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Low- and middle-income countries sustain the majority of pediatric cancer burden, with significantly poorer survival rates compared to high-income countries. Collaboration between institutions in low- and middle-income countries and high-income countries is one of the ways to improve cancer outcomes.Patient characteristics and effects of a pediatric neuro-oncology twinning program between the Hospital for Sick Children in Toronto, Canada and several hospitals in Karachi, Pakistan over 7 years are described in this article.A total of 460 patients were included in the study. The most common primary central nervous system tumors were low-grade gliomas (26.7%), followed by medulloblastomas (18%), high-grade gliomas (15%), ependymomas (11%), and craniopharyngiomas (11.7%). Changes to the proposed management plans were made in consultation with expert physicians from the Hospital for Sick Children in Toronto, Canada. On average, 24% of the discussed cases required a change in the original management plan over the course of the twinning program. However, a decreasing trend in change in management plans was observed, from 36% during the first 3.5 years to 16% in the last 3 years. This program also led to the launch of a national pediatric neuro-oncology telemedicine program in Pakistan.Multidisciplinary and collaborative efforts by experts from across the world have aided in the correct diagnosis and treatment of children with brain tumors and helped establish local treatment protocols. This experience may be a model for other low- and middle-income countries that are planning on creating similar programs.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown.This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database.At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P .001) and a thalamic location (P .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes.The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients.

The clinical, radiological, surgical, and pathological findings of 16 children with a primary central nervous system (CNS) sarcoma are reported. There were 8 (50%) girls and 8 (50%) boys ranging in age from 4 months to 14 years (mean age 4.8 years). Four patients (23%) were in their 1st year of life. Fourteen children (87%) had an intracranial sarcoma, and 2 (13%) had intraspinal tumors. Nine intracranial tumors (60%) were supratentorial. The parietal and temporal regions were the most frequently involved sites. Characteristic imaging findings included tumor cysts in 7 patients and marked tumoral enhancement in 9 (69%) with intratumoral calcification and hemorrhage. All patients underwent at least one operation to surgically remove the tumor with the aim of maximal resection and 3 patients underwent a second resection due to a recurrent tumor. Resection was total in 9 (53%) patients and subtotal in another 7 (41%). Dural attachment by tumor was confirmed in 7 (44%) patients and parenchymal invasion was present in 9 (56%). In one-third of the patients there was a well-defined plane of dissection around the tumor. Postoperative radiation was used in 10 patients. Postoperative chemotherapy was used in all but 2 patients. Immunohistochemical studies were available in 13 patients with the most consistent finding being strong vimentin positivity. Five out of the 6 patients in whom the proliferation markers were obtained demonstrated a high proliferation index (Ki-67 labeling index, 20–50%). The mean length of survival in the group was 4.6 years (range 1 month to 16 years). Children who presented in the 1st year of life had shorter survival than those who presented at an older age. Six patients (40%) had cerebrospinal fluid (CSF) dissemination of the tumor. CSF dissemination was associated with a shorter mean survival of 1.9 years. Our review of this series of patients indicates the requirement for adjuvant therapy and for continued efforts to classify tumor subtypes aimed at optimizing future treatments for patients with a primary CNS sarcoma.

Neurenteric cysts (NCs) are endothelium-lined structures of presumed endodermal origin. There have been few pediatric series of intracranial NCs reported previously. The authors present their experience in the management of these lesions.A retrospective chart review of all cases of NCs identified between 1977 and 2007 was carried out. Demographics, details of clinical presentation, surgical therapy, and outcome data were extracted.Eleven cases were identified, involving 6 girls and 5 boys. The patients' average age was 4.6 years (range 1 day-14 years). Limb weakness was the most common presenting symptom. The location of the cysts was cervical in 2 cases, cervicothoracic in 4 cases, and thoracic in 3 cases. One cyst was anterior to the pons with extension to the left cerebellopontine angle and 1 cyst was at the craniocervical junction. Five patients had an apparently complete initial excision, with 1 recurrence. Four patients were initially treated with incomplete excision and/or cyst drainage, usually into an Ommaya reservoir. A neonate with a large cervicothoracic cyst died of multiple congenital anomalies without any intervention. All other patients were alive at last follow-up. One patient with a radiologically identified presumed cyst, which remained stable, was simply followed up. Several patients required multiple procedures and 1 patient developed hydrocephalus after aseptic meningitis and was treated with CSF shunting.Neurenteric cysts are rare in the pediatric population. Total resection, if possible, provides the best long-term outcome. Incomplete excision may lead to multiple procedures, including cyst drainage, but can lead to long-term stability.

Moyamoya vasculopathy is characterized by progressive stenosis of the major arteries of the Circle of Willis, resulting in compromised cerebral blood flow and increased risk of stroke. The objectives of the current study were to examine intellectual and executive functioning of children with moyamoya and to evaluate the impact of moyamoya type, stroke (clinical or silent), vasculopathy laterality, and disease duration on neurocognitive abilities. Thirty pediatric participants (mean age 10 y 10 mo, SD 4 y; 18 females, 12 males) completed age-appropriate Wechsler Intelligence Scales before any therapeutic revascularization procedures. Reports of executive function were obtained from parents and teachers using the Behavior Rating Index of Executive Function. Children with moyamoya scored significantly lower than the test standardization samples on all indices of intelligence and ratings of executive functioning (p0.001). Patients did not differ by type of moyamoya or history of stroke. Patients with bilateral disease and stroke scored significantly lower than those with unilateral disease on measures of overall intellectual function (p=0.035) and verbal comprehension (p=0.04). Deficits in metacognitive executive functions were also more pronounced in bilateral patients according to teacher ratings. Children with moyamoya are at risk for intellectual and executive problems, exacerbated by bilateral disease and clinical stroke history.

Extraaxial infections of the CNS, including subdural empyema and epidural abscess, are rare but potentially life-threatening conditions. Symptoms are usually progressive, and early diagnosis is therefore important. Early intervention with appropriate treatment offers the best opportunity for eradicating the infection and promoting maximal neurological recovery.The medical records of children with extraaxial CNS infection over the last 24 years at the Hospital for Sick Children were analyzed. Only those patients with radiological and/or operative confirmation of the diagnosis of subdural empyema or epidural abscess were included in the study. Demographic and clinical data were collected to determine the outcomes after such infections and factors that predict for such outcomes.The authors identified 70 children who fulfilled the inclusion criteria. Sinusitis was the most common etiology and was seen in 38 patients. All of these patients were older than 7 years of age at diagnosis. Subdural empyemas were diagnosed in 13 patients following bacterial meningitis, and they were found primarily in infants within the 1st year of life. Other etiological factors included otogenic infection (4 cases), postneurosurgical infection (7 cases), and hematogenous spread of infection (7 cases including 6 cases of spinal epidural abscess). Streptococcus anginosus and Staphylococcus aureus were the most common pathogens identified. Sixty-four patients (91.4%) underwent at least 1 neurosurgical procedure. Seizures and cerebral edema from cortical vein thrombosis were the most common complications.Due to variable etiology, identification of the responsible microorganism through neurosurgical drainage followed by long-term intravenous antibiotics remains the mainstay in treating extraaxial CNS infections. Optimal outcome is achieved with early diagnosis and therapy.

Pediatric brainstem tumors (BST) comprise a heterogeneous group of entities. Data regarding treatment options and outcome of BST, specifically brainstem low grade tumors (BSLGT) are limited. In order to better define risk groups and evaluate treatment options for pediatric BST, we performed a comprehensive analysis of all BST patients treated in our hospital during the MRI era.We retrospectively analyzed clinical, imaging, and pathology data at presentation, treatment, and outcome of all BST patients followed at the Hospital for Sick Children in Toronto over the last 25 years.Of 1,801 children with brain tumors, 223 (12%) had a brainstem primary location. Tumors without pontine involvement were BSLGT in 98.3%, whereas 75% of tumors involving the pons were high grade (P = 0.0001). Patients with BSLGT had 5-year progression-free survival (PFS) and overall survival (OS) of 57 ± 3% and 89 ± 5%, respectively. Upfront observation of tumor residual conferred no survival disadvantage with 5-year PFS and OS of 57 ± 5% and 93 ± 3%, respectively. In the group of patients requiring further treatment, 5-year PFS and OS were comparable between chemotherapy and radiotherapy with 53 ± 12% and 93 ± 4% and 66 ± 11% and 83 ± 6%, respectively (P = 0.26 and 0.3, respectively).BST without pontine involvement are almost invariably BSLGT. Children with BSLGT have an excellent outcome even with careful initial observation. No clear benefit was observed for radiotherapy over chemotherapy when adjuvant treatment was needed. A conservative approach may be warranted for children with non-pontine brainstem lesions.

Chemotherapy is widely accepted as first-line therapy for pediatric low-grade gliomas (LGG). Treatment modalities for further progression are not clearly established. The aim of the study was to determine the feasibility and long-term outcome of repeated chemotherapy for children with recurrent LGG.The study group consisted of patients who received a second line of chemotherapy at progression of their LGG. We compared toxicity, progression-free survival (PFS), and overall survival (OS) of patients treated with chemotherapy at the time of initial diagnosis and patients who received another treatment with chemotherapy at further progression.Between 1985 and 2009, 118 patients received chemotherapy as primary treatment for LGG, 38 had repeated chemotherapy at further progression. Chemotherapy was tolerated extremely well. Ninety-two percent of patients completed their second line protocol and toxicity was comparable between initial and second line chemotherapy. Five-year OS and PFS were 86 ± 6% and 37 ± 8%, respectively, which were similar to first-line chemotherapy (P = 0.14). Repeated chemotherapy courses were not associated with worsening of visual, neuroendocrine, or other long-term organ sequelae.This study demonstrates high feasibility and low mortality of repeated chemotherapy treatment for progressive LGG. The chronic nature of LGG concerning tumor progression justifies consideration of non-toxic second-line treatment regimens at the time of recurrence. Prospective studies focusing on toxicity and long-term outcome are needed to substantiate this approach.