Male Childhood Cancer Survivors Research Articles

The Proliferation of Pre-Pubertal Porcine Spermatogonia in Stirred Suspension Bioreactors Is Partially Mediated by the Wnt/β-Catenin Pathway.

Male survivors of childhood cancer are at risk of suffering from infertility in adulthood because of gonadotoxic chemotherapies. For adult men, sperm collection and preservation are routine procedures prior to treatment; however, this is not an option for pre-pubertal children. From young boys, a small biopsy may be taken before chemotherapy, and spermatogonia may be propagated in vitro for future transplantation to restore fertility. A robust system that allows for scalable expansion of spermatogonia within a controlled environment is therefore required. Stirred suspension culture has been applied to different types of stem cells but has so far not been explored for spermatogonia. Here, we report that pre-pubertal porcine spermatogonia proliferate more in bioreactor suspension culture, compared with static culture. Interestingly, oxygen tension provides an avenue to modulate spermatogonia status, with culture under 10% oxygen retaining a more undifferentiated state and reducing proliferation in comparison with the conventional approach of culturing under ambient oxygen levels. Spermatogonia grown in bioreactors upregulate the Wnt/ β-catenin pathway, which, along with enhanced gas and nutrient exchange observed in bioreactor culture, may synergistically account for higher spermatogonia proliferation. Therefore, stirred suspension bioreactors provide novel platforms to culture spermatogonia in a scalable manner and with minimal handling.

Family Formation and Socio-Economic Status among 35-Year-Old Men Who Have Survived Cancer in Childhood and Early Adulthood: A Register-Based Cohort Study

Introduction: The number of children and young adults who survive cancer has steadily increased over the past decades. Consequently, life circumstances after cancer have gained increasing importance. The aim of this study was to explore family formation and socio-economic status among 35-year-old men having survived cancer in childhood or early adulthood compared to an age-matched comparison group. Methods: This study is a national, register-based cohort study among 35-year-old men. Men diagnosed with cancer in childhood and early adulthood were registered between 1978 and 2016. At the time of diagnosis, each patient was randomly matched with 150 men without cancer from the background population within the same birth year. Those still alive at the age of 35 years were included in the study population. Results: The study population consisted of 4,222 men diagnosed with cancer in childhood or early adulthood and 794,589 men in the age-matched comparison group. Men who have survived cancer during childhood or early adulthood have a reduced probability of having children, and lower probability of getting married or of cohabitation than those from an age-matched comparison group. Men who have survived CNS cancer also have a lower probability of having a higher education than high school and a higher probability of being outside the workforce than those from an age-matched comparison group. Discussion/Conclusion: Many men who have survived cancer during childhood or early adulthood are influenced by their cancer later in life, which was apparent in family formation, educational achievements, and labour market attachment. Continued focus on rehabilitation and needs for support among the male survivors of childhood and youth cancer is warranted.

Increased health-related quality of life impairments of male and female survivors of childhood cancer: DCCSS LATER 2 psycho-oncology study.

BackgroundThe objective of this study was to compare the health‐related quality of life (HRQOL) of Dutch adult male and female childhood cancer survivors (CCSs) to general population references and to study medical determinants.MethodsCCSs from the Dutch Childhood Cancer Survivor Study LATER cohort (1963‐2001) part 2, who were 18 years old or older (time since diagnosis ≥ 5 years), were invited to complete the TNO‐AZL Questionnaire for Adult Health‐Related Quality of Life. Domain scores and proportions of CCSs with impaired HRQOL (score < 25th percentile of the reference scores) were compared with references via Mann‐Whitney U tests and logistic regression analyses corrected for age and sex (P < .004). Interactions of group with sex were included if they were significant (P < .05). Moreover, medical determinants were analyzed with multivariable logistic regression analyses.ResultsHRQOL scores for 1766 CCSs (mean age, 35.9 years [standard deviation, 9.4 years]; male, 51%; response rate, 71%) differed from references on most domains with small effect sizes. Both male and female CCSs were more often impaired in gross and fine motor functioning, cognitive functioning, sleep, and vitality with odds ratios (ORs) > 1.4. In addition, female CCSs were more often impaired in daily activities, pain, and sexuality (ORs, 1.4‐1.9) and were less often aggressive (OR, 0.6). CCCs of central nervous system (CNS) tumors, bone tumors, and retinoblastoma and those with cranial, abdominopelvic, or lower extremity radiotherapy were at increased risk of impairment in 1 or more domains.ConclusionsDutch adult CCSs, especially females, have impaired HRQOL in several domains; this is most pronounced in cognitive functioning. The vulnerabilities of subgroups at risk, such as CCSs of CNS tumors, were confirmed. Surveillance of HRQOL and multidisciplinary survivor care are recommended.Lay Summary The health‐related quality of life in a Dutch nationwide cohort of 1766 survivors of childhood cancer was studied.Survivors of childhood cancer were found to have lower health‐related quality of life in several domains (eg, motor functioning and vitality) in comparison with the general population.They most often reported low cognitive functioning (eg, memory and attention).Females had low health‐related quality of life in more domains than males.Survivors of brain tumors had low health‐related quality of life in most domains.Monitoring health‐related quality of life regularly and collaborating between disciplines in survivor care is recommended.

Parent-Adolescent Concordance Regarding Fertility Perspectives and Sperm Banking Attempts in Adolescent Males With Cancer.

Approximately half of male childhood cancer survivors experience impaired fertility, yet fertility preservation (FP) remains underutilized. Although parent recommendation influences adolescents' decision-making, parents may be uncertain and/or underrate their sons' parenthood goals. This study assessed parent-adolescent and family-level concordance regarding adolescent fertility perspectives (i.e., values, goals) and associations with FP attempts. A prospective pilot study examined the impact of a family-centered values clarification tool (FAST) on banking attempts among adolescent males newly diagnosed with cancer at risk for infertility. The FAST assessed adolescent and parent perceptions of adolescents' fertility values and goals (i.e., perceived threat of infertility, perceived benefits/barriers to banking). Parent-adolescent concordance and family-level concordance on fertility perspectives were examined, along with associations with banking attempts and salient demographic factors. Ninety-eight participants (32 adolescents aged 12-20, 37 mothers, 29 fathers) from 32 families completed the FAST before treatment initiation. Parent-adolescent dyads were concordant on approximately one-half of responses. Banking attempts were associated with higher family-level concordance regarding perceived benefits, r(32) = .40, p = .02. Older adolescent age was associated with higher family-level concordance regarding perceived threat, r(31) = .37, p = .04, and benefits, r(32) = .40, p = .03. Fathers' education was associated with higher family-level concordance regarding barriers, r(21) = .53, p = .01. When parents were concordant with their son's fertility values and goals, particularly perceived benefits, adolescents were more likely to attempt FP. Clinicians should facilitate sharing of fertility perspectives within families before cancer treatment, especially with younger adolescents. Psychosocial support for families facing FP decisions is recommended at diagnosis and across the care continuum.

Satisfaction with Fertility Preservation Decisions among Adolescent Males with Cancer: A Mixed Methods Study.

Simple SummaryFertility impairment is common among male childhood cancer survivors and negatively impacts quality of life. Sperm banking, before starting cancer treatment, is an established fertility preservation option, yet it remains underutilized at many pediatric centers. Although survivors often report regret about missed banking opportunities, little is known about short-term decisional satisfaction. The aim of this mixed methods study was to examine decisional satisfaction one month after diagnosis by comparing satisfaction among families of adolescents who did or did not attempt to bank. Quantitatively, families reported satisfaction regardless of the banking decision, while qualitatively, families of adolescents who did not attempt to bank reported potential for future regret. Thus, decisional dissatisfaction may not present after one month but could emerge in the future. The findings underscore the importance of longitudinal research to examine satisfaction over time, and why quantitative and qualitative discrepancies exist, as well as psychosocial support across the care continuum as survivors approach their reproductive years.Half of male childhood cancer survivors experience treatment-related fertility impairment, which can lead to distress. Survivors often regret forgoing fertility preservation (FP), and decisional dissatisfaction is associated with a lower quality of life. This mixed methods study examined short-term FP decisional satisfaction among families of male adolescents newly diagnosed with cancer who received an initial fertility consult and completed an FP values clarification tool. One-two months after the FP decision, thirty-nine families completed the Brief Subjective Decision Quality measure. Decisional satisfaction was compared for participants (mothers, fathers, adolescents) who did and did not attempt to bank. Semi-structured interviews included the following question: How do you/your family feel about the banking decision now/in the future? Decisional quality scores were moderate-high (M = 5.74–6.33 out of 7), with no significant differences between non-attempter (n = 15) and attempter (n = 24) families (adolescents: p = 0.83, d = 0.08; mothers: p = 0.18, d = 0.45; fathers: p = 0.32, d = 0.44). Three qualitative themes emerged among non-attempter families: (1) satisfaction with decision (50% of participants), (2) acceptance of decision (60%), and (3) potential for future regret (40%). Satisfaction with decision was the only theme identified in attempter families (93%). Quantitively, short-term decisional satisfaction was high regardless of the banking attempt. However, the qualitative findings suggest that the experiences of families who did not bank may be more nuanced, as several participants discussed a potential for future regret, highlighting the importance of ongoing support.

Pediatric and Adolescent Oncofertility in Male Patients-From Alpha to Omega.

This article reviews the latest information about preserving reproductive potential that can offer enhanced prospects for future conception in the pediatric male population with cancer, whose fertility is threatened because of the gonadotoxic effects of chemotherapy and radiation. An estimated 400,000 children and adolescents aged 0–19 years will be diagnosed with cancer each year. Fertility is compromised in one-third of adult male survivors of childhood cancer. We present the latest approaches and techniques for fertility preservation, starting with fertility preservation counselling, a clinical practice guideline used around the world and finishing with recent advances in basic science and translational research. Improving strategies for the maturation of germ cells in vitro combined with new molecular techniques for gene editing could be the next scientific keystone to eradicate genetic diseases such as cancer related mutations in the offspring of cancer survivors.

Evaluation of the Modified Reproductive Concerns Scale Among Emerging Adult Cancer Survivors.

Purpose: The reproductive concerns of emerging adult survivors of childhood cancer are not well described, and valid measurement tools tailored to this population are lacking. The purpose of this analysis was to evaluate a modified version of the Reproductive Concerns Scale (mRCS) among male and female survivors of childhood cancer. Methods: This is a secondary analysis of cross-sectional survey data collected from patients enrolled on an infertility-educational intervention study. Participants completed the mRCS at baseline. Cancer treatment data were abstracted from participant medical records. Principal component analyses were conducted to evaluate the factor structure of the mRCS for males, females, and the entire sample. Internal consistency was evaluated using Cronbach's alpha. Open-ended responses were analyzed and used to assess the validity of relevant quantitative items on the mRCS. Results: The sample consisted of N = 98 participants who were an average of 19.1 (±1.1) years of age, 45.9% were male, and 61.2% were non-Hispanic white. Factor analyses revealed three domains: Fertility Concerns (Cronbach's alpha = 0.77), Health Concerns (α = 0.74), and Information Seeking (α = 0.57). Sex-specific factor analyses identified differences in scale items for males. The open-ended responses aligned well with participant scores on the Fertility Concerns subscale. Conclusion: The mRCS consists of three subscales relevant to emerging adult survivors of childhood cancer. Further analysis by sex suggests that separate scales for males and females are warranted. Future research is warranted to determine the clinical utility of using the mRCS as a screening tool to identify and address reproductive concerns among emerging adult survivors.

Family communication about fertility preservation in adolescent males newly diagnosed with cancer.

Approximately half of male childhood cancer survivors experience fertility impairment, which can cause psychological distress. Sperm banking remains underutilized among adolescent males with cancer. Parent recommendation influences banking decisions, yet multi-informant studies have not been conducted to examine fertility preservation (FP) communication and decision making in this population. This study explored FP communication among mothers, fathers, and their male adolescents newly diagnosed with cancer. Thirty-three male adolescents, 32 mothers, and 22 fathers completed semi-structured interviews 1-2months after cancer diagnosis addressing this question: Tell me more about conversations you had about fertility preservation/sperm banking with your health care providers, parents/son, other family members, or anyone else. Interviews were audio-recorded and transcribed verbatim for thematic content analysis. Five process themes emerged: (1) reliance on health care team and social support networks to facilitate FP decisions (only parents); (2) withholding parental opinion and deferring the decision to the adolescent; (3) ease of communication (primarily adolescents); (4) communication barriers/facilitators; (5) not being present or not remembering details of FP conversations with health care providers (primarily fathers and adolescents). Four content themes included: (1) preference for biological (grand)parenthood; (2) consideration of adolescent's future partner's desire for biological parenthood (primarily parents); (3) banking while it is a viable option; (4) openness to alternative parenthood options (e.g., adoption/fostering, primary parents). Understanding variation in what family members discuss and consider relevant when making FP decisions is an important step toward improving pediatric oncofertility care. Interventions are needed to facilitate family FP-related conversations and optimize decisional satisfaction over time.

Spermatogonia Loss Correlates with LAMA 1 Expression in Human Prepubertal Testes Stored for Fertility Preservation.

Fertility preservation for male childhood cancer survivors not yet capable of producing mature spermatozoa, relies on experimental approaches such as testicular explant culture. Although the first steps in somatic maturation can be observed in human testicular explant cultures, germ cell depletion is a common obstacle. Hence, understanding the spermatogonial stem cell (SSC) niche environment and in particular, specific components such as the seminiferous basement membrane (BM) will allow progression of testicular explant cultures. Here, we revealed that the seminiferous BM is established from 6 weeks post conception with the expression of laminin alpha 1 (LAMA 1) and type IV collagen, which persist as key components throughout development. With prepubertal testicular explant culture we found that seminiferous LAMA 1 expression is disrupted and depleted with culture time correlating with germ cell loss. These findings highlight the importance of LAMA 1 for the human SSC niche and its sensitivity to culture conditions.

Leydig cell function in male survivors of childhood cancer: A report from the St Jude lifetime cohort study

This retrospective study, with cross-sectional health outcomes analysis, evaluated Leydig cell function in 1516 childhood cancer survivors at a median duration of 22.0 years after cancer diagnosis. These patients are part of the St Jude Lifetime Cohort. An age- and sex-matched community control group was recruited among friends and relatives of patients. Leydig cell failure (LCF) was defined as serum total testosterone <250 ng/dl and LH >9.85 IU/l, while Leydig cell dysfunction (LCD) was defined as testosterone ≥250 ng/dl and LH >9.85 IU/l. Follow-up data were available on 683 participants (45.2%). The point prevalence of LCF and LCD at the most recent evaluation was 6.9% and 14.7%, respectively; 42/104 patients with LCF (40.4%) used hormone replacement therapy. Eight controls, (4.8%) were receiving testosterone, but the indications for treatment were not available. No control had LCF, while 4 individuals had LCD. Independent risk factors for LCF included: age ≥26 years at assessment, testicular radiotherapy, and alkylating agents at cyclophosphamide equivalent doses ≥4000 mg/m2. LCF was also associated with: abdominal obesity, diabetes mellitus, erectile dysfunction (ED), muscle weakness, and all-cause mortality. Hormone-treated LCF was associated with increased waist circumference, ED, muscle weakness, and depression, but not with all-cause mortality. LCD was associated with unilateral orchiectomy and the same risk factors as LCF. No significant associations of LCF and LCD with adverse physical or psychosocial outcomes were found.

Sperm DNA integrity in adult survivors of paediatric leukemia and lymphoma: A pilot study on the impact of age and type of treatment

Male childhood cancer survivors (CCS) show reduced fertility, mostly due to low sperm count. The links between DNA damage caused by cancer and its treatment, pubertal stage at diagnosis and future infertility are still unclear. This Canadian pilot study analysed reproductive parameters and sperm characteristics in adult survivors of childhood leukaemia and lymphoma, divided into 2 groups according to whether cancer diagnosis occurred before or after puberty. They were compared to age-matched men with no history of cancer. No differences were observed in mean serum testosterone and FSH levels, but 4 CCS had FSH levels >8 U/ml. No differences in average sperm count or motility were observed across groups, but 5 of the 13 CCS were affected by azoo/oligozoospermia, regardless of the time at cancer diagnosis. Analysis of sperm chromatin and DNA integrity revealed no differences among the groups. The authors observed a significant negative correlation between sperm count and the cumulative dose of alkylating agent, determined by the cyclophosphamide equivalent dose, and a strong positive correlation between the cumulative dose of anthracyclines and the DNA fragmentation index. A limitation of the study is the small sample size, which makes it difficult to generalize the results. It is noteworthy that both groups of CCS had a similar prevalence of azoo/oligozoospermia, supporting the hypothesis that the prepubertal testis is not protected from damage in children who undergo cancer treatment.

A Novel Locus Predicts Spermatogenic Recovery among Childhood Cancer Survivors Exposed to Alkylating Agents.

Exposure to high doses of alkylating agents is associated with increased risk of impaired spermatogenesis among nonirradiated male survivors of childhood cancer, but there is substantial variation in this risk. Here we conducted a genetic study for impaired spermatogenesis utilizing whole-genome sequencing data from 167 nonirradiated male childhood cancer survivors of European ancestry from the St. Jude Lifetime Cohort treated with cyclophosphamide equivalent dose (CED) ≥4,000 mg/m2. Sperm concentration from semen analysis was assessed as the primary outcome. Common variants (MAF > 0.05) were adjusted for age at cancer diagnosis, CED, and top principal components. Rare/low-frequency variants (MAF ≤ 0.05) were evaluated jointly by various functional annotations and 4-kb sliding windows. A novel locus at 7q21.3 containing TAC1/ASNS was associated with decreased sperm concentration (rs7784118: P = 3.5 × 10-8). This association was replicated in two independent samples of SJLIFE survivors of European ancestry, including 34 nonirradiated male survivors treated with 0 < CED < 4,000 mg/m2 (P = 3.1 × 10-4) and 24 male survivors treated with CED ≥4,000 mg/m2 and radiotherapy <40 Gray (P = 0.012). No association was observed among survivors not exposed to alkylating agents included in the CED (P > 0.29). rs7784118 conferred 3.48- and 9.73-fold increases in risk for clinically defined oligospermia and azoospermia and improved prediction of normospermic, oligospermic, and azoospermic states by 13.7%, 5.3%, and 21.7%. rs7784118 was associated with decreased testosterone level, increased levels of follicle stimulating and luteinizing hormones, and 8.52-fold increased risk of Leydig cell failure. Additional research is warranted to determine how this SNP influences spermatogenesis and to assess its clinical utility in characterizing high-risk survivors and guiding intervention strategies. SIGNIFICANCE: The identified genetic markers harbor potential clinical utility in characterizing high-risk survivors and guiding intervention strategies including pretreatment patient counseling and use of fertility preservation services.

Identifying clusters of health risk behaviors and their predictors in adult survivors of childhood cancer: A report from the French Childhood Cancer Survivor Study.

Health risk behaviors (HRB) of childhood cancer survivors (CCS) are generally studied separately, despite the evidence suggesting that HRB are not independent. To our knowledge, few studies have examined HRB profiles in the former pediatric cancer patients. In this study, we identified HRB profiles and examined predictors engaging in unhealthy behaviors in CCS. We used data from a French cohort of CCS that includes five-year survivors diagnosed between 1945 and 2000 and treated before reaching age 18, in five centers in France. A total of 2961 adult CCS answered a self-reported questionnaire pertaining to HRB. Latent class analysis was used to identify HRB profiles combining physical activity, smoking, cannabis use, and alcohol drinking. Multinomial logistic analyses examined predictors for engaging in unhealthy behaviors. Three HRB patterns emerged: "Low-risk" (n = 1846, 62.3%) included CCS who exhibited the highest frequency for usual physical activity and the lowest probabilities for current smoking or cannabis use, but most drank at least moderately; "Moderate-risk behaviors" (n = 291, 9.8%), and "High-risk behaviors" (n = 824, 27.8%) for CCS who exhibited the highest frequencies for current smoking, cannabis use, and heavy drinking. The multivariable regression revealed that male CCS, less educated or not married were significantly more likely to be in the high-risk behaviors group than the low-risk group. As CCS remain a vulnerable population, screening for HRB should be routinized in long-term follow-up care and interventions targeting multiple HRB simultaneously among survivors should be developed.

"We Can Always Adopt": Perspectives of Adolescent and Young Adult Males with Cancer and Their Family on Alternatives to Biological Parenthood.

Purpose: Approximately half of male childhood cancer survivors experience impaired fertility, which is known to cause psychological distress. Yet, less than 50% of at-risk adolescent and young adult (AYA) males pursue fertility preservation (FP) at diagnosis. Alternatives to biological parenthood (e.g., adoption/sperm donation) may be considered, but little is known about perspectives regarding these alternatives among AYA males and their families. Methods: Families of AYAs were recruited for a mixed-method study examining FP decisions at cancer diagnosis. One month later, 48 participants from 20 families (18 male AYAs, 12-22 years of age, 19 mothers, 11 fathers) completed semistructured interviews, including two questions about: (a) alternative routes to biological parenthood, and (b) their knowledge about the processes involved and/or challenges associated with such alternatives. Verbatim transcripts were coded for thematic content using the constant comparison method. Results: Three main themes were identified, of which two represent both ends of considering alternative parenthood: (a) Willingness to consider alternatives to biological parenthood, primarily adoption; (b) No consideration/discussion of alternative family building options; and (c) Variable knowledge of alternatives and/or associated challenges. Notably, more AYAs than parents mentioned a specific preference for biological children. Conclusions: One-month postcancer diagnosis, most parents reported willingness to consider alternatives to biological parenthood for their sons, while AYA males were less knowledgeable or open to these options. Future research should prospectively examine how these attitudes affect FP decisions before treatment. Medical and psychosocial providers should counsel patients and survivors accordingly to optimize reproductive outcomes and prevent psychosocial distress if parenthood goals are unfulfilled.

Low bone mineral density is associated with hypogonadism and cranial irradiation in male childhood cancer survivors

SummaryWe investigated if bone mineral density was related to testosterone deficiency and/or previous cancer treatment in men who were childhood cancer survivors. Men with untreated testosterone deficiency or previous treatment with cranial irradiation were at increased risk of impaired bone health. Prevention of osteoporosis should be considered in their follow-up.IntroductionChildhood cancer survivors (CCS) are at increased risk of hypogonadism. Reduced bone mineral density (BMD) has been reported in CCS but it is unclear whether this is due to hypogonadism or a direct effect of cancer therapy. This study investigated BMD in CCS, and association with hypogonadism, previous treatment and cancer type.MethodsInvestigation of 125 CCS (median age 33.7 at inclusion; 9.6 at diagnosis) and 125 age-matched population controls. Serum testosterone and luteinizing hormone were assayed and BMD at total hip and lumbar spine L1–L4 measured. The mean difference in BMD (g/cm2; 95% CI) between CCS and controls was analysed. Odds ratios (OR; 95% CI) for low BMD were also calculated.ResultsOverall, BMD in the CCS cohort did not significantly differ from controls. However, compared with eugonadal CCS, the CCS with untreated hypogonadism had lower BMD at the hip (mean difference − 0.139 (− 0.210; − 0.067); p < 0.001) and spine (− 0.102 (− 0.174; − 0.030); p = 0.006). They also had a higher risk of low hip BMD (OR 4.1 (1.3; 14); p = 0.018). CCS treated with cranial irradiation also had lower BMD (hip − 0.076 (− 0.133; − 0.019); p = 0.009; spine − 0.071 (− 0.124; − 0.018); p = 0.009) compared with controls. The latter associations remained statistically significant after adjustment for hypogonadism.ConclusionsCCS with hypogonadism or previously treated with cranial irradiation are at increased risk of impaired bone health. Prevention of osteoporosis should be considered as an important part in future follow-up of these men.

Sperm DNA integrity in adult survivors of paediatric leukemia and lymphoma: A pilot study on the impact of age and type of treatment.

Childhood cancer survivors (CCS) are more likely than siblings to report low sperm count and to use assisted reproductive technologies. Yet, it is still unclear if the sperm produced many years after remission of cancer display DNA and chromatin damage linked to male infertility and poor embryo development. As well, the importance of the age at diagnosis in relation to puberty is poorly understood. In this pilot study, we compared reproductive parameters and sperm damage from adult survivors of childhood leukemia and lymphoma, sub-divided into those diagnosed before or after puberty, to men with no history of cancer. Our data indicate that CCS, independently of the age of diagnosis, have a high risk of low sperm count and when sperm are present, chances of DNA and chromatin abnormalities appear similar to those seen in the general population. Exposure to alkylating agents is correlated with low sperm count whereas exposure to anthracyclines, and doxorubicin in particular, could have long-term consequences on sperm integrity. This study highlights the need for further research on fertility among male CCS and the importance of informing families about the potential long-term impact of chemotherapy on male fertility regardless of age at diagnosis.

Testicular Function of Childhood Cancer Survivors: Who Is Worse?

Background: A multi-disciplinary approach has led to an improvement in prognosis of childhood cancers. However, in parallel with the increase in survival rate, there is a greater occurrence of long-term toxicity related to antineoplastic treatment. Hypogonadism and infertility are among the most frequent endocrinological sequelae in young adult childhood cancer survivors. The aim of this study was to identify which category of patients, grouped according to diagnosis, therapy, and age at treatment, shows the worst reproductive function in adulthood. Methods: We evaluated morpho-volumetric development of the testis, endocrine function of the hypothalamic–pituitary–gonadal axis, and sperm parameters in 102 young adult childhood cancer survivors. Results: Overall, about one-third of patients showed low total testicular volume, total testosterone (TT) <3.5 ng/mL, and altered sperm count. Hodgkin’s disease, hematopoietic stem cell transplantation, and non-cranial irradiation associated to chemotherapy were risk factors for poor gonadal function. Patients treated in pubertal age showed lower total testicular volume; however, the difference was due to more gonadotoxic treatment performed in older age. Testicular volume was more predictive of spermatogenesis than follicle-stimulating hormone (FSH), while anti-Müllerian hormone (AMH) was not useful in the evaluation of testicular function of male childhood cancer survivors. Conclusions: Pre-pubertal subjects at high risk of future infertility should be candidates for testicular tissue cryopreservation.

Leydig Cell Function in Male Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study.

Direct assessment of Leydig cell function in childhood cancer survivors has been limited. The objectives of this study were to describe the prevalence of and risk factors for Leydig cell failure (LCF), Leydig cell dysfunction (LCD), and associated adverse health outcomes. In this retrospective study with cross-sectional health outcomes analysis, we evaluated 1,516 participants (median age, 30.8 years) at a median of 22.0 years after cancer diagnosis. LCF was defined as serum total testosterone less than 250 ng/dL (or 8.67 nmol/L) and luteinizing hormone greater than 9.85 IU/L, and LCD by testosterone as 250 ng/dL or greater and luteinizing hormone greater than 9.85 IU/L. Polytomous logistic regression evaluated associations with demographic and treatment-related risk factors. Log-binomial regression evaluated associations with adverse physical and psychosocial outcomes. Piecewise exponential models assessed the association with all-cause mortality. The prevalence of LCF and LCD was 6.9% and 14.7%, respectively. Independent risk factors for LCF included an age of 26 years or older at assessment, testicular radiotherapy at any dose, and alkylating agents at cyclophosphamide equivalent doses of 4,000 mg/m2 or greater. The risk increased with older age, higher doses of testicular radiotherapy, and cyclophosphamide equivalent doses. LCF was significantly associated with abdominal obesity, diabetes mellitus, erectile dysfunction, muscle weakness, and all-cause mortality. LCD was associated with unilateral orchiectomy and the same risk factors as LCF; no significant associations were found with adverse physical or psychosocial outcomes. Older age, testicular radiotherapy, and exposure to alkylating agents were associated with LCF, which was associated with adverse physical and psychosexual outcomes. LCD, although having similar risk factors, was not associated with adverse health outcomes. Additional studies are needed to investigate the role of sex hormone replacement in mitigating the burden from adverse outcomes in survivors.

Perceptions of participating in family-centered fertility research among adolescent and young adult males newly diagnosed with cancer: A qualitative study.

Over half of male childhood cancer survivors experience infertility after treatment, which is known to cause distress and impact future quality of life. Sperm banking rates remain low, and little is known about how adolescent and young adult (AYA) males and their families make fertility preservation (FP) decisions. This study examined AYA and parent perceptions of participating in a research study focused on testing a new FP decision tool at the time of cancer diagnosis. Forty-four participants (19 mothers, 11 fathers, 14 male AYAs 12-25 years old) from 20 families completed brief assessments at diagnosis and approximately one month later, including a qualitative interview exploring the impact of study participation. Verbatim transcripts were coded through thematic content analysis using the constant comparison method. Two major themes emerged: (1) a positive effect of participating in the study and (2) a neutral effect (no positive/negative effect of participation). Subthemes that emerged for participants who noted a positive effect included (a) participation prompted deeper thinking, (b) participation influenced family conversations, and (c) participation resulted in altruism/helping others. No participant reported a negative effect. This study demonstrates that participation in family-centered research focused on FP among AYA males, before treatment begins, is perceived as beneficial or neutral at the time of a new cancer diagnosis. These findings provide support for future family-centered FP interventions for this population.

Donor spermatogenesis in de novo formed seminiferous tubules from transplanted testicular cells in rhesus monkey testis.

Can transplanted primate testicular cells form seminiferous tubules de novo, supporting complete spermatogenesis? Cryopreserved testicular cells from a prepubertal monkey can reorganize in an adult monkey recipient testis forming de novo seminiferous tubular cords supporting complete spermatogenesis. De novo morphogenesis of testicular tissue using aggregated cells from non-primate species grafted either subcutaneously or in the testis can support spermatogenesis. Two postpubertal rhesus monkeys (Macaca mulatta) were given testicular irradiation. One monkey was given GnRH-antagonist treatment from 8 to 16 weeks after irradiation, while the other received sham injections. At 16 weeks, cryopreserved testicular cells from two different prepubertal monkeys [43 × 106 viable (Trypan-blue excluding) cells in 260 μl, and 80 × 106 viable cells in 400 μl] were transplanted via ultrasound-guided injections to one of the rete testis in each recipient, and immune suppression was given. The contralateral testis was sham transplanted. Testes were analyzed 9 months after transplantation. Spermatogenic recovery was assessed by testicular volume, weight, histology and immunofluorescence. Microsatellite genotyping of regions of testicular sections obtained by LCM determined whether the cells were derived from the host or transplanted cells. Transplanted testis of the GnRH-antagonist-treated recipient, but not the sham-treated recipient, contained numerous irregularly shaped seminiferous tubular cords, 89% of which had differentiating germ cells, including sperm in a few of them. The percentages of donor genotype in different regions of this testis were as follows: normal tubule, 0%; inflammatory, 0%; abnormal tubule region, 67%; whole interior of abnormal tubules, >99%; adluminal region of the abnormal tubules, 92%. Thus, these abnormal tubules, including the enclosed germ cells, were derived de novo from the donor testicular cells. Not applicable. The de novo tubules were observed in only one out of the two monkeys transplanted with prepubertal donor testicular cells. These findings may represent a promising strategy for restoration of fertility in male childhood cancer survivors. The approach could be particularly useful in those exposed to therapeutic agents that are detrimental to the normal development of the tubule somatic cells affecting the ability of the endogenous tubules to support spermatogenesis, even from transplanted spermatogonial stem cells. This work was supported by research grants P01 HD075795 from Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD/NIH) to K.E.O and Cancer Center Support Grant P30 CA016672 from NCI/NIH to The University of Texas MD Anderson Cancer Center. The authors declare that they have no competing interests.