AT/RTs are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes

Johann, PD, (2016) Cancer Cell (Link to Abstract)


This German group utilized DNA methylation and expression profiles to subtype AT/RTs into 3 separate subgroups – tyrisonase (TYR), sonic hedgehog (SHH), and MYC. These 3 subgroups are characterized by the active pathways in them as well as by the location of enhancers and the relative importance of different transcription factors. The finding of different activated elements in tumors that are generally mutationally quiet (other than SMARCB1) mutations may allow for more targeted therapies which the authors start to show with in-vitro apoptosis achieved using a MITF inhibitor in the TYR group.

* This study is part of the worldwide (unfortunately uncoordinated) effort to subgroup embryonal tumors in a manner parallel to the successful medulloblastoma classification. While this study seems convincing, it is not consistent with another study (Torchia et al., Lancet Oncology 2015) showing only 2 subgroups of AT/RT with different features. The degree of overlap between these two classification systems is yet to be seen.

Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children's Oncology Group ACNS0423 study

akacki, R, (2016) Neuro-Oncology,  (Link to Abstract)

Authors report results of COG ACNS0423, a phase 2 study evaluating efficacy of temozolomide and lomustine combination in maintenance therapy in childhood high-grade glioma. Results are retrospectively compared to previous study ACNS0126 where temozolomide only was used. In the current study, it was shown that combination temozolomide and lomustine in 108 patients improves 3-year EFS to 22% (compared to 11% in ACNS0126). On the other hand this treatment was accompanied by significant hematological toxicity requiring dose reductions in 68% patients.

* The addition of lomustine to temozolomide as adjuvant therapy in ACNS0423 was associated with significantly improved outcome compared with the preceding COG ACNS0126 HGG study in which participants received temozolomide alone.

Assessment of Primary Site Response in Children With High-Risk Neuroblastoma: An International Multicenter Study

Bagatell, R (2016) JCO (Link to Abstract)


Staging in neuroblastoma has transitioned from INSS which is a pathological system to INRGSS which is based on CT and MRI imaging.  The purpose of this study was to look at the best way to evaluate tumor response comparing serial measurements of 3 dimensions of lesions to calculate volume, to one dimension of the lesions as per Response Evaluation Criteria in Solid Tumors (RECIST).  Response of ≥30% reduction in longest diameter was used for RECIST, ≥50% reduction in volume as per INRC or ≥60% reduction in volume (because 30% reduction in diameter corresponds to 60% reduction in volume of sphere).

Data from 229 children with high-risk neuroblastoma from 7 centers were analyzed.  Sensitivity to detect response in survivors was higher for volume response measures than single measure but there was low specificity of all response evaluations (to detect poor response in those who died). None of the response measures predicted outcome or extent of resection.

* Volume or single diameter response measurements on imaging does not predict survival in high-risk neuroblastoma, but still remains important to monitor for progression and overall response to treatment.  As it is more complex to do 3-dimension measurements, and there was no difference in outcome prediction, the revised International Neuroblastoma Response criteria will use RECIST criteria using longest diameter going forward in future studies.

Prospective Study of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites

Sadowski, S (2016) JCO (Link to Abstract)


68Ga-DOTA-TATE PET/CT can be used to image tumors that express somatostatin including neuro-endocrine tumors (NET) and neuroblastoma.  This was a prospective cohort study in adults to assess the utility of 68Ga-DOTA-TATE PET/CT to diagnose and stage Gastro-entero-pancreatic (GEP) NET compared to current approved imaging modalities (111In-pentetreotide SPECT/CT) and/or MRI. 

131 patients with biochemically or radiologically suspected or proven GEP NETs underwent imaging: 68Ga-DOTA-TATE PET/CT detected 95% lesions (45% MRI and 31% 111In-pentetreotide SPECT/CT).   They compared surgical specimens with imaging techniques and 68Ga-DOTA-TATE PET/CT correctly found primary, Lymph node, and distant metastases in 64% compared to 22%, and 38%, respectively, with other imaging modalities).  With additional findings from the imaging, clinical management was changed in a third of cases.  In patients with symptoms of carcinoid syndrome, negative serum chromogranin A and urinary 5-HIAA levels,  68Ga-DOTA-TATE PET/CT also detected lesions in 65% of patients when the majority of these were not found on the other imaging techniques.

68Ga-DOTA-TATE PET/CT is better than 111In-pentetreotide SPECT/CT and anatomical imaging in detecting and staging Gastro-entero-pancreatic NET and may find lesions even if biochemical markers are absent.  This study suggests 68Ga-DOTA-TATE PET/CT should be used in initial management and follow-up of adults with NETs.  There are only limited studies in children with NETs and also neuroblastoma ,which expressed Somatostatin receptors, and targeted therapy with 177Lu-DOTA-TATE is being investigated.

Genome-Wide Profiles of Extra-cranial Malignant Rhabdoid Tumors Reveal Heterogeneity and Dysregulated Developmental Pathways

Chun, HJE, (2016) Cancer Cell (Link to abstract)


This study analyzes genomes, transcriptomes, DNA methylation, histone signatures, and microRNA in extracranial rhabdoid tumors. There are many different findings reported in this paper but in their totality they are evidence that rhabdoid tumors have heterogeneous molecular features despite all being initially driven by SMARCB1 mutations. Different techniques reveal slightly different subgroups but it is likely that there are two major groups of rhabdoid tumors – each seems to arise from a different neural crest cell precursor.

* When compared with similar studies in AT/RT – a very similar tumor, this study doesn’t appear to reveal as many clinically-relevant findings. However, this is the first comprehensive analysis of rhabdoid tumor molecular features and is therefore an important starting point for treating these very difficult tumors.

Randomized Double-Blind Trial of Pregabalin Versus Placebo in Conjunction with Palliative Radiotherapy for Cancer-Induced Bone Pain

Fallon, M, (2016) Journal of Clinical Oncology (Link to abstract)


Pregabalin is a Calcium-channel blocker which is used for neuropathic pain treatment. This RCT in adults compared pregabalin vs placebo in the treatment of bone pain. Patients were also allowed to receive palliative radiotherapy. All patients were adults and most had breast, lung, or prostate cancer. All patients had at least 4/10 bone pain at the time of enrollment. A total of 233 patients were randomly allocated and although there were withdrawals in each arm, an intention-to-treat analysis was used. There was no difference between the groups in time to decreased pain scores, lower pain overall, lower opioid requirement, or in functional ability.

* This is a well designed trial that strongly argues against using pregabalin to treat pain related to bone metastases. It is mostly in adult patients with carcinoma but unless there is a model showing that the pathophysiology of cancer bone pain is different in sarcomas, embryonal tumors, or hematological malignancies there is not a strong argument to redo this expensive trial in children nor to use pregabalin for this indication. 

Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination

Ham, J, (2016) Cancer Cell (Link to abstract)


This group used a drug screen to identify two molecules (ABT-263 and ABT-199) that inhibit growth in MYCN-amplified neuroblastoma cell lines. Through several lines of evidence, they show that MYCN amplification makes cells more prone to apoptosis and that apoptosis can be triggered by inhibiting BCL-2 as these molecules do. They then show that the degree of apoptosis is even greater when these molecules are combined with alisertib (an Aurora Kinase inhibitor) which seems to further reduce the apoptosis threshold in these cells. They finally show that the combination of these drugs induces sustained remission in xenograft mouse models. None of these effects are seen in wild type MYCN neuroblastoma.

* This is the first study to show quite conclusively that MYCN can be targeted with clinically available drugs. Alisertib has already been tested in phase I/II studies in neuroblastoma alone and in combination with irinotecan/ temozolamide; the barriers to testing this combination in humans will be lower than usual. As always, a mouse xenograft is not the same as a spontaneous arising human tumor so we should still maintain a level of skepticism in the face of these optimistic results.

Tandem high-dose chemotherapy with thiotepa and busulfan-melphalan and autologous stem cell transplantation in very high-risk neuroblastoma patients.

Pasqualini, C 2016, BMT (Link to abstract)

This is a European study (2004-2011) of very high risk (VHR) NBL patients (HR patients who had metastatic disease at end of induction) had therapy intensified to received two tandem autologous HSCTs with thiotepa, then busulfan-melphalan, with a two-month interval between.  Defibrotide VOD prophylaxis was standard practice.   26 patients received tandem transplants and only 5 were MYCN amplified.  Six patients (25%) developed VOD, one died, toxicity was otherwise typical of autologous HSCT, but higher rate and severity with the second transplant.  6/24 patients achieved CR, 7 PR, 10 stable disease.  OS at 3 years was 69%, EFS was 37.3%.

[*In comparison, following ANBL0532 HR NB study, COG recommends the use of tandem transplant consolidation (with thiotepa/cyclophosphamide then carbo, etop, melphalan (CEM)) for patients greater than 18 months of age with INSS stage 4 neuroblastoma or those of any age with INSS stage 2B, 3 or 4 and MYCN amplification high-risk neuroblastoma based upon the significantly improved 3- year EFS following tandem transplant.]

* The outcome in this cohort was promising and it appeared to be safe to perform tandem transplant with VHR NBL.  An upcoming SIOPEN study will compare tandem HDC with thiotepa and BuMEL (this protocol) with mIBG/BuMel autoHSCT.

Identification of Novel Fusion Genes in Testicular Germ Cell Tumors

Hoff, AM, (2016) Cancer Research (Link to abstract)

Testicular GCTs are mutationally quiet other than frequent gain at 12p but had not yet been comprehensively examined for gene fusions. Next generation RNA sequencing is now the best available technology for detecting fusions not visible through standard techniques such as FISH or RT-PCR. The group examined embryonal carcinoma cell lines as well as 24 testicular GCTs with different histologic subtypes. They found 8 previously undescribed fusion transcripts commonly involving the RCC1 gene or internal translocations of ETV6.

* This study reveals that testicular GCTs are more marked by fusions than by mutations similar to childhood sarcomas.

TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors.

Valentijn, L (2015),Nature Genetics (Link to abstract)

Whole-genome sequencing of 75 high-risk neuroblastoma tumor samples detected structural rearrangements and overexpression of TERT in 23%. This is the second most common alteration in HR-neuroblastomas after MYCN and associated with poor prognosis. TERT rearrangements, MYCN amplifications and ATRX deletions define 3 distinct, non-overlapping subgroups of high-risk neuroblastoma.

* Another paper in a series of recent studies showing that telomerase activation is common in high-risk neuroblastoma, mutually exclusive with ATRX deletion and MYCN amplification and associated with poor outcome.

Germline Mutations in Predisposition Genes in Pediatric Cancer

Jinghui Zhang, (2015), NEJM Link to abstract:


The authors performed whole-genome, whole-exome, or both types of sequencing on germline DNA in 1120 pediatric cancer patients younger than 20 years of age in order to identify the prevalence of predisposing mutations. The cohort represented a wide array of the most common childhood cancers of hematologic and solid nature. 8.5% of the patients with cancer had a mutation that was considered to be pathogenic or probably pathogenic. Common mutated genes were TP53, APC, BRCA2, NF1, PMS2, RB1 and RUNX1.

Current methods identify about 8.5% of pediatric patients to harbor a pathogenic or probably pathogenic cancer-predisposing mutation in their germline DNA.

Mutations in the transcriptional repressor REST predispose to Wilms tumor.

Mahamdallie , S (2015) Nature Genetics (Link to abstract)


Analysis of whole exome sequencing data of familial Wilms tumor samples revealed several pathogenic mutations in the REST gene (encoding RE1-silencing transcription factor). The authors further analyzed (presumably) non-familial WT and found pathogenic mutations in a small percentage of patients. All 11 different mutations clustered in the DNA-binding domain of REST.

* REST mutations account for 2% of WT, similar to germline WT1. The authors suggest that screening for REST mutations in familial WT would be prudent and facilitate surveillance of relatives.