Validation of a simplified scatter correction method for 3D brain PET with <Superscript>15</Superscript>O

Objective

Positron emission tomography (PET) enables quantitative measurements of various biological functions. Accuracy in data acquisition and processing schemes is a prerequisite for this. The correction of scatter is especially important when a 3D PET scanner is used. The aim of this study was to validate the use of a simplified calculation-based scatter correction method for ¹⁵O studies in the brain.

Methods

We applied two scatter correction methods to the same ¹⁵O PET data acquired from patients with cerebrovascular disease (n = 10): a hybrid dual-energy-window scatter correction (reference method), and a deconvolution scatter correction (simplified method). The PET study included three sequential scans for ¹⁵O-CO, ¹⁵O-O₂, and ¹⁵O-H₂O, from which the following quantitative parameters were calculated, cerebral blood flow, cerebral blood volume, cerebral metabolic rate of oxygen, and oxygen extraction fraction.

Results

Both scatter correction methods provided similar reconstruction images with almost identical image noise, although there were slightly greater differences in white-matter regions compared with gray matter regions. These differences were also greater for ¹⁵O-CO than for ¹⁵O-H₂O and ¹⁵O-O₂. Region of interest analysis of the quantitative parameters demonstrated that the differences were less than 10 % (except for cerebral blood volume in white-matter regions), and the agreement between the methods was excellent, with intraclass correlation coefficients above 0.95 for all the parameters.

Conclusions

The deconvolution scatter correction despite its simplified implementation provided similar results to the hybrid dual-energy-window scatter correction. We consider it suitable for application in a clinical ¹⁵O brain study using a 3D PET scanner.

     

Effects of the Cessation of Mass Screening for Neuroblastoma at 6 Months of Age: A Population-Based Study in Osaka,Japan

Background

In 2004, the Japanese government halted the 6-month mass screening program for neuroblastoma. We investigated whether its cessation had led to an increase not only in mortality due to this disease but also in the incidence of advanced-stage disease among older children.

Methods

Study subjects were neuroblastoma patients retrieved from the population-based Osaka Cancer Registry. Trends of incidence and mortality from neuroblastoma were analyzed by calendar year and birth cohort. Prognostic factors, including stage and v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) oncogene status, were compared before and after the cessation of mass screening.

Results

Age-standardized incidence rates in 2005–2009 (the cessation period of mass screening; 11.1 per million) were similar to those in 1975–1979 (the pre-screening period; 8.6 per million). Age-standardized mortality rates tended to decrease from 1975–1979 (4.0 per million) to 2005–2009 (2.7 per million) in parallel with the improvement in survival. Analysis by birth cohort indicated that the mortality rates in 2004–2005 (after cessation) for children 0–4 years of age were lower than those in 1975–1979 (O:E ratio 0.25; 95% confidence interval, 0.03–0.90). For children 1–9 years of age, there was a not significant difference in the distribution of stage, MYCN oncogene status, and DNA ploidy between 1991–2003 (the mass screening period) and 2004–2008 (after cessation).

Conclusions

The cessation of mass screening for neuroblastoma does not appear to have increased mortality due to this disease or incidence of advanced-stage disease among older children.Key words: neuroblastoma, cessation, screening, mortality, incidence     

Neuronal susceptibility to beta‐amyloid toxicity and ischemic injury involves histone deacetylase‐2 regulation of endophilin‐B1

Histone deacetylases (HDACs) catalyze acetyl group removal from histone proteins, leading to altered chromatin structure and gene expression. HDAC2 is highly expressed in adult brain, and HDAC2 levels are elevated in Alzheimer's disease (AD) brain. We previously reported that neuron‐specific splice isoforms of Endophilin‐B1 (Endo‐B1) promote neuronal survival, but are reduced in human AD brain and mouse models of AD and stroke. Here, we demonstrate that HDAC2 suppresses Endo‐B1 expression. HDAC2 knockdown or knockout enhances expression of Endo‐B1. Conversely, HDAC2 overexpression decreases Endo‐B1 expression. We also demonstrate that neurons exposed to beta‐amyloid increase HDAC2 and reduce histone H3 acetylation while HDAC2 knockdown prevents Aβ induced loss of histone H3 acetylation, mitochondrial dysfunction, caspase‐3 activation, and neuronal death. The protective effect of HDAC2 knockdown was abrogated by Endo‐B1 shRNA and in Endo‐B1‐null neurons, suggesting that HDAC2‐induced neurotoxicity is mediated through suppression of Endo‐B1. HDAC2 overexpression also modulates neuronal expression of mitofusin2 (Mfn2) and mitochondrial fission factor (MFF), recapitulating the pattern of change observed in AD. HDAC2 knockout mice demonstrate reduced injury in the middle cerebral artery occlusion with reperfusion (MCAO/R) model of cerebral ischemia demonstrating enhanced neuronal survival, minimized loss of Endo‐B1, and normalized expression of Mfn2. These findings support the hypothesis that HDAC2 represses Endo‐B1, sensitizing neurons to mitochondrial dysfunction and cell death in stroke and AD.     

UCN-01 (7-Hydroxystaurosporine) Enhances 5-Fluorouracil Cytotoxicity through Down-regulation of Thymidylate Synthetase Messenger RNA

UCN-01 (7-hydroxystaurosporine) is a newly developed cell cycle inhibitor known to have several modes of action, including inhibition of cyclin-dependent kinase, induction of p21 and suppression of pRb phosphorylation. In order to test a combination therapy of UCN-01 and 5-fluorouracil (5-FU), growth inhibition of CRL 1420 (MIA PaCa-2; undifferentiated pancreatic carcinoma) by four different treatments was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The treatments used were UCN-01 alone, 5-FU alone, 5-FU followed by UCN-01 (5-FU/UCN-01) and UCN-01 followed by 5-FU (UCN-01/5-FU). We also assessed changes in thymidylate synthetase (TS) mRNA levels, TS activity, and 5-FU incorporation by RNA (FRNA) for each treatment. Although treatment with UCN-01 alone, 5-FU alone, and 5-FU/UCN-01 inhibited CRL 1420 growth in a concentration-dependent manner, treatment with UCN-01/5-FU inhibited the growth of CRL 1420 synergistically at less than 1 μg/ml drug concentration. The down-regulation of TS mRNA by UCN-01 resulted in stable total TS and decreased free TS, and UCN-01/5-FU resulted in enhanced thymidylate synthetase inhibition rate (TSIR) compared to UCN-01 alone and 5-FU/UCN-01. This increased TSIR due to UCN-01 pretreatment was accompanied by elevated F-RNA concentrations in the UCN-01/5-FU treatment. The suppression of TS mRNA and TS activity by UCN-01 may lead to higher sensitivity of tumor cells to 5-FU and may explain the synergistic antitumor effect of UCN-01/5-FU. In conclusion, low concentrations of UCN-01 (from 0.01 to 1 μg/ml) may be clinically useful, affording low cytotoxicity of UCN-01, while enhancing the antitumor effect of 5-FU.