Magimairajan Issai Vanan

DIPG in Children – What Can We Learn from the Past?

Brainstem tumors represent 10–15% of pediatric central nervous system tumors and diffuse intrinsic pontine glioma (DIPG) is the most common brainstem tumor of childhood. DIPG is almost uniformly fatal and is the leading cause of brain tumor-related death in children. To date, radiation therapy (RT) is the only form of treatment that offers a transient benefit in DIPG. Chemotherapeutic strategies including multi-agent neoadjuvant chemotherapy, concurrent chemotherapy with RT, and adjuvant chemotherapy have not provided any survival advantage. To overcome the restrictive ability of the intact blood–brain barrier (BBB) in DIPG, several alternative drug delivery strategies have been proposed but have met with minimal success. Targeted therapies either alone or in combination with RT have also not improved survival. Five decades of unsuccessful therapies coupled with recent advances in the genetics and biology of DIPG have taught us several important lessons (1). DIPG is a heterogeneous group of tumors that are biologically distinct from other pediatric and adult high grade gliomas (HGG). Adapting chemotherapy and targeted therapies that are used in pediatric or adult HGG for the treatment of DIPG should be abandoned (2). Biopsy of DIPG is relatively safe and informative and should be considered in the context of multicenter clinical trials (3). DIPG probably represents a whole brain disease so regular neuraxis imaging is important at diagnosis and during therapy (4). BBB permeability is of major concern in DIPG and overcoming this barrier may ensure that drugs reach the tumor (5). Recent development of DIPG tumor models should help us accurately identify and validate therapeutic targets and small molecule inhibitors in the treatment of this deadly tumor.

Validation of the Symptom Screening in Pediatrics Tool in Children Receiving Cancer Treatments

Abstract Background The objective was to evaluate the reliability and validity of the self-report Symptom Screening in Pediatrics Tool (SSPedi) from the perspective of children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients. Methods In this multicenter study, respondents were children age eight to 18 years who had cancer or had received HSCT, and their parents. Two different child respondent populations were targeted. More symptomatic respondents were receiving active treatment for cancer, admitted to the hospital, and expected to be in the hospital three days later. Less symptomatic respondents were in maintenance therapy for acute lymphoblastic leukemia or had completed cancer therapy. Children completed SSPedi and then responded to validated self-report measures of mucositis, nausea, pain, and global quality of life. Children in the more symptomatic group repeated SSPedi and a global symptom change scale three days later. Parent proxy-report was optional. Reliability was evaluated using intraclass correlations while convergent validity was evaluated using Spearman correlations. Results Of 502 children enrolled, 302 were in the more symptomatic group and 200 were in the less symptomatic group. Intraclass correlation coefficients were 0.88 (95% confidence interval [CI] = 0.82 to 0.92) for test-retest reliability and 0.76 (95% CI = 0.71 to 0.80) for inter-rater reliability. The mean difference in SSPedi scores between more and less symptomatic groups was 7.8 (95% CI = 6.4 to 9.2). SSPedi was responsive to change in global symptoms. All hypothesized relationships among measures were observed. Conclusions SSPedi is a self-report symptom bother tool for children with cancer and HSCT recipients that is reliable, valid, and responsive to change. SSPedi can be used for clinical and research purposes. Future work should focus on integration into care delivery.

Targeting Epigenetic Pathways in the Treatment of Pediatric Diffuse (High Grade) Gliomas

Progress in the treatment of adult high-grade gliomas (HGG), including chemoradiation with concurrent and adjuvant temozolomide for glioblastoma, has not translated into significant therapeutic advances for pediatric HGG, where overall survival has plateaued at 15% to 20%, especially when considering specialized pediatric treatment in tertiary care centers, maximal safe neurosurgical resection, optimized delivery of involved field radiation, and improvements in supportive care. However, recent advances in our understanding of pediatric HGG, including the application of next-generation sequencing and DNA methylation profiling, have identified mutations in the histone variant H3.3 and canonical H3.1 genes, respectively. These mutations are relatively specific to neuroanatomic compartments (cortex, midline structures, thalamus, brainstem) and are often associated with other mutations, especially in specific growth factor receptor tyrosine kinases. Targeting epigenetic pathways affected by these histone mutations, alone or in combination with small molecule inhibitors of growth factor receptor signaling pathways, will inform new treatment strategies for pediatric HGG and should be incorporated into novel cooperative group clinical trial designs.

Pharmacological inhibition of the protein kinase MRK/ZAK radiosensitizes medulloblastoma

Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient–derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage–induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patient–derived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects. Mol Cancer Ther; 15(8); 1799–808. ©2016 AACR.

Describing symptoms using the Symptom Screening in Pediatrics Tool in hospitalized children with cancer and hematopoietic stem cell transplant recipients

Objectives were to describe any bothersome symptom and severely bothersome symptoms in inpatient children with cancer and hematopoietic stem cell transplant (HSCT) recipients. We included children 8–18 years of age with cancer or HSCT recipients who were receiving active treatment for cancer, admitted to hospital, and expected to be in hospital 3 days later. We administered the self‐report Symptom Screening in Pediatrics Tool (SSPedi). We described those who identified any degree of symptom bother (at least “a little”) and those who rated the degree of bother as severe (“a lot” or “extremely”). Factors associated with severe symptoms and total SSPedi scores were examined using multiple logistic and linear regression. Among the 302 patients, 298 (98.7%) reported having any bothersome symptom and 181 (59.9%) had at least one severely bothersome symptom. In multiple regression, older children were significantly more likely to have at least one severely bothersome symptom (15–18 and 11–14 years vs. 8–10 years; P = 0.008) and to have higher total SSPedi scores (P = 0.0003). Those with relapsed disease were more likely to have at least one severely bothersome symptom (odds ratio 2.1, 95% confidence interval 1.1–4.3; P = 0.037) and HSCT recipients were more likely to have higher symptom scores (β = 3.48, standard error = 1.6; P = 0.030). Almost all children receiving cancer therapies experience bothersome symptoms and 60% have at least one severely bothersome symptom. Older children experienced more severely bothersome symptoms and higher symptom scores. Future studies should follow children longitudinally to better understand the symptom trajectory and should institute interventions to manage symptoms.

Reirradiation in Patients with Diffuse Intrinsic Pontine Gliomas: The Canadian experience

Clinical trials have failed to demonstrate a survival benefit of adjuvant chemotherapy in diffuse intrinsic pontine gliomas (DIPG). Radiation therapy (RT) is the only effective treatment thus far and reirradiation (rRT) has become an option at the time of progression. The aim of this study was to review the Canadian experience of DIPG rRT with a focus on the safety and possible efficacy of this approach.

High-Grade Glioma

High-grade gliomas (HGGs) constitute approximately 10 % of all childhood brain tumors and include AA (anaplastic astrocytoma), anaplastic oligodendroglioma (AO), and glioblastoma (GBM). Clinical symptomatology varies greatly with age and can be nonspecific, especially in younger children. Conventional MRI along with functional imaging has increased the diagnostic yield and improved surgical management of these patients. Routine histopathologic diagnosis is based on tissue obtained from biopsy or preferably resection of the tumor; central neuropathological review is recommended. The majority of pediatric HGGs are biologically distinct from adult malignant gliomas; these differences may explain responses to therapy and clinical outcomes. The recently proposed integrated genomic classification identifies six distinct biological subgroups of GBM in children and adults. Driver mutations in genes affecting histone H3.3 (K27M and G34R/V) coupled with mutations involving specific proteins (TP53, ATRX, DAXX) induce defects in chromatin remodeling and may play a central role in the genesis of pediatric HGGs. The current standard of care in pediatric HGGs include surgical resection followed by RT (in children >3years) with concurrent and adjuvant chemotherapy with temozolomide. However, these multimodality treatment strategies have had a minimal impact on improving survival. Ongoing clinical trials are investigating new molecular targets, chemoradiation sensitization of tumor cells, and immunotherapy. Future clinical trials of pediatric HGGs should incorporate the distinction between GBM subgroups and stratify patients using group-specific molecular markers.

31 Intracranial growing teratoma syndrome (IGTS): An international retrospective study

BACKGROUND: IGTS is a rare phenomenon of paradoxical germ cell tumor (GCT) growth during or following treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of IGTS in patients in 21 North-American and Australian institutions. METHODS: Patients with IGTS diagnosed from 2000-2017 were retrospectively evaluated. RESULTS: Out of 739 GCT diagnoses, IGTS was identified in 33 patients (4.5%). IGTS occurred in 9/191 (4.7%) mixed-malignant GCTs, 4/22 (18.2%) immature teratomas (ITs), 3/472 (0.6%) germinomas/germinomas with mature teratoma, and in 17 secreting non-biopsied tumours. Median age at GCT diagnosis was 10.9 years (range 1.8-19.4). Male gender (84%) and pineal location (88%) predominated. Of 27 patients with elevated markers, median serum AFP and Beta-HCG were 70 ng/mL (range 9.2-932) and 44 IU/L (range 4.2-493), respectively. IGTS occurred at a median time of 2 months (range 0.5-32) from diagnosis, during chemotherapy in 85%, radiation in 3%, and after treatment completion in 12%. Surgical resection was attempted in all, leading to gross total resection in 76%. Most patients (79%) resumed GCT chemotherapy/radiation after surgery. At a median follow-up of 5.3 years (range 0.3-12), all but 2 patients are alive (1 succumbed to progressive disease, 1 to malignant transformation of GCT). CONCLUSION: IGTS occurred in less than 5% of patients with GCT and most commonly after initiation of chemotherapy. IGTS was more common in patients with IT-only on biopsy than with mixed-malignant GCT. Surgical resection is a principal treatment modality. Survival outcomes for patients who developed IGTS are favourable.

Diffuse Intrinsic Pontine Glioma

Diffuse intrinsic pontine gliomas (DIPGs) are almost uniformly fatal, predominantly affect children, and are the most common brainstem tumors of childhood. DIPG is diagnosed based on characteristic magnetic resonance imaging (MRI) findings in a child with typical clinical features, and routine biopsy for tissue diagnosis is not currently part of the standard of care. Surgical resection is not considered an option due to critical tumor location, and the beneficial effects of radiation therapy are only transient and at best considered palliative. Chemotherapy, given as single or multiple agents, with and without radiation, has had no demonstrable impact on the outcome of these tumors. Multiple clinical trials using novel treatment strategies and new therapeutic agents have not improved prognosis in the past two decades. Recent integrated genomic studies identify many DIPG as distinct from the pediatric and adult supratentorial high-grade gliomas (HGG). Chromatin remodeling defects in the developing brain due to recurrent somatic driver mutations affecting the histone 3 variant protein, H3.3 (H3.3-K27M) in association with mutations involving specific genes (TP53, PDGFRA, MYC/PVT1) may play a pivotal role in the pathogenesis of DIPG tumors. Future clinical trials should be based on molecular classification of tumor tissue obtained from biopsy, as this will help in better treatment stratification and more specific targeted therapies.