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The effect of many contemporary chemotherapeutic drugs on pregnancy and livebirth is not well established. We aimed to establish the effects of these drugs on pregnancy in male and female survivors of childhood cancer not exposed to pelvic or cranial radiotherapy. We used data from a subset of the Childhood Cancer Survivor Study cohort, which followed 5-year survivors of the most common types of childhood cancer who were diagnosed before age 21 years and treated at 27 institutions in the USA and Canada between 1970 and 1999. We extracted doses of 14 alkylating and similar DNA interstrand crosslinking drugs from medical records. We used sex-specific Cox models to establish the independent effects of each drug and the cumulative cyclophosphamide equivalent dose of all drugs in relation to pregnancies and livebirths occurring between ages 15 years and 44 years. We included siblings of survivors as a comparison group. We included 10 938 survivors and 3949 siblings. After a median follow-up of 8 years (IQR 4–12) from cohort entry or at age 15 years, whichever was later, 4149 (38%) survivors reported having or siring a pregnancy, of whom 3453 (83%) individuals reported at least one livebirth. After a median follow-up of 10 years (IQR 6–15), 2445 (62%) siblings reported having or siring a pregnancy, of whom 2201 (90%) individuals reported at least one livebirth. In multivariable analysis, survivors had a decreased likelihood of siring or having a pregnancy versus siblings (male survivors: hazard ratio [HR] 0·63, 95% CI 0·58–0·68; p<0·0001; female survivors: 0·87, 0·81–0·94; p<0·0001) or of having a livebirth (male survivors: 0·63, 0·58–0·69; p<0·0001; female survivors: 0·82, 0·76–0·89; p<0·0001). In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide (HR 0·60, 95% CI 0·51–0·71; p<0·0001), ifosfamide (0·42, 0·23–0·79; p=0·0069), procarbazine (0·30, 0·20–0·46; p<0·0001) and cisplatin (0·56, 0·39–0·82; p=0·0023). Cyclophosphamide equivalent dose in male survivors was significantly associated with a decreased likelihood of siring a pregnancy (per 5000 mg/m2 increments: HR 0·82, 95% CI 0·79–0·86; p<0·0001). However, in female survivors, only busulfan (<450 mg/m2 HR 0·22, 95% CI 0·06–0·79; p=0·020; ≥450 mg/m2 0·14, 0·03–0·55; p=0·0051) and doses of lomustine equal to or greater than 411 mg/m2 (0·41, 0·17–0·98; p=0·046) were significantly associated with reduced pregnancy; cyclophosphamide equivalent dose was associated with risk only at the highest doses in analyses categorised by quartile (upper quartile vs no exposure: HR 0·85, 95% CI 0·74–0·98; p=0·023). Results for livebirth were similar to those for pregnancy. Greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer. However, our findings should provide reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain, given that chemotherapy-specific effects on pregnancy were generally few. Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximise the reproductive potential of all adolescents newly diagnosed with cancer. National Cancer Institute, National Institutes of Health, and the American Lebanese–Syrian Associated Charities.

Maintenance of adult tissues depends on stem cell self-renewal in local niches. Spermatogonial stem cells (SSC) are germline adult stem cells necessary for spermatogenesis and fertility. We show that testicular endothelial cells (TECs) are part of the SSC niche producing glial cell line-derived neurotrophic factor (GDNF) and other factors to support human and mouse SSCs in long-term culture. We demonstrate that FGF-2 binding to FGFR1 on TECs activates the calcineurin pathway to produce GDNF. Comparison of the TEC secretome to lung and liver endothelial cells identified 5 factors sufficient for long-term maintenance of human and mouse SSC colonies in feeder-free cultures. Male cancer survivors after chemotherapy are often infertile since SSCs are highly susceptible to cytotoxic injury. Transplantation of TECs alone restores spermatogenesis in mice after chemotherapy-induced depletion of SSCs. Identifying TECs as a niche population necessary for SSC self-renewal may facilitate fertility preservation for prepubertal boys diagnosed with cancer. Self-renewal of spermatogonial stem cells (SSC) is necessary for spermatogenesis and male fertility. Here the authors identify testicular endothelial cells (TECs) as a source of 5 key growth factors for self-renewal and expansion of human and mouse SSCs.

In the human testis, beginning at [almost equal to]2 months of age, gonocytes are replaced by adult dark (Ad) and pale (Ap) spermatogonia that make up the spermatogonial stem cell (SSC) pool. In mice, the SSC pool arises from gonocytes [almost equal to]6 days after birth. During puberty in both species, complete spermatogenesis is established by cells that differentiate from SSCs. Essentially pure populations of prepubertal human spermatogonia and mouse gonocytes were selected from testis biopsies and validated by confirming the presence of specific marker proteins in cells. Stem cell potential of germ cells was demonstrated by transplantation to mouse testes, following which the cells migrated to the basement membrane of the seminiferous tubule and were maintained similar to SSCs. Differential gene expression profiles generated between germ cells and testis somatic cells demonstrated that expression of genes previously identified as SSC and spermatogonial-specific markers (e.g., zinc-finger and BTB-domain containing 16, ZBTB16) was greatly elevated in both human spermatogonia and mouse gonocytes compared to somatic cells. Several genes were expressed at significantly higher levels in germ cells of both species. Most importantly, genes known to be essential for mouse SSC self-renewal (e.g., Ret proto-oncogene, Ret; GDNF-family receptor α1, Gfrα1; and B-cell CLL/lymphoma 6, member B, Bcl6b) were more highly expressed in both prepubertal human spermatogonia and mouse gonocytes than in somatic cells. The results indicate remarkable conservation of gene expression, notably for self-renewal genes, in these prepubertal germline cells between two species that diverged phylogenetically [almost equal to]75 million years ago.

Anthracycline-induced cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Aberrant DNA methylation plays a role in de novo cardiovascular disease. Epigenetic processes could play a role in anthracycline-induced cardiomyopathy but remain unstudied. We sought to examine if genome-wide differential methylation at ‘CpG’ sites in peripheral blood DNA is associated with anthracycline-induced cardiomyopathy. This report used participants from a matched case–control study; 52 non-Hispanic White, anthracycline-exposed childhood cancer survivors with cardiomyopathy were matched 1:1 with 52 survivors with no cardiomyopathy. Paired ChAMP (Chip Analysis Methylation Pipeline) with integrated reference-based deconvolution of adult peripheral blood DNA methylation was used to analyze data from Illumina HumanMethylation EPIC BeadChip arrays. An epigenome-wide association study (EWAS) was performed, and the model was adjusted for GrimAge, sex, interaction terms of age at enrollment, chest radiation, age at diagnosis squared, and cardiovascular risk factors (CVRFs: diabetes, hypertension, dyslipidemia). Prioritized genes were functionally validated by gene knockout in human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 technology. DNA-methylation EPIC array analyses identified 32 differentially methylated probes (DMP: 15 hyper-methylated and 17 hypo-methylated probes) that overlap with 23 genes and 9 intergenic regions. Three hundred and fifty-four differential methylated regions (DMRs) were also identified. Several of these genes are associated with cardiac dysfunction. Knockout of genes EXO6CB , FCHSD2, NIPAL2, and SYNPO2 in hiPSC-CMs increased sensitivity to doxorubicin. In addition, EWAS analysis identified hypo-methylation of probe ‘cg15939386’ in gene RORA to be significantly associated with anthracycline-induced cardiomyopathy. In this genome-wide DNA methylation profile study, we observed significant differences in DNA methylation at the CpG level between anthracycline-exposed childhood cancer survivors with and without cardiomyopathy, implicating differential DNA methylation of certain genes could play a role in pathogenesis of anthracycline-induced cardiomyopathy.

Background Anthracycline-induced cardiomyopathy is a leading cause of morbidity and mortality in survivors of childhood cancer. The mitochondrion is a key mediator of the cytotoxic effects of anthracycline treatment and mitochondrial dysfunction is a hallmark of cardiomyopathy and heart failure. We sought to evaluate whether mitochondrial processes differ between anthracycline-exposed childhood cancer survivors who developed cardiomyopathy versus those who did not. Methods Peripheral blood was collected from 40 childhood cancer survivors who developed cardiomyopathy (cases) and 64 matched survivors who did not (controls). From these samples, gene expression was determined by RNA-Sequencing. Following bioinformatic processing, differential gene expression at the mRNA-level between cases and controls was determined. Human MitoCarta3.0, was utilized to determine if genes involved in mitochondrial processes were enriched for differential expression, and to identify differentially regulated mitochondrial pathways at the mRNA-level. Results 900 genes were identified as differentially expressed at the mRNA-level. The odds of a gene being differentially expressed were 2.43 times greater if it encodes for a protein that localizes to the mitochondria. Mitochondrial processes that were enriched for differentially expressed genes at the mRNA-level included electron transport chain complexes; reactive oxygen species metabolism; apoptosis, mitophagy, and autophagy; mitochondrial ribosome; mitochondrial transport and chaperones; and heme synthesis and processing. Additionally, we observed that a measure of pro-apoptotic balance (BAX to BCL-2 gene expression at the mRNA-level) was highest in severe cardiomyopathy, intermediate in mild cardiomyopathy, and lowest in survivors without cardiomyopathy. Conclusions We observed substantial evidence that the expression of genes involved in mitochondrial processes differs in childhood cancer survivors who develop cardiomyopathy versus those who do not.

Background Anthracycline-induced cardiomyopathy is a well-established adverse consequence in childhood cancer survivors. Altered mRNA expression in the peripheral blood has been found at the level of genes and pathways among anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. However, the role of aberrant alternative splicing in anthracycline-induced cardiomyopathy remains unexplored. The present study examined if transcript-specific events, due to alternative splicing occur in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Methods Participants were anthracycline-exposed childhood cancer survivors with cardiomyopathy (cases) matched with anthracycline-exposed childhood cancer survivors without cardiomyopathy (controls; matched on primary cancer diagnosis, year of diagnosis, and race/ethnicity). mRNA sequencing was performed on total RNA from peripheral blood in 32 cases and 32 matched controls. Event-level splicing tool, rMATS (replicate Multivariate Analysis of Transcript Splicing) was used for quantitative profiling of alternative splicing events. Results A total of 45 alternative splicing events in 36 genes were identified. Using a prioritization strategy to filter the alternative splicing events, intron retention in RPS24 and skipped exon of PFND5 showed differential expression of altered transcripts. Conclusions We identified specific alternative splicing events in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Our findings suggest that differential alternative splicing events can provide additional insight into the peripheral blood transcriptomic landscape of anthracycline-induced cardiomyopathy. Graphical abstract Central Illustration. Aberrant alternative splicing and anthracycline-induced cardiomyopathy. This study sought to identify alternative splice variants that are differentially abundant between anthracycline-exposed childhood cancer survivors that developed cardiomyopathy (cases) versus those who did not (controls). We observed dysregulated alternative splicing of PFDN5 and RPS24 is associated with the development of cardiomyopathy.Splicing defects in PFDN5 impair cytoskeletal protein folding, while RPS24 dysregulation affects their translation, disrupting actin and tubulin homeostasis. Together, these alterations destabilize cardiomyocyte structure, contributing to sarcomere disorganization and the development of cardiomyopathy. Created in BioRender. Singh, P. (2025) https://BioRender.com/59zmgls .

Cyclophosphamide continues to have an important role in the treatment of renal disease, including nephrotic syndrome and lupus nephritis, despite known complications of gonadotoxicity and potential infertility in both male and female patients. It is important that the physician recommending this therapy mitigates the effect of the drug on fertility by adhering to recommendations on dosing limits and offering fertility-preserving strategies. In addition to well-established methods, such as sperm banking and embryo cryopreservation, advances in reproductive technology have yielded strategies such as oocyte cryopreservation, resulting in more fertility-preserving options for the pediatric patient. Despite these advances, there continues to be a significant barrier to referral and access to sperm banks and fertility specialists. These issues are further complicated by ethical issues associated with the treatment of pediatric patients. In this review we explore the development of recommended dosing limits and include a discussion of the available fertility-preserving methods, strategies for increasing access to fertility specialists, and the ethical considerations facing the pediatric healthcare provider.

STUDY QUESTION Twenty years after the inception of the first fertility preservation programme for pre-pubertal boys, what are the current international practices with regard to cryopreservation of immature testicular tissue? SUMMARY ANSWER Worldwide, testicular tissue has been cryopreserved from over 3000 boys under the age of 18 years for a variety of malignant and non-malignant indications; there is variability in practices related to eligibility, clinical assessment, storage, and funding. WHAT IS KNOWN ALREADY For male patients receiving gonadotoxic treatment prior to puberty, testicular tissue cryopreservation may provide a method of fertility preservation. While this technique remains experimental, an increasing number of centres worldwide are cryopreserving immature testicular tissue and are approaching clinical application of methods to use this stored tissue to restore fertility. As such, standards for quality assurance and clinical care in preserving immature testicular tissue should be established. STUDY DESIGN, SIZE, DURATION A detailed survey was sent to 17 centres within the recently established ORCHID-NET consortium, which offer testicular tissue cryopreservation to patients under the age of 18 years. The study encompassed 60 questions and remained open from 1 July to 1 November 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS Of the 17 invited centres, 16 completed the survey, with representation from Europe, Australia, and the USA. Collectively, these centres have cryopreserved testicular tissue from patients under the age of 18 years. Data are presented using descriptive analysis. MAIN RESULTS AND THE ROLE OF CHANCE Since the establishment of the first formal fertility preservation programme for pre-pubertal males in 2002, these 16 centres have cryopreserved tissue from 3118 patients under the age of 18 years, with both malignant (60.4%) and non-malignant (39.6%) diagnoses. All centres perform unilateral biopsies, while 6/16 sometimes perform bilateral biopsies. When cryopreserving tissue, 9/16 centres preserve fragments sized ≤5 mm3 with the remainder preserving fragments sized 6–20 mm3. Dimethylsulphoxide is commonly used as a cryoprotectant, with medium supplements varying across centres. There are variations in funding source, storage duration, and follow-up practice. Research, with consent, is conducted on stored tissue in 13/16 centres. LIMITATIONS, REASONS FOR CAUTION While this is a multi-national study, it will not encompass every centre worldwide that is cryopreserving testicular tissue from males under 18 years of age. As such, it is likely that the actual number of patients is even higher than we report. Whilst the study is likely to reflect global practice overall, it will not provide a complete picture of practices in every centre. WIDER IMPLICATIONS OF THE FINDINGS Given the research advances, it is reasonable to suggest that cryopreserved immature testicular tissue will in the future be used clinically to restore fertility. The growing number of patients undergoing this procedure necessitates collaboration between centres to better harmonize clinical and research protocols evaluating tissue function and clinical outcomes in these patients. STUDY FUNDING/COMPETING INTEREST(S) K.D. is supported by a CRUK grant (C157/A25193). R.T.M. is supported by an UK Research and Innovation (UKRI) Future Leaders Fellowship (MR/S017151/1). The MRC Centre for Reproductive Health at the University of Edinburgh is supported by MRC (MR/N022556/1). C.L.M. is funded by Kika86 and ZonMW TAS 116003002. A.M.M.v.P. is supported by ZonMW TAS 116003002. E.G. was supported by the Research Program of the Research Foundation—Flanders (G.0109.18N), Kom op tegen Kanker, the Strategic Research Program (VUB_SRP89), and the Scientific Fund Willy Gepts. J.-B.S. is supported by the Swedish Childhood Cancer Foundation (TJ2020-0026). The work of NORDFERTIL is supported by the Swedish Childhood Cancer Foundation (PR2019-0123; PR2022-0115), the Swedish Research Council (2018-03094; 2021-02107), and the Birgitta and Carl-Axel Rydbeck’s Research Grant for Paediatric Research (2020-00348; 2021-00073; 2022-00317; 2023-00353). C.E is supported by the Health Department of the Basque Government (Grants 2019111068 and 2022111067) and Inocente Inocente Foundation (FII22/001). M.P.R. is funded by a Medical Research Council Centre for Reproductive Health Grant No: MR/N022556/1. A.F. and N.R. received support from a French national research grant PHRC No. 2008/071/HP obtained by the French Institute of Cancer and the French Healthcare Organization. K.E.O. is funded by the University of Pittsburgh Medical Center and the US National Institutes of Health HD100197. V.B-L is supported by the French National Institute of Cancer (Grant Seq21-026). Y.J. is supported by the Royal Children’s Hospital Foundation and a Medical Research Future Fund MRFAR000308. E.G., N.N., S.S., C.L.M., A.M.M.v.P., C.E., R.T.M., K.D., M.P.R. are members of COST Action CA20119 (ANDRONET) supported by COST (European Cooperation in Science and Technology). The Danish Child Cancer Foundation is also thanked for financial support (C.Y.A.). The authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A.

Over the past several decades, pediatric oncologists have seen the growth in the number of patients surviving their cancer. This is in large part due to the use of multimodal therapy including chemotherapy, surgery, and radiotherapy. As the number of survivors of pediatric cancer continues to grow, however, we need to begin to focus on improving the quality of the lives that are being saved. Unfortunately, many regimens used today to cure pediatric cancer patients are gonadotoxic. Therefore, many of our survivors must contend with infertility. It is critical that pediatric oncologists consider the likelihood of gonadotoxicity prior to beginning therapy in this patient population in order to counsel patients and their families properly in order to potentially offer fertility preservation options. Conclusion : Infertility is a critical quality of life issue for pediatric cancer survivors and their families. Fertility preservation techniques need to continue to be studied and developed in order to lessen the likelihood that future cancer survivors will be infertile. This review outlines the risk for infertility, provides an assessment of the survivors reproductive functioning, and summarizes the currently available methods of preserving fertility in pediatric cancer survivors.

Purpose Survivors of pediatric brain tumors often have neurodevelopmental late effects, such as inattention. Symptoms may mirror those of attention-deficit/hyperactivity disorder (ADHD), which affects ~ 5–8% of the general population. This retrospective study of survivors followed at a large tertiary care center examined the prevalence of a clinical diagnosis of ADHD, and risk factors associated with ADHD diagnosis and ADHD-related medication use. Methods A retrospective chart review of brain tumor survivors (n = 528), diagnosed between 2000 and 2015, who were at least 6 years old and 2 years from the end of tumor-directed therapy or from diagnosis, if no interventions were received. Clinical and demographic data were extracted from the medical record. Results Survivors were 55.7% male with mean age 8.15 ± 4.4 (0.0–16.0) years at brain tumor diagnosis. The most common diagnoses were low-grade glioma, medulloblastoma, and craniopharyngioma, with 52.5% of tumors supratentorial. Of the survivors, 81.3% received surgery, 40.0% radiation therapy, and 36.6% chemotherapy. Sixty-nine survivors (13.1%) had ADHD diagnoses, 105 (19.9%) had symptoms of ADHD without diagnoses, and 64 (12.1%) had ADHD medication use. ADHD diagnosis was associated with younger age at tumor diagnosis (p = 0.05) and supratentorial tumor location (p = 0.001). ADHD diagnosis was not associated with gender, tumor type, or treatment type. Conclusions Survivors of brain tumors are at increased risk of ADHD and related symptoms. The greatest increase in risk occurs for survivors with diagnoses at younger ages and supratentorial tumors. Additional research is warranted, as select survivors may benefit from behavioral or pharmacologic ADHD treatments to optimize functioning.