Comprehensive Analysis of Hypermutation in Human Cancer.

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.

Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

A Need for a Novel Survival Risk Scoring System for Intensive Care Admissions Due to Sepsis in Pediatric Hematology/Oncology Patients.

Background: Children with hemato-oncological diseases or following stem cell transplantation (SCT) are at high risk for life-threatening infections; sepsis in this population constitutes a substantial proportion of pediatric intensive care unit (PICU) admissions. The current pediatric prognostic scoring tools to evaluate illness severity and mortality risk are designed for the general pediatric population and may not be adequate for this vulnerable subpopulation. Methods: Retrospective analysis was performed on all PICU admissions for sepsis in children with hemato-oncological diseases or post-SCT, in a single tertiary pediatric hospital between 2008 and 2021 (n = 233). We collected and analyzed demographic, clinical, and laboratory data and outcomes for all patients, and evaluated the accuracy of two major prognostic scoring tools, the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) and the Pediatric Risk of Mortality III (PRISM III). Furthermore, we created a new risk-assessment model that contains additional parameters uniquely relevant to this population. Results: The survival rate for the cohort was 83%. The predictive accuracies of PELOD-2 and PRISM III, as determined by the area under the curve (AUC), were 83% and 78%, respectively. Nine new parameters were identified as clinically significant: age, SCT, viral infection, fungal infection, central venous line removal, vasoactive inotropic score, bilirubin level, C-reactive protein level, and prolonged neutropenia. Unique scoring systems were established by the integration of these new parameters into the algorithm; the new systems significantly improved their predictive accuracy to 91% (p = 0.01) and 89% (p < 0.001), respectively. Conclusions: The predictive accuracies (AUC) of the PELOD-2 and PRISM III scores are limited in children with hemato-oncological diseases admitted to PICU with sepsis. These results highlight the need to develop a risk-assessment tool adjusted to this special population. Such new scoring should represent their unique characteristics including their degree of immunosuppression and be validated in a large multi-center prospective study.

Cutaneous Reactions in Pediatric Patients Treated with MEK Inhibitors: A Retrospective Single-Center Study.

INTRODUCTION: Mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors are in use for several indications for adults and children. Cutaneous toxicities are among the most common adverse effects. We aimed to describe the spectrum of cutaneous adverse events, its frequency, and severity in a cohort of pediatric patients. METHODS: We reviewed all records of patients in our tertiary treatment center treated with MEK inhibitors between January 2016 and January 2023 for all indications. RESULTS: Among 33 patients, 76% reported cutaneous adverse effects. The highest prevalence was in the group of patients treated with trametinib (90%), followed by the group treated with selumetinib (50%) and the group treated with a combination of trametinib and B-Raf proto-oncogene serine/threonine-protein kinase inhibitor (dabrafenib, 34%). Xerosis, dermatitis, paronychia, and hair heterochromia were most frequently reported. Severity was graded 1 or 2 for most adverse events, and 237 visits to the dermatology clinic related to these adverse events were recorded. CONCLUSIONS: Cutaneous adverse events are common in the pediatric population as in adults, but the clinical spectrum is different. Although considered mild, multiple dermatological consultations reflect the distress caused by these events. Dermatologists have a central role in the multidisciplinary care of pediatric patients receiving these agents.

Optic pathway glioma and endocrine disorders in patients with and without NF1.

BACKGROUND: Optic pathway gliomas (OPGs) are classified by anatomic location and the association with neurofibromatosis type 1 (NF1). Children with OPGs face sequelae related to tumor location and treatment modalities. We assessed the prevalence of endocrine dysfunction in children with OPGs and compared outcomes between those with and without NF1. METHODS: We performed a retrospective medical record review of medical history, and clinical and laboratory data, of children diagnosed with OPGs (n = 59, 61% with NF1) during 1990-2020, followed at a tertiary endocrine clinic. Growth and puberty parameters and occurrence of endocrine dysfunction were evaluated. RESULTS: Isolated optic nerve involvement was higher among patients with than without NF1. Patients without NF1 were younger at OPG diagnosis and more often treated with debulking surgery or chemotherapy. At the last endocrine evaluation, patients without NF1 had comparable height SDS, higher BMI SDS, and a higher rate of endocrine complications (78.3% vs. 41.7%, p = 0.006). Younger age at diagnosis, older age at last evaluation, and certain OPG locations were associated with increased endocrine disorder incidence. CONCLUSIONS: Endocrine dysfunction was more common in patients without NF1; this may be related to younger age at presentation, tumor locations, a greater progressive rate, and more aggressive treatments. IMPACT: The literature is sparse regarding sporadic OPGs, and the mean duration of follow-up is shorter than at our study. Our data show a higher rate of endocrine dysfunction in patients with OPGs than previously described. We also found a higher prevalence of endocrine dysfunctions among patients without compared to those with NF-1. A better understanding of the true prevalence of endocrine disabilities that may evolve along time can help in guiding physicians in the surveillance needed in patients with OPG.

A Comprehensive Review of Neuropsychologic Studies Supports the Concept That Adequate Folinic Acid Rescue Prevents Post Methotrexate Neurotoxicity.

PURPOSE: To review all studies providing evidence of the correlation between folinic acid (FA) rescue inadequacy and long-term cognitive damage in neuropsychological studies of children with acute lymphoblastic leukemia or osteogenic sarcoma treated under protocols using high-dose methotrexate and FA rescue. METHODS: A comprehensive literature search was performed of all databases of the Web of Science Citation Index, during 1990-2020, for the terms: neuropsychological, neurocognitive, and cognitive, together with acute lymphoblastic (and lymphocytic) leukemia and osteogenic sarcoma. English-language peer-reviewed articles on neuropsychological assessments of children who had been treated with high-dose methotrexate without irradiation, and which included details of methotrexate and FA schedules, were selected. In addition, a personal database of over 500 reprints of articles from over 130 journals was reviewed on the subjects of methotrexate and FA and their side effects. RESULTS: Three groups of studies were found and analyzed, with (1) no evidence of cognitive deterioration, (2) evidence of cognitive deterioration, and (3) more than 1 protocol grouped together, preventing separate analysis of any protocols, Protocols without cognitive deterioration reported adequate FA rescue, and those with cognitive deterioration reported inadequate FA rescue. CONCLUSION: Neuropsychological evaluation supported inadequate FA being the cause of neurocognitive damage after high-dose methotrexate and that adequate FA rescue prevents this complication.

Di-genic inheritance of germline POLE and PMS2 pathogenic variants causes a unique condition associated with pediatric cancer predisposition.

Polymerase proofreading-associated polyposis (PPAP) and Lynch syndrome, caused by mutated POLE and mismatch repair (MMR) genes, respectively, are associated with adult-onset cancer. PPAP and MMR-deficient tumors are both hypermutated, and each has a unique mutational signature. We describe a 4.5-year-old boy with multiple café au lait spots who presented with metastatic Sonic Hedgehog-activated medulloblastoma, with partial response to intensive chemotherapy and immunotherapy. The tumor showed microsatellite stability, loss of PMS2 nuclear expression, and an exceptionally high tumor mutational burden of 276 Mut/Mb. Germline molecular analysis revealed an inherited heterozygous pathogenic POLE variant and a de novo heterozygous PMS2 pathogenic variant. The tumor featured the MMR, POLE, and POLE+MMR mutational signatures. This is the first description of a di-genic condition, which we named "POL-LYNCH syndrome," manifested by an aggressive ultra-mutant pediatric medulloblastoma with a unique genomic signature.

COVID-19 infection in pediatric patients treated for cancer.

BACKGROUND: COVID-19, the novel coronavirus, has caused a global pandemic affecting millions of people around the world. Risk factors for critical disease in adults are advanced age and underlying medical comorbidities, including cancer. Data are sparse on the effect of COVID-19 infection on pediatric patients with cancer during their active antineoplastic therapy. The optimal management of antineoplastic treatment during COVID-19 infection in this unique population is controversial. AIM: To describe the severity and clinical course of COVID-19 infection in pediatric patients with cancer during active antineoplastic treatment and to study their course of treatment. METHODS: Clinical and laboratory data were collected from medical files of patients diagnosed with COVID-19, confirmed by polymerase chain reaction (PCR), who received active antineoplastic treatment between March 2020 and May 2021 in a large tertiary pediatric medical center. RESULTS: Eighteen patients with diverse pediatric cancers are described. They were infected with COVID-19 at different stages of their antineoplastic treatment regimen. Eight had an asymptomatic COVID-19 infection, nine had mild symptoms, and one had severe disease. All of them recovered from COVID-19 infection. Two patients experienced delays in their antineoplastic treatment; none of the other patients had delays or interruptions, including patients who were symptomatic for COVID-19. CONCLUSION: In pediatric patients with cancer who test positive for COVID-19, yet are asymptomatic or have mild symptoms, the continuance of antineoplastic therapy may be considered.

Hyperlactatemia in children following brain tumor resection: prevalence, associated factors, and clinical significance.

PURPOSE: Hyperlactatemia is associated with worse outcome among critically ill patients. The prevalence of hyperlactatemia in children following craniotomy for intracranial tumor resection is unknown. This study was designed to assess the prevalence, associated factors, and significance of postoperative hyperlactatemia in this context. METHODS: A retrospective study was conducted at an intensive care unit of a tertiary, pediatric medical center. Children younger than 18 years admitted following craniotomy for brain tumor resection between October 2004 and November 2019 were included. RESULTS: Overall, 222 elective craniotomies performed in 178 patients were analyzed. The mean age ± SD was 8.5 ± 5.5 years. All but two patients survived to discharge. All were hemodynamically stable. Early hyperlactatemia, defined as at least one blood lactate level ≥ 2.0 mmol/L during the first 24 h into admission, presented following 74% of the craniotomies; lactate normalized within a mean ± SD of 11 ± 6.1 h. The fluid balance per body weight at 12 h and 24 h into the intensive care unit admission was similar in children with and without hyperlactatemia [7.0 ± 17.6 vs 3.5 ± 16.4 ml/kg, p = 0.23 and 4.0 ± 27.2 vs 4.6 ± 29.4 ml/kg, p = 0.96; respectively]. Hyperlactatemia was associated with higher maximal blood glucose, older age, and a pathological diagnosis of glioma. Intensive care unit length of stay was similar following craniotomies with and without hyperlactatemia (p = 0.57). CONCLUSIONS: Hyperlactatemia was common in children following craniotomy for brain tumor resection. It was not associated with hemodynamic impairment or with a longer length of stay.

Postoperative hydrocephalus management may cause delays in adjuvant treatment following paediatric posterior fossa tumour resection: a multicentre retrospective observational study.

INTRODUCTION: Hydrocephalus persists in 10-40% of children with posterior fossa tumours (PFT). A delay in commencement of adjuvant therapy (AT) can negatively influence survival. The objective of this study was to determine whether postoperative cerebrospinal fluid (CSF) diversion procedures caused potentially preventable delays in AT. METHODS: A retrospective study of children diagnosed with PFT requiring AT from 2004 to 2018 from two large centres was conducted. Data on histology, timing of ventriculo-peritoneal shunt (VPS) insertion, and AT was collected. The modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) score was calculated. The primary outcome was delay in AT beyond 40 days post-resection. Progression-free and overall survival were assessed. RESULTS: Out of 196 primary PFT resections, 144 fitted the inclusion criteria. Mean age was 6.57 ± 4.62. Histology was medulloblastoma (104), ependymoma (27), and others (13). Forty patients had a VPS inserted; 17 of these experienced a delay in AT. A total of 104 patients were not shunted; 15 of these had delayed AT (p = 0.0007). Patients who had a VPS insertion had longer intervals from surgery to commencement of AT (34.5 vs 30.8, p = 0.05). There was no significant difference in mCPPRH score between those who had a VPS (4.03) and those who did not (3.61; p = 0.252). Multivariable linear regression modelling did not show a significant effect of VPS or mCPPRH on progression-free survival or OS. CONCLUSION: CSF diversion procedures may cause a preventable delay in the initiation of adjuvant therapy. Early post-operative VP shunt insertion, rather than a 'wait and see policy' should be considered in order to reduce this delay.

Incorporation of somatic panels for the detection of haematopoietic transformation in children and young adults with leukaemia predisposition syndromes and with acquired cytopenias.

Detection of somatic mutations may help verify the diagnosis of myelodysplastic syndrome (MDS) in patients with persistent cytopenias or with MDS-predisposition syndromes, prior to the development of overt leukemia. However, the spectrum and consequences of acquired changes in paediatric patients have not been fully evaluated, and especially not in the context of an underlying syndrome. We incorporated a targeted next-generation-sequencing panel of 54 genes for the detection of somatic mutations in paediatric and young adult patients with inherited or acquired cytopenias. Sixty-five patients were included in this study, of whom 17 (26%) had somatic mutations. We detected somatic mutations in 20% of individuals with inherited MDS-predisposition syndromes, including in patients with severe congenital neutropenia and Fanconi anaemia, and with germline mutations in SAMD9L. Thirty-eight per cent of children with acquired cytopenias and suspected MDS had somatic changes, most commonly in genes related to signal transduction and transcription. Molecularly abnormal clones often preceded cytogenetic changes. Thus, routine performance of somatic panels can establish the diagnosis of MDS and determine the optimal timing of haematopoietic stem cell transplantation, prior to the development of leukaemia. In addition, performing somatic panels in patients with inherited MDS-predisposition syndromes may reveal their unique spectrum of acquired mutations.

Paediatric systemic lupus erythematosus as a manifestation of constitutional mismatch repair deficiency.

Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1 and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency (CMMRD) syndrome. In addition to a very high tumour risk, the CMMRD phenotype is often characterised by the presence of signs reminiscent of neurofibromatosis type 1. Although paediatric systemic lupus erythematosus (pSLE) has been reported so far in three patients with CMMRD, it has not been considered a diagnostic feature of the syndrome. We report here two additional female patients with pSLE and CMMRD due to biallelic pathogenic variants in MSH6 Hence, there are a total of five out of approximately 200 (2.5%) currently reported patients with CMMRD that also have pSLE, suggesting pSLE should raise the suspicion of a diagnosis of CMMRD, especially if supported by additional indicative features.

Delayed diagnosis and treatment of children with cancer during the COVID-19 pandemic.

BACKGROUND: COVID-19, the novel coronavirus has caused a global pandemic affecting millions of people around the world. Although children, including children with cancer, have been found to be affected less commonly and less severely than adults, indirect effects of the pandemic on the diagnosis and treatment of children with cancer have been less described. METHODS: A survey was performed in the four largest tertiary pediatric hematology-oncology medical centers in Israel. Clinical and laboratory data were collected from the medical files of patients diagnosed or treated with cancer during April-October 2020. RESULTS: Seventeen patients are described, who had a significant delay in diagnosis or treatment of cancer. These represent approximately 10% of all pediatric cancer diagnosed during the study period in these centers. A main cause of delay was fear of exposure to COVID-19 (fears felt by the patient, parent, physician, or decision-makers at the institution; or the implementation of national guidelines). Delays also resulted from co-infection with COVID-19 and the attribution of the oncologic symptoms to the infection. In addition, treatment was delayed of patients already diagnosed with cancer, due to COVID-19 infection detected in the patient, a family member, or a bone marrow donor. CONCLUSION: Fear from the COVID-19 pandemic may result in delayed diagnosis and treatment of children with cancer, which may carry a risk to dismal prognosis. It is crucial that pediatricians and patients alike remember that other diseases still prevail and must be thought of and treated in a timely fashion.

Trametinib for orbital plexiform neurofibromas in young children with neurofibromatosis type 1.

INTRODUCTION: Plexiform neurofibromas (PNF) in neurofibromatosis type 1 (NF1) are usually diagnosed in childhood and can grow rapidly during this period. In 10% of patients, PNF involve the orbital-periorbital area and may cause visual problems including glaucoma, visual loss from amblyopia (deprivational, strabismic, or refractive), optic nerve compression, or keratopathy. Ptosis, proptosis, and facial disfigurement lead to social problems and decreased self-esteem. Complete surgical removal involves significant risks and mutilation, and regrowth after debulking is not uncommon. Inhibitors of the RAS/MAPK pathway have recently been investigated for their activity in PNF. We administered the oral MEK inhibitor trametinib to five young children with NF1 and PNF of the orbital area, with visual compromise and progressive tumor growth; and followed them clinically and by volumetric MRI. METHODS: Treatment was initiated at a mean age of 26.8 months (SD ± 12.8) and continued for a median 28 months (range 16-51). Doses were 0.025 mg/kg/day for children aged > 6 years and 0.032 mg/kg/day for those aged < 6 years. RESULTS: Volumetric MRI measurements showed a reduction of 2.9-33% at 1 year after treatment initiation, with maximal reductions of 44% and 49% in two patients, at 44 and 36 months, respectively. No change in visual function was recorded during treatment. One child reported decreased orbital pain after 2 weeks; and another, with involvement of the masseters, had increased ability to chew food. Toxicities were mostly to skin and nails, grades 1-2. CONCLUSIONS: Trametinib can decrease tumor size in some young children with orbital PNF and may prevent progressive disfigurement.

The great mimicker: Phenotypic overlap between constitutional mismatch repair deficiency and Tuberous Sclerosis complex.

Constitutional mismatch repair deficiency is a rare cancer predisposition syndrome caused by biallelic mutations in one of the four mismatch repair genes. Patients are predisposed to various tumors including hematological malignancies, brain tumors and colorectal carcinomas. Phenotypic overlap with Neurofibromatosis-1 is well known, with most patients presenting with café-au-lait macules. Other common features include axillary and/or inguinal freckling and intracranial MRI foci of high T2W/FLAIR signal intensity similar to the typical FASI seen in Neurofibromatosis-1. In this cohort of eight patients with constitutional mismatch repair deficiency we describe overlapping phenotypical features with Tuberous Sclerosis complex. In addition to "ash-leaf like" hypomelanotic macules (five patients), we detected intracranial tuber-like lesions (three patients), renal cysts (three patients) and renal angiomyolipomas (two patients). All our patients also had Neurofibromatosis-1 like features, mainly café-au-lait macules. This study suggests that features of Tuberous sclerosis especially when overlapping with those of Neurofibromatosis 1 or malignancies atypical for these syndromes should raise the possibility of constitutional mismatch repair deficiency. Correct diagnosis is essential for appropriate genetic counseling and pre-emptive cancer surveillance.

Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study.

Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.

Bevacizumab for NF2-associated vestibular schwannomas of childhood and adolescence.

Seventeen children at six institutions with neurofibromatosis type 2 (NF2)-related vestibular schwannomas received bevacizumab. Eight of the 13 patients with initial hearing loss (61%) showed objective hearing improvement within six months of treatment. No patients showed hearing deterioration during therapy; however, only two patients showed objective radiological response. Seven of eight patients had tumor progression or worsening hearing loss upon cessation of treatment. Bevacizumab was well tolerated with no patients discontinuing therapy. Bevacizumab appears to postpone hearing loss in childhood NF2-associated vestibular schwannomas, but responses are not durable, suggesting that either longer maintenance therapy or new strategies are required.

Proptosis due to intraorbital space-occupying lesions in children.

PURPOSE: To report the 10-year experience of two tertiary medical centers with children presenting with proptosis due to an intraorbital space-occupying lesion. METHODS: Patients were identified by file review. Data were collected on demographics, findings on ophthalmologic and imaging evaluations, etiology, treatment, and outcome. RESULTS: Nineteen children (7 male) were included. Eleven patients had optic nerve glioma, including 9 with substantially decreased visual acuity. Treatment consisted of chemotherapy alone or with radiation, resection or anti-VEGF agents, MEK inhibitor, or observation only (n = 1). Visual and cosmetic outcomes were poor in all cases. Outcome for arteriovenous malformations was good following corticosteroid treatment (n = 1), but catheterization led to persistent proptosis and fluctuating visual acuity (n = 1). Compound capillary hemangioma (n = 1) was treated with laser and systemic beta blockers with satisfactory results. Rhabdomyosarcoma had a good prognosis in one patient treated with resection and radiation but was fatal in another even after chemotherapy. Juvenile xanthogranuloma, frontal bone osteoma, and localized hypertrophic neuropathy of the supraorbital nerve (n = 1 each) were treated by resection with good visual and cosmetic outcomes. CONCLUSIONS: Proptosis accompanied by visual loss is an uncommon presentation in children and suggests an orbital tumor. We found that visual outcome was better when the nerve was not involved by tumor. Optic nerve glioma was the most common cause and failed to respond to various treatments. Catheterization for arteriovenous malformation did not prevent proptosis, and final visual acuity fluctuated. Surgery for rhabdomyosarcoma and xanthogranuloma led to remission with preservation of vision in 2 of 3 cases.

Improved Outcome in Local Ewing Sarcoma With an Intensified Pilot Treatment Protocol SCMCIE 94.

This study evaluated the effect of an intensified pilot protocol, SCMCIE 94, on the outcome of Ewing sarcoma (EWS). The cohort included 121 patients with local or metastatic EWS treated at a tertiary pediatric medical center with the SCMCIE 94 (protocol 3, 1994 to 2011) or an earlier protocol (protocol 2, 1988 to 1994; protocol 1, 1985 to 1988). All protocols included 4 to 6 courses of chemotherapy, radiation, and surgery. Clinical data were collected retrospectively by chart review. Survival rates for protocol 3 were as follows: all patients-5-year event-free survival (EFS): 52.5%±5.6%, 10-year EFS: 49.3%±5.8%, 5-year overall survival (OS): 68.8%±5.3%, and 10-year OS: 51.1%±6.3%; patients with localized disease (any site)-5-year EFS: 63.5%±6.0% and 5-year OS: 77.2%±5.3%; patients with localized extremity disease-5-year EFS: 78.95%±8.3%, 10-year EFS: 68.6%±10.0%, 5-year OS: 90.7%±6.2%, and 10-year OS: 71.1%±11.2%. Protocol 3 was associated with an increase in 10-year EFS of 16% overall and 33% in patients with localized extremity disease compared with protocols 1+2, and a significant improvement in 5-year EFS and OS in patients with any localized disease (P=0.001). No survival benefit was found for metastatic disease. On multivariate analysis, protocol and metastatic disease were significantly independent prognostic factors. The intensified SCMCIE 94 protocol seems to increase survival in patients with localized but not metastatic EWS.

Likelihood of Diagnosing Neuroblastoma in Isolated Horner Syndrome.

BACKGROUND: The need for an extensive evaluation for neuroblastoma in children with Horner syndrome is controversial. METHODS: A retrospective study design was used. The cohort included 47 children with anisocoria who were diagnosed with Horner syndrome and 135 children with neuroblastoma evaluated at a pediatric medical center between 2007 and 2015. To detect neuroblastoma, patients with Horner syndrome underwent brain and cervical MRI, abdominal ultrasound, and/or measurement of urinary vanillylmandelic acid (VMA). The neuroblastoma group was evaluated for signs/symptoms of Horner syndrome at the time of diagnosis. RESULTS: Seven patients with Horner syndrome were lost to follow-up, and the findings of the remaining 40 were categorized according to the age of the patient. Horner syndrome most frequently was idiopathic (58%), and in only 1 patient did the discovery of neuroblastoma precede the appearance of Horner syndrome. In the 21 patients aged 1-18 years, Horner syndrome was acquired in 15 patients and congenital in 6. The most common etiology was trauma (62%). Imaging was performed in 14 patients and VMA testing in 13. Neuroblastoma was diagnosed in 5 patients; in none was it related to Horner syndrome. In the 135 patients with neuroblastoma, most of the tumors were diagnosed at Stage 4 (60%) or Stage 3 (30%) with 53% originating in the abdomen. In one patient (0.74%) with signs/symptoms of Horner syndrome at diagnosis of neuroblastoma, the tumor had been identified prenatally and the diagnosis confirmed by imaging postnatally. CONCLUSIONS: The absence of occult neuroblastoma in children with Horner syndrome and of signs/symptoms of Horner syndrome in the children diagnosed with neuroblastoma suggests that Horner syndrome might not be as frequent a cause of neuroblastoma as previously thought. We recommend that full investigation for neuroblastoma be reserved for suspicious cases associated with additional systemic signs or symptoms.