Preliminary experience with diffusion tensor imaging before and after re-irradiation treatments in children with progressive diffuse pontine glioma

Purpose

The purpose of this study is to evaluate quantitative changes in diffusion tensor imaging (DTI) tractography and fractional anisotropy (FA) of the pons along with clinical correlation, in patients who receive re-irradiation for progressive diffuse intrinsic pontine glioma (DIPG).

Methods

A retrospective case review of children with progressive DIPG who received re-irradiation at our institution from 2007 to 2011 after approval from the Institutional Review Board was performed. Tractography analysis and FA were analyzed pre and post-re-irradiation, and correlation with clinical features and MR imaging was performed.

Results

DTI analysis showed reduced values of FA on tumor progression. Increase in the FA values was noted after re-irradiation in these patients. This correlated with clinical improvement. These changes were concordant with the 3D tractography analysis which showed better visualization of the corticospinal tracts as they course through brainstem and posterior transverse pontine fibers following re-irradiation.

Conclusion

Serial changes in the FA values using DTI could provide clinically more correlative information in patients with progressive DIPG, who receive re-irradiation. Though the use and results of this modality has been reported in the newly diagnosed DIPG before, evaluation of DTI in children who receive re-irradiation for progressive DIPG has not been reported earlier. Though limited by the small sample size and treatment variability, this study for the first time shows the preliminary experience, potential, and likely efficacy of complementing DTI analysis to routine neuroimaging also in patients re-irradiated for progressive DIPG to better assess treatment response.     

IGFBP2 is overexpressed by pediatric malignant astrocytomas and induces the repair enzyme DNA-PK

To identify targets critical to malignant childhood astrocytoma, we compared the expression of receptor tyrosine kinase- associated genes between low-grade and high-grade pediatric astrocytomas. The highest differentially overexpressed gene in high-grade astrocytoma is insulin-like growth factor- binding protein-2 (P = .0006). Immunohistochemistry confirmed overexpression of insulin-like growth factor-binding protein-2 protein (P = .027). Insulin-like growth factor- binding protein-2 stimulation had no effect on astrocytoma cell growth and migration, and minimally inhibited insulin-like growth factor-1-mediated migration, but not insulin-like growth factor-2-mediated migration. However, insulin-like growth factor-binding protein-2 stimulation significantly upregulated the major DNA repair enzyme gene, DNA-PKcs, and induced DNA-dependent protein kinase catalytic subunit protein expression in a time-dependent and dose-dependent manner, whereas insulin-like growth factor-1 had no effect. DNA-PKcs is also highly overexpressed by high-grade astrocytomas. These findings suggest insulin-like growth factor-binding protein-2 plays a role in astrocytoma progression by promoting DNA-damage repair and therapeutic resistance.     

Recurrent pure CNS germinoma with markedly elevated serum and cerebrospinal fluid human chorionic gonadotropin-beta (HCGβ)

Controversy continues regarding what level of serum and/or cerebrospinal fluid (CSF) human chorionic gonadotrophin-beta (HCGβ) is consistent with pure germinoma of the central nervous system (CNS). We report a 10-year female with biopsy-proven pure germinoma and normal serum and CSF HCGβ who experienced subsequent biopsy-proven recurrences of germinoma. At recurrence, serum and CSF HCGβ levels were 560 and 3,202 mIU/ml, respectively, although final autopsy demonstrated pure germinoma. This case illustrates the need to re-evaluate the assumption that pathologically pure germinomas may be associated with high levels of HCGβ which are unrelated to nongerminomatous germ cell tumor (NGGCT)/choriocarcinomatous elements.     

NADPH-induced oxidative damage of rat liver microsomes: protective role of chlorpromazine and trifluoperazine

Two widely used antipsychotic drugs, chlorpromazine (CPZ) and trifluoperazine (TFZ) inhibit NADPH-induced microsomal lipid peroxidation (LPO). Study of microsomal membrane fluidity revealed considerable disorganization in its architecture in the presence of NADPH, which can be restored back in the presence of CPZ and TFZ. NADPH-dependent microsomal LPO is catalyzed by NADPH: cytochrome P450 reductase. These drugs also inhibit the activity of this enzyme. TFZ always shows stronger inhibitory effect than CPZ. TFZ contains a trifluromethyl group (CF3) in its second position that gives rise to stronger electron abstraction tendency by which LPO and NADPH: cytochrome P450 reductase activity is inhibited more potently than by CPZ which contains a chlorine ligand in the same position. Due to the stronger antioxidant property of TFZ, it can be prescribed as a better therapeutic agent, which plays a protective role for the cellular system.     

Plasma lipids and blood glucose in infants of toxemic mothers

Maternal and cord blood of 34 toxemic and 27 non-toxemic mothers and their infants were studied for lipids and glucose. All the lipid fractions in cord blood were significantly lower (P < .001) than that of the mother in all groups due to relative impermeability of the placenta. AFD infants of toxemic mothers had significantly higher (P < .001) value of FFA and triglyceride as compared with AFD infants of non-toxemic mothers. However SFD infants of toxemic mothers had higher FFA only when compared with that of non-toxemic mother. This is possibly due to sympathetic stimulation related to placental insufficiency with hypoxia and hypoglycemia that lead to mobilisation of adipose tissue into FFA and glycerol in fetus. Plasma phospholipid, cholesterol, HDLC, LDLC of infants of toxemic mothers were significantly lower (P < .001), more so in SFD infants, possibly due to impaired liver function, 53% of infants of toxemic mothers also had hyperbilirubinemia. Cord blood glucose in toxemic group was significantly lower (P < .05) than AFD infants of non-toxemic group.     

Early growth of term SFD infants in relation to caloric intake

Growth and development of 100 term SFD infants divided into 3 groups with body weight of 1·5 kg or less (I), 1·51–1·75 kg (II), 1·76–2·25 kg (III) and 100 AFD term infants was determined longitudinally. Group I and II infants remained smaller and had delayed milestones of development throughout the 1st year of life, with limited catch up only in body weight in the first 3 months. Their milk intake was low (132 ml/kg). Group III infants, who had comparatively better growth parameters at birth, showed effective catch up growth in all the parameters to reach the level of those of AFD infants within 3–10 months by increased consumption of milk (186 ml/kg). Their milestones of development were at par with that of AFD infants who consumed 160 ml of milk/kg/day in the first 2–4 months. The low consumption of milk by group I and II infants with severe intrauterine malnutrition is possibly related to the reduced appetite geared to a small body size.     

Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201

Journal of Neuro-Oncology - Smoking is agreed to be a major health risk factor, but it is debated whether it has an influence on perioperative adverse events (AEs) in elective cranial tumor...     

Successful radiation therapy for supratentorial primitive neuroectodermal tumor and epidermolysis bullosa simplex

Epidermolysis bullosa simplex (EBS) is a heritable skin disorder characterized by skin fragility and blistering. While its most severe variant, dystrophic epidermolysis bullosa (DEB) is associated with squamous cell carcinoma (SCC), the development of extracutaneous neoplasms in EBS is extremely rare. We report a novel case of supratentorial primitive neuroectodermal tumor (sPNET) in a 7‐year male with EBS. Experience of radiation therapy and its challenges in children with EBS has rarely been reported. Pediatr Blood Cancer 2010; 54:170–172. © 2009 Wiley‐Liss, Inc.     

Inhibition of LINE-1 and Alu retrotransposition by exosomes encapsidating APOBEC3G and APOBEC3F

Human cytidine deaminases, including APOBEC3G (A3G) and A3F, are part of a cellular defense system against retroviruses and retroelements including non-LTR retrotransposons LINE-1 (L1) and Alu. Expression of cellular A3 proteins is sufficient for inhibition of L1 and Alu retrotransposition, but the effect of A3 proteins transferred in exosomes on retroelement mobilization is unknown. Here, we demonstrate for the first time that exosomes secreted by CD4⁺H9 T cells and mature monocyte-derived dendritic cells encapsidate A3G and A3F and inhibit L1 and Alu retrotransposition. A3G is the major contributor to the inhibitory activity of exosomes, however, the contribution of A3F in H9 exosomes cannot be excluded. Additionally, we show that exosomes encapsidate mRNAs coding for A3 proteins. A3G mRNA, and less so A3F, was enriched in exosomes secreted by H9 cells. Exosomal A3G mRNA was functional in vitro. Whether exosomes inhibit retrotransposons in vivo requires further investigation.