Polymerase proofreading‐associated polyposis (PPAP) and Lynch syndrome, caused by mutated POLE and mismatch repair (MMR) genes, respectively, are associated with adult‐onset cancer. PPAP and ...MMR‐deficient tumors are both hypermutated, and each has a unique mutational signature. We describe a 4.5‐year‐old boy with multiple café au lait spots who presented with metastatic Sonic Hedgehog‐activated medulloblastoma, with partial response to intensive chemotherapy and immunotherapy. The tumor showed microsatellite stability, loss of PMS2 nuclear expression, and an exceptionally high tumor mutational burden of 276 Mut/Mb. Germline molecular analysis revealed an inherited heterozygous pathogenic POLE variant and a de novo heterozygous PMS2 pathogenic variant. The tumor featured the MMR, POLE, and POLE+MMR mutational signatures. This is the first description of a di‐genic condition, which we named “POL‐LYNCH syndrome,” manifested by an aggressive ultra‐mutant pediatric medulloblastoma with a unique genomic signature.
We describe a 4.5‐year‐old boy with multiple café au lait spots and metastatic medulloblastoma, which showed microsatellite stability and an exceptionally high tumor mutational burden. Germline molecular analysis revealed an inherited heterozygous pathogenic POLE variant and a de novo heterozygous PMS2 pathogenic variant.
Diffuse intrinsic pontine glioma (DIPG) is an incurable disease with a median overall survival of 10 months. Immune modulating antibodies have recently emerged as a highly promising treatment ...modality in multiple cancer types. We present results from the first study to evaluate the immune modulating antibody MDV9300 (pidilizumab) in pediatric patients with DIPG. All patients aged 3 years and older, diagnosed with DIPG between February 2014 and June 2015 in Israel, were offered to participate in the study. Enrolled patients were started on biweekly 6 mg/kg MDV9300 after radiation completion. Treatment was continued until disease progression on imaging. Patients were followed biweekly for the occurrence of neurological deficit toxicities and side effects. Secondary endpoints were event free survival and overall survival. Of 13 children diagnosed with DIPG during the study period, nine were enrolled in the study. The patients underwent radiotherapy and none had chemotherapy. A total of 83 cycles of MDV9300 (range 2–16) were applied. The main side effects were neutropenia (CTCAE grade 1–3), mild to moderate fatigue, and acute elevation of blood pressure. Four patients died within 1 year of the diagnosis, another three died within 2 years and two children are still alive nearly 30 months from diagnosis, with stable disease. The median event free survival is 9.3 months (range 6.8–24) and the median overall survival is 15.6 months (range 6.9–28). Preliminary results demonstrate that MDV9300 treatment is safe and may be effective in the treatment of children with DIPG.
Amplification of the
C19MC
oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In ...this study, we sought to evaluate the diagnostic specificity of
C19MC
and LIN28, and the clinical and biological spectra of
C19MC
amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that
C19MC
alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas.
C19MC
amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.
Summary
Detection of somatic mutations may help verify the diagnosis of myelodysplastic syndrome (MDS) in patients with persistent cytopenias or with MDS‐predisposition syndromes, prior to the ...development of overt leukemia. However, the spectrum and consequences of acquired changes in paediatric patients have not been fully evaluated, and especially not in the context of an underlying syndrome. We incorporated a targeted next‐generation‐sequencing panel of 54 genes for the detection of somatic mutations in paediatric and young adult patients with inherited or acquired cytopenias. Sixty‐five patients were included in this study, of whom 17 (26%) had somatic mutations. We detected somatic mutations in 20% of individuals with inherited MDS‐predisposition syndromes, including in patients with severe congenital neutropenia and Fanconi anaemia, and with germline mutations in SAMD9L. Thirty‐eight per cent of children with acquired cytopenias and suspected MDS had somatic changes, most commonly in genes related to signal transduction and transcription. Molecularly abnormal clones often preceded cytogenetic changes. Thus, routine performance of somatic panels can establish the diagnosis of MDS and determine the optimal timing of haematopoietic stem cell transplantation, prior to the development of leukaemia. In addition, performing somatic panels in patients with inherited MDS‐predisposition syndromes may reveal their unique spectrum of acquired mutations.
Abstract
INTRODUCTION
TTFields are an established treatment for glioblastoma (GBM) in adults and have been shown to prolong OS, PFS and long-term survival with minimal side-effects. TTFields are not ...yet approved for children and the device (Optune®) was provided on a compassionate basis to all patients in this case series. We report our experience with TTFields at 4 major pediatric oncology centers in Israel.
METHODS
Since September 2017 Optune has been offered to 7 pediatric patients of whom 5 (3 female, 2 male) gave consent immediately. These patients were aged 11.1 - 17.7 years at time of diagnosis. 4/5 had a midline diffuse glioma H3.3K27M positive and started Optune together with temozolomide following biopsy/subtotal resection and radiation. The fifth patient had a gross total resection of a right parietal GBM positive for the H3.3G34R mutation. He was treated with radiation and adjuvant temozolomide and had a multifocal right sided relapse at 20 months, and was then treated with Avastin and Optune.
RESULTS
Two patients reported device-related mild itchy skin, which was easily treated topically. Four patients continued all normal activities despite carrying the device during school attendance, trips abroad and even at a waitressing job. One male refused to attend school and continues home learning. Three patients had programmable shunts, without any interference with Optune. Compliance was >90% in 3 patients, 80% in 1 individual and 60% in the relapsed patient. 2/5 patients have stopped treatment due to progression after 86 and 142 days on Optune, however all patients are still alive at the time of the report.
CONCLUSION
In summary TTFields is a feasible and tolerable treatment even in children as young as 11 years. TTFields had no additional systemic side-effects and showed good acceptance rate. Further studies in pediatric patients are needed to evaluate efficacy in pediatric high-grade glioma.
Abstract
BACKGROUND
Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor. Genomic alterations of RAF are common oncogenic drivers in pLGG. Tovorafenib is an investigational, ...selective, CNS-penetrant, type II RAF inhibitor.
METHODS
FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib monotherapy. Registrational arm 1 enrolled patients aged 6 months–25 years of age with recurrent or progressive LGG harboring an activating BRAF alteration. Tovorafenib 420 mg/m2 (600 mg max) was administered weekly (tablet or liquid suspension). Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints.
RESULTS
As of December 22 2022, 69 (RANO-HGG) and 76 (RANO-LGG) of 77 patients in arm 1 were evaluable at baseline and had ≥9 months of follow-up. Median age at enrollment was 8 years (range 2–21), and 60% (n = 46) patients had received prior MAPK inhibitor (MAPKi) therapy. Among the evaluable patients, the ORR was 62% (RANO-HGG, n = 69) and 45% (RANO-LGG, n = 76), respectively. The ORR in patients previously treated with MAPKis (n = 41 RANO-HGG; n = 45 RANO-LGG) was 68% (4 CRs; 24 PRs) (RANO-HGG) and 44% (5 PRs; 15 MRs) (RANO-LGG). In MAPKi-naïve patients (28 RANO-HGG; 31 RANO-LGG), the ORR was 54% (15 PRs) (RANO-HGG) and 45% (7 PRs; 7 MRs) (RANO-LGG). Among 136 patients in arms 1 and 2 of FIREFLY-1, the most common treatment-related adverse events (TRAEs) of any grade were hair color changes (71%), fatigue (40%) and maculopapular rash (38%). Tovorafenib dose modifications occurred in 39 (29%) and discontinuations in 4 (3%) patients due to TRAEs.
CONCLUSIONS
Tovorafenib provided clinically meaningful tumor responses, including those with a best response reported of SD or PD using another MAPKi, in patients with BRAF-altered pLGG regardless of prior MAPKi therapy, and has a manageable safety profile.
Constitutional mismatch repair deficiency is a rare cancer predisposition syndrome caused by biallelic mutations in one of the four mismatch repair genes. Patients are predisposed to various tumors ...including hematological malignancies, brain tumors and colorectal carcinomas. Phenotypic overlap with Neurofibromatosis‐1 is well known, with most patients presenting with café‐au‐lait macules. Other common features include axillary and/or inguinal freckling and intracranial MRI foci of high T2W/FLAIR signal intensity similar to the typical FASI seen in Neurofibromatosis‐1. In this cohort of eight patients with constitutional mismatch repair deficiency we describe overlapping phenotypical features with Tuberous Sclerosis complex. In addition to “ash‐leaf like” hypomelanotic macules (five patients), we detected intracranial tuber‐like lesions (three patients), renal cysts (three patients) and renal angiomyolipomas (two patients). All our patients also had Neurofibromatosis‐1 like features, mainly café‐au‐lait macules. This study suggests that features of Tuberous sclerosis especially when overlapping with those of Neurofibromatosis 1 or malignancies atypical for these syndromes should raise the possibility of constitutional mismatch repair deficiency. Correct diagnosis is essential for appropriate genetic counseling and pre‐emptive cancer surveillance.
CMMRD is a rare cancer predisposition syndrome
Phenotypic overlap with NF‐1 is well known and described in the literature
This study presents phenotypic overlap with Tuberous sclerosis as well
Patients had intracranial tubers‐like lesions (A), renal angiomyolipomas (B) and cysts and hypopigmented macules (arrow, C). Also shown are café‐au‐lait macules typical of Neurofibromatosis 1 (arrowhead, C)
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