Long-term follow-up to assess criteria for ovarian tissue cryopreservation for fertility preservation in young women and girls with cancer.

STUDY QUESTION: Do the Edinburgh Selection Criteria correctly identify female cancer patients under the age of 18 who are at risk of premature ovarian insufficiency (POI) as candidates for ovarian tissue cryopreservation (OTC)? SUMMARY ANSWER: Patient assessment using these criteria accurately identifies those at risk of POI, who can be offered OTC and future transplantation as a means of fertility preservation. WHAT IS KNOWN ALREADY: Treatment for childhood cancer can have adverse consequences on future fertility; at the time of diagnosis, fertility risk assessment should be undertaken in order to identify patients to whom fertility preservation should be offered. The Edinburgh selection criteria, based on planned cancer treatment and patient health status, are utilized to identify those at high risk and therefore eligible for OTC. However, this procedure is not without risk and there are few data on the efficacy of the procedure in prepubertal patients. As such, long-term follow-up of reproductive outcomes is necessary, to ensure that OTC is being offered appropriately. STUDY DESIGN, SIZE, DURATION: Cohort study encompassing all females diagnosed with cancer under the age of 18 in South East Scotland, from 1 January 1996 to 30 April 2020. Patients were followed up for reproductive outcomes to assess for diagnosis of POI. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 638 eligible patients were identified; patients under the age of 12 or deceased before the age of 12 were excluded from the study, leaving a study population of 431 patients. Electronic records were reviewed for reproductive function, assessed by current menstruation, pregnancy (in the absence of POI diagnosis), reproductive hormone measurements, pubertal progression, or diagnosis of POI. Patients on hormonal contraception (other than for treatment of POI or panhypopituitarism with no history of gonadatoxic treatment) were excluded from analysis (n = 9). Analysis on remaining 422 patients was carried out using the Kaplan-Meier methods, with POI as the defined event, and Cox proportional hazards model. MAIN RESULTS AND THE ROLE OF CHANCE: In the study population of 431 patients, median ages at diagnosis and analysis were 9.8 and 22.2 years, respectively. Reproductive outcomes were unavailable in 142 patients; the assumption was made that these patients did not have POI, but a subanalysis excluding these patients was also performed. Of the 422 patients aged >12 at analysis and not taking hormonal contraception, OTC was offered to 37 patients and successfully performed in 25 patients. Of the 37 patients offered OTC (one at time of relapse), nine (24.3%) developed POI. Of the 386 not offered OTC, 11 (2.9%) developed POI. The probability of developing POI was significantly higher in those offered OTC (hazard ratio [HR] 8.7 [95% CI 3.6-21]; P < 0.0001), even when those patients with unknown outcomes were excluded from the analysis (HR 8.1 [95% CI 3.4-20]; P < 0.001). All patients offered OTC who developed POI did so after treatment for primary disease; in those not offered OTC, five patients (45.5%) developed POI after treatment for disease relapse. LIMITATIONS, REASONS FOR CAUTION: A significant number of patients had unknown reproductive outcomes; many of these patients were engaged in ongoing follow-up but did not have documented reproductive assessment. This may have introduced bias to the analysis and highlights the need for reproductive follow-up as part of routine cancer aftercare. In addition, the relatively young age of the patient population and short duration of follow-up in some cases demonstrates the need for ongoing follow-up of this cohort. WIDER IMPLICATIONS OF THE FINDINGS: The prevalence of POI after childhood cancer is low, but the Edinburgh selection criteria remain a robust tool for selecting those at high risk at the time of diagnosis, to offer OTC appropriately. However, disease relapse necessitating more intensive treatments remains a challenge. This study additionally highlights the importance of routine assessment and documentation of reproductive status in haematology/oncology follow-up. STUDY FUNDING/COMPETING INTEREST(S): K.D. is supported by a CRUK grant (C157/A25193). This work was undertaken in part in the MRC Centre for Reproductive Health, (supported by MRC grant MR/N022556/1). R.A.A. has received consulting fees from Ferring and Roche Diagnostics; payment from Merck and IBSA for educational events; and laboratory materials from Roche Diagnostics. The other authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Survivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the heart was exposed, are at increased risk of cardiomyopathy. Symptomatic cardiomyopathy is typically preceded by a series of gradually progressive, asymptomatic changes in structure and function of the heart that can be ameliorated with treatment, prompting specialist organisations to endorse guidelines on cardiac surveillance in at-risk survivors of cancer. In 2015, the International Late Effects of Childhood Cancer Guideline Harmonization Group compiled these guidelines into a uniform set of recommendations applicable to a broad spectrum of clinical environments with varying resource availabilities. Since then, additional studies have provided insight into dose thresholds associated with a risk of asymptomatic and symptomatic cardiomyopathy, have characterised risk over time, and have established the cost-effectiveness of different surveillance strategies. This systematic Review and guideline provides updated recommendations based on the evidence published up to September, 2020.

A rare presentation of a bilateral intracranial parameningeal embryonal rhabdomyosarcoma mimicking vestibular schwannoma in a two-year-old child: a case report.

Intracranial parameningeal rhabdomyosarcomas are rare, aggressive, rapidly progressive paediatric malignancies that carry a poor prognosis. The authors report a case of a 2-year-old boy who initially presented with a left facial palsy, ataxia and, shortly after, bloody otorrhoea. MRI imaging was initially suggestive of a vestibular schwannoma. However, there was rapid progression of symptoms and further MRI imaging showed very rapid increase in tumour size with mass effect and development of a similar tumour on the contralateral side. A histological diagnosis of bilateral parameningeal embryonal rhabdomyosarcoma was made. Despite treatment, progression led to hydrocephalus and diffuse leptomeningeal disease, from which the patient did not survive. Few intracranial parameningeal rhabdomyosarcomas have previously been reported and these report similar presenting symptoms and rapid disease progression. However, this is the first reported case of a bilateral intracranial parameningeal embryonal rhabdomyosarcoma which, on initial presentation and imaging, appeared to mimic a vestibular schwannoma.

Guideline for the management of long tunnelled external ventricular drains in chronic hydrocephalus.

This article reports on the journey of a child with an inoperable hypothalamic-origin pilocytic astrocytoma causing hydrocephalus, which was refractory to treatment with shunts, and required a new approach. With multidisciplinary support, excellent nursing care and parental education, the child's hydrocephalus was managed long term in the community with bilateral long-tunnelled external ventricular drains (LTEVDs). This article describes the patient's journey and highlights the treatment protocols that were created to achieve this feat. Despite the difficulties in initially setting up these protocols, they proved successful and thus the team managing the patient proposed that LTEVDs are a viable treatment option for children with hydrocephalus in the context of inoperable tumours to help maximise quality of life.

qPET - a quantitative extension of the Deauville scale to assess response in interim FDG-PET scans in lymphoma.

BACKGROUND: Interim FDG-PET is used for treatment tailoring in lymphoma. Deauville response criteria consist of five ordinal categories based on visual comparison of residual tumor uptake to physiological reference uptakes. However, PET-response is a continuum and visual assessments can be distorted by optical illusions. OBJECTIVES: With a novel semi-automatic quantification tool we eliminate optical illusions and extend the Deauville score to a continuous scale. PATIENTS AND METHODS: SUVpeak of residual tumors and average uptake of the liver is measured with standardized volumes of interest. The qPET value is the quotient of these measurements. Deauville scores and qPET-values were determined in 898 pediatric Hodgkin's lymphoma patients after two OEPA chemotherapy cycles. RESULTS: Deauville categories translate to thresholds on the qPET scale: Categories 3, 4, 5 correspond to qPET values of 0.95, 1.3 and 2.0, respectively. The distribution of qPET values is unimodal with a peak representing metabolically normal responses and a tail of clearly abnormal outliers. In our patients, the peak is at qPET = 0.95 coinciding with the border between Deauville 2 and 3. qPET cut values of 1.3 or 2 (determined by fitting mixture models) select abnormal metabolic responses with high sensitivity, respectively, specificity. CONCLUSIONS: qPET methodology provides semi-automatic quantification for interim FDG-PET response in lymphoma extending ordinal Deauville scoring to a continuous scale. Deauville categories correspond to certain qPET cut values. Thresholds between normal and abnormal response can be derived from the qPET-distribution without need for follow-up data. In our patients, qPET < 1.3 excludes abnormal response with high sensitivity.

Recommendations for fertility preservation in patients with lymphoma, leukemia, and breast cancer.

Fertility issues should be addressed to all patients in reproductive age before cancer treatment. In men, cryopreservation of sperm should be offered to all cancer patients in reproductive age regardless of the risk of gonadal failure. In women, the recommendation of fertility preservation should be individualized based on multiple factors such as the urgency of treatment, the age of the patient, the marital status, the regimen and dosage of cancer treatment.

External validation of nomogram for the decline in serum anti-Müllerian hormone in women: a population study of 15,834 infertility patients.

The value of anti-müllerian hormone (AMH) as a marker of the ovarian reserve is becoming clear in a range of clinical contexts.This study reports the external validation of a quadratic model-based AMH­age nomogram using a cohort of 15,834 US women. All models previously investigated for the decline in ovarian reserve (i.e. linear, bi-linear, decay curve, power and quadratic models) tended to overestimate AMH by approximately 11% versus the published nomogram, indicating some between-population heterogeneity. Bootstrapping of 1000 datasets indicated that the quadratic model provided the best fit, confirming the choice of this model in the AMH­age nomogram. This nomogram can therefore be used with confidence for the interpretation of AMH in clinical populations.

Management of relapsed and refractory classical Hodgkin lymphoma in children and adolescents.

There are a number of options for salvage treatment in children and adolescents with relapsed and refractory classical Hodgkin Lymphoma. These include salvage with standard dose chemotherapy, high dose chemotherapy with autologous stem cell transplant, allogeneic stem cell transplant or other novel approach. Radiotherapy has an important role in the salvage of some patients as part of a combined modality approach. This review outlines these salvage approaches and discusses whether the evidence from paediatric studies justifies a risk-adapted approach to salvage for individual patients or whether all patients should receive consolidation with high dose chemotherapy and autologous stem cell transplantation, which is often described as standard salvage management in adults. The important prognostic factors and how these may be used to allocate patients to standard versus high dose chemotherapy regimens are discussed. The role of allogeneic transplantation, novel agents and late effects will also be discussed.

Long-term follow-up of survivors of childhood cancer.

Today more than 75% of children treated for cancer will be cured, and attention is focusing on the late effects of treatments for these long-term survivors. Treatment-related morbidity is diverse, with potential effects on the endocrine system (growth, puberty, fertility, pituitary, thyroid and other disorders), cardiovascular, pulmonary and renal complications, second tumours, cognitive, education, neuropsychological and social manifestations. Multi-disciplinary long-term follow-up of these patients is essential to monitor, treat, and prevent morbidity. Depending on the nature of the treatment delivered, long-term follow-up of the survivor of childhood cancer can be individualised and delivered by a wide range of health professionals either in hospital or in primary care. In this review we describe the chronic health problems encountered by survivors and discuss the development of a long-term follow-up service for childhood cancer survivors.