A Children’s Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor

This study was performed to gain a better understanding of the genetic changes which lead to the development of Wilms tumours.
117 high-risk Wilms tumors (favorable histology tumors which had relapsed, or tumors with diffuse anaplasia) were evaluated through whole genome sequencing, analysis of mRNA and miRNA expression, DNA copy number, and DNA methylation status.
Commonly affected genes were those previously known - CTNNB1, DGCR8, DROSHA, MLLT1, MYCN, SIX1, SIX2, TP53, WT1, and AMER1. Other mutations not previously described were also reported here. CTNNB1 was the gene most commonly mutated in Wilms tumors. Germline mutations were found in 10 % of patients with Wilms tumors. Subgroups were proposed based on expression patterns and DNA methylation patterns. While some mutations and copy number variations segregate with these groups, they do not have any clear clinical significance.
This study was based on genetic and methylation analysis of Wilms tumor, and did not evaluate protein expression profiles. The extent of DNA methylation analysis was limited. Only "high risk" tumors were investigated.
The results demonstrate that many different genetic changes occur in Wilms tumors, which may converge on common pathways. The epigenetic regulation of transcription in early renal development is likely an important area to explore in future studies.

A phase 1 study of the c-Met inhibitor, tivantinib (ARQ197) in children with relapsed or refractory solid tumors: A Children’s Oncology Group study phase 1 and pilot consortium trial (ADVL1111)

A phase 1 and pharmacokinetic trial evaluating tivantinib (oral small molecule that inhibits the c-Met receptor tyrosine kinase) was conducted by the COG for children with relapsed/refractory solid tumors. The goals of this trial were to define a recommended dose for subsequent phase 2 pediatric studies, describe the pharmacokinetics of tivantinib in pediatric patients when administered as either a solid or power form with food, do a preliminary investigation of any impact of CYP2C19 genotype and c-Met expression on pharmacokinetic or clinical parameters.
A rolling-six design was used for dose escalation. In Part A, oral capsules were administered in 28-day cycles. Three doses (170, 200, 240mg/m2/dose) were evaluated. In Part B, participants received the drug in powder sprinkled on food at the phase 2 dose from Part A.
Thirty-six participants were enrolled (20 in Part A, 6 in a pharmacokinetic expansion cohort, 10 in Part B). Fifteen patients had primary CNS tumors and 21 had solid tumors. There were no dose-limiting toxicities in Part A. One patient with a progressive brain tumor in the pharmacokinetic cohort (240mg/m2) developed a grade 4 intracranial hemorrhage. The grade 1 or 2 toxicities occurring in more than 10% of evaluable patients included anemia, lymphopenia, leukopenia, neutropenia, fatigue, vomiting, nausea, hypoalbuminemia, and thrombocytopenia. There were highly variable pharmacokinetics amongst participants. Sprinkled power did not alter exposure. The best response was stable disease in 2 patients.
Only 26 patients were evaluable for toxicity assessment (10 did not receive 80% of the prescribed study drug so were not evaluable). The 10 who were not evaluable did not experience dose-limiting toxicities.
Oral tivantinib was well tolerated when delivered with food in children with relapsed refractory solid tumors. The recommended phase 2 dose was 240mg/m2/dose. Objective responses were not observed in this trial, multi-agent treatment strategies might be more promising.

Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma

This is a phase 1/2 study of sonidegib, an inhibitor of upstream components of the sonic hedgehog pathway (Hh, PATCH and Smoothened-driven tumors) in patients with relapsed disease (MB and other solid tumors). For the phase 2 component, this agent was tested in children/adults with relapsed MB.
Phase 1: Children with histologically confirmed recurrent MB, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, or high grade glioma were eligible. Sonidegib was given once daily orally. Recommended phase 2 dose (RP2D) was the highest tolerated dose with at least 6 patients evaluated.
Phase 2: Children and adults with recurrent MB were included for study at the RP2D. Tumor response was assessed every 8 weeks.
Sixty pediatric patients were enrolled (59 on phase 1, 1 on phase 2). Thirty-nine of these patients had MB. For phase 2, 16 adults were enrolled. RP2D was found to be 680 mg/m2/dose. Median treatment exposure was 55 days for pediatric patients and 97 days for adults. Grade 3/4 CPK elevation occurred in 2 pediatric patients and 5 adults, with no evidence of renal dysfunction in the pediatric patients. Three children showed evidence of growth plate closure while on study.
Response was seen in 2/60 pediatrics patients and 3/16 adult patients (2 CRs and 1 PR), all of whom had MB. All 5 responses were within the SHH group. Both pediatric patients with CR stopped treatment after 9 months. Duration of response was 21 months in one of these patients, and the other remains in remission at 49 months. For the adult responders, duration was 1.6 and 8.7 months for the patients in CR and 4.8 for the patient in PR. Stable disease was seen in 11 patients (5 pediatric, 6 adult, all with MB). All other patients had progressive disease.
Not all tissue was evaluated for SHH activation. The tissue that was evaluated could not differentiate between upstream vs downstream activation of the SHH pathway (sonidegib inhibits in the upstream portion of the pathway). The study did not require tissue from the time of recurrence to assess for additional alterations, so archival tissue may not represent changes as a result of radiation or chemotherapy. It is unclear why some patients had stable disease in the absence of SHH pathway activation.
Sonidegib has activity as a targeted agent for some patients with recurrent SHH MB in this phase 1/2 trial. Toxicities observed include CPK elevation without organ impairment and concern for premature growth plate closure in pediatric patients.

Intracystic interferon-alpha in pediatric craniopharyngioma patients: an international multicenter assessment on behalf of SIOPE and ISPN

Craniopharyngioma is a hypothalamic tumor in children with difficult treatment due to the location of this tumor given the neurologic, endocrine, metabolic and optic complications that can arise from surgery or radiation. Given that most craniopharyngiomas in children are cystic, and the epithelial cells share their origin with squamous epithelium, intracystic interferon (IFN) has been used. Institutional reports have previously been published demonstrating some promise of activity, but this is the first international cohort published. The report describes efficacy with delay or prevention of progression and need for definitive therapy (radiation/surgery), as well as toxicity and clinical outcome.
Patients from SIOPE and ISPN from 0-18 years of age with histologically proven or radiologically suspected craniopharyngioma who were treated with intracystic IFN alpha were included for the study.
Fifty-six patients from 21 centers were included. Twenty-two patients had purely or predominantly cystic lesions.
Intracystic IFN was first line therapy in 13 patients, with remaining patients treated with cyst fenestration/aspiration, surgical excision, radiation or radioisotope therapy upfront. Seventeen patients had been treated with radiation prior to intracystic IFN with median time to progression 2 years (range 0.3-9 years).
Median follow up after IFN therapy was 2.7 years. Five patients died (2 from tumor progression, 1 from endocrinopathy induced electrolyte imbalance and 2 from unrelated infections). IFN seemed to delay time to progression compared to each child's previous treatment. Further review revealed that delay was seen only in the group with predominantly cystic lesions, compared to those solid/cystic lesions. Forty-two patients had disease progression following IFN, median time 14 months (range 0-8 years). Twenty-three patients had no adverse side effects.
This is a retrospective study with limited patient numbers. Most patients had been previously treated and different regimens and number of cycles of intracystic IFN were used across different centers. The use of interferon was based on physician and patient preference. This is largely descriptive and it is difficult to make definitive conclusions based on this data.
Intracystic IFN remains a promising agent, and this study shows a prolonged PFS in predominantly cystic lesions compared to previous treatments with less morbidity than current standard therapy.

Perioperative management of hypertensive neuroblastoma: A study from the Italian Group of Pediatric Surgical Oncologists (GICOP).

Retrospective multicenter survey of patients with Neuroblastoma and hypertension from the Italian Registry of Neuroblastoma who underwent surgical resection between 2006 and 2014.
Hypertension (HT) defined as BP higher than 99th percentile + 5mm Hg. Of 1126 patients with NB, only 25 patients had HT (2.2%). Of 25 patients with HT and NB, 21 patients underwent surgical resection and were included in the analysis
Median age 15 months, Stage 1 (24%), Stage 2 (43%), Stage 4 (34%), MYCN amplification neg. in 95%, VMA/HVA – 57% normal. 89% of normal BP patients had elevated VMA/HVA versus 43% of HT patients. Norepinephrine only analyzed in 3 high BP patients – all elevated. Renal pedicle involvement – 38%. Renal size – normal in all patients. No evidence of cardiac HT-related complications on preop echo analysis. 86% received an antihypertensive treatment (various agents). Intraoperative HT peaks treated predominantly with alpha1 blockers (5 patients). 6 patients had persistent HTN despite complete tumor resection in 4.
Small number of patients, No analysis of renal artery stenosis, renal flow etc. so while no evidence of renal parenchymal size change, incomplete analysis. Heterogenous treatment of HT preoperatively means no definite therapeutic protocol can be recommended.
Given limited number of patients, this retrospective review doesn't add markedly to the literature, however, the incidence of postresection HT and the risk factors for same (renal pedicle involvement) might be helpful for prognostication.

MIBG avidity correlates with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children’s Oncology Group

Neuroblastomas that are MIBG non-avid may have more favorable characteristics compared with MIBG avid tumors. Prior work from this group demonstrated that MIBG non-avid tumors lead to superior event-free survival (EFS) compared to MIBG avid tumors in high-risk disease. The goal of this study was to compare clinical features, tumor biology, and clinical outcomes between patients with MIBG avid and non-avid disease for patients with intermediate- and high-risk disease. This study was conducted by the COG.
Patients had metastatic high- or intermediate-risk neuroblastoma and treated on COG protocols A3973 or A3961. Clinical and biologic features according to MIBG avidity were compared. EFS and overall survival (OS) were compared.
Three-hundred and six patients had high-risk disease, and 37 had intermediate-risk disease. Thirty of 343 patients (8.7%) had MIBG non-avid disease. Non-avid tumors were less likely to have adrenal primary tumors, bone metastases, and positive urine catecholamines compared with MIBG avid tumors. Non-avid tumors were more likely to be MYCN amplified and had lower norepinephrine transporter expression. The 5-year EFS for MIBG non-avid tumors was 50% compared with 38.7% for MIBG avid tumors (p=0.028). In high-risk patients, MIBG avidity was the sole adverse prognostic factor for EFS.
This analysis was limited to patients with metastatic disease. It is not clear if these results can be generalized to non-metastatic disease.
Patients with MIBG non-avid tumors had superior outcomes compared with MIBG avid disease, despite a higher likelihood of MYCN amplification.

A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study

Low grade gliomas (LGGs) are the most common type of brain tumor in children with excellent overall survival. Still, patients with incomplete resection and treatment/tumor progression can be affected with significant morbidity. MAP kinase pathway overexpression was commonly encountered (BRAF V600E mutation and BRAF:KIAA1549 fusion are the most commonly described). Selumetinib is an oral MEK inhibitor (downstream from BRAF in MAPK pathway), which has shown efficacy in xenografts and adults (for pediatrics, see recent NEJM article). This is the phase 1 study for selumetinib in LGG to describe the toxicity profile, phase 2 dose recommendation and pharmacokinetics.
Patients between 3-21 years of age with pathologically proven LGG were included who have been treated with 1 or more previous regimens. Patients with optic pathway gliomas and prior BRAF or MEK inhibitors treatment were excluded.
Pharmacokinetics were measured after the first dose of selumetinib. Pathology specimens were tested for MAPK pathway activation using immunohistochemistry for ERK (downstream from BRAF). Where possible, FISH was done to look for BRAF fusion and PCR was done to look for BRAF mutation.
Thirty-eight patients were enrolled on the study. Most patients had pilocytic astrocytoma (n=22) and were previously treated with chemotherapy (n=20) or chemotherapy plus radiation (n=18). All patients with pathology evaluated (n=20) had evidence of MAPK activation with IHC positive for ERK. 25 mg/m2/dose were identified as the recommended dose for phase 2 with 3/24 patients experiencing DLTs (all were over 12 years of age, and rash, diarrhea and elevated CPK being the most common).
There were 5 PRs at the recommended dose level (3 with BRAF fusion or mutation, 1 with both - fusion and mutation - and 1 with tissue that could not be evaluated). Seventeen patients progressed (7 while on treatment, 10 after discontinuing selumetinib. Median follow up in patients who did NOT progress was 7.7 months.
PK values were consistent through different doses and age groups.
There is no standard for measuring response to LGG through different studies. Another limitation is that not all patients had tissue to characterize the method of activation of MAPK pathway. The authors only screened for the most common alterations. This may be important given that previous studies have demonstrated paradoxical activation of the MAPK pathway with progression seen in patients with BRAF fusion who are given a BRAF inhibitor (i.e. dabrafenib), however this did not seem to be the case in this trial.
Selumetinib is tolerable in children, and the RP2D is 25 mg/m2/dose. Some activity was seen although further studies are needed with stratification based on type of alteration and NF-1 status.

Paratesticular rhabdomyosarcoma in children and adolescents-Outcome and patterns of relapse when utilizing a nonsurgical strategy for lymph node staging: Report from SIOP Malignant Mesenchymal Tumour 89 and 95 studies.

Surgical staging with ipsilateral retroperitoneal lymph node sampling is currently required for all children aged 10 years and older with paratesticular rhabdomyosarcoma on COG-STS studies. However, node dissection was not routine in Europe for adolescents with resected paratesticular rhabdomyosarcoma. Many European investigators relied on radiographic, rather than surgical-pathologic assessment, for retroperitoneal lymph node involvement because of the high morbidity of the surgical assessment. This study aims to review all patients with nonmetastatic paratesticular RMS enrolled in International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumour (MMT) 89 and 95 trials and to report the outcomes and patterns of relapse when utilizing a nonsurgical strategy for lymph node (LN) staging.
Patients with paratesticular rhabdomyosarcoma were evaluated with imaging but did not undergo routine ipsilateral lymph node sampling. Biopsy or fine-needle aspiration cytology was performed on regional nodes if there was clinical or radiologic uncertainty about LN involvement.
159 patients with localized paratesticular RMS were included in this study between 1989 and 2003. 25% of these patients were more than 10 years of age. Thirty-one percent of stage N0 patients of age ≥10 years developed node relapse, compared with
8% of N0 patients aged 5 years (42%) and three nodal relapses occurred in 15 patients with tumors >5 cm (20%, P = 0.27) (size was unknown for one patient).
When nodal relapse occurred in this group, it was predominantly in patients with tumors >5 cm. This was not statistically significant likely due to the size of the population. This study did not explore if there is a superiority of one of the 3 different radiological imaging (US, CT, MRI). Finally, the utilization of PET scan as part of the disease staging is also a possible way to improve staging without the morbidity of surgical assessment. It is something that can eventually be explored.
Older patients with paratesticular rhabdomyosarcoma (≥10 years) have a significant risk of LN relapse. These results support a surgical approach to LN staging in this subgroup of patients. The SIOP MMT group subsequently recommended ipsilateral lymph node sampling for all patients aged 10 years and older.

45 Gy is not sufficient radiotherapy dose for Group III orbital embryonal rhabdomyosarcoma after less than complete response to 12weeks of ARST0331 chemotherapy

In this paper, the COG retinoblastoma group assessed the efficacy of 45 Gy local radiotherapy in patients with Group III orbital embryonal rhabdomyosarcoma (ERMS) enrolled on the low-risk study ARST0331. More particularly, they assessed whether initial response to chemotherapy predicted outcome for patients with unresected orbital ERMS.
62 patients on ARST0331 had orbital Group III disease. Patients received four cycles of VAC followed by four cycles of VA over 22 weeks and RT starting after 12 weeks of chemotherapy. Complete response (CR) was defined as complete disappearance of the tumor by exam and imaging. Local recurrences, EFS and OS were also reported.
The 5-year EFS and OS for the entire cohort of 62 patients was 87% and 97% respectively. Fifty-three patients were evaluable for the response analysis. Fifteen patients had a CR to VAC chemotherapy. Local control on this study was worse than in the previous IRS-IV study with more intensive therapy.
Although none of the patients with early CR relapsed, this difference did not reach statistical significance.
This study was not the primary outcome of ARST0331 and was apparently underpowered to detect small differences. Also, this study did not explore the utilization of PET CT as a way to assess response after 12 weeks.
For patients with Group III orbital ERMS with CR after induction chemotherapy, the ARST0331 treatment algorithm is associated with lower poorer local control than was achieved on the more intensive IRS-IV therapy and warrants consideration of different local treatment algorithms. Dose escalation to 50.4 Gy for patients with Group III
orbital ERMS on a backbone of ARST0331 chemotherapy could be an option to explore.

Open-label, multicentre, randomised, phase II study of EpSSG and the ITCC evaluating the addition of bevacizumab to chemotherapy in childhood and adolescent patients with metastatic soft tissue sarcoma (the BERNIE study)

This paper reported on the results of a European pediatric Soft tissue sarcoma Group (EpSSG) and the European Innovative Therapies for Children with Cancer (ITCC) consortium. It was a multi-center, randomized phase II study that evaluated the addition of bevacizumab to standard chemotherapy in children and adolescents with metastatic rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).
Patients were randomized to receive standard induction chemotherapy ( IVADo/IVA) or standard chemotherapy plus bevacizumab (7.5mg/kg every 3 weeks), surgery and/or radiotherapy, followed by maintenance chemotherapy (low dose cyclophosphamide and vinorelbine) with bevacizumab added to the experimental arm at 5mg/kg every 2 weeks of each cycle. The primary objective was event free survival (EFS).
154 patients in the study. 80 with standard chemotherapy and 74 standard chemotherapy plus bevacizumab. Disease histologies were evenly matched in the two arms.
The addition of bevacizumab to the chemotherapy backbone used in metastatic soft tissue sarcoma appeared tolerable but the primary end-point of event free survival did not show statistically significant improvement.
The lack of statistical significance for the primary end point may reflect the fact that the sample size, although realistic for this rare tumor population, was inadequate to show a treatment effect.
While the addition of bevacizumab to standard chemotherapy for metastatic soft tissue sarcoma in children and adolescents was well tolerated the primary end-point of event free survival did not show statistically significant improvement.

Therapeutic and Prognostic Implications of the BRAF V600E in Pediatric Low-Grade Gliomas

Pediatric low-grade gliomas (PLGGs) are a heterogeneous group of tumours. BRAF V600E-mutatant PLGGs are thought to represent a unique, more aggressive subtype, however this is controversial. BRAF V600E is a potentially targetable mutation.
Retrospective study. Genetic, clinical, treatment, and outcome data from an unselected group of patients with PLGGs from a single centre database (Toronto, n=405) compared to outcomes from an independent cohort of patients with BRAF V600E-mutated PLGG from 18 collaborating international pediatric centres (n= 180).
BRAF V600E mutation was detected in 17% patients with PLGG in the Toronto cohort and these patients had worse outcome compared to wild-type PLGGs with 10-year PFS 27% vs 60% and OS 84% vs 92%. PFS and OS were similar when compared to independent cohort outcomes. Multivariate analysis identified that patients with BRAF V600E mutation, CDKN2A deletion and incomplete resection had the worst prognosis. Six patients treated with BRAF inhibitor after progression with conventional therapy had significant response, median follow up 18.5 months.
Single centre study but compared outcomes to smaller international cohort which demonstrates similar outcomes. Too few patients from one centre to truly understand the role of BRAF inhibitors in this patient population.
BRAF V600E PLGGs are unique group with worse disease course. May be beneficial to biopsy all LGGs to assist with treatment decisions.

The clinical significance of equivocal findings on spinal MRI in children with medulloblastoma

Children with medulloblastoma and spinal metastasis receive an increased dose of craniospinal irradiation (CSI). This article aimed to describe cases of equivocal abnormalities (nerve root clumping, linear vascular enhancement, nerve root enhancement and other vague findings) as they relate to prognosis. This is a single-centre, retrospective review.
Children ≥ 3 years of age diagnosed with medulloblastoma between 1988 and 2012 who were treated with upfront CSI were included. Blinded reviewers assessed the initial spinal MRI for equivocal findings.
100 patients were included, with equivocal findings in 48%. Most (94%) had MRI imaging preoperatively. A higher proportion of the sonic hedgehog (SHH) subgroup patients had equivocal findings (statistically significant). 5-year OS of children with equivocal findings did not differ from those with normal MRI findings (80 vs 84%).
Limitations of this study include retrospective nature and variety of treatment protocols across the time period, limiting comparison of survival outcomes. The imaging reviewers were not all radiologists although one radiologist reviewed each scan.
The presence of equivocal findings were not associated with worse OS compared to patients with normal MRIs, though the significance of the study results should be validated prospectively in the context of contemporary treatment protocols.

Management of adrenal masses in patients with Beckwith–Wiedemann syndrome

This study seeks to outline recommendations for managing incidental adrenal masses in children with Beckwith-Wiedemann syndrome (BWS). Adrenal findings from children followed at the Children’s Hospital of Philadelphia were described.
Adrenal findings of patients in the institutional database were reviewed. A literature review and institutional experience were used to create the guidelines. The COG approach to subdividing age and size classification was used.
Most adrenal masses were detected incidentally on screening ultrasounds done to detect Wilms tumours or hepatoblastomas. 47 patients had adrenal masses - 3 neuroblastoma, 5 pheochromocytoma, 1 adrenocorticocarcinoma. The proposed guidelines risk-stratify patients based on age and clinical features. Patients 6 months, cystic masses can be observed for size increase by ultrasound every 3 months. The evaluation of solid masses depends on MIBG and urine HVA/VMA results and hormone levels (random cortisol, ACTH, 17(OH) progesterone, DHEAS, androstenedione, testosterone).
The details of the literature review were not described so it is unclear if it was performed in a systematic way. These guidelines, though comprehensive, have not been validated prospectively. Many of the patients were not confirrmed to have Beckwith Wiedemann Syndrome (hemihyperplasia by itself is not sufficient for diagnosis) and it is possible that there is a bias towards reporting more aggressive tumours such as neuroblastoma.
This article proposes an approach to evaluating and managing adrenal masses in children with BWS based on age and high-risk features. It is unclear how the data in this paper is used to create these guidelines and so they are best thought of as expert opinion.

Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma.

This research aimed to find an immunotherapeutic target in neuroblastoma other than GD2 with low expression in normal tissue in order to develop new therapies that may be less toxic than dinituximab or to use in relapsed/refractory patients.
Publicly available RNA sequencing data from TARGET (high risk neuroblastoma) and GTeX (control) data were initially used. The group identified membrane-associated proteins highly expressed in neuroblastoma and not in normal tissues. Further studies were then done with the best target (GPC2) to validate its expression levels and to assess its role in neuroblastoma growth. Finally an antibody-cytotoxic conjugate was developed and tested both in cell lines and in a patient-derived xenograft murine model.
GPC2 protein was found to be expressed on the membrane in most neuroblastoma cell lines, tumors, and patient-derived xenografts but at varying levels. It was expressed at lower levels in the esophagus and skin but the tumour-associated protein was a different isoform. Tumors with MYCN amplification and 7q gain had high GPC2 expression. The protein was found to be essential for growth and proliferation of cell lines as was expected as it has been previously shown to be a growth factor receptor. An antibody conjugate against GPC2 was effective both in cell lines and in a patient-derived xenograft murine model. Interestingly, GPC2 is also highly expressed in medulloblastomas and retinoblastomas.
The antibody-drug conjugate hasn't yet been tested in humans and the pharmacokinetics may be different from those in mice.
Very nicely done study indicating a new therapeutic target in neuroblastoma (and potentially also in medulloblastoma and retinoblastoma). Furthermore, this RNA sequencing approach could potentially be used in other difficult tumours to develop immunotherapy.

Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial

Survival for children with high risk neuroblastoma remains approximately 50%. Neuroblastoma cells are sensitive to mTOR inhibitors (such as temsirolimus) in vitro and in vivo. Dinutuximab is a chimeric antibody targeting GD2, which is expressed on neuroblastoma cells. This trial was designed to determine whether dinituximab or temsirolimus should be used in the next front-line trial in combination with chemotherapy.
This open-label, randomized, phase 2 "pick-the-winner" COG trial (ANBL 1221) included patients of any age with neuroblastoma or ganglioneuroblastoma at first designation of relapse, progression, or refractory disease. Patients were excluded if bone marrow was the only site of disease or if they were previously treated for refractory or relapsed disease (including if they previously received irinotecan-temozolomide). Patients all received irinotecan and temozolamide with the randomized addition of either temsirolimus or dinutuximab (plus GM-CSF) in 21-day cycles up to a maximum of 17 cycles. The primary endpoint was the proportion of patients achieving an objective response (complete or partial) after 6 cycles.
Between February 2013 and March 2015, 18 patients received irinotecan-temozolomide-temsirolimus and 17 patients received irinotecan-temozolomide-dinutuximab. Only 1 patient on the temsirolimus arm achieved a partial response while 9 patients on the dinutuximab arm had objective responses. In 7 of the 9 patients who responded to dinutuximab, the best response was seen after only 2 cycles. The toxicity profile of irinotecan-temozolomide-dinutuximab was manageable. Adverse events known to accompany dinutuximab (pain, fever, electrolyte abnormalities) were seen although hematological toxicity was relatively modest.
Small sample size is a limitation. As well, only patients with first episode of relapsed or refractory disease were included, so the role of this therapy in other settings remains unclear. Overall survival may be impacted by other factors such as other therapy following the study treatment. It is unclear how many cycles therapy should be given for.
Irinotecan-temozolomide-dinutuximab showed notable anti-tumor activity in patients with relapsed or refractory neuroblastoma and met criteria for selection as the combination meriting further study. ANBL1221 is an ongoing study now with a single arm but responses in the relapsed population are encouraging as an initial strategy for patients with relapsed/refractory neuroblastoma who have not previously received dinutuximab and can tolerate toxicities of therapy.

A Phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma (protocol POG 9631): A report from the COG

Standard treatment at Children's Oncology Group (COG) institutions for children over the age of 3 years with high-risk medulloblastoma currently includes craniospinal radiation with concurrent chemotherapy, followed by maintenance chemotherapy. This is a Phase II feasibility study from the COG to assess if using oral etoposide concurrently with radiation therapy could improve survival.
This is a cohort study that enrolled patients with high-risk medulloblastoma. All patients underwent surgical debulking, followed by craniospinal radiation and daily oral etoposide on days 1-21 and 29-49 at 50 mg/m^2 per day. A dose limiting toxicity of dysphagia/esophagitis was noted with this dose of etoposide, and therefore the final 38 patients were treated with a lower dose of etoposide (35 mg/m^2). After radiotherapy, the patients received further maintenance chemotherapy.
This study enrolled 53 patients between the ages of 3 and 21 who had high-risk medulloblastoma between November 1998 and October 2002. There was an excellent response to the radiation and oral etoposide, with 19 (40.4%) showing a complete response, 24 (51.1%) showing a partial response and four (8.5%) with no recorded response. Overall 2 and 5 year overall survival (OS) was 80.9% and 76.6% respectively, which is comparable to previous studies. There was no significant difference in outcome between the higher and lower dose treatment groups.
The limitations of this study include the small size of the patient cohort, and also the lack of specific histologic or molecular stratification of tumors. This trial was also run in an era before molecular subgroups were known which limits its current generalizability.
Treatment of high-risk medulloblastoma patients with oral etoposide concurrent with craniospinal radiation shows encouraging survival results when combined with standard adjuvant maintenance chemotherapy. Further studies are required to confirm effect and to identify dose-limiting toxicities. However, these studies may not be done given the current focus on treatment based on molecular subgroup.

Maintenance therapy with everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis (the EMINENTS study)

Everolimus is an mTOR inhibitor which is used in the treatment of patients with tuberous sclerosis (TS), specifically those with subependymal giant cell astrocytomas (SEGAs) which cannot be curatively resected. Current protocols involve daily treatment with everolimus on an ongoing basis, though it has been hypothesized that once the disease has stabilized that the dose may be reduced. This is an important consideration given that, while the short term side effects are considered acceptable, long term side effects of everolimus therapy remain less known. This study is a single arm prospective trial designed to evaluate the efficacy and safety of a dose reduced everolimus maintenance therapy following initial disease treatment and stabilization.
Ten patients with TS-related SEGAs were included in this trial. Following at least 12 months of treatment therapy with everolimus resulting in tumor reduction and stabilization, patients were given a reduced dose (3 doses/week rather than daily) of everolimus over the subsequent 12 months. The primary outcome was the proportion of patients with stable disease.
The tumors all increased in size after reduction in therapy but the increase occurred in the first 90 days after which there was stabilization. Given the a priori criterion for progression as a 50% increase in volume, this was not considered a statistically significant difference. No recurrence of symptoms from the tumors were noted. Adverse events were less severe and less frequent with reduced treatment compared with the daily standard everolimus treatment.
Limitations of this study include lack of randomization and very small patient cohort, a criterion for progression (50% tumor increase) which could be challenged, and the risk of noncompliance when the medication was only ordered for three times per week.
Dose reducing everolimus in patients with TS related SEGAs following initial treatment and disease stabilization is a feasible strategy; however, further studies with larger patient cohorts should be done to confirm this finding.

Systemic neoadjuvant chemotherapy for Group B intraocular retinoblastoma (ARET0331): A report from the Children’s Oncology Group

Group B retinoblastoma currently treated with systemic chemotherapy (carboplatin, vincristine, etoposide) and local ophthalmic therapies with the goal of avoiding enucleation and external beam radiation and the long term morbidity and mortality associated with these therapies. However, patients still exposed to etoposide thus concerns about secondary leukemia. Goal of this study was to demonstrate that the removal of etoposide would not significantly alter EFS.
Multicentre, single arm trial comparing the 2-year EFS of vincristine and carboplatin compared to the historical 2-year EFS of 96% with 3 drug therapy. Twenty-one patients (25 eyes) were treated with six cycles of VC, accompanied by local ophthalmic therapies after cycle 1. All examinations under anaesthesia were reviewed centrally to confirm group B retinoblastoma.
All patients had tumor regression after the first cycle of VC and only two patients had progression during therapy. There were seven treatment failures resulting in a 2-year EFS of 65% and early study closure in accordance with the statistical design. All treatment failures were local and salvaged with additional therapy (OS 100%). The 2-year cumulative incidence of enucleation and radiation therapy was 15% and 10% respectively. Suggested explanations for altered EFS were removal of etoposide, multicentre study (instead of single institution w/ significant retinoblastoma expertise), or due to delay of local ophthalmic therapy until after cycle 1.
Single arm study of small cohort with short follow up.
Removal of etoposide in treatment of Group B intraocular retinoblastoma resulted in worse EFS compared to 3 drugs, however OS was 100%.

Upfront Window Vincristine/Irinotecan Treatment of High-Risk Hepatoblastoma: A Report From The Children’s Oncology Group AHEP0731 Study Committee

This original article shows the result of the AHEP0731 study conducted by the COG. This study explores the efficacy of a new chemotherapy regimen (2 cycles of VI administered in an upfront window) for high risk hepatoblastoma by assessing the response rate and the outcome.
The study population included newly-diagnosed high risk hepatoblastoma. Patients received vincristine (V) on days 1 and 8 with irinotecan (I) on days 1 to 5. Response was assessed after 2 cycles and "response" was defined as either radiologic or decrease in AFP. Responders received 2 additional cycles of VI intermixed with 6 cycles of C5VD (cisplatin, 5-FU, vincristine and doxorubicine). Patients who were nonresponders received 6 cycles of C5VD without further VI. Two study radiologists used RECIST criteria to determine overall response for all patients.
32 patients were enrolled. 14/30 evaluable patients were responders (RECIST and AFP in 6 patients, RECIST only in 3 patients, and AFP only in 5 patients). However, an additional group of 15 patients had some decrease in AFP (7%-89%) in response to VI. The median AFP decline after 2 cycles of VI for the entire group was 85% of the initial AFP. The 3-year event-free and overall survival rates were 49% (95% CI, 30%-65%) and 62% (95% CI, 42%-77%), respectively.
- Small number of patients.
- The way they assess their primary outcome may have impacted their ability to demonstrate the efficacy of this new regimen. This underlines the importance of using the appropriate assessment tool (any AFP decline versus a real cut-off of 90% decline).
Although VI regimen did not meet predetermined criteria for demonstrating sufficient disease control, it appears to have a substantial activity in a large group of newly diagnosed patients with high-risk HB. Its role remains to be determined.

Treatment pathway of bone sarcoma in children, adolescents, and young adults

This review presents a pathway through different types of management of bone sarcomas in children, adolescents, and young adults.

Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors

Sub-type specific mutations have been identified in many pediatric brain tumors, and are critical to developing and initiating targeted therapy. This report from Boston describes their experience in pediatric neuro-oncology with targeted exome sequencing and genome-wide copy number analysis of the tumour using a CLIA approved test.
Clinical data was extracted from the chart and histology was reviewed. OncoPanel was used for targeted exome sequencing (surveys 300 cancer genes) and classified into 4 tiers (Tier 1 is a well described mutation with evidence confirming clinical utility). Clinical array comparative genomic hybridization (aCGH) was used to identify copy number alterations, known as OncoCopy. Whole genome sequencing was also done. Medulloblastomas underwent further DNA-based molecular analysis to determine subgroup.
OncoPanel was requested on 142 tumors and clinical data was available on 120 of these patients. OncoCopy was requested with results available on 146 patients during time of study. Sixty patients had both tests performed. Clustering of copy number variations was shown to predict histology (i.e. HGG clustered together with embryonal tumors, LGG clustered together in a separate group, etc.). OncoPanel identified relevant alterations in 56% of patients with 38% having tier 1-3 mutations and an additional 17% having an actionable target. Eight out of 37 patients with an actionable target were treated with a small molecule inhibitor. Rearrangements (fusions) were identified in 25/115 samples, most commonly BRAF:KIAA1549 in LGGs. Novel fusions were found and verified using whole exome sequencing. There is further description regarding medulloblastoma, HGG and LGG methods and specific findings.
Germline DNA was not assessed and therefore germline variants couldn't be evaluated which would be needed to be sure about the identified variants in the tumor being somatic (arising in the tumor rather than associated with cancer predispositions). While the authors mention how many patients received targeted therapy (a small minority), they do not discuss the response of these patients to this treatment. Most of this information was not used to influence patient treatment, rather for better understanding. They do not discuss the outcomes of patients with particular alterations (i.e. BRAF V600E mutation) to learn more about how these molecular events influence response to treatment.
Targeted exome sequencing and copy number alterations can be used to identify previously-known and novel mutations and fusions. This testing is already underway and offered at other institutions. This may influence if a patient may be eligible/benefit from certain phase 1 studies, but generally is not being using to guide treatment.

Desmoid Tumors and Celecoxib with Sorafenib

2 case reports of adults with FAP and refractory abdominal desmoid tumors with long term response to a combination of celecoxib and sorafenib.
A potential new treatment for a difficult disease - may only be applicable in patients with FAP. If feasible, larger clinical trials would provide better data.

Surgery alone is sufficient therapy for children and adolescents with low-risk synovial sarcoma: A joint analysis from the European paediatric soft tissue sarcoma Study Group and the Children's Oncology Group

Approaches to synovial sarcomas (SS) have involved multimodal therapy using chemotherapy, surgery and radiation therapy. Retrospective analysis has suggested that low-risk SS may be treated with surgery alone. European and North American clinical trials in Non-rhabdomyosarcoma soft tissue sarcoma used a risk-based approach to therapy. This analysis reports on the pooled the data from the European (EpSSG NRSTS 2005) and North American (COG ARST0332) sarcoma trials.
Subset analysis of prospective study: 60 patients with synovial sarcoma under age 21 enrolled on European paediatric Soft tissue sarcoma Study Group (N=24) and Children Oncology Group (COG) trials (N=36), who had received surgery alone with complete resection. Median tumor size was 3 cm.
3-year EFS was 90% (82%, 98%), OS 100%. 8 local tumor recurrences; all were salvaged with combinations of surgery, chemotherapy and/or radiation therapy. Small tumor size of 3cm was predictive of EFS but clinical trial approach, age, gender, grade and site did not predict EFS.
Difference in patients eligible for surgery-only approach for SS patients in different trials. Limited number patients with large tumors.
This study showed that small synovial sarcomas ≤ 5cm that are completely resected with negative margins can be treated with surgery alone.

Review of phase I and II trials for Wilms’ tumour - Can we optimise the search for novel agents?

This is a review of 63 published phase 1 and phase 2 studies (2005-2016) which included patients with relapsed/refractory Wilms Tumors. The authors discuss availability and trial recruitment in WT, poor clinical outcome of patients, poor responses of WT to novel agents to date, and future drug development for these patients.

Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation

Mosaic Variegated Aneuploidy (MVA) is a syndrome marked by constitutional aneuploidy and features of developmental delay, seizures, and - in some cases - tumor predisposition. The tumors most frequently reported in this syndrome are Wilms tumors and rhabdomyosarcomas. While some causative mutations have been identified, many cases still do not have a genetic explanation.
Whole exome sequencing (WES) of 20 families with MVA followed by targeted sequencing of TRIP13 in 12 additional children. Functional studies were done but will not be reported in this summary.
WES found 6 children with MVA and biallelic TRIP13 loss of function mutations. The exact mutations were the same in each child and each of these children had a Wilms tumor. Parents of these children were heterozygous for the mutation and unaffected supporting an autosomal recessive inheritance pattern. All 3 children were of Kashmiri origin and so 11 further children with Wilms tumor (but not with known MVA) whose families originated from Kashmir were sequenced - 2 of them harbored the same biallelic TRIP 13 mutation. One of these children had other syndromic features of MVA. A sixth child with MVA and a Wilms Tumor but of Norwegian origin harbored a different biallelic loss of function mutation of TRIP13.
Whole exome sequencing does not detect non-coding mutations nor copy number alterations. It is unclear why there is some variance in the phenotype in children with the same mutation.
TRIP13 mutations should be considered in children with Wilms tumors and other syndromic features such as microcephaly, developmental delay, and seizures. They should be especially considered in children of Kashmiri origin.

Landscape of combination immunotherapy and targeted therapy to improve cancer management

Targeted drugs aim to inhibit molecular pathways that are crucial for tumour growth and maintenance. Immunotherapy endeavours to stimulate a host immune response. Combining these strategies might be more effective and improve clinical outcomes.
Over 13,000 somatic profiles of adult patients were analyzed to identify targetable mutations according to the NCI-MATCH list. Theoretical response to checkpoint inhibitors is based on available exomewide non-synonymous mutations counts, which can vary by tumor and stage.
In this study, 8.9% of cases from 17 tumor types, displayed profiles that could benefit from combination therapy. Frequently targetable mutations identified were: PIK3CA, BRAF, NF1, NRAS, and PTEN. High burden of NsM (non-synonymous mutations)
were found in cases with targetable mutations in SMO, DDR2, FGFR1,
PTCH1, FGFR2, and MET.
Limitations of the study: the samples are limited by availability from the database. Also, the NSM as clinical relevant predictor to checkpoint inhibitors has not been validated. Whether the combination strategy will be clinically relevant remains unclear.
This study has shown that in adult solid tumors such as melanoma, lung adenocarcinoma and squamous-cell carcinoma, colon, bladder and gastric cancer the combination strategy of targeted therapy and checkpoint inhibitors is theoretically feasible in about 10% of the patients. If this is clinically relevant, remains unclear. Whether results would be applicable to pediatric solid tumors is unknown and further research is needed to predict efficacy of individualized regiments in pediatric cancer patients.

Reduced and Compressed Cisplatin-Based Chemotherapy in Children and Adolescents With Intermediate-Risk Extracranial Malignant Germ Cell Tumors: A Report From the Children’s Oncology Group

Children with intermediate risk (IR) germ cell tumors (GCT; Stage II-IV testicular, II-III ovarian and I-II extra-gonadal, stage I with recurrence after surgery alone) have excellent outcomes when treated with 4 cycles of PEb (Cisplatin, Etoposide, Bleomycin every 3 weeks). However, the risk of significant late effects such as hearing loss, neuropathy, nephrotoxicity, second malignancies, and cardiovascular disease has prompted the COG to study the effectiveness of a dose reduction strategy for these patients based on non-inferiority data on a similar regimen in adults with GCT, albeit with weekly Bleomycin.
This was a phase 3, single arm trial (from 2003 to 2011) with a stopping threshold of an EFS of
210 patients were enrolled and treated with 3 cycles of PEb with compression from 5 days to 3 days per cycle. EFS was 89% with a 4 year OS of 97% but enrollment was stopped early due to EFS less than the 92% target. However, post hoc analysis revealed that Stage I and II patients treated with 3 cycles had similar outcomes to historical controls treated with 4. The EFS was significantly worse for Stage IV patients when compared to historical counterparts. More grade 3/4 neutropenia was seen on the 3 day regimen.
This study was limited by its single arm design, relatively small sample size and patient heterogeneity.
The data from this study do not support a reduction of therapy to 3 compressed cycles for all IR GCTs. However, it is not known whether the use of weekly Bleomcyin would compensate for the reduction of cycles as this was not tested. A subset of patients with lower stage tumors may still benefit from a reduction to 3 cycles and this needs further dedicated study.

Feasibility, toxicity and response of upfront metaiodobenzylguanidine therapy therapy followed by German Pediatric Oncology Group Neuroblastoma 2004 protocol in newly diagnosed stage 4 neuroblastoma patients.

The primary aim of this German study was to determine the feasibility and toxicity of upfront MIBG therapy followed by a standard high risk protocol in high risk neuroblastoma.
This study is a retrospective, multi-centre analysis of a cohort pilot regimen which included all consecutive newly diagnosed stage 4 neuroblastoma patients. The protocol involved two courses of upfront MIBG therapy, followed by the standard high risk arm of the GPOH NB 2004 protocol (6 courses of induction chemotherapy), followed by surgery. Patients who achieved a response continued on to autologous stem cell transplant followed by radiation to the primary tumor site and retinoic acid. Response rates were assessed post MIBG cycles, post induction chemotherapy and post stem cell transplant.
Upfront MIBG therapy was given to 21 of 32 patients (11/32 were MIBG non-avid). Twenty out of 21 patients received MIBG within two weeks of diagnosis, which was the target for feasibility. Response rate following stem cell transplant was improved for the MIBG group compared to the chemotherapy-only group (71% vs 36%) and was comparable to other MIBG treatment studies.
The main limitation to this study is the fact that it is not a randomized trial, and there was selection bias implicit in the different arms, which was compounded by the small numbers included in the trial.
Upfront MIBG therapy in stage 4 neuroblastoma is feasible, the toxicity is acceptable compared to chemotherapy only regimens and it shows a similar response rate to other MIBG treatment trials; however, there continue to be questions around the optimal time point for the incorporation of MIBG therapy into neuroblastoma treatment protocols.

Quality assessment of lymph node sampling in rhabdomyosarcoma: A surveillance, epidemiology, and end results (SEER) program study

Regional lymph node sampling is an important part of management of paratesticular rhabdomyosarcoma (RMS) in boys over 10 years of age and for staging in extremity RMS. This study aimed to determine the compliance of regional lymph node (LN) sampling in a pediatric population with extremity RMS and paratesticular RMS over the age of 10 years.
The retrospective study used SEER registry data for patients in the USA with histologically confirmed RMS who had LN sampling data and age documented (from 2003 to 2008). 537 patients with extremity RMS (aged ≤19 years) and 65 pts with paratesticular RMS (10-19 years) were analysed.
138 of 537 (25.7%) patients with a RMS of the extremities and 31 of 65 (47.7%) had LN sampling done. Lack of LN sampling/excision had a significant impact with decreased patient survival (HR 0.176, p=0.02). Mean follow up was 39 months.
Data excluded patients with missing LN sampling documentation (54% extremity RMS and 59% paratesticular RMS, so difficult to interpret if this is under-reporting or absence of LN sampling. Unable to interpret why sampling was not carried out. No indication on whether procedures were done in pediatric or adult centres. 17 cancer registries were included, so results may not be generalizable.
Lymph node dissection is standard of care in management of patients with paratesticular RMS and this study indicates that there are discrepancies in adherence to surgical guidelines in RMS which could impact survival. Ongoing awareness and education of LN sampling for surgeons and oncologists is needed but results may not be applicable to all pediatric oncology centres.

A comparison of safety and efficacy of cytotoxic versus molecularly targeted drugs in pediatric phase I solid tumor oncology trials

Until now there was no direct comparison of toxicity and efficacy data between cytotoxic and targeted agents in paediatric oncology clinical trials. This systematic review collected safety and response data for classes of anticancer agents based on a review of past clinical trial results to help guide future phase I/II clinical trial designs for novel targeted drugs.
Systematic review of pediatric phase I recurrent/refractory solid tumor trials. Published reports were evaluated for patient characteristics, toxicity information, and response rates. 143 phase I paediatric solid tumor clinical trials were identified, enrolling 3,896 children. 61 trials investigated 53 targeted drugs and 82 trials evaluated 48 cytotoxic agents.
Cytotoxic drugs had a higher objective response rate but also higher dose limiting toxicities and hematologic toxicities. There was no difference between cytotoxic and targeted agents in non-hematologic toxicities and progression free survival.
The biggest limitation is that meta-analyses of small underpowered trials are likely to result in false positives and negatives. This was a high degree of heterogeneity amongst the included articles. For example, there was no universally accepted method of reporting toxicities.
Keeping in mind the inherent limitations, cytotoxic agents were found to have a significantly higher response rate and toxicity profile compared to targeted agents. Hematologic toxicity profiles of targeted agents are generally more tolerable and may be more favourable for relapsed patients.

Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: A matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group.

Overall survival of patients with diffuse intrinsic pontine glioma (DIPG) is poor. Current treatment approach consists of upfront irradiation followed by best supportive care. With this strategy, a transient reduction in symptoms can be achieved in most patients but subsequent deterioration and death usually occur within one year. Survival time benefits were shown in smaller pilot studies using re-irradiation at secondary deterioration with acceptable toxicity. The purpose of this study was to analyze benefit and toxicity of re-irradiation at first progression of diffuse intrinsic pontine glioma (DIPG).
This is a multicenter retrospective matched-cohort analysis of children aged 2-16 years with characteristic features of DIPG or biopsy-proven high-grade glioma after first progression. An interval of ≥3 months after upfront radiotherapy was required before re-irradiation. Thirty-one children with DIPG, underwent re-irradiation (dose 19.8–30.0 Gy) alone (N=16) or combined with systemic therapy (N=15). Thirty-nine patients fulfilling the same criteria receiving radiotherapy at diagnosis formed the matched comparative cohort. They were followed by best supportive care (n = 20) or systemic therapy (n = 19) but without re-irradiation at progression. Thirty-nine patients without re-irradiation received best supportive care or systemic therapy only.
Significant benefit in median OS (13.7 versus 10.3 months; P = .04) was observed in favor of patients undergoing re-irradiation. Clinical improvement with re-irradiation was observed in 24/31 (77%) patients. Re-irradiation was well tolerated with no recorded grade 4–5 toxicities. Re-irradiation itself and the interval between upfront radiotherapy and re-irradiation remained independent prognostic factors for OS. A risk score using five categories was useful to predict time of survival at first progression.
This is a retrospective study, and reasons for choosing re-irradiation or another treatment are not revealed. Surprisingly, progression-free survival was not affected by radiotherapy at progression which raises questions about the main outcome of the study.
Re-irradiation was associated with prolonged overall survival in this retrospective analysis with median OS of 3.4 months for patients with DIPG undergoing re-irradiation at the first progression without major toxicity. More importantly, symptom improvement was observed in nearly 80% of the patients. The study and SIOP-E recommendations, suggest re-irradiation of children with DIPG at the first progression can be considered.

Prevention of radiotherapy-induced neurocognitive dysfunction in survivors of paediatric brain tumours: the potential role of modern imaging and radiotherapy techniques.

Neurocognitive dysfunction is the leading cause of reduced quality of life in long-term survivors of pediatric brain tumours with radiotherapy being a main contributor to this. This is a review of the potential role of modern imaging and innovative radiotherapy techniques with the goal of minimizing neurocognitive sequelae in children with brain tumours and how to integrate such strategies into further research. Such techniques include evaluation of photon radiotherapy such as image-guided radiotherapy, volumetric nodulated arc therapy, helical tomotherapy and adapative radiotherapy along with proton beam radiation and heavy in therapy.
This article is a descriptive summary of various advanced techniques in radiotherapy to limit long term sequelae as well as proposing strategies to integrate such advances in further research. The only technique thus far that has achieved some success to limit long-term sequelae is avoidance of radiation particularly in those less than 3 years of age, and reduction of the total radiation dose and brain volume irradiated.
Minimizing neurocognitive sequalae in children with brain tumors is challenging. Avoidance of radiation especially in under 3 years and reduction of radiation dose and brain volume irradiated, are the most successful strategies to date.

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

As part of the Cancer Genome Atlas project, this study aimed to provide a comprehensive genomic characterization of Pheochromocytomas (PCC) and Paragangliomas (PGL) (n=173).
Molecular profiling was undertaken using 6 different tools: whole-exome sequencing (for mutations), SNP array (copy number variations), mRNA sequencing (gene expression, aberrant fusions), microRNA sequencing, DNA methylation and reverse-phase protein arrays.
Overall, these rare endocrine tumors have a low incidence of genomic alterations. In addition to the 2 subgroups already described in previous transcription studies - "pseudohypoxia" (including alterations in genes involved in regulation of hypoxia transcription factors VHL, EPAS, SDH, FH, MDH2, and IDH1) and "kinase signaling" (RET, HRAS, NF1), the group describes 2 additional transcriptional groups:
The "Wnt-altered" cluster of tumors is characterized by WNT pathway activation; novel MAML3 fusion gene and CSDE1 somatic mutation correlate with poor clinical outcome. This group of tumors expressed the highest levels of chromogranin A (CHGA, a clinical marker of neuroendocrine tumors that correlates with metastatic disease).
The forth cluster of "cortical admixture" tumors: despite higher content of normal tissue/leukocyte infiltration these had specific genetic alterations, such as MAX mutations, suggesting that they are a separate entity.
27% of the tumors were associated with a known germline mutation and exome sequencing did not reveal any novel germline mutations.
PCC/PGL comprise 4 different subgroups with specific genetic drivers. Amongst the many genetic drivers identified, specific mutations - both germline and somatic - were mutually exclusive.
Implications for clinical practice are the confirmation/identification of molecular markers of aggressive disease (SDHB, mutations ATRX and MAML3 fusions) and a rationale to explore targeted therapies (such as HIF in "pseudohypoxia" tumors and WNT proteins in "WNT signalling" tumors.

Posterior fossa syndrome: Review of the behavioral and emotional aspects in pediatric cancer patients

About 25% of children after posterior fossa tumor resection develop posterior fossa syndrome consisting of varying degrees of mutism, ataxia/hypotonia, and emotional lability. This review outlines the current knowledge of this entity including therapeutic approaches.
Posterior fossa syndrome is a very challenging entity for patients, their families, and clinicians alike and this review is a good summary.

Needle tract seeding after percutaneous biopsy of sarcoma: Risk/benefit considerations

Needle tract seeding after percutaneous biopsy of sarcomas is a common fear but is based on case reports or series mainly. This review summarizes current data on needle tract seeding after percutaneous biopsy.
Needle tract seeding after percutaneous biopsy of sarcomas with recurrence of the tumor was very low in available data (below 1%) despite significantly higher prevalence of malignant cells in excised needle tracts (4 to 22%).

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