MRI Features of Histologically Diagnosed Supratentorial Primitive Neuroectodermal Tumors and Pineoblastomas in Correlation with Molecular Diagnoses and Outcomes: A Report from the Children's Oncology Group ACNS0332 Trial.

BACKGROUND AND PURPOSE: Supratentorial primitive neuroectodermal tumors and pineoblastomas have traditionally been grouped together for treatment purposes. Molecular profiling of these tumors has revealed a number of distinct entities and has led to the term "CNS-primitive neuroectodermal tumors" being removed from the 2016 World Health Organization classification. The purpose of this study was to describe the MR imaging findings of histologically diagnosed primitive neuroectodermal tumors and pineoblastomas and correlate them with molecular diagnoses and outcomes. MATERIALS AND METHODS: Histologically diagnosed primitive neuroectodermal tumors and pineoblastomas were enrolled in this Children's Oncology Group Phase III trial, and molecular classification was retrospectively completed using DNA methylation profiling. MR imaging features were systematically studied and correlated with molecular diagnoses and survival. RESULTS: Of the 85 patients enrolled, 56 met the inclusion criteria, in whom 28 tumors were in pineal and 28 in nonpineal locations. Methylation profiling revealed a variety of diagnoses, including pineoblastomas (n = 27), high-grade gliomas (n = 17), embryonal tumors (n = 7), atypical teratoid/rhabdoid tumors (n = 3), and ependymomas (n = 2). Thus, 39% overall and 71% of nonpineal tumor diagnoses were discrepant with histopathology. Tumor location, size, margins, and edema were predictors of embryonal-versus-nonembryonal tumors. Larger size and ill-defined margins correlated with poor event-free survival, while metastatic disease by MR imaging did not. CONCLUSIONS: In nonpineal locations, only a minority of histologically diagnosed primitive neuroectodermal tumors are embryonal tumors; therefore, high-grade glioma or ependymoma should be high on the radiographic differential. An understanding of molecularly defined tumor entities and their relative frequencies and locations will help the radiologist make more accurate predictions of the tumor types.

Treatment of pediatric cerebral radiation necrosis: a systematic review.

Cerebral radiation necrosis (CRN) is a toxicity of radiation therapy that can result in significant, potentially life-threatening neurologic deficits. Treatment for CRN has included surgical resection, corticosteroids, hyperbaric oxygen therapy (HBOT), and bevacizumab, but no consensus approach has been identified. We reviewed the available literature to evaluate efficacy of treatment approaches. Using methods specified in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines when possible, we conducted searches of Ovid MEDLINE, Embase and Pubmed to identify studies reporting on outcomes for children (≤21 years old) with CRN. Eligible studies from 1990 to 2014 describing central nervous system (CNS) radiation necrosis with details of both treatment and outcomes were included. Eleven studies meeting criteria were identified. Of the nine studies with total patient denominators, 37 of 806 patients developed CRN (incidence = 4.6 %). Patients received treatment courses of steroids alone (n = 13), steroids with bevacizumab (n = 11) or HBOT (n = 12). Patients who failed to respond to steroids were more likely to be older than steroid-responsive patients (p = 0.009). With the exception of steroid-related adverse events, there was only one report of an adverse event (brainstem stroke) potentially attributable to intervention (bevacizumab). Those who received proton beam RT were both younger (p = 0.001) and had a shorter time to development of CRN (p = 0.079). The most common treatment following steroid initiation was addition of bevacizumab or HBOT, with good success and minimal toxicity. However, randomized controlled trials are needed to establish a definitive treatment algorithm that can be applied to children affected by CRN.

Unusual serological findings associated with ceftriaxone-induced immune hemolytic anemia in a child with disseminated low-grade glioma.

Ceftriaxone-induced immune hemolytic anemia (CIHA) is the second most common cause of drug-induced hemolytic anemia. Prompt recognition of this drug reaction is essential because brisk hemolysis can be deadly. The extent to which ceftriaxone antibodies persist after CIHA is unknown; rechallenging patients who have experienced CIHA is not recommended. We report a case of CIHA in a neurooncology patient, which is the first to show anticeftriaxone antibodies with Rh specificity and persisted for 8 months after the drug reaction. These findings have implications for understanding the mechanism of CIHA.

Distinct roles for fibroblast growth factor signaling in cerebellar development and medulloblastoma.

Cerebellar granule neurons are the most abundant neurons in the brain, and a critical element of the circuitry that controls motor coordination and learning. In addition, granule neuron precursors (GNPs) are thought to represent cells of origin for medulloblastoma, the most common malignant brain tumor in children. Thus, understanding the signals that control the growth and differentiation of these cells has important implications for neurobiology and neurooncology. Our previous studies have shown that proliferation of GNPs is regulated by Sonic hedgehog (Shh), and that aberrant activation of the Shh pathway can lead to medulloblastoma. Moreover, we have demonstrated that Shh-dependent proliferation of GNPs and medulloblastoma cells can be blocked by basic fibroblast growth factor (bFGF). But while the mitogenic effects of Shh signaling have been confirmed in vivo, the inhibitory effects of bFGF have primarily been studied in culture. Here, we demonstrate that mice lacking FGF signaling in GNPs exhibit no discernable changes in GNP proliferation or differentiation. In contrast, activation of FGF signaling has a potent effect on tumor growth: treatment of medulloblastoma cells with bFGF prevents them from forming tumors following transplantation, and inoculation of tumor-bearing mice with bFGF markedly inhibits tumor growth in vivo. These results suggest that activators of FGF signaling may be useful for targeting medulloblastoma and other Shh-dependent tumors.

Inhibitory activity for chitin synthase II from Saccharomyces cerevisiae by tannins and related compounds.

In the course of search for potent inhibitors of chitin synthase II from natural resources, seven tannins and related compounds were isolated from the aerial part of Euphorbia pekinensis and identified as gallic acid (1), methyl gallate (2), 3-O-galloyl-(-)-shikimic acid (3), corilagin (4), geraniin (5), quercetin-3-O-(2"-O-galloyl)-beta-D-glucoside (6), and kaempferol-3-O-(2"-O-galloyl)-beta-D-glucoside (7). These and nine related compounds, (-)-quinic acid (8), (-)-shikimic acid (9), ellagic acid (10), kaempferol (11), quercetin (12), quercitrin (13), rutin (14), quercetin-3-O-(2"-O-galloyl)-beta-D-rutinoside (15) and 1,3,4,6-tetra-O-galloyl-beta-D-glucose (16), were evaluated for the inhibitory activity against chitin synthase II and III. They inhibited chitin synthase II with IC(50) values of 18-206 microM, except for two organic acids, (-)-quinic acid (8) and (-)-shikimic acid (9). Among them, 3-O-galloyl-(-)-shikimic acid (3) was the most potent inhibitor against chitin synthase II of Saccharomyces cerevisiae with an IC(50) value of 18 microM. The inhibition appears to be selective for chitin synthase II, as they did not appreciably inhibit chitin synthase III.

Phellinsin A, a novel chitin synthases inhibitor produced by Phellinus sp. PL3.

Phellinsin A, a novel chitin synthases inhibitor was isolated from the cultured broth of fungus PL3, which was identified as Phellinus sp. PL3. Phellinsin A was purified by solvent partition, silica gel, ODS column chromatographies, and preparative HPLC, consecutively. The structure of phellinsin A was assigned as a phenolic compound on the basis of various spectroscopic analyses including UV, IR, Mass, and NMR. Its molecular weight and formula were found to be 358 and C18H14O8, respectively. Phellinsin A selectively inhibited chitin synthase I and II of Saccharomyces cerevisiae with an IC50 value of 76 and 28 microg/ml, respectively, in our cell free assay system. This compound showed antifungal activity against Colletotrichum lagenarium, Pyricularia oryzae, Rhizoctonia solani, Aspergillus fumigatus, and Trichophyton mentagrophytes.

Chaetoatrosin A, a novel chitin synthase II inhibitor produced by Chaetomium atrobrunneum F449.

Chaetoatrosin A, a novel chitin synthase II inhibitor, was isolated from the culture broth of fungus F449, which was identified as Chaetomium atrobrunneum F449. Chaetoatrosin A was purified by solvent partition, silica gel, ODS, preparative TLC, and Sephadex LH-20 column chromatographies, consecutively. The structure of chaetoatrosin A was assigned as 1,8-dihydroxy-3(2-hydroxypropionyl)-6-methoxynaphthalene on the basis of various spectroscopic analyses including UV, IR, mass spectral, and NMR. Its molecular weight and formula were found to be 262 and C14H14O5, respectively. ,Chaetoatrosin A inhibited chitin synthase II by 50% at the concentration of 104 microg/ml in an enzyme assay system. This compound showed antifungal activities against Rhizoctonia solani, Pyricularia oryzae, Botrytis cinerea, Cryptococcus neoformans and Trichophyton mentagrophytes.

Chitin synthase II inhibitory activity of ursolic acid, isolated from Crataegus pinnatifida.

Two triterpenoid compounds, ursolic acid and uvaol, were isolated from Crataegus pinnatifida Bunge leaves. Ursolic acid inhibits chitin synthase II from S. cerevisiae with an IC50 value of 0.84 microgram/ml and the inhibition appears to be selective for chitin synthase II, whereas uvaol has no inhibitory activity up to 280 micrograms/ml. Oleanolic acid, alpha-hederin hydrate, and betulic acid inhibited the chitin synthase II activity under the same conditions with an IC50 of 5.6, 64.3, and 98.7 micrograms/ml, respectively.

Inhibition of chitin synthase II by catechins from stem bark of Taxus cuspidata.

Two flavonoids, (+/-)-catechin and (-)-epicatechin, were isolated from the stem bark of Taxus cuspidata by monitoring chitin synthase II inhibitory activity. The compounds inhibit chitin synthase II with an IC50 of 15 and 29 micrograms/ml, respectively and appear to be selective for chitin synthase II. They did not inhibit chitin synthase III.