Tailored radiation dose according to margin width for patients with ductal carcinoma in situ after breast-conserving surgery.

A 2 mm resection margin is considered adequate for ductal carcinoma in situ (DCIS). We assessed the effectiveness of a tailored radiation dose for margins < 2 mm and the appropriate margin width for high-risk DCIS. We retrospectively evaluated 137 patients who received adjuvant radiotherapy after breast-conserving surgery for DCIS between 2013 and 2019. The patients were divided into three- positive, close (< 2 mm), and negative (≥ 2 mm) margin groups. Radiation dose to the tumor bed in equivalent dose in 2 Gy fractions were a median of 66.25 Gy, 61.81 Gy, and 59.75 Gy for positive, close, and negative margin groups, respectively. During a median follow-up of 58 months, the crude rates of local recurrence were 15.0%, 6.7%, and 4.6% in the positive, close, and negative margin groups, respectively. The positive margin group had a significantly lower 5-year local recurrence-free survival (LRFS) rate compared to the close and negative margin groups in propensity-weighted log-rank analysis (84.82%, 93.27%, and 93.20%, respectively; p = 0.008). The difference in 5-year LRFS between patients with the high- and non-high-grade tumors decreased as the margin width increased (80.4% vs. 100.0% for margin ≥ 2 mm, p < 0.001; 92.3% vs. 100.0% for margin ≥ 6 mm, p = 0.123). With the radiation dose tailored for margin widths, positive margins were associated with poorer local control than negative margins, whereas close margins were not. Widely clear margins (≥ 2 mm) were related to favorable local control for high-grade DCIS.

Characteristics of brain glucose metabolism and metabolic connectivity in noise-induced hearing loss.

The purpose of this study was to evaluate the differences in cerebral glucose metabolism and metabolic connectivity between noise-induced hearing loss (NIHL) subjects and normal subjects. Eighty-nine subjects who needed close observation for NIHL or were diagnosed with NIHL and 89 normal subjects were enrolled. After pre-processing of positron emission tomography images including co-registration, spatial normalization, and smoothing, a two-sample t-test was conducted to compare cerebral glucose metabolism between the two groups. To evaluate metabolic connectivity between two groups, BRAPH-BRain Analysis using graPH theory, a software package to perform graph theory analysis of the brain connectome was used. NIHL subjects showed hypometabolism compared to normal subjects in both insulae (x - 38, y - 18, z 4; × 42, y - 12, z 4) and right superior temporal gyrus (× 44, y 16, z - 20). No brain regions showed hypermetabolism in the NIHL subjects. In metabolic connectivity analysis, NIHL subjects showed decreased average strength, global efficiency, local efficiency, and mean clustering coefficient when compared with normal subjects. Decreased glucose metabolism and metabolic connectivity in NIHL subject might reflect decreased auditory function. It might be characteristic of sensorineural hearing loss.

Effect of high-dose radiation therapy on positive margins after breast-conserving surgery for invasive breast cancer.

PURPOSE: Positive margins after breast-conserving surgery are associated with poor oncological outcomes and warrant additional surgery. This study aimed to evaluate the effectiveness of high-dose radiation therapy for positive margins by comparing local recurrence between patients with positive and negative margins. METHODS: We retrospectively evaluated 550 patients treated with adjuvant radiation therapy after breast-conserving surgery for invasive breast cancer between 2013 and 2019. The total equivalent dose in 2 Gy fractions (EQD2) to the tumor bed ranged from 65.81 to 66.25 Gy for positive margins and 59.31-61.81 Gy for negative margins. The differences in local recurrence between the positive and negative margin groups were analyzed. RESULTS: After a median follow-up of 58 months, the crude local recurrence rate was 7.3% in the positive margin group (n = 55) and 2.4% in the negative margin group (n = 495). Positive margins were associated with higher local recurrence without statistical significance in the entire cohort (p = 0.062). Among patients aged <60 years, those with positive margins had a significantly lower 5-year local recurrence-free survival rate than those with negative margins (89.16% vs. 97.57%, respectively; p = 0.005). In contrast, there was no significant difference in the 5-year local recurrence-free survival rate between patients with positive and negative margins among those aged ≥60 years (100.00% vs. 94.38%, respectively; p = 0.426). CONCLUSION: In this study, positive margins were not associated with poor local control in older patients after a high-dose boosts. Further prospective studies are needed to verify our findings.

Effect of Obesity and Osteocalcin on Brain Glucose Metabolism in Healthy Participants.

We evaluated the effects of obesity and osteocalcin on glucose metabolism in the brain. A total of 179 healthy men were enrolled in this study. After preprocessing positron emission tomography images, including by performing coregistration, spatial normalization, and smoothing, regression analysis was conducted to identify the correlation between body mass index, osteocalcin, and brain glucose metabolism. Body mass index was positively correlated with brain glucose metabolism in the anterior lobe of the right cerebellum, the anterior and posterior lobes of the left cerebellum, the right middle frontal gyrus (Brodmann area 9), the right cingulate gyrus (Brodmann area 32), the right anterior cingulate (Brodmann area 32), the left middle frontal gyrus (Brodmann area 10), and the subgyral area of the left frontal lobe. Osteocalcin was negatively correlated with glucose metabolism in the anterior lobe of the left cerebellum. Body mass index was positively correlated with brain glucose metabolism in the prefrontal cortex and cerebellum. Osteocalcin levels were negatively correlated with brain glucose metabolism in the left cerebellum.

High expression of the phosphoinositide 3-kinase p11γ isoform can predict poor prognosis of non-small cell lung cancer.

The protein p110γ is an isoform of the catalytic subunit of class I phosphoinositide 3-kinases (PI3Ks). PI3Ks are involved in the regulation of cell survival, growth, proliferation, and migration and have been implicated in the oncogenesis of various cancers. In this study, p110γ expression in non-small cell lung cancer (NSCLC) and its association with clinicopathological factors and patient survival were evaluated. A total of 230 NSCLC tumors were immunohistochemically stained for p110γ. Of these, 174 (75.7%) and 56 (24.3%) were placed in the low and high expression groups, respectively. The positive rate of p110γ was significantly higher in adenocarcinoma than in squamous cell carcinoma (p⟨0.001). Advanced stage NSCLCs showed higher p110γ expression than those at an early stage (p=0.002). Irrespective of the histological tumor type, the patients with high p110γ expression had significantly worse overall survival than those with low p110γ expression (p=0.004). p110γ expression was an independent poor prognostic factor in the multivariate analysis. Our results suggest that p110γ may be involved in the development and progression of NSCLC, and that p110γ has promising potential as a prognostic factor or novel therapeutic target for NSCLC.

No association of Brain-derived neurotrophic factor with striatal dopamine transporter availability in healthy subjects.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a key role in brain plasticity, synaptic function, neuronal survival, learning, and memory formation. We aimed to investigate the association of BDNF with dopamine transporter (DAT) availabilities measured by positron emission tomography (PET) in healthy subjects. METHODS: Thirty-five healthy, male subjects without brain injury, neuropsychological disorders were included in this study. The emission data were acquired over 90 mins with 50 frames after injection of 18F-FP-CIT using PET. Binding potentials (BPNDs) of ventral striatum (VST), caudate nucleus, putamen were measured with the simplified reference tissue method. The serum BDNF level (pg/mL) was measured through enzyme-linked immunosorbent assay method. RESULTS: Thirty-five healthy males with a mean age of 24.4 ± 2.7 years were included in this study. Multiple regression was done to investigate the association between striatal BPNDs from VST, caudate nucleus, putamen and serum BDNF after adjusting for age. None of striatal BPNDs from VST (p=0.8450), caudate nucleus (p=0.4783), and putamen (p=0.7994) were associated with serum BDNF. CONCLUSION: Striatal DAT availabilities measured from PET were not associated with the serum BDNF in healthy subjects.

Effect of white matter hyperintensity on dopamine transporter availability of striatum measured by F-18 FP-CIT PET.

PURPOSE: We aimed to evaluate the white matter hyperintensity (WMH) effect on dopamine transporter availability (DAT) of striatum. MATERIALS AND METHODS: A total of 48 patients who showed visually normal F-18 FP-CIT uptake were included in this study. Each FP-CIT image were pre-processed using SPM12. Co-registration and spatial normalization of FP-CIT image conducted using T1-weighted magnetic resonance imaging (MRI). And then smoothing of normalized FP-CIT image was performed. Intensity normalization was performed using cerebellum as a reference region. With pre-defined volume of interest template, the specific binding ratio (SBR) of both side of caudate nucleus and putamen was calculated. Fluid attenuated inversion recovery MRI scans were used to evaluate WMH number and volume. RESULTS: SBRs of left and right caudate nucleus were correlated with age (r = - 0.615; p < 0.0001; n = 48, r = - 0.607; p < 0.0001; n = 48, respectively), high density lipoprotein cholesterol (r = 0.296; p = 0.041; n = 48, r = 0.29; p = 0.0455; n = 48, respectively), and WMH number (r = - 0.459; p = 0.001; n = 48, r = - 0.481; p = 0.0005; n = 48, respectively) and volume (r = - 0.407; p = 0.0041; n = 48, r = - 0.428; p = 0.0024; n = 48, respectively). CONCLUSION: DAT availability of patients who showed visually normal F-18 FP-CIT uptake was correlated with number and volume of WMH.

The association of DAT gene methylation with striatal DAT availability in healthy subjects.

BACKGROUND: DNA methylation inhibits gene expression by preventing transcription factors from binding to DNA. Functioning of nigrostriatal dopaminergic neurons is influenced by the expression of the dopamine transporter (DAT), and genetic variations in the gene encoding DAT contribute to differences in reward processing. We aimed to investigate the action of DAT methylation on DAT protein expression measured by positron emission tomography (PET). METHODS: The emission data were acquired over 90 min with 50 frames after injection of 18F-FP-CIT using PET. Binding potentials (BPNDs) of ventral striatum, caudate nucleus, putamen were measured with the simplified reference tissue method. Genomic DNA was extracted from subjects' blood sampling. Methylation of 4 regions in SLC6A3 gene was assessed using bisulfite pyrosequencing. The mean percentage of methylation (%) for each cluster was calculated by taking the average of all CpG site methylation levels measured within the cluster. Subjects were assessed with the Generalized Reward and Punishment Expectancy Scales (GRAPES) that consists of 30 items related with the reward and punishment that individuals expect for their behaviors. RESULTS: Thirty-five healthy males, with an age range between 20 and 30 years, and a mean age of 24.4 ± 2.7 years, were included in this study. The mean percentage of methylation (%) from cluster C showed a trend of positive correlation with DAT availability of ventral striatum (rho = 0.3712, p = 0.0281), not significant after correction for multiple comparisons, and a significant correlation with GRAPES A: reward expectancy scale (rho = 0.7178, p < 0.0001). CONCLUSION: DAT methylation from peripheral blood showed a trend of positive correlation with DAT availability of ventral striatum in healthy subjects; however, it was not significant after correction for multiple comparison. The degrees of methylation from cluster C of DAT in peripheral blood were significantly correlated with reward scales of GRAPES A: reward expectancy scale. The association between DAT methylation and DAT expression needs to be investigated further.

Relationship between 18F-FDG uptake and heat shock protein 90α expression in colorectal cancer.

OBJECTIVE: We investigated whether heat shock protein 90α (HSP90α) expression is associated with fluorine-18-labeled fluoro-2-deoxy-D-glucose (18F-FDG) uptake and whether 18F-FDG positron emission tomography/computed tomography (PET/CT) can be used to predict the status of HSP90α expression in colorectal cancer (CRC). SUBJECTS AND METHODS: The medical records and preoperative 18F-FDG PET/CT studies of 51 patients with newly diagnosed CRC who underwent surgical treatment were retrospectively reviewed. The maximum standardized uptake value (SUVmax) of the primary tumor was calculated from the level of 18F-FDG uptake. HSP90α expression was determined by immunohistochemistry. The relationship between SUVmax and HSP90α expression was analyzed. RESULTS: Colorectal cancer with high HSP90α expression had significantly higher SUVmax than CRC with low HSP90α expression (18.88±10.06 vs. 12.38±5.04, P=0.003). There was a significant correlation between HSP90α expression and 18F-FDG uptake (r=0.354, P=0.011). The highest accuracy for determining HSP90α status (68.6%) was obtained with a SUVmax cut-off of 15.4. Maximum SUV was the only predictor of HSP90α expression on multivariate logistic regression analysis (Odds Ratio=5.384, P=0.016). CONCLUSION: The expression status of HSP90α was significantly related to 18F-FDG uptake in CRC.

Effect of sex on aging-related decline of dopamine transporter in healthy subjects.

OBJECTIVE: Aging decreases dopamine transporter (DAT) availability of striatum both in humans and rodents. We aimed to investigate the relationship of DAT availabilities from ventral striatum, caudate nucleus, and putamen with aging in healthy subjects. METHODS: 123I-FP-CIT single photon emission computed tomography (SPECT) was performed in all subjects. Specific binding of 123I-FP-CIT regarding DAT was calculated using a volume-of-interest-based analysis of ventral striatum, caudate nucleus, putamen. The cerebellum was chosen as a reference region. Specific binding ratios (SBRs) were calculated as follows: SBR = (target- cerebellum)/cerebellum. RESULTS: A total of 166 healthy subjects (109 males and 57 females) were included in this study. SBRs of ventral striatum, caudate nucleus, and putamen were negatively correlated with age. In young males, SBRs of ventral striatum and putamen were not correlated with aging. However, SBRs of caudate nucleus showed the trend toward negative correlation with age in the young group. In old males, SBR of caudate nucleus was negatively correlated with age and SBR of ventral striatum showed a trend toward negative correlation with age. Slopes of regression lines were not significantly different according to age groups in ventral striatum, caudate nucleus, or putamen. SBRs of ventral striatum, caudate nucleus, and putamen were negatively correlated with age in young females, but not in old females. Interestingly, slopes of regression line were significantly different between young and old females in ventral striatum, caudate nucleus, and putamen. CONCLUSIONS: We have shown that slopes of regression lines of DAT availabilities and age were significantly different between young and old subjects in females, not in males. Therefore, sex has an impact on aging-related decline of striatal DAT availability.

Sex difference in cerebral blood flow and cerebral glucose metabolism: an activation-likelihood estimation meta-analysis.

OBJECTIVES: Sex differences exist in a variety of aspects including neurochemicals as well as behavioral traits of cognition, language, and aggression. We performed a meta-analysis of studies using a coordinate-based technique of activation-likelihood estimation (ALE) to identify the pooled estimated effect of sex difference. METHODS: We performed a systematic search of MEDLINE and EMBASE for English-language publications using the keywords of 'positron emission tomography (PET)', 'single-photon emission computed tomography (SPECT)', and 'sex'. A threshold of uncorrected P < 0.001 (minimum volume of 200 mm3) was applied to the resulting ALE map. RESULTS: Cerebral blood flow (CBF) in right precuneus, left superior temporal gyrus, left inferior temporal, left inferior frontal gyrus, right cerebellar tonsil, and right middle temporal gyrus was higher in females than males. CBF in left anterior cingulate was higher in males than females. Whereas, the cerebral metabolic rate for glucose (CMRglu) in left thalamus, left cingulate gyrus, right inferior parietal lobule, left medial frontal gyrus, right middle frontal gyrus, right midbrain, and left inferior parietal lobule was higher in females than males. However, there was no brain region that showed higher CMRglu in males than females. CONCLUSION: Regional CBF and CMRglu from PET and SPECT showed the difference between males and females.

Prognostic significance of glucose-related protein 94 in colorectal cancer.

AIMS: The expression of glucose-related protein 94 (GRP94), a member of the heat shock protein 90 family, was correlated with a variety of clinicopathological factors and patient survival in a large colorectal cancer (CRC) cohort. We aimed to elucidate the role of GRP94 in the prognosis of CRC patients. METHODS: Tissue microarray blocks were generated from 709 CRC samples and immunohistochemically stained for GRP94. RESULTS: Of the 709 tumours, 164 (23.1%) and 545 (76.9%) were classified in the low and high expression groups, respectively. GRP94 expression was high in CRC cases with larger tumours (p =  0.005) and advanced pT stage (p =  0.021). GRP94 expression was higher in females than males (p =  0.024). In univariate and multivariate survival analyses, high GRP94 expression was unexpectedly associated with better overall survival in CRC patients younger than 65 years of age (p =  0.001) CONCLUSION: Our conflicting results indicate that GRP94 has the ability to switch between oncogenic and tumour-suppressive roles depending on the conditions and microenvironment of the tumour cells. Furthermore, GRP94 could be a candidate biomarker to predict better prognosis in CRC patients.

Effects of animal handling on striatal DAT availability in rats.

OBJECTIVE: Positron emission tomography (PET) is a non-invasive technique measuring quantification of physiological and biochemical processes in the living organism. However, there are many considerations including anesthesia and fasting to acquire small animal imaging. We aimed to evaluate the effects of anesthesia and fasting of rats in dopamine transporter (DAT) imaging acquisition. METHODS: Male Sprague Dawley (SD) rats aged 7 weeks and weighing 180-260 g were used in this study. Rats were randomly divided by 4 groups. Group A was kept under anesthesia for 40 min and fasted over 12 h. Group B was only fasted over 12 h. Group C was only kept under anesthesia for 40 min. Group D was neither kept under anesthesia nor fasted over 12 h. PET scans were started at 40 min after 18F-FP-CIT injection and obtained for 20 min. Volumes-of-interest for striatum and extrastriatal area were used for 18F-FP-CIT PET analysis. Cerebellum was considered as a reference region. Specific binding ratio (SBR) was calculated as follows: [(uptake of target-uptake of cerebellum)]/(uptake of cerebellum). RESULTS: SBR without fasting and anesthesia (group D) was significantly lower than those of other groups (vs group A, p = 0.0004; vs group B, p = 0.0377; vs group C, p = 0.0134). However, SBRs of extrastriatal area (p = 0.5120) were not affected by fasting and anesthesia. CONCLUSIONS: In conclusion, the SBR of striatum was increased after anesthesia by isoflurane and fasting. When designing an experiment using DAT imaging, the effects of isoflurane and fasting should be considered.

Effects of Maturation on Striatal Dopamine Transporter Availability in Rats.

OBJECTIVES: We investigated the effects of maturation on dopamine transporter (DAT) availability in the rat via longitudinal monitoring with positron emission tomography (PET). METHODS: Eight 5-week-old male Sprague-Dawley rats (113-186 g) were used. Four 18F-FP-CIT PET scans were taken at 5, 10, 15, and 20 weeks. Baseline PET images were manually fused with the built-in magnetic resonance imaging template; volumes of interest (VOIs) were manually defined by placing a spherical region around the hot spot with the maximum count rate. VOIs were placed on bilateral caudate and putamen (CPu), nucleus accumbens (NAc), and cerebellum. Specific binding ratios (SBRs) were calculated as follows: (mean uptake of bilateral targets - mean uptake of bilateral cerebellum)/(mean uptake of bilateral cerebellum). RESULTS: In CPu, SBRs at 5 weeks (3.25 ± 0.66) were lower than those at 10 weeks (4.59 ± 0.78, p = 0.1151) and at 15 weeks (5.56 ± 0.92, p = 0.0182). In NAc, SBRs at 5 weeks (1.41 ± 0.47) were lower than those at 10 weeks (2.03 ± 0.36, p = 0.1960) and at 15 weeks (2.43 ± 0.50, p = 0.0427). SBRs in CPu and NAc significantly increased with maturation until 15 weeks. However, differences in SBR between 15 and 20 weeks were not significant. CONCLUSIONS: Striatal DAT availability increases until 15 weeks postnatally, then remains stable, reflecting maturation of the dopaminergic system in rats.

Differential expression of HSP90 isoforms and their correlations with clinicopathologic factors in patients with colorectal cancer.

Heat shock protein 90 (HSP90), a molecular chaperone, plays critical roles in cellular protection against various stressful stimuli and in the regulation of cellular growth and apoptosis. HSP90 has four human isoforms; HSP90α, HSP90ß, glucose related protein 94 (GRP94), and tumor necrosis factor (TNF) receptor-associated protein 1 (TRAP1). We evaluated the differential expression of these HSP90 isoforms in colorectal cancer (CRC) and correlated their expression levels with clinicopathological factors and patient survival rates. We performed immunohistochemical staining for HSP90α, HSP90ß, GRP94, and TRAP1 in 129 CRC tumor samples and found that HSP90α expression was significantly associated with advanced pT stage (P = 0.011) and shorter recurrence-free survival (RFS) (P = 0.010), whereas GRP94 expression was correlated with low grade (P = 0.029) and better RFS (P < 0.001). HSP90ß and TRAP1 had no prognostic impact, although HSP90ß expression was positively correlated with tumor size (P = 0.008). Based on our results, HSP90α and GRP94 are potential prognostic biomarkers of CRC. In addition, the differences in expression and functional activities among four HSP90 isoforms imply that isoform selectivity should be seriously considered when HSP90 inhibitors are studied or adopted for the treatment of CRC.