Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome.

We previously molecularly and clinically characterized Mazzanti syndrome, a RASopathy related to Noonan syndrome that is mostly caused by a single recurrent missense variant (c.4A > G, p.Ser2Gly) in SHOC2, which encodes a leucine-rich repeat-containing protein facilitating signal flow through the RAS-mitogen-associated protein kinase (MAPK) pathway. We also documented that the pathogenic p.Ser2Gly substitution causes upregulation of MAPK signaling and constitutive targeting of SHOC2 to the plasma membrane due to the introduction of an N-myristoylation recognition motif. The almost invariant occurrence of the pathogenic c.4A > G missense change in SHOC2 is mirrored by a relatively homogeneous clinical phenotype of Mazzanti syndrome. Here, we provide new data on the clinical spectrum and molecular diversity of this disorder and functionally characterize new pathogenic variants. The clinical phenotype of six unrelated individuals carrying novel disease-causing SHOC2 variants is delineated, and public and newly collected clinical data are utilized to profile the disorder. In silico, in vitro and in vivo characterization of the newly identified variants provides evidence that the consequences of these missense changes on SHOC2 functional behavior differ from what had been observed for the canonical p.Ser2Gly change but converge toward an enhanced activation of the RAS-MAPK pathway. Our findings expand the molecular spectrum of pathogenic SHOC2 variants, provide a more accurate picture of the phenotypic expression associated with variants in this gene and definitively establish a gain-of-function behavior as the mechanism of disease.

Adrenocortical tumours in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Adrenocortical tumours (ACTs) are rare during childhood. A complete surgical resection provides the best chance of cure, but the role and efficacy of the adjuvant therapy are still controversial. Various histologic criteria of malignancy for ACTs adopted in children do not facilitate comparative studies and are not completely shared. Therefore, a sharp demarcation between benign and malignant lesions has not been recognised, making it difficult to identify who potentially needs perioperative therapy. This manuscript presents the internationally harmonised recommendations for the diagnosis and treatment of ACTs in children and adolescents, established by the European Cooperative Study Group for Paediatric Rare Tumours (EXPeRT) group within the EU-funded project PARTNER (Paediatric Rare Tumours Network - European Registry).

An eHealth Framework for Managing Pediatric Growth Disorders and Growth Hormone Therapy.

BACKGROUND: The use of technology to support health and health care has grown rapidly in the last decade across all ages and medical specialties. Newly developed eHealth tools are being implemented in long-term management of growth failure in children, a low prevalence pediatric endocrine disorder. OBJECTIVE: Our objective was to create a framework that can guide future implementation and research on the use of eHealth tools to support patients with growth disorders who require growth hormone therapy. METHODS: A total of 12 pediatric endocrinologists with experience in eHealth, from a wide geographical distribution, participated in a series of online discussions. We summarized the discussions of 3 workshops, conducted during 2020, on the use of eHealth in the management of growth disorders, which were structured to provide insights on existing challenges, opportunities, and solutions for the implementation of eHealth tools across the patient journey, from referral to the end of pediatric therapy. RESULTS: A total of 815 responses were collected from 2 questionnaire-based activities covering referral and diagnosis of growth disorders, and subsequent growth hormone therapy stages of the patient pathway, relating to physicians, nurses, and patients, parents, or caregivers. We mapped the feedback from those discussions into a framework that we developed as a guide to integration of eHealth tools across the patient journey. Responses focused on improved clinical management, such as growth monitoring and automation of referral for early detection of growth disorders, which could trigger rapid evaluation and diagnosis. Patient support included the use of eHealth for enhanced patient and caregiver communication, better access to educational opportunities, and enhanced medical and psychological support during growth hormone therapy management. Given the potential availability of patient data from connected devices, artificial intelligence can be used to predict adherence and personalize patient support. Providing evidence to demonstrate the value and utility of eHealth tools will ensure that these tools are widely accepted, trusted, and used in clinical practice, but implementation issues (eg, adaptation to specific clinical settings) must be addressed. CONCLUSIONS: The use of eHealth in growth hormone therapy has major potential to improve the management of growth disorders along the patient journey. Combining objective clinical information and patient adherence data is vital in supporting decision-making and the development of new eHealth tools. Involvement of clinicians and patients in the process of integrating such technologies into clinical practice is essential for implementation and developing evidence that eHealth tools can provide value across the patient pathway.

Exploring heterogeneity of adrenal cortical tumors in children: The French pediatric rare tumor group (Fracture) experience.

INTRODUCTION: Pediatric adrenal cortical tumors are characterized by a wide spectrum of behavior. Questions remain regarding intermediate disease stages with isolated tumor rupture or relapse. OBJECTIVES: To describe clinical characteristics, treatment strategy, and outcome of patients depending on disease stage, tumor rupture, or in case of a refractory tumor, to discuss optimal management. MATERIAL AND METHODS: Pediatric patients with histological material reviewed and treated between 2000 and 2018 in 23 French oncology centers were included. RESULTS: Among 95 cases, 59% of patients had stage I tumors (n = 55), 16% had stage II tumors (n = 16), 19% had stage III tumors (n = 17), and 5% had stage IV tumors (n = 5) (missing data: 2). Overall, 27% of patients (n = 25) had an unfavorable histology. Initial tumor resection was performed for 90% of patients (n = 86). Systemic therapies included mitotane in 20 cases and chemotherapy in 13 cases. Among 17 stage III patients, 12 had microscopic residual tumor due to an initial biopsy (n = 5), intraoperative rupture (n = 8), or surgical resection with microscopic residue or tumor spillage surgery (n = 1) (two patients with two modalities). After a median follow-up of 96 months (25-119), four early progressions and two relapses occurred. A total of seven patients died, including five of disease. Stage III diseases due to microscopic residual disease correlated with a worse prognosis: 5-year progression-free survival 44% (95% CI, 22-87%) versus 82% (95% CI, 73-91%) for the whole cohort (P < .0001). Among the 14 patients with refractory disease, only 3 were alive and free of disease after multimodal second-line therapy. CONCLUSIONS: Stage III diseases due to a microscopic residual tumor have a dismal prognosis, arguing for the systematic use of adjuvant therapy. Patients with a relapsed disease should be included in experimental studies.

Revisiting the role of the pathological grading in pediatric adrenal cortical tumors: results from a national cohort study with pathological review.

The prognosis of malignant pediatric adrenocortical tumors is closely related to disease stage, which is used to guide perioperative treatment recommendations. However, current scoring systems are inadequate to distinguish between benign and malignant adrenocortical tumors. Robust microscopic prognostic features that could help determine perioperative therapy are also lacking. The aim of this national study was to review the prognostic value of the Wieneke scoring criteria and Ki67 labeling index in unselected pediatric adrenocortical tumors. Using strict definitions previously defined by expert pathologists, a Wieneke score was re-attributed to each tumor after an independent and centralized review. In addition, Ki67 proliferation index was performed and reviewed for each case. A total of 95 cases were selected; all were treated between 2000 and 2018 and had histopathologic material and sufficient outcome-related information available. Localized disease was found in 88% of patients. Among those with advanced disease, 6% had tumor extension into adjacent organs and 5% had metastases at diagnosis. Median follow-up was 5 years and 3 months. The 5-year PFS was 82%, 95% CI [73%-91%]. Tumor stage significantly correlated with PFS (p < 0.0001). Tumor weight up to 200 g, extra-adrenal extension and initial non-complete surgical resection were statistically associated with worse outcomes. No recurrences nor metastases occurred when the Ki67 index was < 15%. Up to two of the following five factors including tumor necrosis, adrenal capsular invasion, venous invasion, mitotic count > 15/20 high-power fields, and Ki67 index > 15%, significantly correlated with worse outcomes. We propose a pathological scoring system incorporating the Ki67 index as part of a two-step approach after disease staging to guide adjuvant treatment in pediatric adrenocortical tumors, especially after incomplete resection. These results should be validated in an independent cohort.

Report of two novel mutations in PTHLH associated with brachydactyly type E and literature review.

Autosomal-dominant brachydactyly type E is a congenital limb malformation characterized by small hands and feet as a result of shortened metacarpals and metatarsals. Alterations that predict haploinsufficiency of PTHLH, the gene coding for parathyroid hormone related protein (PTHrP), have been identified as a cause of this disorder in seven families. Here, we report three patients affected with brachydactyly type E, caused by PTHLH mutations expected to result in haploinsufficiency, and discuss our data compared to published reports.

Ovarian reserve after treatment with alkylating agents during childhood.

STUDY QUESTION: What is the effect of different alkylating agents used without pelvic radiation to treat childhood cancer in girls on the ovarian reserve in survivors? SUMMARY ANSWER: Ovarian reserve seems to be particularly reduced in survivors who received procarbazine (in most cases for Hodgkin lymphoma) or high-dose chemotherapy; procarbazine but not cyclophosphamide dose is associated with diminished ovarian reserve. WHAT IS KNOWN ALREADY: A few studies have demonstrated diminished ovarian reserve in survivors after various combination therapies, but the individual role of each treatment is difficult to assess. STUDY DESIGN: Prospective cross-sectional study, involving 105 survivors and 20 controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: One hundred and five survivors aged 17-40 years and 20 controls investigated on Days 2-5 of a menstrual cycle or Day 7 of an oral contraceptive pill-free interval. MAIN OUTCOME MEASURES: ovarian surface area (OS), total number of antral follicles (AFC), serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol and anti-Müllerian hormone (AMH). MAIN RESULTS AND THE ROLE OF CHANCE: Survivors had a lower OS than controls: 3.5 versus 4.4 cm(2) per ovary (P = 0.0004), and lower AMH levels: 10.7 versus 22 pmol/l (P = 0.003). Ovarian markers (OS, AMH, AFC) were worse in patients who received high-dose compared with conventional-dose alkylating agents (P = 0.01 for OS, P = 0.002 for AMH, P < 0.0001 for AFC). Hodgkin lymphoma survivors seemed to have a greater reduction in ovarian reserve than survivors of leukaemia (P = 0.04 for AMH, P = 0.01 for AFC), sarcoma (P = 0.04 for AMH, P = 0.04 for AFC) and other lymphomas (P = 0.04 for AFC). A multiple linear regression analysis showed that procarbazine but not cyclophosphamide nor ifosfamide dose was associated with reduced OS (P = 0.0003), AFC (P = 0.0007), AMH (P < 0.0001) and higher FSH levels (P < 0.0001). LIMITATIONS, REASONS FOR CAUTION: The small percentage of participating survivors (28%) from the total cohort does not allow conclusion on fertility issues because of possible response bias. The association between procarbazine and HL makes it impossible to dissociate their individual impacts on ovarian reserve. The number of controls is small, but ovarian volume and AMH levels in survivors were compared with published normal values and results were unchanged. WIDER IMPLICATIONS OF THE FINDINGS: Early detection and follow-up of compromised ovarian function after cancer therapy should help physicians to counsel young survivors about their fertility window. However, longitudinal follow-up is required to determine the rate of progression from low ovarian reserve to premature ovarian failure. STUDY FUNDING/COMPETING INTERESTS: La Ligue contre le Cancer (grant no., PRAYN7497). The authors have no competing interests to disclose.

Dose-Effect Relationship of Alkylating Agents on Testicular Function in Male Survivors of Childhood Lymphoma.

The purpose of our study was to assess the gonadal function in male survivors of childhood lymphoma. We studied 171 male survivors of childhood lymphoma (83 with B-cell non-Hodgkin lymphoma [B-NHL], 32 with T-cell non-Hodgkin lymphoma [T-NHL], 50 with Hodgkin lymphoma [HL], and 6 with anaplastic large-cell lymphoma [ALCL]), measuring follicle-stimulating hormone [FSH] and luteinizing hormone [LH] levels at a median age of 21.1 (17-30.4) years after a median delay of 9.3 (2-22.4) years from treatment. FSH levels were above normal range (≥10 IU/L) in 42.1% and LH levels ≥8 IU/L in only 8.9% of survivors. In multivariate analysis, only the following chemotherapeutic agents were associated with higher FSH or LH levels: cyclophosphamide (P < .0001, .04), lomustine (CCNU; P = .002, 0.04), and procarbazine (P < .0001, .07). No significant correlation was found between FSH or LH levels and age or pubertal status at diagnosis. Mean FSH level was significantly lower in NHL survivors treated more recently: 6 ± 5.1 IU/L in B-NHL survivors treated since 1986 versus 12.3 ± 5.4 IU/L for those treated before 1981 (P = .0001), and 6.8 ± 9.6 IU/L in T-NHL survivors treated since 1989 versus 9.4 ± 5.7 IU/L for those treated before 1989 (P = .035). In HL, mean FSH level was 12.4 ± 9.9 IU/L following procarbazine containing chemotherapy versus 3.4 ± 1.9 IU/L in the absence of procarbazine and increased significantly with the number of MOPP/OPPA (mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone/Oncovin, procarbazine, and prednisone, and Adriamycin [doxorubicin]) courses received, from 6.8 ± 5.7 IU/L for 1-2 MOPP/OPPA to 12.6 ± 7.5 for 3-4 MOPP/OPPA and 19.6 ± 13.3 for more than 4 MOPP/OPPA (P for trend = .006). Testicular toxicity of alkylating agents on childhood lymphoma survivors is dose dependent and not correlated to diagnosis, age, or pubertal status at diagnosis.

Diagnosis and management of congenital hypopituitarism in children.

Hypopituitarism (or pituitary deficiency) is a rare disease with an estimated prevalence of between 1/16,000 and 1/26,000 individuals, defined by insufficient production of one or several anterior pituitary hormones (growth hormone [GH], thyroid-stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], prolactin), in association or not with diabetes insipidus (antidiuretic hormone [ADH] deficiency). While in adults hypopituitarism is mostly an acquired disease (tumors, irradiation), in children it is most often a congenital condition, due to abnormal pituitary development. Clinical symptoms vary considerably from isolated to combined deficiencies and between syndromic and non-syndromic forms. Early signs are non-specific but should not be overlooked. Diagnosis is based on a combination of clinical, laboratory (testing of all hormonal axes), imaging (brain magnetic resonance imaging [MRI] with thin slices centered on the hypothalamic-pituitary region), and genetic (next-generation sequencing of genes involved in pituitary development, array-based comparative genomic hybridization, and/or genomic analysis) findings. Early brain MRI is crucial in neonates or in cases of severe hormone deficiency for differential diagnosis and to inform syndrome workup. This article presents recommendations for hormone replacement therapy for each of the respective deficient axes. Lifelong follow-up with an endocrinologist is required, including in adulthood, with multidisciplinary management for patients with syndromic forms or comorbidities. Treatment objectives include alleviating symptoms, preventing comorbidities and acute complications, and optimal social and educational integration.

Diagnosis and management of children and adult craniopharyngiomas: a French Endocrine Society/French Society for Paediatric Endocrinology & Diabetes Consensus Statement.

Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up.

Age at menopause and its influencing factors in a cohort of survivors of childhood cancer: earlier but rarely premature.

STUDY QUESTION: Is the age at menopause in a cohort of childhood cancer survivors earlier and what are the risk factors associated with earlier age at menopause? SUMMARY ANSWER: Menopause occurred at a median age of 44 years in this cohort which is earlier than in the general population, but premature menopause was uncommon. Main risk factors for non-surgical menopause were exposure to and dose of alkylating agents, especially during adolescence, radiation dose to the ovaries and oophorectomy. WHAT IS KNOWN ALREADY: While survivors of childhood cancer are known to be at increased risk for developing premature menopause, data on its risk factors are limited. STUDY DESIGN: A cohort study of 1109 still-living female survivors of childhood solid cancer treated between 1945 and 1985, of whom 863 (78%) returned a follow-up questionnaire. Of them, 157 were excluded. PARTICIPANTS AND METHODS: Seven hundred and six women, among whom 32% have attained 40 years of age, were included in this study. A Cox regression model was used to determine risk factors influencing the age at menopause. MAIN RESULTS: Ninety seven women have reached menopause at a median age of 44 years. Menopause has been surgically induced in 36% of women. In multivariate analysis, risk factors for non-surgical menopause included exposure to alkylating agents, increasing radiation dose to the ovaries, procarbazine dose, cyclophosphamide dose and unilateral oophorectomy. The highest risk ratio for non-surgical menopause was observed for women treated after the onset of puberty with alkylating agents, either alone (RR = 9, 95% CI: 2.7-28, P = 0.0003) or associated with even a low dose of radiation to the ovaries (RR = 29, 95% CI: 8-108, P < 0.0001). Exposure to unilateral oophorectomy is associated with a 7-year earlier age at menopause. By the age of 40, only 2.1% had non-surgical premature menopause and its main risk factors were age at diagnosis, cyclophosphamide dose, exposure to melphalan and radiation dose to the ovaries. LIMITATIONS: The information on menopause was based on self-reported data without confirmation by FSH levels. Participants to this study have been treated for cancer from 1945 to 1985 and one can expect an increase in premature menopause incidence with more recent protocols using high-dose alkylating agents. WIDER IMPLICATIONS OF THE FINDINGS: This study provides data on risk factors for a reduced fertility window in order to inform survivors at risk and help oncologists to design new therapeutic protocols avoiding this risk. This study does not confirm the high rate of premature menopause reported by the Childhood Cancer Survivor Study, but this population differs from theirs (no leukemia and a lower percentage of lymphoma).

Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study.

BACKGROUND: Children and young adults treated with total body or abdominal radiotherapy have an increased risk of insulin resistance and diabetes mellitus. However, little is known of the effect of pancreas irradiation on the risk of diabetes. We assessed the relation between radiation exposure and occurrence of diabetes in a large cohort of long-term childhood cancer survivors. METHODS: We sent a questionnaire to 3468 survivors of a childhood cancer treated in eight centres in France and the UK between 1946 and 1985, of which 2520 were returned. Each self-declaration of diabetes was confirmed by contacting the patients' medical doctors. We estimated the radiation dose received by the tail, head, and body of the pancreas and 185 other anatomical sites during each course of radiotherapy from 1990 to 1995 for each child after reconstruction of the conditions in which irradiation was delivered. We investigated the relation between radiation dose to the pancreas and the risk of a subsequent diabetes diagnosis. FINDINGS: 65 cases of diabetes were validated. The risk of diabetes increased strongly with radiation dose to the tail of the pancreas, where the islets of Langerhans are concentrated, up to 20-29 Gy and then reached a plateau for higher radiation doses. The estimated relative risk at 1 Gy was 1·61 (95% CI 1·21-2·68). The radiation dose to the other parts of the pancreas did not have a significant effect. Compared with patients who did not receive radiotherapy, the relative risk of diabetes was 11·5 (95% CI 3·9-34·0) in patients who received 10 Gy or more to the tail of the pancreas. Results were unchanged after adjustment for body-mass index, despite its strong independent effect (p<0·0001), and were similar between men and women. Children younger than 2 years at time of radiotherapy were more sensitive to radiation than were older patients (relative risk at 1 Gy 2·1 [95% CI 1·4-4·3] vs 1·4 [95% CI 1·1-2·2] in older patients; p=0·02 for the difference). For the 511 patients who had received more than 10 Gy to the tail of the pancreas, the cumulative incidence of diabetes was 16% (95% CI 11-24). INTERPRETATION: Our study provides evidence of a dose-response relation between radiation exposure of pancreas and subsequent risk of diabetes. Because of the risks observed and the frequency of diabetes in general population, this finding raises important public health issues. The pancreas needs to be regarded as a critical organ when planning radiation therapy, particularly in children. Follow-up of patients who received abdominal irradiation should include diabetes screening.

Risk factors for obesity in adulthood among survivors of childhood cancer.

OBJECTIVE: The aim of this study was to identify risk factors for obesity in childhood cancer survivors (CCSs). METHODS: The study included 3199 patients of the French Childhood Cancer Survivor Study cohort, with 303 patients with obesity who had returned the self-questionnaire. Analyses were adjusted for social deprivation index and sex. RESULTS: CCSs were less likely to have obesity (9.5%; 95% CI: 8.5%-10.5%) than expected from the general French population rates (12.5%; p = 0.0001). Nevertheless, brain tumor survivors were significantly more likely to develop obesity than the general French population (p = 0.0001). Compared with patients who did not receive radiotherapy to the pituitary gland, those who received a dose >5 Gy had an increased risk of obesity: relative risk 1.9 (95% CI: 1.2-3.1), 2.5 (95% CI: 1.7-3.7), and 2.6 (95% CI: 1.6-4.3), respectively, for participants with 6 to 20 Gy, 20 to 40 Gy, and ≥40 Gy of radiation. Etoposide administration significantly increased the risk of obesity (relative risk 1.7; 95% CI: 1.1-2.6). High social deprivation index was also a risk factor, just like BMI at diagnosis. CONCLUSIONS: Long-term follow-up of CCSs should include weight follow-up during adulthood.

Relationship between the brain radiation dose for the treatment of childhood cancer and the risk of long-term cerebrovascular mortality.

To date, very little is known about the long-term risk of death from cerebrovascular sequelae following childhood cancer treatment. The purpose of this study was to assess the role of treatment in very long-term cerebrovascular mortality following childhood cancer. We studied 4227 5-year survivors of a childhood cancer. Information on chemotherapy was collected and the radiation dose delivered to 11 anatomical sites in the brain was estimated. The main outcome that was considered was death due to cerebrovascular disease occurring before 1 January 2008. After a median follow-up of 29 years, 23 deaths due to cerebrovascular diseases had occurred. In the brain, the radiation dose delivered to the prepontine cistern seemed to play a greater role than the average radiation dose received throughout the brain or the dose to any other specific anatomical site in the brain. The risk of death from cerebrovascular disease increased linearly with the local radiation dose to the prepontine cistern. Each unit of absorbed radiation (Gray) delivered to this area increased the risk by 22% (95% confidence interval: 1-44%). Compared with patients who had not received radiotherapy or who had received <0.1 Gray in the prepontine cistern area, those who had received >50 Gray had a 17.8-fold (4.4-73.0) higher hazard ratio of death from cerebrovascular disease. In conclusion, among 5-year survivors of childhood cancer, the radiation dose to the brain during radiotherapy was significantly associated with long-term cerebrovascular mortality.

Health care expenditures among long-term survivors of pediatric solid tumors: Results from the French Childhood Cancer Survivor Study (FCCSS) and the French network of cancer registries (FRANCIM).

BACKGROUND: Childhood cancer survivors (CCS) may require lifelong medical care due to late effects of cancer treatments. Little is known about of their healthcare utilization and expenditures at long-term especially in publicly funded health care system. We aim to estimate and describe the health care expenditures among long-term CCS in France. METHODS: A total of 5319 five-year solid CCS diagnosed before the age of 21 between 1945 and 2000 in France were identified in the French Childhood Cancer Survivors Study cohort (FCCSS) and the French cancer registry. Information about health care expenditure was taken from the French national health data system between 2011 and 2016, and was described according to survivors' characteristics. Generalized linear models were used to determine associations between health care expenditures and survivors' characteristics. RESULTS: Mean annual amount of healthcare expenditures was € 4,255. Expenditures on hospitalizations and pharmacy represents 60% of total expenditures. Mean annual of healthcare expenditures were higher at increasing age, among women survivors (€ 4,795 vs € 3,814 in men) and in central nervous system (CNS) tumor survivors (€ 7,116 vs € 3,366 in lymphoma and € 3,363 in other solid tumor survivors). CONCLUSIONS: Childhood cancer survivorship is associated with a substantial economic burden in France. We found that female gender and CNS primary cancer were associated with increased healthcare expenditures.

Long-term hospitalisations in survivors of paediatric solid tumours in France.

The late effects of treatments for childhood cancers may lead to severe and multiple health conditions requiring hospitalisation. We aimed to estimate the hospitalisation rate among childhood cancer survivors (CCS) in France, to compare them with the general population and to investigate the associated factors. We matched total of 5439 5-year solid CCS diagnosed before the age of 21 between 1945 and 2000 by sex, birth year and region of residence to 386,073 individuals of the French general population. After linkage with the national hospital discharge database, we estimated the relative hospitalisation rate (RHR), the absolute excess risks (AERs) and the relative bed-day ratio (RBDR) during 2006-2018. We used generalised linear models to estimate associations between hospitalisation and survivor characteristics. Overall, the RHR was 2.49 (95% confidence interval [CI] 2.46-2.52) and the RBDR was 3.49 (95% CI 3.46-3.51). We found that neoplasm-related hospitalisations had the highest AER (105.8 per 1000 person-years), followed by genitourinary system diseases (34.4 per 1000 person-years) and cardiovascular diseases (19.2 per 1000 person-years). In adjusted analysis, CCS treated with chemotherapy (risk ratio [RR] 1.62, 95% CI 1.53-1.70), radiotherapy (RR 2.11, 95% CI 1.99-2.24) or both (RR 2.59, 95% CI 2.46-2.73) had a higher risk of hospitalisation than the ones who had not received any of these treatments. CCS treated during the past decades by chemotherapy and/or radiotherapy now had a higher hospitalisation risk for all main categories of diagnosis than the general population. Prevention strategies and medical surveillance programmes may promote a long-term decrease in the hospitalisation rate among CSS.

Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors.

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

Determinants of Final Height in Patients Born Small for Gestational Age Treated with Recombinant Growth Hormone.

INTRODUCTION: About 8% of children born small for gestational age (SGA) do not reach a final height within the normal range. Recombinant human growth hormone (rhGH) has been shown to be effective in increasing the final height in children born SGA. Our objective was to identify predictive factors of final height in children born SGA treated with rhGH. MATERIALS AND METHODS: In this retrospective study, conducted in a tertiary pediatric endocrinology referral center, we recruited all patients born SGA (defined as birth length or weight <10th percentile) treated with rhGH for more than 12 months for whom final height data were available. Some patients had received gonadotropin-releasing hormone (GnRH) analog therapy. RESULTS: We included 252 patients with an average birth length of -2.0 ± 0.7 SD and birth weight of -1.7 ± 1.0 SD. After 4.6 ± 2.8 years of rhGH treatment, their height increased from -2.2 ± 0.9 SD to -1.5 ± 0.9 SD. In multivariate analysis, we identified 8 factors that predict 46% of the final height, namely, cause of SGA (p < 0.0001), GnRH analog therapy >2 years (p = 0.006), birth length (p < 0.02), height at the start of rhGH (p < 0.0001), IGF-1 level at the start of rhGH (p = 0.0002), growth velocity during the 1st year of treatment (p = 0.0002), and age and height at the onset of puberty (p < 0.0001, p = 0.0007, respectively). CONCLUSION: In this large cohort of SGA patients who had reached their final height, we were able to confirm that growth hormone increases final height in short SGA children. In addition, we identified several factors associated with a better response to growth hormone treatment.

Risk Factors of Subsequent Central Nervous System Tumors after Childhood and Adolescent Cancers: Findings from the French Childhood Cancer Survivor Study.

BACKGROUND: Childhood or adolescent cancer survivors are at increased risks of subsequent primary neoplasms (SPN) of the central nervous system (CNS) after cranial irradiation. In a large multicentric cohort, we investigated clinical and therapeutic factors associated with the long-term risk of CNS SPN, and quantified the dose-response relationships. METHODS: We selected all CNS SPN cases diagnosed up to 2016 among members of the French Childhood Cancer Survivor Study at least 5 years after first cancer diagnosis in 1946-2000. Four controls per case were randomly selected within the cohort and matched by sex, year of/age at first cancer diagnosis, and follow-up time. On the basis of medical and radiological reports, cumulative radiation doses received to the SPN or matched location were retrospectively estimated using mathematical phantoms. We computed conditional logistic regression models. RESULTS: Meningioma risk significantly increased with higher radiation doses [excess OR per Gy (EOR/Gy) = 1.377; P < 0.001; 86 cases; median latency time = 30 years], after adjustment for reported genetic syndromes and first CNS tumor. It was higher among youngest individuals at first cancer diagnosis, but did not vary with follow-up time. On the opposite, radiation-related glioma risk (EOR/Gy = 0.049; P = 0.11; 47 cases; median latency time = 17 years) decreased over time (P for time effect = 0.05). There was a significant association between meningioma risk and cumulative doses of alkylating agents, but no association with growth hormone therapy. CONCLUSIONS: The surveillance of patients with cranial irradiation should continue beyond 30 years after treatment. IMPACT: The identified risk factors may inform long-term surveillance strategies.

Influence of growth hormone therapy on the occurrence of a second neoplasm in survivors of childhood cancer.

CONTEXT: Growth hormone (GH) deficiency is a common late effect of cranial irradiation. However, concerns have been raised that GH treatment might lead to an increased risk of a second neoplasm (SN). OBJECTIVE: To study the impact of GH treatment on the risk of SN in a French cohort of survivors of childhood cancer (CCS) treated before 1986. DESIGN AND SETTING: Cohort study and nested case-control study. PARTICIPANTS: Of the 2852 survivors, with a median follow-up of 26 years, 196 had received GH therapy (median delay from cancer diagnosis: 5.5 years). MAIN OUTCOME MEASURES: Occurrence of SN. RESULTS: In total, 374 survivors developed a SN, including 40 who had received GH therapy. In a multivariate analysis, GH treatment did not increase the risk of secondary non-meningioma brain tumors (RR: 0.6, 95% CI: 0.2-1.5, P = 0.3), secondary non-brain cancer (RR: 0.7, 95% CI: 0.4-1.2, P = 0.2), or meningioma (RR: 1.9, 95% CI: 0.9-4, P = 0.09). Nevertheless, we observed a slight non-significant increase in the risk of meningioma with GH duration: 1.6-fold (95% CI: 1.2-3.0) after an exposure of less than 4 years vs 2.3-fold (95% CI: 0.9-5.6) after a longer exposure (P for trend = 0.07) confirmed by the results of a case-control study. CONCLUSION: This study confirms the overall safety of GH use in survivors of childhood cancer, which does not increase the risk of a SN. The slight excess in the risk of meningioma in patients with long-term GH treatment is non-significant and could be due to difficulties in adjustment on cranial radiation volume/dose and/or undiagnosed meningioma predisposing conditions.