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.

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.

The Severity of Congenital Hypothyroidism With Gland-In-Situ Predicts Molecular Yield by Targeted Next-Generation Sequencing.

INTRODUCTION: Congenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH. METHODS: Targeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. Thyroid-stimulating hormone at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded. RESULTS: NGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L. CONCLUSION: NGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L.

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.

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.

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.

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.

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.

Personalized Massive Open Online Course for Childhood Cancer Survivors: Behind the Scenes.

BACKGROUND: Today, in France, it is estimated that 1 in 850 people aged between 20 and 45 years has been treated for childhood cancer, which equals 40,000 to 50,000 people. As late effects of the cancer and its treatment affect a large number of childhood cancer survivors (CCS) and only 30% of them benefit from an efficient long-term follow-up care for prevention, early detection, and treatment of late effects, health education of CCS represents a challenge of public health. OBJECTIVES: Massive open online courses (MOOCs) are a recent innovative addition to the online learning landscape. This entertaining and practical tool could easily allow a deployment at a national level and make reliable information available for all the CCS in the country, wherever they live. METHODS: The MOOC team brings together a large range of specialists involved in the long-term follow-up care, but also associations of CCS, video producers, a communication consultant, a pedagogical designer, a cartoonist and a musician. We have designed three modules addressing transversal issues (lifestyle, importance of psychological support, risks of fertility problems) and eight modules covering organ-specific problems. Detailed data on childhood cancer treatments received were used to allocate the specific modules to each participant. RESULTS: This paper presents the design of the MOOC entitled "Childhood Cancer, Living Well, After," and how its feasibility and its impact on CCS knowledge will be measured. The MOOC about long-term follow-up after childhood cancer, divided into 11 modules, involved 130 participants in its process, and resulted in a 170-minute film. The feasibility study included 98 CCS (31 males vs. 67 females; p < 0.0001). CONCLUSION: Such personalized, free, and online courses with an online forum and a possible psychologist consultation based on unique characteristics and needs of each survivor population could improve adherence to long-term follow-up without alarming them unnecessarily.

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.

Risk Factors for Small Adult Height in Childhood Cancer Survivors.

PURPOSE: Between 10% and 20% of childhood cancer survivors (CCS) experience impaired growth, leading to small adult height (SAH). Our study aimed to quantify risk factors for SAH or growth hormone deficiency among CCS. METHODS: The French CCS Study holds data on 7,670 cancer survivors treated before 2001. We analyzed self-administered questionnaire data from 2,965 CCS with clinical, chemo/radiotherapy data from medical records. SAH was defined as an adult height ≤ 2 standard deviation scores of control values obtained from a French population health study. RESULTS: After exclusion of 189 CCS treated with growth hormone, 9.2% (254 of 2,776) had a SAH. Being young at the time of cancer treatment (relative risk [RR], 0.91 [95% CI, 0.88 to 0.95] by year of age), small height at diagnosis (≤ 2 standard deviation scores; RR, 6.74 [95% CI, 4.61 to 9.86]), pituitary irradiation (5-20 Gy: RR, 4.24 [95% CI, 1.98 to 9.06]; 20-40 Gy: RR, 10.16 [95% CI, 5.18 to 19.94]; and ≥ 40 Gy: RR, 19.48 [95% CI, 8.73 to 43.48]), having received busulfan (RR, 4.53 [95% CI, 2.10 to 9.77]), or > 300 mg/m2 of lomustine (300-600 mg/m2: RR, 4.21 [95% CI, 1.61 to 11.01] and ≥ 600 mg/m2: RR, 9.12 [95% CI, 2.75 to 30.24]) were all independent risk factors for SAH. Irradiation of ≥ 7 vertebrae (≥ 15 Gy on ≥ 90% of their volume) without pituitary irradiation increased the RR of SAH by 4.62 (95% CI, 2.77 to 7.72). If patients had also received pituitary irradiation, this increased the RR by an additional factor of 1.3 to 2.4. CONCLUSION: CCS are at a high risk of SAH. CCS treated with radiotherapy, busulfan, or lomustine should be closely monitored for growth, puberty onset, and potential pituitary deficiency.

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.

The role of irradiated heart and left ventricular volumes in heart failure occurrence after childhood cancer.

BACKGROUND: Paediatric cancer survivors have a high risk of developing cardiac diseases, and the most frequent cardiac disease is heart failure (HF). The radiation dose-volume effects in the heart and cardiac substructures have not been explored in childhood cancer survivors (CCS). Therefore, the role of irradiated heart volume in the occurrence of HF among this population remains unclear. The aims of this study were to determine the doses and irradiated volumes of the heart and left ventricle (LV) related to the risk of HF in CCS and to investigate the impact of anthracycline exposure on this risk. METHODS AND RESULTS: A case-control study nested in the French Childhood Cancer Survivors Study cohort. The mean heart and left ventricular doses and volumes indicators were estimated by reconstruction of individual treatments. A total of 239 HF cases and 1042 matched controls were included. The median age of HF diagnosis was 25.1 years. The median volume of the heart that received ≥ 30 Gy was 61.1% for cases and 16.9% for controls. In patients who did not receive anthracycline, the risk of HF was increased 3.6-fold when less than 10% of the LV received ≥ 30 Gy when compared to patients who were not exposed to any cardiac radiation and anthracycline. CONCLUSIONS: Small irradiated volumes of the heart or LV were significantly associated with HF risk. To the author's knowledge, this is the first study to report a dose-response relationship based on dose-volume indicators in CCS, which can be translated efficiently into current clinical practice.

Mitotane (op'DDD) restores growth and puberty in nine children with Cushing's disease.

To investigate whether low-dose mitotane (up to 2 g/day) could be a temporary therapeutic alternative to transsphenoidal surgery (TSS) in pediatric Cushing's disease (CD). Twenty-eight patients with CD aged 12.2 years (± 2.2) were referred to our center. We compared nine patients treated with mitotane alone for at least 6 months to 13 patients cured after surgery. Primary outcomes were changes in growth velocity, BMI and pubertal development. The following results were obtained: (1) Mitotane improved growth velocity z-scores (-3.8 (±0.3) vs -0.2 (±0.6)), BMI z-scores (2.1 (±0.5) vs 1.2 (±0.5) s.d.) and pubertal development. After 1 year on mitotane, the mean BMI z-score was not significantly different in both groups of patients. (2) Control of cortisol secretion was delayed and inconsistent with mitotane used as monotherapy. (3) Side effects were similar to those previously reported, reversible and dose dependent: unspecific digestive symptoms, concentration or memory problems, physical exhaustion, adrenal insufficiency and hepatitis. (4) In one patient, progressive growth of a pituitary adenoma was observed over 40 months of mitotane treatment, allowing selective adenomectomy by TSS. In conclusions, low-dose mitotane can restore growth velocity and pubertal development and decrease BMI in children with CD, even without optimal control of cortisol secretion. It may promote pituitary tumor growth thus facilitating second-line TSS. However, given its possibly life-threatening side effects (transient adrenal insufficiency and hepatitis), and in the absence of any reliable follow-up procedures, this therapy may be difficult to manage and should always be initiated and monitored by specialized teams.

Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the role of radiation dose received to the circle of Willis (WC) during radiation therapy (RT) and of potential dose-response modifiers on the risk of stroke after treatment of childhood cancer. METHODS: We evaluated the risk factors for stroke in a cohort of 3172 5-year survivors of childhood cancer who were followed up for a median time of 26 years. Radiation doses to the WC and brain structures were estimated for each of the 2202 children who received RT. RESULTS: Fifty-four patients experienced a confirmed stroke; 39 were ischemic. Patients not receiving RT had a stroke risk similar to that of the general population, whereas those who received RT had an 8.5-fold increased risk (95% confidence interval [CI]: 6.3-11.0). The excess of incidence of stroke increased yearly. The dose of radiation to the WC, rather than to other brain structures, was found to be the best predictor of stroke. The relative risk was 15.7 (95% CI: 4.9-50.2) for doses of 40 Gy or more. At 45 years of age, the cumulative stroke incidence was 11.3% (95% CI: 7.1%-17.7%) in patients who received 10 Gy or more to the WC, compared with 1% expected from general population data. Radiation doses received to the heart and neck also increased the risk. Surgery for childhood brain cancer was linked to hemorrhagic strokes in these patients. CONCLUSION: The WC should be considered as a major organ at risk during RT for childhood brain cancers. The incidence of radiation-induced ischemic stroke strongly increases with long-term follow-up.

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.