Current Open Trials and Molecular Update for Pediatric Embryonal Tumors.

BACKGROUND: Embryonal tumors are highly malignant cancers of the central nervous system, with a relatively high incidence in infants and young children. Even with intensive multimodal treatment, the prognosis of many types is guarded, and treatment-related toxicity is significant. Recent advances in molecular diagnostics allowed the discovery of novel entities and inter-tumor subgroups, with opportunities for improved risk-stratification and treatment approaches. SUMMARY: Medulloblastomas separate into four distinct subgroups with distinct clinicopathologic characteristics, and data from recent clinical trials for newly diagnosed medulloblastoma support subgroup-specific treatment approaches. Atypical teratoid rhabdoid tumor (ATRT), embryonal tumor with multilayered rosettes (ETMR), and pineoblastoma, as well as other rare embryonal tumors, can be distinguished from histologically similar tumors by virtue of characteristic molecular findings, with DNA methylation analysis providing a strong adjunct in indeterminate cases. Methylation analysis can also allow further subgrouping of ATRT and pineoblastoma. Despite the dire need to improve outcomes for patients with these tumors, their rarity and lack of actionable targets lead to a paucity of clinical trials and novel therapeutics. KEY MESSAGES: (1) Embryonal tumors can be accurately diagnosed with pediatric-specific sequencing techniques. (2) Medulloblastoma risk stratification and treatment decisions should take into account molecular subgroups. (3) There is a dire need for a novel collaborative clinical trial design to improve outcomes is rare pediatric embryonal tumors.

Recent progress and novel approaches to treating atypical teratoid rhabdoid tumor.

Atypical teratoid rhabdoid tumors (AT/RT) are malignant central nervous system (CNS) tumors that occur mostly in young children and have historically carried a very poor prognosis. While recent clinical trial results show that this tumor is curable, outcomes are still poor compared to other central nervous system embryonal tumors. We here review prior AT/RT clinical trials and highlight promising pre-clinical results that may inform novel clinical approaches to this aggressive cancer.

Early removal of a permanent catheter during the acute management of the unstable pediatric hemato-oncology patient with suspected catheter-related bloodstream infection: a multi-disciplinary survey and review of the literature.

There are no guidelines for the optimal manner and timing of permanent central catheter removal in the hemodynamically unstable pediatric hemato-oncology patient with suspected catheter-related bloodstream infections (CRBSI). Our goals were to examine current practices of permanent central catheter management and choice of removal in the hemodynamically unstable pediatric patient with suspected CRBSI among practitioners in diverse subspecialties. We performed a literature review on the subject, and conducted a multi-disciplinary survey included pediatric oncologists, pediatric emergency medicine physicians, and pediatric intensive care physicians whom we queried about their choice of permanent central catheter management and removal while treating the hemodynamically unstable pediatric patient with suspected CRBSI. Most of the 78 responders (n = 47, 59%) preferred to utilize the existing permanent central catheter for initial intravenous access rather than an alternative access. There were no significant differences between physician subspecialties (p = 0.29) or training levels (p = 0.14). Significantly more pediatric emergency medicine physicians preferred not to remove the permanent central catheter at any time point compared to the pediatric hemato-oncologists, who preferred to remove it at some point during the acute presentation (44.4% vs. 9.4%, respectively, p = 0.02). CONCLUSION: Our study findings reflect the need for uniform guidelines on permanent central catheter use and indications for its removal in the hemodynamically unstable pediatric patient. We suggest that permanent central catheter removal should be urgently considered in a deteriorating patient who failed to be stabilized with medical treatment. WHAT IS KNOWN: • There are no guidelines for the optimal choice and timing of permanent central catheter removal in the hemodynamically unstable pediatric hemato-oncology patient with suspected catheter-related bloodstream infection (CRBSI). WHAT IS NEW: • We found variations in practices among pediatricians from diverse subspecialties and conflicting data in the literature. • There is a need for prospective studies to provide uniform guidelines for optimal management of suspected CRBSI in the hemodynamically unstable pediatric patient.

Multi-institutional study of the frequency, genomic landscape, and outcome of IDH-mutant glioma in pediatrics.

BACKGROUND: The incidence and biology of IDH1/2 mutations in pediatric gliomas are unclear. Notably, current treatment approaches by pediatric and adult providers vary significantly. We describe the frequency and clinical outcomes of IDH1/2-mutant gliomas in pediatrics. METHODS: We performed a multi-institutional analysis of the frequency of pediatric IDH1/2-mutant gliomas, identified by next-generation sequencing (NGS). In parallel, we retrospectively reviewed pediatric IDH1/2-mutant gliomas, analyzing clinico-genomic features, treatment approaches, and outcomes. RESULTS: Incidence: Among 851 patients with pediatric glioma who underwent NGS, we identified 78 with IDH1/2 mutations. Among patients 0-9 and 10-21 years old, 2/378 (0.5%) and 76/473 (16.1%) had IDH1/2-mutant tumors, respectively. Frequency of IDH mutations was similar between low-grade glioma (52/570, 9.1%) and high-grade glioma (25/277, 9.0%). Four tumors were graded as intermediate histologically, with one IDH1 mutation. Outcome: Seventy-six patients with IDH1/2-mutant glioma had outcome data available. Eighty-four percent of patients with low-grade glioma (LGG) were managed observantly without additional therapy. For low-grade astrocytoma, 5-year progression-free survival (PFS) was 42.9% (95%CI:20.3-63.8) and, despite excellent short-term overall survival (OS), numerous disease-related deaths after year 10 were reported. Patients with high-grade astrocytoma had a 5-year PFS/OS of 36.8% (95%CI:8.8-66.4) and 84% (95%CI:50.1-95.6), respectively. Patients with oligodendroglioma had excellent OS. CONCLUSIONS: A subset of pediatric gliomas is driven by IDH1/2 mutations, with a higher rate among adolescents. The majority of patients underwent upfront observant management without adjuvant therapy. Findings suggest that the natural history of pediatric IDH1/2-mutant glioma may be similar to that of adults, though additional studies are needed.

Molecular genetics of paediatric brain tumours and opportunities for precision medicine - a focus on infant tumours.

PURPOSE OF REVIEW: The last few decades have seen an explosion in our understanding of the molecular drivers of childhood brain tumours. These insights have opened the possibility for precision medicine approaches for some tumour types. However, a different spectrum of tumours is more likely to occur in infants and young children, who face additional therapeutic challenges. This review focuses on recent advances in molecular genetics of common infant brain tumours and their implication for diagnosis, prognostication and utilization of precision oncology approaches. RECENT FINDINGS: Infant tumours have different biology and outcomes than similar tumours in older children and adults. For low-grade gliomas, targeted MAPK inhibition is well tolerated and likely efficacious. In high-grade gliomas, common tyrosine kinase alterations offer compelling targets for inhibition that are currently being evaluated. Paediatric-specific sequencing and methylation analysis offer insights into the driving biology of infant medulloblastoma, atypical teratoid rhabdoid tumours, embryonal tumours with multilayered rosettes, ependymoma and choroid plexus tumours, with molecular subgrouping shedding insights into distinct driving biology and clinical outcomes. SUMMARY: Infant brain tumours are rare and heterogenous, with overall poor outcomes. Advances in molecular genetics have been incorporated into their diagnostic criteria and allow for accurate subgrouping and improved prognostication. The utilization of targeted agents appears beneficial for many low-grade gliomas and a subset of high-grade gliomas, but further research is urgently needed to improve outcomes for other tumour entities.

Upfront molecular targeted therapy for the treatment of BRAF-mutant pediatric high-grade glioma.

BACKGROUND: The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. METHODS: We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. RESULTS: Nineteen patients were identified, with a median age of 11.7 years (range, 2.3-21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4-5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3-6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. CONCLUSIONS: Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children's Oncology Group ACNS1723 clinical trial.

Tramadol Treatment for Chemotherapy-induced Mucositis Pain in Children.

Mucositis, a painful and debilitating condition, is a common side effect of chemotherapy. The role of tramadol in the treatment of mucositis in pediatric patients has not yet been determined. In this retrospective study, we evaluate whether tramadol as single agent achieved a reduction of pain intensity among oncologic children admitted for mucositis. In total, 34 of 54 (63%) episodes were treated with tramadol alone and achieved adequate pain relief. Tramadol's side effects were mild and manageable.

Outcome of Benign Acute Childhood Myositis: The Experience of 2 Large Tertiary Care Pediatric Hospitals.

OBJECTIVE: The aims of the study were to determine the evolution of benign acute childhood myositis in children and to assess the relationship between creatine phosphokinase (CPK) values and myoglobinuria. STUDY DESIGN: A retrospective study of patients with benign acute childhood myositis seen in 2 tertiary care university-affiliated pediatric hospitals during overlapping 4-year periods. METHODS: Demographic data, historical details, clinical, and laboratory results were extracted from the charts of children younger than 16 years with a CPK greater than 3 times normal. Complications, treatments, and outcomes were recorded. RESULTS: Fifty-four children were included, 43 (80%) were male, and mean age was 7.3 years (median [range], 6 [3-16] years), none showed abnormal neurological findings, manifested hematuria, or developed renal failure. Mean CPK level at presentation was 1872 IU/L (range, 511-8086 IU/L). None developed renal failure, and there were no adverse outcomes on follow-up. CONCLUSIONS: Acute childhood myositis is a predominantly benign disease. Neurological examination is usually normal and rhabdomyolysis is rare. Although severe pathological comorbid conditions must be excluded, a complete history and examination, coupled with simple blood and urine tests, can help minimize unnecessary diagnostic investigations.

[A PROSPECTIVE FOLLOW-UP OF NON-PALPABLE TESTES IN NEONATES].

INTRODUCTION: Cryptorchidism is the most common genitourinary disorder in male neonates, with an incidence of 2-5% in term neonates and 30% in preterm infants. Known complications of this condition include impaired fertility and an increased risk of malignancy. This leads to a high frequency of imaging tests, specifically ultrasonography. Use of ultrasound aims to identify non-palpable testis, however current literature does not support such an approach. GOALS: To evaluate the efficacy of clinical follow-up of cryptorchidism in neonates and to evaluate the need for ultrasonography. METHODS: This prospective study was performed at the Lis Maternity Hospital in the Tel Aviv Sourasky Medical Center during a 14 month period. During that period some 4,500 male neonates were born at our hospital. Every newborn was examined within 8 hours of delivery by a pediatrician skilled in neonatal physical examinations. Excluded from the study were preterm infants, neonates in which prenatal examination demonstrated genitourinary abnormalities and neonates with additional congenital abnormalities. Healthy term babies in which one or both testes were not palpable were re-examined within a day by a senior neonatologist (M.B.) to establish their diagnosis, and then reexamined daily by the same physician until their discharge from the hospital. Babies who had one or both testis which were not palpable on discharge were followed-up weekly at a hospital clinic for 2 more weeks. RESULTS: Of 4,500 male neonates born during the study period, 41 (0.9%) were diagnosed with a non-palpable testis, and 8 (0.18%) had bilateral non-palpable testes; 5 babies were lost to followup and excluded from the analysis; 26 of 44 testes (29%) became palpable before discharge from the nursery, by the 3rd day of life. After a weekly follow up from discharge, 13 (29%) additional testes became palpable over the 4-14th day of life. Overall, 88% of non-palpable testes became palpable by 14 days of age. CONCLUSIONS: Close clinical follow-up during the first weeks after birth allows localizing most congenitally non-palpable testing and clarifying the need for performing imaging studies not routinely necessary to diagnose and refer babies with cryptorchidism for further treatment.

Critical analysis of risk factors and outcome of placenta previa.

OBJECTIVE: To investigate risk factors and pregnancy outcome of patients with placenta previa. METHODS: A population-based study comparing all singleton pregnancies of women with and without placenta previa was conducted. Stratified analysis using multiple logistic regression models was performed to control for confounders. RESULTS: During the study period, there were 185,476 deliveries, of which, 0.42% were complicated with placenta previa. Using a multivariable analysis with backward elimination, the following risk factors were independently associated with placenta previa: infertility treatments (OR 1.97; 95% CI 1.45-2.66; P < 0.001), prior cesarean delivery (CD; OR 1.76; 95% CI 1.48-2.09; P < 0.001) and advanced maternal age (OR 1.08; 95% CI 1.07-1.09; P < 0.001). Placenta previa was significantly associated with adverse outcomes such as peripartum hysterectomy (5.3 vs. 0.04%; P < 0.001), previous episode of second trimester bleeding (3.9 vs. 0.05%; P < 0.001), blood transfusion (21.9 vs. 1.2%; P < 0.001), maternal sepsis (0.4 vs. 0.02%; P < 0.001), vasa previa (0.5 vs. 0.1%; P < 0.001), malpresentation (19.8 vs. 5.4%; P < 0.001), postpartum hemorrhage (1.4 vs. 0.5%; P = 0.001) and placenta accreta (3.0 vs. 1.3%; P < 0.001). Placenta previa was significantly associated with adverse perinatal outcomes such as higher rates of perinatal mortality (6.6 vs. 1.3%; P < 0.001), an Apgar score <7 after 1 and 5 min (25.3 vs. 5.9%; P < 0.001, and 7.1 vs. 2.6%, P < 0.001, respectively), congenital malformations (11.5 vs. 5.1%; P < 0.001) and intrauterine growth restriction (3.6 vs. 2.1%; P = 0.003). Using another multivariable logistic regression model, with perinatal mortality as the outcome variable, controlling for confounders, such as preterm birth, maternal age, etc., placenta previa was not found as an independent risk factor for perinatal mortality (weighted OR 1.018; 95% CI 0.74-1.40; P = 0.910). CONCLUSIONS: Infertility treatments, prior cesarean section, and advanced maternal age are independent risk factors for placenta previa. An increase in the incidence of these risk factors probably contributes to a rise in the number of pregnancies complicated with placenta previa and its association with adverse maternal and perinatal outcomes. Careful surveillance of these risk factors is recommended with timely delivery in order to reduce the associated complications.