Pediatric Sertoli-Leydig Cell Tumors of the Ovary: An Integrated Study of Clinicopathological Features, Pan-cancer-Targeted Next-generation Sequencing and Chromosomal Microarray Analysis From a Single Institution.

Sertoli-Leydig cell tumors (SLCTs) are currently classified into 3 molecular subtypes: DICER1 -mutant (younger patient age), FOXL2 -mutant, and DICER1/FOXL2 -wildtype. However, it is not clear whether all pediatric SLCTs are DICER1 -mutant molecular subtypes and whether other molecular genetic aberrations besides DICER1 are involved in the pathogenesis and prognosis of these tumors. We studied comprehensive data for 8 cases of pediatric SLCTs, including clinicopathological features, pan-cancer-targeted next-generation sequencing/OncoKids panel, and chromosomal microarray analysis, to further analyze the correlation among clinicopathological features, molecular genetic aberrations, and prognosis. The ages of the patients ranged from 4 to 16 years (median, 14 y). Seven cases were moderately differentiated, and one was poorly differentiated with heterologous mesenchymal elements. Two cases had heterologous epithelium or retiform elements. Follow-up was available for all 8 patients (median, 49.5 mo). Seven patients were alive without evidence of recurrence or metastasis, and only case 5 developed metastases (synchronous bilateral pulmonary tumors with rhabdomyosarcomatous differentiation). All 8 tumors were found to harbor somatic hotspot DICER1 mutations, and 5 patients carried germline DICER1 mutations (2 of them had the phenotype of DICER1 syndrome). Together with recent studies, the DICER1 mutation frequency is 100% in pediatric SLCTs (n=27, age≤16 y). Copy number alterations were detected in 3 tumors; the only recurrent copy number alterations was the gain of whole chromosome 6 in case 5 and case 8. This is the first report describing clinicopathological features and molecular alterations in pediatric SLCTs. Our results demonstrate that all pediatric SLCTs belong to the DICER1 -mutant molecular subtype, highlighting that somatic hotspot DICER1 mutation detection has high sensitivity (100%) for the auxiliary diagnosis of pediatric SLCTs (age ≤16 y). Some pediatric SLCTs harbor molecular genetic aberrations other than DICER1 mutation, and their significance needs further study.

Cushing Syndrome in Childhood.

We describe a 15-year-old boy who presented with low back pain due to vertebral compression fractures, growth deceleration, excessive weight gain, rounded facies, dorsocervical fat pad, and hypertension. He was diagnosed as having Cushing syndrome (CS) due to primary pigmented nodular adrenocortical disease resulting in excess cortisol produced by the adrenal glands, leading to disruption of the hypothalamic-pituitary-adrenal axis. The most common cause of CS is exogenous glucocorticoids, with endogenous causes being extremely rare, often leading to delay in diagnosis or misdiagnosis. Herein, we review clinical presentation, screening for hypercortisolism, and decision-making in the diagnosis of CS, as well as therapeutic approaches. The wide range of clinical presentations in pediatric CS and the rarity of the condition can lead to difficulty in the recognition, diagnosis, and subsequent management of these patients. CS can be difficult to differentiate from more common exogenous obesity, and outpatient screening of cortisol excess is challenging. Early recognition and treatment of CS is necessary to avoid multisystemic complications, and patients with suspected endogenous CS should be referred to a tertiary care center with experienced pediatric endocrinology and surgery specialists. Further confirmatory diagnostic tests are necessary to distinguish corticotropin-independent from corticotropin-dependent forms of CS, including a high-dose dexamethasone suppression test, a corticotropin-releasing hormone stimulation test, and imaging. There can be challenges to the evaluation of CS, including complex inpatient testing and difficulty with localization on imaging. Long-term sequelae of CS, including adrenal insufficiency, obesity, hypertension, and mental health disorders, may remain despite definitive surgical treatment, meriting close follow-up with the primary care clinician and subspecialists.

Outcomes of multi-gestational pregnancies affected by esophageal atresia - tracheoesophageal fistula.

BACKGROUND: Contemporary outcomes of infants with esophageal atresia with or without tracheoesophageal fistula (EA/TEF) from multi-gestational pregnancies compared to those of singleton pregnancies have not been reported. METHODS: A single-center retrospective review of EA/TEF patients born from 1999 to 2013 was performed. Patient demographics, gestational age (GA), birth weight, associated anomalies, requirement for gastrostomy tube and mortality were reviewed. RESULTS: Singleton EA/TEF patients outnumbered those from multi-gestational pregnancies nearly 10:1 (214 vs 22 patients). EA/TEF patients from multi-gestational pregnancies were more likely to be premature (77% vs. 32%), have lower birth weight (mean 1766 g vs. 2695 g), have associated duodenal atresia (18% vs. 6%) and require gastrostomy tube (41% vs. 33%) for feeding challenges compared to EA/TEF singletons. Mortality was also significantly greater for multi-gestational EA/TEF patients compared to singleton EA/TEF patients (18% vs. 6%). CONCLUSION: EA/TEF infants from multi-gestational pregnancies have greater clinical complexity and mortality than singleton EA/TEF patients. Parents of EA/TEF multi-gestational infants should be appropriately counseled and supported.

Surgical intervention in pediatric trauma at a level 1 trauma hospital: a retrospective cohort study and report of cost data.

BACKGROUND: Given that the management of severely injured children requires coordinated care provided by multiple pediatric surgical subspecialties, we sought to describe the frequency and associated costs of surgical intervention among pediatric trauma patients admitted to a level 1 trauma centre in southwestern Ontario. METHODS: All pediatric (age < 18 yr) trauma patients treated at the Children's Hospital - London Health Sciences Centre (CH-LHSC) between 2002 and 2013 were included in this study. We compared patients undergoing surgical intervention with a nonsurgical group with respect to demographic characteristics and outcomes. Hospital-associated costs were calculated only for the surgical group. RESULTS: Of 784 injured children, 258 (33%) required surgery, 40% of whom underwent orthopedic interventions. These patients were older and more severely injured, and they had longer lengths of stay than their nonsurgical counterparts. There was no difference in mortality between the groups. Seventy-four surgical patients required intervention within 4 hours of admission; 45% of them required neurosurgical intervention. The median cost of hospitalization was $27 571 for the surgical group. CONCLUSION: One-third of pediatric trauma patients required surgical intervention, of whom one-third required intervention within 4 hours of arrival. Despite the associated costs, the surgical treatment of children was associated with comparable mortality to nonsurgical treatment of less severely injured patients. This study represents the most recent update to the per patient cost for surgically treated pediatric trauma patients in Ontario, Canada, and helps to highlight the multispecialty care needed for the management of injured children.

CONTEXTE: La prise en charge des enfants grièvement blessés nécessite la coordination des soins fournis dans le contexte de plusieurs surspécialités chirurgicales pédiatriques. Dans ce contexte, nous avons cherché à décrire la fréquence et les coûts des interventions chirurgicales chez les patients pédiatriques victimes de trauma admis dans un centre de traumatologie de niveau 1 dans le sud-ouest de l'Ontario. MÉTHODES: Tous les patients pédiatriques (moins de 18 ans) ayant subi un trauma traités à l'Hôpital pour enfants du Centre des sciences de la santé de London entre 2002 et 2013 ont été retenus pour l'étude. Nous avons comparé les caractéristiques démographiques et les résultats cliniques des patients ayant subi une intervention chirurgicale et de ceux n'en ayant pas subi. Les coûts d'hospitalisation n'ont été calculés que pour le premier groupe. RÉSULTATS: Parmi les 784 enfants à l'étude, 258 (33 %) avaient eu besoin d'une intervention chirurgicale; 40 % de ceux-ci avaient subi des interventions orthopédiques. Ces patients étaient plus âgés et plus grièvement blessés que les enfants n'ayant pas subi d'intervention chirurgicale, et leur séjour à l'hôpital était généralement plus long. Nous n'avons relevé aucune différence entre les 2 groupes quant à la mortalité. En outre, 74 des patients ayant subi une intervention chirurgicale ont dû être opérés dans les 4 heures suivant l'admission; 45 % d'entre eux ont eu besoin d'une intervention neurochirurgicale. Le coût médian d'une hospitalisation était de 27 571 $. CONCLUSION: Le tiers des patients pédiatriques victimes de trauma ont eu besoin d'une intervention chirurgicale, et le tiers de ceux-ci ont dû être opérés dans les 4 heures suivant leur arrivée. Malgré les coûts, le traitement chirurgical des enfants était associé à un taux de mortalité comparable à celui du traitement non chirurgical des patients blessés moins grièvement. Cette étude est la source d'information la plus récente sur le coût par patient associé au traitement chirurgical des enfants victimes de trauma en Ontario, et elle met en évidence le besoin de soins de multiples spécialités.

Neurodevelopmental outcomes of infants with esophageal atresia and tracheoesophageal fistula.

BACKGROUND: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is a complex disorder, and most outcome data are confined to mortality and feeding-related morbidities. Our objective was to examine mortality, growth and neurodevelopmental outcomes in a large recent cohort of infants with EA/TEF. METHODS: Single center study of EA/TEF infants referred from January 2000 to December 2015. Data collected included associated defects, neonatal morbidity and mortality and growth and neurodevelopmental outcomes at age 12-36months. Multiple regression analysis was used to determine variables associated with adverse outcome. RESULTS: Of the 253 infants identified, 102 infants (40%) were preterm. Overall mortality was 8.3%, the majority from major cardiac malformations (p<0.001) Neurodevelopmental assessments (n=182) showed that 76% were within normal, while some delay was seen in 24%, most often in expressive and receptive language. Nine infants had hearing impairment and 5 had visual impairment. Gastrostomy tubes were required in 47 patients and 15% continued to have weight growth velocities less than the 10th centile. A number of specialist interventions were required, Speech/Language being frequent. CONCLUSION: Mortality in EA/TEF is primarily related to concomitant anomalies, especially cardiac. Multidisciplinary follow up is important for early identification and intervention for growth failure and developmental delay. TYPE OF STUDY: Retrospective study LEVEL OF EVIDENCE: Level II.

Long-term burden of care and radiation exposure in survivors of esophageal atresia.

BACKGROUND: Patients with esophageal atresia with or without tracheoesophageal fistula (EA/TEF) historically have had a high risk of neonatal mortality but the majority of patients are now expected to live into adulthood. However, the long-term burden of care among recent EA/TEF survivors has not been documented. METHODS: A single-institution retrospective review of newborns with EA/TEF treated from 2001-2005 was conducted, including initial and total hospitalization length of stay, and number of clinic visits and procedures requiring general anesthesia in the first three years of life. Exposure to and number of radiological studies involving ionizing radiation (IR) were recorded. RESULTS: Seventy-one of 78 (91%) patients survived to discharge and 69 were included for analysis. Mean length of initial hospital stay was 51.3 (range 9-390) days. By age 3 years, patients required 4.5 (mean, range 1-23) procedures performed under general anesthesia, attended 13.5 (mean, range 3-40) outpatient visits and were exposed to 17.4 mSv (mean, range 3.0-59.9) of IR from 40 (mean, range 5-165) radiological studies. CONCLUSION: Patients with EA/TEF need complex and frequent hospital-based care from infancy to early childhood. Opportunities to critically review clinical services and imaging needs should be explored to improve the experience of patients and their families.

Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response.

PURPOSE: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation. EXPERIMENTAL DESIGN: Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry, and positron emission tomography (PET) imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 patients with localized prostate cancer treated with curative-intent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan-Meier method. RESULTS: Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry, and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately before irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (P = 0.0106). CONCLUSION: Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio.

Contributions of AMPK and p53 dependent signaling to radiation response in the presence of metformin.

BACKGROUND AND PURPOSE: Metformin is commonly prescribed to treat type 2 diabetes, and has additional potential as a cancer prophylactic and therapeutic. Metformin activates AMPK that in turn can launch a p53-dependent metabolic checkpoint. Possible interactions between metformin and radiation are poorly understood. Since radiation-induced signaling also involves AMPK and p53, we investigated their importance in mediating responses to metformin and radiation. MATERIALS AND METHODS: A549 cells, HCT116 cells wildtype or knockout for p53 or MEFs wildtype or double knockout for AMPKα1 and α2 were irradiated in the presence or absence of metformin. The impact of metformin on oxygen consumption and proliferation rates was determined, as well as clonogenic radiation survival. RESULTS: Metformin resulted in moderate radiation protection in all cell lines, irrespective of AMPK and p53. Loss of AMPK sensitized cells to the anti-proliferative effects of metformin, while loss of p53 promoted both the growth inhibitory and toxic effects of metformin. Consequently, overall cell death after radiation was similar with and without metformin irrespective of AMPK or p53 genotype. CONCLUSIONS: The anti-proliferative activity of metformin may confer benefit in combination with radiotherapy, and this benefit is intensified upon loss of AMPK or p53 signaling.