Pharmacogenomic studies of fertility outcomes in pediatric cancer survivors - A systematic review.

For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This study aims to: (i) review the genetic contributions to infertility, (ii) search for pharmacogenomic studies looking at interactions of cancer treatment, genetic predisposition and fertility-related outcomes. Systematic searches in MEDLINE Ovid, Embase Classic+Embase, and PubMed were conducted using the following selection criteria: (i) pediatric, adolescent, and young adult cancer survivors, below 25 years old at the time of diagnosis, (ii) fertility outcome measures after cancer therapy, (iii) genetic considerations. Studies were excluded if they were (i) conducted in animal models, (ii) were not published in English, (iii) editorial letters, (iv) theses. Articles were screened in Covidence by at least two independent reviewers, followed by data extraction and a risk of bias assessment using the Quality in Prognostic Studies tool. Eight articles were reviewed with a total of 29 genes. Outcome measures included sperm concentration, azoospermia, AMH levels, assessment of premature menopause, ever being pregnant or siring a pregnancy. Three studies included replication cohorts, which attempted replication of SNP findings for NPY2R, BRSK1, FANCI, CYP2C19, CYP3A4, and CYP2B6. Six studies were rated with a high risk of bias. Differing methods may explain a lack of replication, and small cohorts may have contributed to few significant findings. Larger, prospective longitudinal studies with an unbiased genome-wide focus will be important to replicate significant results, which can be applied clinically.

The Australian New Zealand Consortium in Children, Adolescents, and Young Adults Oncofertility action plan.

International and national oncofertility networks, including the US-led Oncofertility Consortium, FertiProtekt, and the Danish Network, have played pivotal roles in advancing the discipline of oncofertility over the last decade. Many other countries lack a shared approach to pediatric oncofertility health service delivery. This study aims to describe baseline oncofertility practices at Australian New Zealand Children's Haematology/Oncology Group centers in 2019-2021, describe binational priorities for care, and propose a 5-year action plan for best practice to be implemented by the newly formed Australian New Zealand Consortium in Children, Adolescents, and Young Adults (CAYA) Oncofertility (ANZCO).

Heavy menstrual bleeding and dysmenorrhea in adolescents: A systematic review of self-management strategies, quality of life, and unmet needs.

BACKGROUND: Heavy menstrual bleeding (HMB) and dysmenorrhea (DM) are common gynecological problems. OBJECTIVE: To systematically review the needs, quality of life (QOL), and effectiveness of self-management strategies among young women (12-25 years) with DM or HMB. SEARCH STRATEGY: Relevant terms were searched through PubMed, EBSCO, Google Scholar, ProQuest, and Ovid between 2010 and 2022. SELECTION CRITERIA: Qualitative and quantitative studies published in peer-reviewed journals, females aged 12-25, exploring DM or HMB, reporting supportive care needs, quality of life, self-treatment strategies, and/or treatment-seeking behavior. DATA COLLECTION AND ANALYSIS: Abstracts were reviewed for eligibility by two researchers. Included studies were extracted and assessed for quality independently by two authors, with discrepancies resolved through consensus or the involvement of a third researcher. Data extracted included study details, menstrual history, symptoms, self-care strategies, and quality of life. The Joanna Briggs Institute checklists were used for quality assessment. MAIN RESULTS: The search returned 285 190 studies, of which 55 were eligible for inclusion. Prevalence rates of HMB and DM were in the ranges 4%-63% and 42%-94%, respectively. Over 80% of young women with DM and HMB experienced physical and psychological problems, including pelvic pain, sleep issues, mood disturbance, diarrhea, and nausea. Academic performance and daily activities were severely affected. Most (>62%) named their mothers as their primary source of information, and friends as the secondary source (10%-65%). Few studies explored needs, but they could be inferred and fell under school-related and social needs. QOL was poorer in those who had DM than those who did not. Pain was the most common issue that drove young women to find treatment. More than 70% used medication to reduce pain. More than half chose home remedies (e.g., heat therapy, massages, herbal tea, hot drinks). No studies provided information about the efficacy and dosage of medication and herbal remedies. CONCLUSIONS: HMB and DM have a large impact on daily living, with large areas of unmet need. Limited access to information impairs the management of symptoms and consequent QOL.

A 20-year overview of fertility preservation in boys: new insights gained through a comprehensive international survey.

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 INTERESTS: 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.

Ovarian stimulation and oocyte cryopreservation in females and transgender males aged 18 years or less: a systematic review.

Background: Fertility preservation is an important healthcare focus in the paediatric and adolescent population when gonadotoxic treatments are required. Ovarian stimulation (OS) resulting in oocyte cryopreservation is a well-established fertility preservation option in the adult population. It's utility, however, is little known in young patients. The purpose of this review was to synthesise the available literature on OS in patients ≤18 years old, to identify gaps in current research and provide suggestions for future research directions. Methods: Using PRISMA guidelines, a systematic review of the literature was performed for all relevant full-text articles published in English in Medline, Embase, the Cochrane Library and Google Scholar databases. The search strategy used a combination of subject headings and generic terms related to the study topic and population. Two reviewers independently screened studies for eligibility, extracted data and assessed the risk of bias. Characteristics of the studies, objectives and key findings were extracted and summarised in a narrative synthesis. Results: Database search and manual review identified 922 studies, 899 were eliminated based on defined exclusion criteria. Twenty-three studies were included and comprised 468 participants aged ≤18 years who underwent OS (median 15.2, range 7-18 years old). Only three patients were premenarchal, and four patients were on treatment to suppress puberty. Patients had OS for a broad range of indications including oncology treatment, transgender care and Turner syndrome. A total of 488 cycles of OS were completed, with all but 18 of these cycles (96.3%) successfully resulting in cryopreserved mature oocytes (median 10 oocytes, range 0-35). Fifty-three cycles (9.8%) were cancelled. Complications were rare (<1%). One pregnancy was reported from a female who had OS aged 17 years old. Conclusion: This systematic review demonstrates that OS and oocyte cryopreservation is achievable in young females however there are only a few cases in the literature describing OS in premenarcheal children or those who have suppressed puberty. There is little proof that OS can lead to pregnancy in adolescents, and no proof that this can be achieved in premenarchal girls. Therefore it should be regarded as an innovative procedure for adolescents and experimental for premenarcheal girls. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=265705, identifier CRD42021265705.

Female reproductive health in pediatric, adolescent, and young adult cancer survivors.

An estimated 500,000 cancer survivors of reproductive age in the United States will live to experience the long-term consequences of cancer treatment. Therefore, a focused aspect of cancer care has appropriately shifted to include quality of life in survivorship. Infertility is a late effect of therapy that affects 12% of female survivors of childhood cancer receiving any cancer treatment in large cohort studies and results in a 40% decreased likelihood of pregnancy in young adults of ages 18-39 years. Nonfertility gynecologic late effects such as hypoestrogenism, radiation-induced uterine and vaginal injury, genital graft-versus-host disease after hematopoietic stem cell transplant, and sexual dysfunction also significantly affect quality of life in survivorship but are underdiagnosed and require consideration. Several articles in the special edition "Reproductive Health in Adolescent and Young Adult Cancer Survivorship" address infertility, genital graft-versus-host disease, and psychosexual functioning in survivorship. This review article focuses on other adverse gynecologic outcomes of cancer therapies including hypogonadism and hormone replacement therapy, radiation-induced uterovaginal injury, vaccination and contraception, breast and cervical cancer screening, and pregnancy considerations in survivorship.

Metastatic neuroblastoma in fertility preservation biopsy of clinically normal testis: a case report.

RESEARCH QUESTION: Is there potential for the detection of neuroblastoma malignancy in testicular tissue extracted for fertility preservation for prepubertal boys at the time of tissue freezing? DESIGN: This is a case report. RESULTS: A boy was diagnosed with primary localized left adrenal neuroblastoma, with complete resection of the tumour. During 6 months' surveillance, he developed a relapse in the left para-renal region with progression of molecular and chromosomal features into undifferentiated neuroblastoma. Before highly gonadotoxic treatment, testicular biopsy for fertility preservation was taken, from a clinically normal testis. Histopathological examination of the testicular biopsy revealed metastatic neuroblastoma. CONCLUSIONS: Metastatic neuroblastoma detected histologically in a clinically normal testis highlights the importance of routine histological examination at the time of testicular cryopreservation. The histological evaluation of gonadal tissue for potential malignant contamination before freezing should be mandatory, regardless of the malignancy diagnosis. Advances in sensitive molecular detection and in-vitro maturation are critically required to decrease future risk of disease recurrence in both solid and haematological malignancies.

Pre-Vaccination Human Papillomavirus Genotypes and HPV16 Variants among Women Aged 25 Years or Less with Cervical Cancer.

BACKGROUND: In 2007, Australia introduced a national human papillomavirus (HPV) vaccination program. In 2017, the onset of cervical screening changed from 18 to 25 years of age, utilising human papillomavirus (HPV) nucleic acid testing. The objective of the study is to describe the HPV genotypes and HPV16 variants in biopsies from women ≤ 25 years of age with cervical carcinoma (CC) (cases), compared with those aged >25 years (controls), in a pre-vaccination cohort. METHODS: HPV genotyping of archival paraffin blocks (n = 96) was performed using the INNO-LiPA HPV Genotyping assay. HPV16-positive samples were analysed for variants by type-specific PCR spanning L1, E2 and E6 regions. RESULTS: HPV16 was the commonest genotype in cases (54.5%, 12/22) and controls (66.7%, 46/69) (p = 0.30), followed by HPV18 (36.3%, 8/22 vs. 17.3% 12/69, respectively) (p = 0.08). Furthermore, 90% (20/22) of cases and 84.1% (58/69) of controls were positive for HPV16 or 18 (p = 0.42); 100% (22/22) of cases and 95.7% (66/69) of controls had at least one genotype targeted by the nonavalent vaccine (p = 0.3). The majority of HPV16 variants (87.3%, 48/55) were of European lineage. The proportion of unique nucleotide substitutions was significantly higher in cases (83.3%, 10/12) compared with controls (34.1%, 15/44), (p < 0.003, χ2, OR 9.7, 95%CI 1.7-97.7). CONCLUSIONS: Virological factors may account for the differences in CCs observed in younger compared with older women. All CCs in young women in this study had preventable 9vHPV types, which is important messaging for health provider adherence to new cervical screening guidelines.

Pediatric, adolescent, and young adult breast and reproductive tumors.

Tumors of the breast and reproductive organs that occur in children, adolescents, and young adults (AYA) have different biological features and can present special challenges. Although prognosis for these tumors is generally favorable, the long-term effects of treatment can be debilitating. Treatments are often multimodal and may include surgery as well as chemotherapy and/or radiation, which can cause considerable distress and anxiety related to loss of femininity or masculinity, concern over future fertility, or sexual dysfunction. Thus, tumors of the reproductive organs in pediatric/AYA patients require special consideration of the treatment effects beyond the intended oncologic outcome. Multidisciplinary teams should be involved in their care and address issues of fertility, sexual dysfunction, and psychosexual concerns before treatment begins. This review addresses histology, risk factors, prognosis, staging and treatment of gynecologic, breast and testicular cancers in pediatric and AYA patients.

Predicting successful sperm retrieval in transfeminine adolescents after testicular biopsy.

PURPOSE: Increasing numbers of transgender adolescents are receiving gender-affirming treatments (GAT). Given GAT can impair reproductive function, clinical guidelines advise prior counselling regarding fertility preservation (FP). For transgender adults assigned male at birth, FP is usually achieved via a masturbatory sample and sperm cryopreservation. This is less straightforward in transgender adolescents, since they may not be developmentally ready to masturbate and/or masturbation may cause unacceptable gender dysphoria. Testicular biopsy represents an alternative method for sperm retrieval in these adolescents, but for those in early/mid puberty, it is difficult to predict whether sperm will be found. The purpose of this study was therefore to identify factors that predict successful sperm retrieval for cryopreservation via testicular biopsy. METHODS: A retrospective cohort study was undertaken at a tertiary-referral pediatric gender service. Subjects were included if they'd received a testicular biopsy in association with the commencement of GAT between 2010 and 2019. The primary outcome measure was successful sperm retrieval, and potential predictors included age, testicular volume and serum testosterone, LH and FSH levels. RESULTS: Of 25 subjects who received a biopsy prior to starting any GAT, 17 had successful sperm retrieval. While age, testosterone, LH and FSH levels showed minimal differences, testicular volume was significantly higher in those with successful sperm retrieval, and a threshold of ≥ 10 mL showed 92% sensitivity and 71% specificity in predicting successful retrieval. An additional 6 patients received a biopsy after starting puberty suppression and before commencement of oestrogen, and one of these individuals had sperm successfully retrieved despite > 2 years of regular puberty suppression. CONCLUSION: These findings suggest that testicular volume is most useful in predicting successful sperm retrieval following testicular biopsy in transgender adolescents and are likely to be of relevance to other young people undertaking FP, including those with cancer.

A View from the past into our collective future: the oncofertility consortium vision statement.

PURPOSE: Today, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium. METHODS: The Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process. RESULTS: This interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity. CONCLUSION: The goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.

Recurrent post-coital bleeding: Should colposcopy still be mandatory?

BACKGROUND: Colposcopy has been recommended for all women with recurrent post-coital bleeding (PCB) even if their cervical cytology or co-test (involving oncogenic human papillomavirus (HPV) DNA testing and cytology) are negative. AIMS: To determine the risk of cervical cancer and its precursors among women with recurrent PCB with negative cytology or co-test. MATERIALS AND METHODS: A retrospective analysis of two cohorts of women with PCB referred to a tertiary colposcopy clinic. Cohort (1) (n = 1846) between 1 January 2000 and 31 December 2016 (cytology-based screening) and Cohort (2) (n = 215) from 1 January 2018 to 31 December 2019 after introduction of primary HPV screening. RESULTS: In 1217 (65.9%) women in Cohort (1) referred with negative cytology, there was one cancer (0.08%) and 22 high-grade squamous intraepithelial lesions (HSIL (cervical intraepithelial neoplasia 2/3)) on histopathology. In Cohort (2), there was no cancer or HSIL in 83 women with negative co-tests (negative for oncogenic HPV and cytology). False-negative cytology after a negative referral cytology or co-test was low with 2% of repeat cytology at initial colposcopy showing possible HSIL or worse. CONCLUSIONS: Women presenting with PCB and negative cytology alone have a low risk of cancer and could have HPV testing before being triaged to colposcopy. We showed that with the assurance of a negative co-test and the low likelihood of false-negative cytology, these women could avoid colposcopy unless cervical cancer is clinically suspected. There is a need for a larger cohort study to substantiate our findings with more precision.

Exploring the facilitators and barriers to using an online infertility risk prediction tool (FoRECAsT) for young women with breast cancer: a qualitative study protocol.

INTRODUCTION: As cancer treatments may impact on fertility, a high priority for young patients with breast cancer is access to evidence-based, personalised information for them and their healthcare providers to guide treatment and fertility-related decisions prior to cancer treatment. Current tools to predict fertility outcomes after breast cancer treatments are imprecise and do not offer individualised prediction. To address the gap, we are developing a novel personalised infertility risk prediction tool (FoRECAsT) for premenopausal patients with breast cancer that considers current reproductive status, planned chemotherapy and adjuvant endocrine therapy to determine likely post-treatment infertility. The aim of this study is to explore the feasibility of implementing this FoRECAsT tool into clinical practice by exploring the barriers and facilitators of its use among patients and healthcare providers. METHODS AND ANALYSIS: A cross-sectional exploratory study is being conducted using semistructured in-depth telephone interviews with 15-20 participants each from the following groups: (1) premenopausal patients with breast cancer younger than 40, diagnosed within last 5 years, (2) breast surgeons, (3) breast medical oncologists, (4) breast care nurses (5) fertility specialists and (6) fertility preservation nurses. Patients with breast cancer are being recruited from the joint Breast Service of three affiliated institutions of Victorian Comprehensive Cancer Centre in Melbourne, Australia-Peter MacCallum Cancer Centre, Royal Melbourne Hospital and Royal Women's Hospital, and clinicians are being recruited from across Australia. Interviews are being audio recorded, transcribed verbatim and imported into qualitative data analysis software to facilitate data management and analyses. ETHICS AND DISSEMINATION: The study protocol has been approved by Melbourne Health Human Research Ethics Committee, Australia (HREC number: 2017.163). Confidentiality and privacy are maintained at every stage of the study. Findings will be disseminated through peer-reviewed scholarly and scientific journals, national and international conference presentations, social media, broadcast media, print media, internet and various community/stakeholder engagement activities.