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Background: Infertility is an important late effect of childhood cancer treatment. Ovarian tissue cryopreservation (OTC) is established as a safe procedure to preserve gonadal tissue in (pre)pubertal girls with cancer at high risk for infertility. However, it is unclear whether elective laparoscopic OTC can also be performed safely in infants <1 year with cancer. This systematic review aims to evaluate the reported risks in infants undergoing elective laparoscopy regarding mortality, and/or critical events (including resuscitation, circulatory, respiratory, neurotoxic, other) during and shortly after surgery. Methods: This systematic review followed the Preferred reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guideline. A systematic literature search in the databases Pubmed and EMbase was performed and updated on February 15th, 2023. Search terms included ‘infants’, ‘intubation’, ‘laparoscopy’, ‘mortality’, ‘critical events’, ‘comorbidities’ and their synonyms. Papers published in English since 2000 and describing at least 50 patients under the age of 1 year undergoing laparoscopic surgery were included. Articles were excluded when the majority of patients had congenital abnormalities. Quality of the studies was assessed using the QUIPS risk of bias tool. Results: The Pubmed and Embase databases yielded a total of 12,401 unique articles, which after screening on title and abstract resulted in 471 articles to be selected for full text screening. Ten articles met the inclusion criteria for this systematic review, which included 1778 infants <1 years undergoing elective laparoscopic surgery. Mortality occurred once (death not surgery-related), resuscitation in none and critical events in 53/1778 of the procedures. Conclusion: The results from this review illustrate that morbidity and mortality in infants without extensive comorbidities during and just after elective laparoscopic procedures seem limited, indicating that the advantages of performing elective laparoscopic OTC for infants with cancer at high risk of gonadal damage may outweigh the anesthetic and surgical risks of laparoscopic surgery in this age group. [ABSTRACT FROM AUTHOR]

Study Question: Are Inhibin B and testosterone levels reduced in boys with newly diagnosed cancer prior to therapy?Summary Answer: Pretreatment serum levels of Inhibin B and testosterone are significantly reduced in boys with newly diagnosed cancer, compared to reference values.What Is Already Known: Disease-related gonadal impairment has been demonstrated in girls and young women diagnosed with cancer, prior to therapy.Study Design, Size, Duration: We conducted a descriptive study in boys newly diagnosed with cancer between January 2006 and February 2014.Participants/materials, Setting, Methods: Serum Inhibin B and testosterone levels were determined in 224 boys, up to the age of 18 years, with newly diagnosed cancer prior to therapy. Hormone levels were compared with age-matched reference values. The cohort consisted of patients with acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), Hodgkin lymphoma (HL), non-Hodgkin lym-phoma (NHL), nephroblastoma, neuroblastoma and sarcoma.Main Results and the Role Of Chance: This study demonstrates reduced serum levels of Inhibin B in boys with newly diagnosed cancer, compared to reference values (standard deviation score (SDS) -0.9, P < 0.001). Median Inhibin B level in patients was 103.5 ng/l (range 20-422). Of all patients, 78.6% showed Inhibin B levels below the 50th percentile, and 58.5% had Inhibin B levels below the 25th percentile. Serum testosterone levels were significantly lower than the reference range population (SDS -1.2, P < 0.001). Median testosterone level in pubertal patients was 7.3 nmol/l (range 0.1-23.6). No correlation with clinical signs of general illness and hormone levels were observed.Limitations, Reasons For Caution: In this study, reproductive hormone levels were compared with age-matched reference values. Future studies may compare reproductive hormone levels with case controls.Wider Implications Of the Findings: Future longitudinal studies are necessary to determine whether pretreatment impaired gonadal function at the time of cancer diagnosis is an important determinant of ultimate recovery of spermatogenesis after treatment and later on in adulthood.Study Funding/competing Interests: W.v.D. was supported by the Pediatric Oncology Center Society for Research (KOCR), Rotterdam, The Netherlands. A.-L.L.F.v.d.K. was supported by EU FP7 PanCare LIFE study. The authors have no conflicts of interest. [ABSTRACT FROM AUTHOR]

Objective: To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach., Design: Genome-wide association study., Setting: Not applicable., Patients: A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years)., Exposure: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure., Main Outcome Measure: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis., Results: Three genome-wide significant (<5.0 × 10 -8 ) and 16 genome-wide suggestive (<5.0 × 10 -6 ) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. On the basis of the effect allele frequency (EAF) (>0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): -0.484 (0.091)., Conclusion: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment because the findings of this genome-wide association study were not statistically significant replicated in the replication cohort. Suggestive evidence for the potential importance of 1 variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. Because the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity as well as fertility preservation options for childhood cancer survivors., Competing Interests: Declaration of Interests M.E.M.v.d.P. reports funding from European Union’s Seventh Framework Programme for research (technological development, and demonstration funding), Dutch Cancer Society (grant no. VU 2006-3622), Princess Máxima Center Foundation, and Stichting Kinderoncologisch Centrum Rotterdam (sKOCR), DCOG-LATER VEVO study was funded by the Dutch Cancer Society (grant no. VU 2006-3622) and by the Children Cancer-Free Foundation (Project no. 20) and the St Jude Lifetime Cohort study by NCI U01 CA195547. L.B. has nothing to disclose. Y.Y. reports funding from National Cancer Institute (NCI) U01CA195547 (MPI: Hudson/Ness), St. Jude Lifetime Cohort Study (SJLIFE), NCI P30CA021765 (PI: Roberts) Cancer Center Support Grant (CCSG), and American Lebanese Syrian Associated Charities for the submitted work; funding from NCI U24CA055727 (PI: Armstrong) Childhood Cancer Survivor Study (CCSS), National Institutes of Health (NIH) R03DE029238 (PI: Li/Sun) Innovative Statistical Analysis for Genome-Wide Data with General Interval Censored Outcomes of Oral Health in Childhood Cancer Survivors, NCI R01CA216354 (MPI: Yasui/Zhang) Late Effects Prediction Using Clinical Phenotypes and Whole Genome Sequencing, St Jude Lifetime Cohort study by NCI U01 CA195547, NCI R01CA270157 (MPI: Bhakta/Yasui) Measuring Lifelong Multimorbidity with Patient Perspectives: Implementing and Visualizing the Cumulative Burden Methodology Across Cohorts, NCI R01CA258193 (MPI: Huang/Yasui) Patient-Generated Health Data to Predict Childhood Cancer Survivorship Outcomes (HEALTHSHARE), NIH &MD Anderson Cancer Center R01CA261750-01A1 (MPI: Howell/Mulrooney/Yasui) Personalized Risk Prediction to Reduce Cardiovascular Disease in Childhood Cancer Survivors, NCI &Northwestern University R01CA261898 (MPI: Burridge/Sapkota) Predicting and Preventing Chemotherapy-Induced Cardiotoxicity in African American Children, NC. J.S.E.L. has nothing to disclose. L.L.R. has nothing to disclose. W.J.E.T. has nothing to disclose. B.V. has nothing to disclose. B.V. has nothing to disclose. D.B. has nothing to disclose. G.J.L.K. has nothing to disclose. C.B.L. has nothing to disclose. A.O. has nothing to disclose. J.J.L. has nothing to disclose. C.C.M.B. has nothing to disclose. J.B. has nothing to disclose. C.B. has nothing to disclose. E.C. has nothing to disclose. E.v.D.-d.B. has nothing to disclose. U.D. has nothing to disclose. H.J.v.d.P. has nothing to disclose. A.C.H.d.V. has nothing to disclose. J.F.W. has nothing to disclose. A.R. has nothing to disclose. S.D.F. has nothing to disclose. D.G. has nothing to disclose. M.M. has nothing to disclose. M.K. has nothing to disclose. T.K. has nothing to disclose. J.K. has nothing to disclose. D.M.-M. has nothing to disclose. C.S. has nothing to disclose. O.Z. has nothing to disclose. P.K. has nothing to disclose. L.C.M.K. has nothing to disclose. R.J.B. has nothing to disclose. F.W. has nothing to disclose. J.L.B. has nothing to disclose. A.G.U. has nothing to disclose. A.M.E.B. has nothing to disclose. F.E.v.L. has nothing to disclose. K.K.N. has nothing to disclose. M.M.H. has nothing to disclose. A.-L.L.F.v.d.K. has nothing to disclose. M.M.v.d.H.E. has nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Female childhood cancer survivors (CCSs) carry a risk of therapy-related gonadal dysfunction. Alkylating agents (AA) are well-established risk factors, yet inter-individual variability in ovarian function is observed. Polymorphisms in CYP450 enzymes may explain this variability in AA-induced ovarian damage. We aimed to evaluate associations between previously identified genetic polymorphisms in CYP450 enzymes and AA-related ovarian function among adult CCSs., Methods: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery cohort of adult female CCSs, from the pan-European PanCareLIFE cohort ( n = 743; age (years): median 25.8, interquartile range (IQR) 22.1-30.6). Using two additive genetic models in linear and logistic regression, nine genetic variants in three CYP450 enzymes were analyzed in relation to cyclophosphamide equivalent dose (CED) score and their impact on AMH levels. The main model evaluated the effect of the variant on AMH and the interaction model evaluated the modifying effect of the variant on the impact of CED score on log-transformed AMH levels. Results were validated, and meta-analysis performed, using the USA-based St. Jude Lifetime Cohort ( n = 391; age (years): median 31.3, IQR 26.6-37.4)., Results: CYP3A4*3 was significantly associated with AMH levels in the discovery and replication cohort. Meta-analysis revealed a significant main deleterious effect (Beta (95% CI): -0.706 (-1.11--0.298), p -value = 7 × 10 -4 ) of CYP3A4*3 (rs4986910) on log-transformed AMH levels. CYP2B6*2 (rs8192709) showed a significant protective interaction effect (Beta (95% CI): 0.527 (0.126-0.928), p -value = 0.01) on log-transformed AMH levels in CCSs receiving more than 8000 mg/m 2 CED., Conclusions: Female CCSs CYP3A4*3 carriers had significantly lower AMH levels, and CYP2B6*2 may have a protective effect on AMH levels. Identification of risk-contributing variants may improve individualized counselling regarding the treatment-related risk of infertility and fertility preservation options.

Purpose: Diminished reproductive function can be a major late effect of childhood cancer treatment. This study evaluates the changes, and occurrence of possible recovery, in gonadal function markers in children treated for cancer. Methods: Gonadal function markers were measured before (T0), directly after (T1), and 1 year after (T2) end of treatment of childhood cancer. Anti-Müllerian hormone (AMH) was measured in girls and inhibin B in boys and compared to reference populations. Repeated measures analysis of variance and t -tests were employed for data analysis. Results: Baseline gonadal function markers (T0) at diagnosis were available in 129 girls and 150 boys. Paired gonadal function markers were available in 49 girls and 54 boys for T0-T1, and in 27 girls and 32 boys for T1-T2. Gonadal function markers were significantly lower than the reference population at each time point ( p  < 0.001). Post-menarcheal girls showed a decrease in AMH between T0 and T1 (standard deviation scores [SDS] -0.72 to -1.32, p  = 0.007), and in the boys cohort, a decrease in inhibin B (SDS -1.14 to -1.43, p  = 0.045) was observed. Impaired gonadal function levels (<5th percentile) at T1 were observed in 15 of 27 (56%) girls and in 15 of 32 (47%) boys. However, gonadal function had recovered at T2 in seven girls and six boys. Conclusion: Our data suggest that gonadal function is already compromised at diagnosis and is further decreased by childhood cancer treatment. Nevertheless, about half of the children with gonadal impairment recovered over time. Evaluation of gonadal function markers before 1 year after end of treatment may therefore be unreliable.

Background: Observational studies have suggested that perinatal outcomes are worse in offspring of cancer survivors. We conducted a systematic review and meta-analysis to examine the risks of perinatal complications in female cancer survivors diagnosed before the age of 40 years., Methods: All published articles on pregnancy, perinatal or congenital risks in female cancer survivors were screened for eligibility. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed., Results: Twenty-two studies met the inclusion criteria. Meta-analysis indicates that offspring of cancer survivors are at increased risk of prematurity (relative risk [RR]: 1.56; 95% confidence interval [CI] 1.37-1.77) and low birth weight (RR 1.47; 95% CI 1.24-1.73) but not of being small for gestational age (RR 0.99; 95% CI 0.81-1.22). Cancer survivors have higher rates of elective (RR: 1.38; 95% CI 1.13-1.70) and emergency caesarean section (RR: 1.22; 95% CI 1.15-1.30) as well as assisted vaginal delivery (RR: 1.10; 95% CI 1.02-1.18) and are at increased risk of postpartum haemorrhage (RR: 1.18; 95% CI 1.02-1.36). The risk of congenital abnormalities also appears increased (RR 1.10; 95% CI 1.02-1.20), but this is likely to be an artefact of analysis. Although meta-analysis of the effects of radiotherapy was not possible for all outcomes, there was an increased risk of prematurity (RR 2.27; 95% CI 1.34-3.82) and consistent findings of low birth weight (RR 1.38-2.31). Risk of being small for gestational age was increased only after high uterine radiotherapy dosage., Conclusion: The increased perinatal risks warrant a proactive approach from healthcare providers in both counselling and management of perinatal care for cancer survivors., (Copyright © 2019. Published by Elsevier Ltd.)