Reference standards for follicular density in ovarian cortex from birth to sexual maturity.

RESEARCH QUESTION: Are age-normalized reference values for human ovarian cortical follicular density adequate for tissue quality control in fertility preservation? DESIGN: Published quantitative data on the number of follicles in samples without known ovarian pathology were converted into cortical densities to create reference values. Next, a sample cohort of 126 girls (age 1-24 years, mean ± SD 11 ± 6) with cancer, severe haematological disease or Turner syndrome were used to calculate Z-scores for cortical follicular density based on the reference values. RESULTS: No difference was observed between Z-scores in samples from untreated patients (0.3 ± 3.5, n = 30) and patients treated with (0.5 ± 2.9, n = 48) and without (0.1 ± 1.3, n = 6) alkylating chemotherapy. Z-scores were not correlated with increasing cumulative exposure to cytostatics. Nevertheless, Z-scores in young treated patients (0-2 years -2.1 ± 3.1, n = 10, P = 0.04) were significantly lower than Z-scores in older treated patients (11-19 years, 2 ± 1.9, n = 15). Samples from patients with Turner syndrome differed significantly from samples from untreated patients (-5.2 ± 5.1, n = 24, P = 0.003), and a Z-score of -1.7 was identified as a cut-off showing good diagnostic value for identification of patients with Turner syndrome with reduced ovarian reserve. When this cut-off was applied to other patients, analysis showed that those with indications for reduced ovarian reserve (n = 15) were significantly younger (5.9 ± 4.2 versus 10.7 ± 5.9 years, P = 0.004) and, when untreated, more often had non-malignant haematologic diseases compared with those with normal ovarian reserve (n = 24, 100% versus 19%, P = 0.009). CONCLUSION: Z-scores allow the estimation of genetic- and treatment-related effects on follicular density in cortical tissue from young patients stored for fertility preservation. Understanding the quality of cryopreserved tissue facilitates its use during patient counselling. More research is needed regarding the cytostatic effects found in this study.

Hearing Status in Survivors of Childhood Acute Myeloid Leukemia Treated With Chemotherapy Only: A NOPHO-AML Study.

BACKGROUND: As more children survive acute myeloid leukemia (AML) it is increasingly important to assess possible late effects of the intensive treatment. Hearing loss has only sporadically been reported in survivors of childhood AML. We assessed hearing status in survivors of childhood AML treated with chemotherapy alone according to 3 consecutive NOPHO-AML trials. PROCEDURE: A population-based cohort of children treated according to the NOPHO-AML-84, NOPHO-AML-88, and NOPHO-AML-93 trials included 137 eligible survivors among whom 101 (74%) completed a questionnaire and 99 (72%) had otologic and audiologic examination performed including otoscopy (72%), pure tone audiometry (70%), and tympanometry (60%). Eighty-four of 93 (90%) eligible sibling controls completed a similar questionnaire. RESULTS: At a median of 11 years (range, 4 to 25) after diagnosis, hearing disorders were rare in survivors of childhood AML and in sibling controls, with no significant differences. None had severe or profound hearing loss diagnosed at audiometry. Audiometry detected a subclinical hearing loss ranging from slight to moderate in 19% of the survivors, 5% had low-frequency hearing loss, and 17% had high-frequency hearing loss. CONCLUSIONS: The frequency of hearing disorders was low, and hearing thresholds in survivors of childhood AML were similar to background populations of comparable age.

Cardiac function in survivors of childhood acute myeloid leukemia treated with chemotherapy only: a NOPHO-AML study.

OBJECTIVES: We report cardiac function of patients treated for Childhood acute myeloid leukemia with chemotherapy only according to three consecutive Nordic protocols. METHODS: Ninety-eight of 138 eligible patients accepted examination with standardized echocardiography. Results were compared with age- and sex-matched controls. RESULTS: The median age was 3 yr at diagnosis (range 0-15), and the median time from diagnosis to study was 11 yr (4-25). All but one patient had received doxorubicin and 90% had received mitoxantrone. The median cumulative dose of daunorubicin equivalents was 300 mg/m(2) (210-525). Left ventricular fractional shortening (LVFS) and ejection fraction (LVEF) were lower in patients than in controls (32.6% (SD 4.0) vs. 35.2% (SD 3.4), P = 0.002 and 59.9% (SD 5.5) vs. 64.2% (SD 4.4), P = 0.001). The myocardial performance index (MPI) was higher in patients than in controls (0.32 (SD 0.081) vs. 0.26 (SD 0.074), P < 0.0001). Cumulative dose of doxorubicin but not mitoxantrone was related to lower LVFS (P = 0.037) and LVEF (P = 0.016). Longer follow-up was associated with lower LVFS (P = 0.034). Higher MPI was associated with young age at diagnosis (P = 0.04) and longer follow-up (P = 0.031). CONCLUSIONS: In this study, most patients had cardiac function within normal limits and reported very few cardiac symptoms. However, compared with healthy controls, they had significantly reduced left ventricular function.

Clinical significance in self-rated HRQoL among survivors after childhood cancer - demonstrated by anchor-based thresholds.

BACKGROUND: There is a need to establish clinically relevant thresholds (anchors) for identification of differences in health-related quality of life (HRQoL) and thereby provide stronger evidence regarding the HRQoL of childhood cancer survivors. AIM: To investigate HRQoL in childhood cancer survivors with a standardised instrument and to establish thresholds for clinically significant differences by using qualitative interviews as anchors. An additional aim was to investigate survivors' HRQoL in relation to an age-matched comparison group without cancer experience. MATERIAL AND METHODS: Self-rated HRQoL (KIDSCREEN-27) was assessed in a national cohort of survivors (n = 63, aged 12-22) and a comparison group (n = 257, aged 11-23). Findings from qualitative interview data were also used (n = 61); three subgroups ("Feeling like anyone else"; "Feeling almost like others"; "Feeling different") were identified based on survivors own perception of influence on daily life. Effect size calculations based on means from the KIDSCREEN-27 dimensions were performed using the subgroups as anchors to indicate clinical importance. Furthermore, standard multiple regression analyses were performed. Results. Effect sizes between the subgroups "Feeling like anyone else" and "Feeling almost like others" and the group "Feeling different" were large for all dimensions (1.04-2.07). The multiple regression models showed that being a survivor was significantly associated with one of the dimensions, School Environment, where survivors scored higher HRQoL. Furthermore, female sex and older age (17-23 years) significantly contributed to lower self-rated HRQoL. Conclusion. In clinical practice the KIDSCREEN-27 could be a useful screening tool to identify survivors of childhood cancer in need of extra support, using KIDSCREEN dimension mean values of 45 or less as thresholds. Larger scale studies are recommended to identify and test thresholds with regard to different age groups and time since diagnosis.

Increase in peg-asparaginase clearance as a predictor for inactivation in patients with acute lymphoblastic leukemia.

Asparaginase is an essential component of acute lymphoblastic leukemia (ALL) therapy, yet its associated toxicities often lead to treatment discontinuation, increasing the risk of relapse. Hypersensitivity reactions include clinical allergies, silent inactivation, or allergy-like responses. We hypothesized that even moderate increases in asparaginase clearance are related to later inactivation. We therefore explored mandatory monitoring of asparaginase enzyme activity (AEA) in patients with ALL aged 1-45 years treated according to the ALLTogether pilot protocol in the Nordic and Baltic countries to relate mean AEA to inactivation, to build a pharmacokinetic model to better characterize the pharmacokinetics of peg-asparaginase and assess whether an increased clearance relates to subsequent inactivation. The study analyzed 1631 real-time AEA samples from 253 patients, identifying inactivation in 18.2% of the patients. This inactivation presented as mild allergy (28.3%), severe allergy (50.0%), or silent inactivation (21.7%). A pharmacokinetic transit compartment model was used to describe AEA-time profiles, revealing that 93% of patients with inactivation exhibited prior increased clearance, whereas 86% of patients without hypersensitivity maintained stable clearance throughout asparaginase treatment. These findings enable prediction of inactivation and options for either dose increments or a shift to alternative asparaginase formulations to optimize ALL treatment strategies.

Pubertal development and fertility in survivors of childhood acute myeloid leukemia treated with chemotherapy only: a NOPHO-AML study.

BACKGROUND: More than 60% of children with acute myeloid leukemia (AML) become long-term survivors. Most are cured using chemotherapy without hematopoietic stem cell transplantation (HSCT). We report on pubertal development and compare self-reported parenthood among AML survivors and their siblings. PROCEDURE: We included 137 children treated for AML according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO)-AML-84, -88, and -93 trials, who were alive by June 2007. Patients with relapse or treated with HSCT were excluded. AML survivors participated in a physical and biochemical examination (n = 102) and completed a questionnaire (n = 101). One of their siblings completed an identical questionnaire (n = 84). RESULTS: At a median follow-up of 11 years (range 5-25) after diagnosis of AML the survivors (median age 16 years, range 5-36) were either prepubertal or had entered puberty normally. Serum levels of FSH, LH, testosterone, estradiol, sex hormone binding globulin (SHBG), inhibin A and B, and testicular volumes were within normal ranges. Anti-Müllerian hormone (AMH) levels were decreased in 5 of 40 postpubertal females. Mean reported age at menarche was 13.1 (range 11-17) years. Among survivors 15 years of age or older 31% of females reported pregnancies and 9% of males reported pregnancies in their partners, rates comparable with the frequency reported by their siblings. CONCLUSIONS: Most AML survivors treated with chemotherapy had normal pubertal development and fertility, however, AMH levels were decreased in 13% of postpubertal females. Longer follow-up is necessary to evaluate possible risk of premature ovarian failure.

ProFertil study protocol for the investigation of gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy aiming at fertility protection of young women and teenagers with cancer in Sweden-a phase III randomised double-blinded placebo-controlled study.

BACKGROUND: Gonadotropin-releasing hormone agonists (GnRHa) cotreatment used to transiently suppress ovarian function during chemotherapy to prevent ovarian damage and preserve female fertility is used globally but efficacy is debated. Most clinical studies investigating a beneficial effect of GnRHa cotreatment on ovarian function have been small, retrospective and uncontrolled. Unblinded randomised studies on women with breast cancer have suggested a beneficial effect, but results are mixed with lack of evidence of improvement in markers of ovarian reserve. Unblinded randomised studies of women with lymphoma have not shown any benefit regarding fertility markers after long-term follow-up and no placebo-controlled study has been conducted so far. The aim of this study is to investigate if administration of GnRHa during cancer treatment can preserve fertility in young female cancer patients in a double-blind, placebo-controlled clinical trial. METHODS AND ANALYSIS: A prospective, randomised, double-blinded, placebo-controlled, phase III study including 300 subjects with breast cancer. In addition, 200 subjects with lymphoma, acute leukemias and sarcomas will be recruited. Women aged 14-42 will be randomised 1:1 to treatment with GnRHa (triptorelin) or placebo for the duration of their gonadotoxic chemotherapy. Follow-up until 5 years from end of treatment (EoT). The primary endpoint will be change in anti-Müllerian hormone (AMH) recovery at follow-up 12 months after EoT, relative to AMH levels at EoT, comparing the GnRHa group and the placebo group in women with breast cancer. ETHICS AND DISSEMINATION: This study is designed in accordance with the principles of Good Clinical Practice (ICH-GCP E6 (R2)), local regulations (ie, European Directive 2001/20/EC) and the ethical principles of the Declaration of Helsinki. Within 6 months of study completion, the results will be analysed and the study results shall be reported in the EudraCT database. STUDY REGISTRATION: The National Institutional review board in Sweden dnr:2021-03379, approval date 12 October 2021 (approved amendments 12 June 2022, dnr:2022-02924-02 and 13 December 2022, dnr:2022-05565-02). The Swedish Medical Product Agency 19 January 2022, Dnr:5.1-2021-98927 (approved amendment 4 February 2022). Manufacturing authorisation for authorised medicinal products approved 6 December 2021, Dnr:6.2.1-2020-079580. Stockholm Medical Biobank approved 22 June 2022, RBC dnr:202 253. TRIAL REGISTRATION NUMBER: NCT05328258; EudraCT number:2020-004780-71.

Ways of understanding the ability to have children among young adult survivors of childhood cancer - A phenomenographic study.

PURPOSES: The aim was to explore the ways young adult survivors of childhood cancer with risk of being infertile understand their ability to have children. METHOD: The study has a qualitative design with a phenomenographic approach. Interviews with a purposeful sample of 19 childhood cancer survivors who did not have children (age range 17-27) were carried out and analysed. RESULTS: We identified four qualitatively different ways in which young adult survivors of childhood cancer understand their ability to have children: difficulty in having children is not as important as surviving cancer, having a biological child may be a complicated procedure, having children may be affected by hereditary concerns, having children in the future is a difficult topic to deal with. CONCLUSIONS: The four different ways in which young adult childhood cancer survivors understand their ability to have children did not appear to be solely related to information they had or had not received during treatment but appeared to reflect their current life situation and how they were coping with their cancer experience. Using survivors' understandings of their ability to have children is recommended as a starting point when healthcare personnel initiate communication about fertility issues in survivorship care. Some survivors need psychosocial support for the acceptance and management of both cancer and fertility problems.

Fertility preservation for young adults, adolescents, and children with cancer.

Options for fertility preservation (FP) through cryopreservation methods are currently available for young adults, adolescents, and children. Guidelines for FP have been provided by international clinical societies, and emergency procedures aimed at FP have been implemented into clinical practice worldwide. In this article, we review the current data on clinical standards of emergency FP in patients who are facing gonadotoxic effects of cancer treatment, and we also describe the methods that are still under development, usually denoted as experimental. In Sweden, programmes for FP have been established at large university hospitals, thus covering the whole country. The Swedish publicly financed health care covers both assisted reproduction for treatment of infertility and the cryopreservation of gametes or gonadal tissue when there is a medical indication, such as the risk to become infertile due to oncologic treatment; hence the access to FP is ensured for the whole population. At our centre at Karolinska University Hospital in Stockholm, methods for FP have been offered since 1988. In this article, we also review the oncologic indications for FP in our patient cohort of >3000 individuals during the period 1988-2018.

Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia: Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age.

PURPOSE: Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored. PATIENTS AND METHODS: We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. RESULTS: Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse. CONCLUSION: Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse.