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In this study chemotherapy response in neuroblastoma (NB) was assessed for the first time in a transplantation model comprising non-malignant human embryonic microenvironment of pluripotent stem cell teratoma (PSCT) derived from diploid bona fide hESC. Two NB cell lines with known high-risk phenotypes; the multi-resistant BE(2)-C and the drug sensitive IMR-32, were transplanted to the PSCT model and the tumour growth was exposed to single or repeated treatments with doxorubicin, and thereafter evaluated for cell death, apoptosis, and proliferation. Dose dependent cytotoxic effects were observed, this way corroborating the experimental platform for this type of analysis. Notably, analysis of doxorubicin-resilient BE(2)-C growth in the PSCT model revealed an unexpected 1,5-fold increase in Ki67-index (p<0.05), indicating that non-cycling (G0) cells entered the cell cycle following the doxorubicin exposure. Support for this notion was obtained also in vitro. A pharmacologically relevant dose (1μM) resulted in a marked accumulation of Ki67 positive BE(2)-C cells (p<0.0001), as well as a >3-fold increase in active cell cycle (i.e. cells positive staining for PH3 together with incorporation of EdU) (p<0.01). Considering the clinical challenge for treating high-risk NB, the discovery of a therapy-provoked growth-stimulating effect in the multi-resistant and p53-mutated BE(2)-C cell line, but not in the drug-sensitive p53wt IMR-32 cell line, warrants further studies concerning generality and clinical significance of this new observation.

Background: Hypospadias is a common congenital malformation often related to the effect of androgens in utero. While hypogonadism is associated with many potential health risks including metabolic and cardiovascular disease, the risk of clinical hypogonadism and comorbidities in men with hypospadias later in life has not been studied.Objectives: Investigate the risk of hypogonadism and somatic comorbidities in adolescents and men born with hypospadias. Materials and methods:We conducted a population-based cohort study using Swedish registers. Associations between hypospadias and hypogonadism, delayed puberty, metabolic, and cardiovascular disease respectively were estimated using Cox proportional hazards regression. Body measurements from military conscription were analysed in a subpopulation as indicators of growth and cardiometabolic risk. We used sibling comparison analyses to control for familial confounding.Results: Using register data, a total of 2,165,255 men including 9,714 men born with hypospadias were followed from the age of 10 to a maximum of 60 years. We found an association between hypospadias and hypogonadism (Hazard ratio (HR) 3.27, 95% confidence interval (CI) 2.33-4.59) which was more pronounced in proximal hypospadias.Men with hypospadias had shorter average height than their brothers and the general population. We further found an increased risk of delayed puberty (HR 1.49, 95% CI 1.08-2.07), diabetes mellitus type 2 (HR 1.57, 95% CI 1.18-2.09) and cardiovascular disease (HR 1.47, 95% CI 1.27-1.71). Discussion:We found an increased risk of hypogonadism, metabolic and cardiovascular disease in men born with hypospadias, increasing with severity of phenotype, as well as impacted growth. These results indicate discruptions in androgen function past childhood, although some of the associations may be due to other underlying aetiologies.

ObjectivesThere is a lack of studies on men's individual experiences of living with hypospadias. We aimed to explore the personal experiences of having hypospadias in relation to healthcare and surgery.Subjects and methodsPurposive sampling was used to include men (aged 18 and over) with hypospadias representing different phenotypes (from distal to proximal) and ages in order to maximise the variation and richness of our data. Seventeen informants, aged 20–49, were included in the study. In-depth semi-structured interviews were conducted between 2019 and 2021. Inductive qualitative content analysis was used to analyse the data.ResultsWe identified three categories: (1) Having surgery, which comprised the decision to operate, the experience of having surgery, and the outcomes of surgery; (2) Going to the doctor, which focused on follow-up care, re-entering care in adolescence or adulthood, and the experience of healthcare interactions; (3) Being informed, both about hypospadias in general, as well as about your specific body and medical history. There was overall a large variation in experiences. The latent theme across the data was the importance of owning your own narrative.ConclusionThe experience of men with hypospadias in healthcare is complex and varied, highlighting the difficulty of fully standardised care. Based on our results, we suggest that follow-up should be offered in adolescence, and that ways of accessing care for late onset complications be made clear. We further suggest clearer consideration for the psychological and sexual aspects of hypospadias. Consent and integrity in all aspects and all ages of hypospadias care should be adapted to the maturity of the individual. Access to trustworthy information is key, both directly from educated healthcare staff and if possible, from websites or patient-led forums. Healthcare can play a key role in providing the growing individual with tools to understand and address concerns that may develop relating to their hypospadias through life, giving them ownership over their own narrative.

Background It is not known if impaired fertility in men with hypospadias is caused by decreased semen quality or other factors. Semen quality in men born with hypospadias may be impaired due to effects of androgens or testicular dysgenesis but has been very little studied. Objectives To study semen quality in men with hypospadias using dizygotic twinning rates as an epidemiological indicator. We further aimed to study men treated for cryptorchidism, given a hypothesized mutual etiology for decreased semen quality. Materials and methods We conducted a population‐based study using national Swedish registers. A total of 4,363,165 births between 1964 and 2013 were included. The association between hypospadias and cryptorchidism, and fathering dizygotic multiple births was estimated using logistic regression and presented as odds ratios. The main analyses excluded births conceived using assisted reproductive technology (ART). Results We identified a total of 5317 births with fathers with hypospadias, including 26 dizygotic births conceived unassisted. No significant association was found between hypospadias and dizygotic twinning (OR 1.10, 0.75–1.61). We estimated a significantly increased odds for dizygotic multiple births in men treated for cryptorchidism (OR 1.35, 1.01–1.81) which was decreased after exclusion of ART, but the estimate was not significant (OR 0.75, 0.48–1.18). Discussion Using dizygotic twinning rates as an indicator of semen quality, we did not find any difference between fathers with hypospadias and controls. Due to sample size, we could not analyze phenotypes separately and can therefore not exclude impaired semen quality in severe hypospadias. We could not demonstrate any association between dizygotic twinning and cryptorchidism. Men treated for cryptorchidism were more likely than controls to use ART to conceive. Conclusion Men with hypospadias who conceived without ART were not shown to have impaired semen quality using dizygotic twinning as an epidemiological indicator.