IDH-mutant gliomas with additional class-defining molecular events.

The 2016 WHO classifies IDH-mutant gliomas into oligodendroglioma or diffuse astrocytoma based on co-occurring genetic events. Recent literature addresses the concept of stratifying IDH-mutant gliomas based on prognostically significant molecular events. However, the presence of a second class-defining driver alteration in IDH-mutant gliomas has not been systematically described. We searched the sequencing database at our institutions as well as The Cancer Genome Atlas (TCGA) and cBioPortal for IDH-mutant gliomas with other potentially significant alterations. For each case, we reviewed the clinical information, histology and genetic profile. Of 1702 gliomas tested on our targeted exome sequencing panel, we identified 364 IDH-mutated gliomas, four of which had pathogenic FGFR alterations and one with BRAF V600E mutation. Five additional IDH-mutant gliomas with NTRK fusions were identified through collaboration with an outside institution. Also, a search in the glioma database in cBioPortal (5379 total glioma samples, 1515 cases [28.1%] with IDH1/2 mutation) revealed eight IDH-mutated gliomas with FGFR, NTRK or BRAF pathogenic alterations. All IDH-mutant gliomas with dual mutations identified were hemispheric and had a mean age at diagnosis of 36.2 years (range 16-55 years old). Co-occurring genetic events involved MYCN, RB and PTEN. Notable outcomes included a patient with an IDH1/FGFR1-mutated anaplastic oligodendroglioma who has survived 20 years after diagnosis. We describe a series of 18 IDH-mutant gliomas with co-occurring genetic events that have been described as independent class-defining drivers in other gliomas. While these tumors are rare and the significance of these alterations needs further exploration, alterations in FGFR, NTRK, and BRAF could have potential therapeutic implications and affect clinical trial design and results in IDH-mutant studies. Our data highlights that single gene testing for IDH1 in diffuse gliomas may be insufficient for detection of targets with potential important prognostic and treatment value.

Intracranial growing teratoma syndrome (iGTS): an international case series and review of the literature.

PURPOSE: Intracranial growing teratoma syndrome (iGTS) is a rare phenomenon of paradoxical growth of a germ cell tumor (GCT) during treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of iGTS in Western countries. METHODS: Pediatric patients from 22 North American and Australian institutions diagnosed with iGTS between 2000 and 2017 were retrospectively evaluated. RESULTS: From a total of 777 cases of central nervous system (CNS) GCT, 39 cases of iGTS were identified for an overall frequency of 5%. Pineal region was a more frequent location for iGTS as compared to cases of GCT without iGTS (p < 0.00001). In patients with an initial tissue diagnosis of GCT, immature teratoma was present in 50%. Serum AFP or ßhCG was detectable in 87% of patients (median values 66 ng/mL and 44 IU/L, respectively). iGTS occurred at a median of 2 months (range 0.5-32) from diagnosis, in the majority of patients. All patients underwent surgical resection, leading to gross total resection in 79%. Following surgery, all patients resumed adjuvant therapy or post treatment follow-up for GCT. At a median follow-up of 5.3 years (range 0.2-11.8), 37 (95%) of patients are alive, including 5 with stable residual mass. CONCLUSION: iGTS occurs in 5% of patients with GCT in Western countries. Tumors of the pineal region and GCT containing immature teratoma appear to be associated with a higher risk of developing iGTS. Complete surgical resection is the mainstay of treatment. Overall survival of patients developing iGTS remains favorable.

Bortezomib, Dexamethasone, Mitoxantrone, and Vinorelbine (BDMV): An Active Reinduction Regimen for Children With Relapsed Acute Lymphoblastic Leukemia and Asparaginase Intolerance.

BACKGROUND: Children with relapsed acute lymphoblastic leukemia (ALL) typically receive vincristine-prednisone-L-asparaginase-doxorubicin reinduction chemotherapy similar to contemporary induction regimens. However, up to 20% of patients are unable to receive vincristine-prednisone-L-asparaginase-doxorubicin secondary to asparaginase intolerance. We report our experience with a promising reinduction regimen for children with relapsed ALL who are unable to receive asparaginase. PATIENTS AND METHODS: This is a single institution, retrospective review of the safety and activity of bortezomib, dexamethasone, mitoxantrone, and vinorelbine (BDMV) in patients with relapsed ALL. Complete remission and adverse events after reinduction were study endpoints. Patients treated with BDMV between 2012 and 2015 were identified. Response and adverse events (AEs) were assessed by review of medical records. Standard response criteria were used and AEs were graded based on NCI CTCAEv4.0. RESULTS: Seven of 10 patients achieved complete remission after 1 cycle of BDMV, with 4 achieving minimal residual disease negativity. The most common ≥grade 3 nonhematological toxicities were infection (91%), gastrointestinal (45%), metabolic (45%), and cardiovascular (9%). CONCLUSIONS: BDMV is an active reinduction regimen for children with relapsed ALL who cannot receive asparaginase. The toxicity profile is as expected for this patient population. Further prospective clinical trials are warranted to evaluate the safety and efficacy of BDMV.