the different international perspectives and the German ethical discussion regarding manipulations of germ-line cells.

The "Fetus Protection Law" (Embryonenschutzgesetz ESchG) regulates the abusive use of reproductive techniques, the use of human embryos and the choice of sex. The Bundestag has singled out certain practices as being abusive, prohibited them and put criminal sanctions on them. Individual exemptions from criminal prosecution are made in favour of the surrogate mother who is to be the target of an assisted procreation and the foster-father. The ESchG represents a snapshot of current views on current practices in reproductive medicine. And therefore the ESchG will be rendered obsolete by newly created reproductive technologies if legislation does not adapt the law to these changes.

In this commentary, I shall provide an overview of some recent histories of eugenics and suggest some lessons that this history may have for today. This commentary is not an argument against gene therapy. Rather, it is a plea for historical understanding of what has been done,..."in the name of eugenics."... There is a temptation to parody misgivings about gene therapy. I suggest that there are justified reasons to think about the social consequences of gene therapy. I do not hold that we ought to stop the program now, but I do believe that scientists, physicians, and the public ought to be aware of the slippery slope on which we as a society -- and we are all members of society -- have embarked.