Goji Berry Juice Prevents Tumor Necrosis Factor Alpha-Induced Xerostomia in Human Salivary Gland Cells.

Sjögren's syndrome (SS) is an autoimmune disorder characterized by oral dryness that is primarily attributed to tumor necrosis factor alpha (TNF-α)-mediated reduction in saliva production. In traditional Chinese medicine, goji berries are recognized for their hydrating effect and are considered suitable to address oral dryness associated with Yin deficiency. In the present study, we used goji berry juice (GBJ) to investigate the potential preventive effect of goji berries on oral dryness caused by SS. Pretreatment of human salivary gland cells with GBJ effectively prevented the decrease in aquaporin-5 (AQP-5) mRNA and protein levels induced by TNF-α. GBJ also inhibited histone H4 deacetylation and suppressed the generation of intracellular reactive oxygen species (ROS). Furthermore, GBJ pretreatment reserved mitochondrial membrane potential and suppressed the upregulation of Bax and caspase-3, indicating that GBJ exerted an antiapoptotic effect. These findings suggest that GBJ provides protection against TNF-α in human salivary gland cells and prevents the reduction of AQP-5 expression on the cell membrane. Altogether, these results highlight the potential role of GBJ in preventing oral dryness caused by SS.

Neuroendocrine tumor theranostics.

Theranostics is a term coined by combining the words "therapeutics" and "diagnostics," referring to single chemical entities developed to deliver therapy and diagnosis simultaneously. Neuroendocrine tumors are rare cancers that occur in various organs of the body, and they express neuroendocrine factors such as chromogranin A and somatostatin receptor. Somatostatin analogs bind to somatostatin receptor, and when combined with diagnostic radionuclides, such as gamma-emitters, are utilized for diagnosis of neuroendocrine tumor. Somatostatin receptor scintigraphy when combined with therapeutic radionuclides, such as beta-emitters, are effective in treating neuroendocrine tumor as peptide receptor radionuclide therapy. Somatostatin receptor scintigraphy and peptide receptor radionuclide therapy are some of the most frequently used and successful theranostics for neuroendocrine tumor. In Japan, radiopharmaceuticals are regulated under a complex law system, creating a significant drug lag, which is a major public concern. It took nearly 10 years to obtain the approval for somatostatin receptor scintigraphy and peptide receptor radionuclide therapy use by the Japanese government. In 2021, 111 Lu-DOTATATE (Lutathera), a drug for peptide receptor radionuclide therapy, was covered by insurance in Japan. In this review, we summarize the history of the development of neuroendocrine tumor theranostics and theranostics in general, as therapeutic treatment for cancer in the future. Furthermore, we briefly address the Japanese point of view regarding the development of new radiopharmaceuticals.

High molecular weight amyloid ß1-42 oligomers induce neurotoxicity via plasma membrane damage.

Amyloid ß-protein (Aß) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high MW (HMW) aggregates such as protofibrils, and ultimately fibrils. These Aß species can generally form amyloid plaques implicated in the neurodegeneration of Alzheimer disease (AD), but therapies designed to reduce plaque load have not demonstrated clinical efficacy. Recent evidence implicates amyloid oligomers in AD neuropathology, but the precise mechanisms are uncertain. We examined the mechanisms of neuronal dysfunction from HMW-Aß1-42 exposure by measuring membrane integrity, reactive oxygen species (ROS) generation, membrane lipid peroxidation, membrane fluidity, intracellular calcium regulation, passive membrane electrophysiological properties, and long-term potentiation (LTP). HMW-Aß1-42 disturbed membrane integrity by inducing ROS generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and impaired LTP. The damaging effects of HMW-Aß1-42 were significantly greater than those of LMW-Aß1-42. Therapeutic reduction of HMW-Aß1-42 may prevent AD progression by ameliorating direct neuronal membrane damage.-Yasumoto, T., Takamura, Y., Tsuji, M., Watanabe-Nakayama, T., Imamura, K., Inoue, H., Nakamura, S., Inoue, T., Kimura, A., Yano, S., Nishijo, H., Kiuchi, Y., Teplow, D. B., Ono, K. High molecular weight amyloid ß1-42 oligomers induce neurotoxicity via plasma membrane damage.

5-HT2A receptor activation enhances NMDA receptor-mediated glutamate responses through Src kinase in the dendrites of rat jaw-closing motoneurons.

KEY POINTS: 5-HT increases the excitability of brainstem and spinal motoneurons, including the jaw-closing motoneurons, by depolarizing the membrane potential and decreasing the medium-duration afterhyperpolarization. In this study, we focused on how 5-HT enhances postsynaptic glutamatergic responses in the dendrites of the jaw-closing motoneurons. We demonstrate that 5-HT augments glutamatergic signalling by enhancing the function of the GluN2A-containing NMDA receptor (NMDAR) through the activation of 5-HT2A receptors (5-HT2A Rs) and Src kinase. To enhance glutamatergic responses, activation of the 5-HT2A Rs must occur within ∼60 µm of the location of the glutamate responses. 5-HT inputs to the jaw-closing motoneurons can significantly vary their input-output relationship, which may contribute to wide-range regulation of contractile forces of the jaw-closing muscles. ABSTRACT: Various motor behaviours are modulated by 5-HT. Although the masseter (jaw-closing) motoneurons receive both glutamatergic and serotonergic inputs, it remains unclear how 5-HT affects the glutamatergic inputs to the motoneuronal dendrites. We examined the effects of 5-HT on postsynaptic responses evoked by single- or two-photon uncaging of caged glutamate (glutamate responses) to the dendrites of masseter motoneurons in postnatal day 2-5 rats of either sex. Application of 5-HT induced membrane depolarization and enhanced the glutamate-response amplitude. This enhancement was mimicked by the 5-HT2A receptor (5-HT2A R) agonist and was blocked by the 5-HT2A/2C R antagonist. However, neither the 5-HT2B R nor the 5-HT2C R agonists altered glutamate responses. Blockade of the NMDA receptors (NMDARs), but not AMPA receptors, abolished the 5-HT-induced enhancement. Furthermore, the selective antagonist for the GluN2A subunit abolished the 5-HT-induced enhancement. 5-HT increased GluN2A phosphorylation, while the Src kinase inhibitor reduced the 5-HT-induced enhancement and GluN2A phosphorylation. When exposure to the 5-HT2A R agonist was targeted to the dendrites, the enhancement of glutamate responses was restricted to the loci of the dendrites near the puff loci. Electron microscopic immunohistochemistry revealed that both the NMDARs and the 5-HT2A Rs were close to each other in the same dendrite. These results suggest that activation of dendritic 5-HT2A Rs enhances the function of local GluN2A-containing NMDARs through Src kinase. Such enhancement of the glutamate responses by 5-HT may contribute to wide-range regulation of contractile forces of the jaw-closing muscles.

Early assessment with 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography to predict short-term outcome in clear cell renal carcinoma treated with nivolumab.

BACKGROUND: We reported previously the usefulness of 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) to predict prognosis of renal cell carcinoma (RCC) treated with molecular targeted agents. Herein we describe a preliminary research of nine patients who underwent FDG-PET/CT before and after initiation of nivolumab. METHODS: Patients with metastatic RCC who were treated by nivolumab from October 2016 to March 2017 were enrolled in this study. All patients underwent FDG-PET/CT at baseline and 1 month as a first response assessment, and contrast-enhanced or non-contrast-enhanced CT scan at 4 month as a second response assessment. Logistic regression analysis was performed to assess the association of potential predictors, including age, gender, baseline diameter, baseline maximum standardized uptake value (SUVmax), lung or not lung metastasis, elevation of SUVmax at 1st assessment, and decrease in diameter at 1st assessment with the response at 2nd assessment (decrease in the diameter ≥ 30% or not). RESULTS: There were 9 patients and 30 lesions. Mean days of first assessment with FDG-PET/CT and second assessment by CT scan from initiation of treatment were 32.3 ± 6.4, 115.5 ± 14.9, respectively. Lesions whose diameter decreased ≥30% at second assessment were defined as responding, and lesions whose diameter did not decrease ≥30% were defined as non-responding. There were 18 responding lesions, and 12 non-responding lesions. We compared change in diameter and SUVmax at first assessment with FDG-PET/CT, respectively. All lesions with decreased diameter and elevated SUVmax at first assessment with FDG-PET/CT showed responding at second assessment by CT scan, while most lesions with increased diameter and declined SUVmax at first assessment showed non-responding at second assessment. The multivariate logistic regression analyses revealed that only the elevation of SUVmax at 1 month was an independent predictor (P = 0.025, OR: 13.087, 95%CI: 1.373-124.716). CONCLUSION: Our findings suggest that the early assessment using FDG-PET/CT can be effective to predict the response of RCC to nivolumab. However, larger prospective studies are needed to confirm these preliminary results. TRIAL REGISTRATION: Registered in University Hospital Medical Information Network in JAPAN [ UMIN0000008141 ], registration date: 11 Jun 2012.

New microwave ablation system for unresectable liver tumors that forms large, spherical ablation zones.

BACKGROUND AND AIM: The aim of this study was to assess the efficacy of a new microwave ablation (MWA) system, the Emprint Ablation System, for the ablation of unresectable large liver tumors (≥ 30 mm). METHODS: Twenty-one hepatic tumors (mean diameter, 34.7 mm) from 21 patients who underwent percutaneous MWA were included in this cross-sectional study. A volume analyzer based on computed tomography imaging was used for all patients within the month before and month after the procedure to evaluate the shape and volume of ablation zones. In addition, computed tomography imaging was performed again 3 months after the procedure to evaluate the presence of residual tumors and local recurrence. RESULTS: Mean ablation time was 11.3 min, and mean overall procedure time was 33.4 min. An ablated adrenal gland-induced Takotsubo (stress) cardiomyopathy occurred immediately after MWA as a major complication in one patient. Roundness index A, B, and C presented a mean value of 0.94, 0.94, and 1.01, respectively (all values near 1 is a perfect sphere), indicating that a spherical ablation zone was achieved. The mean ablation volume was larger than the volume of tumors (24.5 vs 41.7 cm3 ). Residual tumors were confirmed in only 4.8% of tumors after a single ablation session. There was no local recurrence. CONCLUSIONS: In our experience, the new MWA system provides an effective treatment option for unresectable large liver tumors. However, to ablate the liver tumors safely, it is necessary to consider the surrounding organs, such as the adrenal glands.

Experimental Study on Involvement of the Central Nervous System in Inferior Alveolar Nerve Damage-Associated Hyperalgesia of the Mental Region.

PURPOSE: Involvement of the central nervous system in sensory disturbances of the mental region occurring after inferior alveolar nerve damage was investigated using a rat model of inferior alveolar nerve damage. PATIENTS AND METHODS: The rat inferior alveolar nerve was damaged by ligation with thread, and the course of behavioral changes after surgery was observed for 42 days. In addition, activation of microglia and astroglia in the trigeminal spinal subnucleus caudalis (Vc) was analyzed using immunohistochemistry. c-Fos-positive cells were quantitatively evaluated to analyze the state of neuron excitement. RESULTS: The withdrawal threshold was significantly decreased 5 days after surgery in the inferior alveolar nerve-ligated (IANL) group compared with that in the sham group and subsequently recovered over time. In addition, microglia and astroglia were activated in the Vc region 5 days after surgery in the model group, and c-fos-positive cells were also significantly more frequent in the IANL group. However, no significant difference in the withdrawal threshold was seen between the IANL and sham groups on day 42, nor were any significant differences seen in the amounts of microglia, astroglia, or c-fos-positive cells. CONCLUSIONS: Interactions among microglia, astroglia, and neurons in the central nervous system might be involved in the progression of inferior alveolar nerve damage-associated mental hyperalgesia to a chronic state.

Three-dimensional multimodality fusion imaging as an educational and planning tool for deep-seated meningiomas.

INTRODUCTION: The utility of surgical simulation with three-dimensional multimodality fusion imaging (3D-MFI) has been demonstrated. However, its potential in deep-seated brain lesions remains unknown. The aim of this study was to investigate the impact of 3D-MFI in deep-seated meningioma operations. MATERIAL AND METHODS: Fourteen patients with deeply located meningiomas were included in this study. We constructed 3D-MFIs by fusing high-resolution magnetic resonance (MR) and computed tomography (CT) images with a rotational digital subtraction angiogram (DSA) in all patients. The surgical procedure was simulated by 3D-MFI prior to operation. To assess the impact on neurosurgical education, the objective values of surgical simulation by 3D-MFIs/virtual reality (VR) video were evaluated. To validate the quality of 3D-MFIs, intraoperative findings were compared. The identification rate (IR) and positive predictive value (PPV) for the tumor feeding arteries and involved perforating arteries and veins were also assessed for quality assessment of 3D-MFI. RESULTS: After surgical simulation by 3D-MFIs, near-total resection was achieved in 13 of 14 (92.9%) patients without neurological complications. 3D-MFIs significantly contributed to the understanding of surgical anatomy and optimal surgical view (p < .0001) and learning how to preserve critical vessels (p < .0001) and resect tumors safety and extensively (p < .0001) by neurosurgical residents/fellows. The IR of 3D-MFI for tumor-feeding arteries and perforating arteries and veins was 100% and 92.9%, respectively. The PPV of 3D-MFI for tumor-feeding arteries and perforating arteries and veins was 98.8% and 76.5%, respectively. CONCLUSIONS: 3D-MFI contributed to learn skull base meningioma surgery. Also, 3D-MFI provided high quality to identify critical anatomical structures within or adjacent to deep-seated meningiomas. Thus, 3D-MFI is promising educational and surgical planning tool for meningiomas in deep-seated regions.

Magnetic Resonance Imaging More Accurately Classifies Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease Than Transient Elastography.

BACKGROUND & AIMS: Noninvasive methods have been evaluated for the assessment of liver fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD). We compared the ability of transient elastography (TE) with the M-probe, and magnetic resonance elastography (MRE) to assess liver fibrosis. Findings from magnetic resonance imaging (MRI)-based proton density fat fraction (PDFF) measurements were compared with those from TE-based controlled attenuation parameter (CAP) measurements to assess steatosis. METHODS: We performed a cross-sectional study of 142 patients with NAFLD (identified by liver biopsy; mean body mass index, 28.1 kg/m(2)) in Japan from July 2013 through April 2015. Our study also included 10 comparable subjects without NAFLD (controls). All study subjects were evaluated by TE (including CAP measurements), MRI using the MRE and PDFF techniques. RESULTS: TE identified patients with fibrosis stage ≥2 with an area under the receiver operating characteristic (AUROC) curve value of 0.82 (95% confidence interval [CI]: 0.74-0.89), whereas MRE identified these patients with an AUROC curve value of 0.91 (95% CI: 0.86-0.96; P = .001). TE-based CAP measurements identified patients with hepatic steatosis grade ≥2 with an AUROC curve value of 0.73 (95% CI: 0.64-0.81) and PDFF methods identified them with an AUROC curve value of 0.90 (95% CI: 0.82-0.97; P < .001). Measurement of serum keratin 18 fragments or alanine aminotransferase did not add value to TE or MRI for identifying nonalcoholic steatohepatitis. CONCLUSIONS: MRE and PDFF methods have higher diagnostic performance in noninvasive detection of liver fibrosis and steatosis in patients with NAFLD than TE and CAP methods. MRI-based noninvasive assessment of liver fibrosis and steatosis is a potential alternative to liver biopsy in clinical practice. UMIN Clinical Trials Registry No. UMIN000012757.

Quantification of temporal changes in calcium score in active atherosclerotic plaque in major vessels by 18F-sodium fluoride PET/CT.

PURPOSE: Our aim was to assess whether 18F-NaF PET/CT is able to predict progression of the CT calcium score. METHODS: Between August 2007 and November 2015, 34 patients (18 women, 16 men; age, mean ± standard deviation, 57.5 ± 13.9 years; age range 19-78 years) with malignancy or orthopaedic disease were enrolled in this study, with approximately 1-year follow-up data. Baseline and follow-up CT images were retrospectively evaluated for the presence of calcification sites in major vessel walls. The maximum and mean CT values (CTmax and CTmean, in Hounsfield units), calcification volumetric score (CVS, in cubic millimetres) and Agatston units score (AU) were evaluated for each site. Subsequent changes in CTmax, CTmean, CVS and AU were calculated and expressed as ΔCTmax, ΔCTmean, ΔCVS and ΔAU, respectively. We then evaluated the relationship between 18F-NaF uptake (using the maximum target-to-background ratio, TBRmax, and the maximum blood-subtracted 18F-NaF activity, bsNaFmax, which was obtained by subtracting the SUVmax of each calcified plaque lesion and NaF-avid site from the SUVmean in the right atrium blood pool) and the change in calcified plaque volume and characteristics obtained after 1 year. RESULTS: We detected and analysed 182 calcified plaque sites and 96 hot spots on major vessel walls. 18F-NaF uptake showed very weak correlations with CTmax, CTmean, CVS, CVS after 1 year, AU and AU after 1 year on both baseline and follow-up PET/CT scans for each site. 18F-NaF uptake showed no correlation with ΔCTmax or ΔCTmean. However, there was a significant correlation between the intensity of 18F-NaF uptake and ΔCVS and ΔAU. CONCLUSION: 18F-NaF uptake has a strong correlation with calcium score progression which was a predictor of future cardiovascular disease risk. PET/CT using 18F-NaF may be able to predict calcium score progression which is known to be the major characteristic of atherosclerosis.

The acceleration of glucose accumulation in renal cell carcinoma assessed by FDG PET/CT demonstrated acquisition of resistance to tyrosine kinase inhibitor therapy.

BACKGROUND: Tyrosine-kinase inhibitor (TKI) targeting angiogenesis improves the prognosis of patients with metastatic renal cell carcinoma (RCC), but its effect is temporary. In order to understand the mechanism by which RCC acquires resistance to TKI, we investigated the change of glucose accumulation in RCC by FDG PET/CT when they demonstrated progression disease (PD) against TKI. METHODS: We monitored the FDG accumulation in RCC of 38 patients treated with TKI by 162 PET/CT sequentially until they were judged to demonstrate PD. Standardized uptake value (SUV), a simplified index of tissue FDG accumulation rate, was measured, and the sequential changes of max SUVmax (the highest SUV in an individual patient) was analyzed. Additionally, the expression of glucose transporter 1 (GLUT-1) and associated proteins in 786-O cells cultured under hypoxia were analyzed. RESULTS: The 10 patients with RCC which FDG accumulation was accelerated after beginning of TKI treatment demonstrated PD soon. The other 28 patients with RCC which FDG accumulation was suppressed by TKI showed longer progression-free survival (3.6 months vs 6.5 months, P = 0.0026), but this suppression in most cases (96%) was temporary and FDG accumulation was accelerated when tumor demonstrated PD. Interestingly, the FDG accumulation at PD was higher than that before TKI treatment in the half cases. The acceleration of FDG accumulation was suppressed by following treatment by mammalian target of rapamycin (mTOR) inhibitor. Additionally, in vitro assay demonstrated that the expression of GLUT-1 was increased in the RCC cells surviving under hypoxia condition via mTOR pathway. CONCLUSIONS: The acceleration of glucose accumulation dependent on mTOR in RCC assessed by FDG PET/CT demonstrated acquisition of resistance to TKI. FDG PET/CT had potential as an assessment method monitoring not only the initial response but also following status of RCC during TKI treatment. TRIAL REGISTRATION: UMIN0000008141 , 11 Jun 2012. This trial was retrospectively registered.

Voxel-wise correlations between cognition and cerebral blood flow using arterial spin-labeled perfusion MRI in patients with Alzheimer's disease: a cross-sectional study.

BACKGROUND: To analyze voxel-wise correlation between cerebral blood flow (CBF) measured using ASL-MRI and cognition in patients with Alzheimer's disease (AD). METHODS: Forty-one patients diagnosed with AD or mild cognitive impairment due to AD were recruited for this study. CBF images were obtained using ASL-MRI (n = 41) with a post-labeling delay (PLD) of 1.5 and 2.5 s (PLD1.5 and PLD2.5, respectively) using a 3 T scanner, in addition to brain perfusion SPECT with N-isopropyl-4-[I-123]iodoamphetamine (n = 28). Voxel-based analyses were performed for ASL-MRI and SPECT using Mini-Mental State Examination (MMSE) scores as covariates. Differences in CBF between PLD1.5 and PLD2.5 were assessed using a paired t-test with SPM12. RESULTS: Significant positive correlations were observed between MMSE scores and CBF at PLD1.5 in the right posterior cingulate cortex (PCC), and both temporo-parietal association cortexes. At PLD2.5, significant positive correlations were determined for MMSE scores and CBF in the superior parietal lobule and the right temporo-parietal association cortex. SPECT showed significant positive correlations in the PCC and both temporo-parietal association cortexes (right-side dominant). PLD1.5 showed significantly higher CBF than PLD2.5 in the proximal areas of vascular territories of the anterior, middle, and posterior cerebral arteries. CONCLUSIONS: Significant positive correlations in CBF, measured with both ASL-MRI and SPECT, with cognition were found in the PCC and temporo-parietal association cortexes. PLD1.5 and PLD2.5 showed similar correlations with cognition, although the CBF images had significant differences.

Clinical Usefulness of Somatostatin Receptor Scintigraphy in Japanese Patients with Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND/AIMS: Somatostatin receptor (SSTR) scintigraphy (SRS) is the standard imaging modality for evaluation of gastroenteropancreatic neuroendocrine tumor (GEP-NET) in Western countries. However, this modality was not approved in Japan until recently. The purpose of this study was to evaluate the clinical efficacy of SRS for detecting GEP-NET in Japanese patients. METHODS: Japanese patients with advanced GEP-NET were enrolled and evaluated by the SRS and CT. We also compared SRS and immunohistochemical expression of SSTR type 2a (SSTR2a). RESULTS: We enrolled 16 patients and the primary sites were the pancreas in 9, the stomach in 1, the small intestine in 2, the colon in 3, and unknown in 1. SRS showed positive findings in 3 (100%) of grade 1 (G1) and in 12 (92.3%) of grade 2 (G2) lesions. In the liver, SRS and CT detected lesions in 13 and 14 cases, respectively. The concordance rate of SSTR2a expression with SRS findings was 93.8% in the whole body and 92.9% in the liver. CONCLUSIONS: SRS could detect almost all of G1 and G2. SRS could be useful to detect lesions, with a high concordance rate with CT and pathological findings. We confirmed that SRS is a useful and reliable modality for Japanese patients.

FDG PET/CT as a prognostic biomarker in the era of molecular-targeting therapies: max SUVmax predicts survival of patients with advanced renal cell carcinoma.

BACKGROUND: Various molecular-targeting therapies have become available for the treatment of advanced renal cell carcinoma (RCC). Accurate prognostication is desirable for choosing the appropriate treatment for individual patients. (18)F-2-fluoro-2-deoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) is a non-invasive tool for evaluating glucose accumulation, which can be an index of biological characteristics of cancer. We prospectively evaluated FDG PET/CT as a prognostic indicator in patients with advanced RCC. METHODS: A total of 101 patients slated for different systematic therapies for advanced RCC were enrolled between 2008 and 2014. A total of 61 patients had recurrent RCC (58 metastatic and 3 regional) and 40 patients had stage IV RCC (36 metastatic and 4 locoregional). Sixteen patients had not undergone nephrectomy. Pre-treatment FDG PET/CT was performed, and the max SUVmax (the highest SUV measurement in each patient) was recorded. The max SUVmax was compared with different clinical risk factors as prognostic indicators. The median observation period was 18 months (range 1-70 months). RESULTS: The max SUVmax of the 101 subjects ranged from undetectable to 23.0 (median 6.9). Patients with high max SUVmax had a poor prognosis. Multivariate analysis with standard risk factors revealed that max SUVmax was an independent predictor of survival (p < 0.001; hazard ratio 1.265; 95% confidence interval 1.159-1.380). A cutoff of 8.8 for max SUVmax advocated in our previous report was highly significant (p < 0.0001). When we subclassified the max SUVmax values, the median overall survival of subjects with max SUVmax < 7.0 was 41.9 months. That of subjects with max SUVmax between 7.0 and 12.0 was 20.6 months. That of subjects with max SUVmax ≥ 12.0 was 4.2 months. The differences were statistically significant. CONCLUSIONS: Pretreatment max SUVmax assessed by FDG PET/CT is a useful prognostic marker for patients with advanced RCC, providing helpful information for clinical decision making.

Diffusion-tensor-based method for robust and practical estimation of axial and radial diffusional kurtosis.

OBJECTIVES: A new method that can estimate diffusional kurtosis image (DKI), estimated DKI (eDKI), parallel and perpendicular to neuronal fibres from greatly limited image data was designed to enable quick and practical assessment of DKI in clinics. The purpose of this study was to discuss the potential of this method for clinical use. METHODS: Fourteen healthy volunteers were examined with a 3-Tesla MRI. The diffusion-weighting parameters included five different b-values (0, 500, 1,500, 2,000 and 2,500 s/mm(2)) with 64 different encoding directions for each of the b-values. K values were calculated by both conventional DKI (convDKI) and eDKI from these complete data, and also from the data that the encoding directions were abstracted to 32, 21, 15, 12 and 6. Error-pixel ratio and the root mean square error (RMSE) compared with the standard were compared between the methods (Wilcoxon signed-rank test: P < 0.05 was considered significant). RESULTS: Error-pixel ratio was smaller in eDKI than in convDKI and the difference was significant. In addition, RMSE was significantly smaller in eDKI than in convDKI, or otherwise the differences were not significant when they were obtained from the same data set. CONCLUSION: eDKI might be useful for assessing DKI in clinical settings. KEY POINTS: • A method to practically estimate axial/radial DKI from limited data was developed. • The high robustness of the proposed method can greatly improve map images. • The accuracy of the proposed method was high. • Axial/radial K maps can be calculated from limited diffusion-encoding directions. • The proposed method might be useful for assessing DKI in clinical settings.

Prognostic implications of diffusion-weighted magnetic resonance imaging in patients with superior sulcus tumors receiving induction chemoradiation therapy.

OBJECTIVE: The aim of this study was to evaluate a diffusion-weighted magnetic resonance imaging to represent therapeutic response of induction chemoradiation and outcome in patients with non-small cell lung cancer of the superior sulcus. METHODS: Seventeen patients with non-small cell lung cancer of the superior sulcus (median age, 57 years; range, 44-70 years) received induction chemoradiation, followed by surgery. Diffusion-weighted magnetic resonance imaging of the lesion using b values of 0 and 800 s/mm(2) was acquired before treatment and after induction chemoradiation. Changes in tumoral apparent diffusion coefficient were compared with clinical and histopathological response. Cumulative disease-free survival and proportion of surviving were estimated by the Kaplan-Meier method. Survival of diffusion responders and non-responders were compared by log-rank test. RESULTS: A significant correlation was observed between changes of diffusion response after induction chemoradiation and overall survival. Using a defined threshold of percent increase in mean apparent diffusion coefficient, nine out of 17 patients (53%) were classified as diffusion responders and had a mean increase in mean apparent diffusion coefficient of 40.7 ± 11.2%, while eight diffusion non-responding patients (47%) had a mean increase of 11.0 ± 15.5% (P < 0.0001). Significant difference was found in overall survival between diffusion responders and diffusion non-responders (88.9 months versus 20.3 months, P = 0.002). CONCLUSIONS: Diffusion-weighted magnetic resonance imaging represented therapeutic effect and prognosis after induction chemoradiation in patients with non-small cell lung cancer of the superior sulcus.

Diagnostic performance and safety of NMK36 (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid)-PET/CT in primary prostate cancer: multicenter Phase IIb clinical trial.

OBJECTIVE: We performed a multicenter Phase IIb clinical trial of NMK36, a novel amino acid analog for positron emission tomography containing trans-1-amino-3-[(18)F]fluorocyclobutanecarboxylic acid, to evaluate its safety and diagnostic performance for primary prostate cancer. METHODS: Sixty-eight subjects with primary prostate cancer scheduled for radical prostatectomy or hormone therapy underwent whole-body positron emission tomography/computed tomography after injection of NMK36. The diagnostic performances of NMK36-positron emission tomography/computed tomography were evaluated for (i) regional lymph node metastasis: comparison with contrast-enhanced computed tomography under setting reference standard (histopathology or 6-month follow-up), (ii) bone metastasis: concordance rate with conventional imaging (combination of bone scintigraphy and contrast-enhanced computed tomography) and (iii) primary lesion: comparison with histopathological findings. RESULTS: The accuracy of NMK36-positron emission tomography/computed tomography and contrast-enhanced computed tomography for regional lymph node metastasis were 85.5 and 87.3%, respectively. NMK36-positron emission tomography/computed tomography showed positive findings for regional lymph nodes with short-axis diameters of 5-9 mm at 23 regions in 13 patients of hormone therapy cohort, but they were not confirmed with reference standard in this study. The concordance rate of NMK36-positron emission tomography/computed tomography with conventional imaging for bone metastases was 83.3%, and seven patients had positive findings only by NMK36-positron emission tomography/computed tomography. The sensitivity and specificity of NMK36-positron emission tomography/computed tomography for primary lesion in six-segment analysis was 92.5 and 90.1%, respectively. Seven of non-serious adverse events were observed in six patients. CONCLUSIONS: This study showed the comparable diagnostic performance of NMK36-positron emission tomography/computed tomography compared with conventional imaging. Some lesions of lymph node and bone were positive solely by NMK36-positron emission tomography/computed tomography, which needs to be confirmed with reference standard in future study to evaluate the usefulness of NMK36-positron emission tomography/computed tomography in staging prostate cancer.

Effects of NRG1 genotypes on orbitofrontal sulcogyral patterns in Japanese patients diagnosed with schizophrenia.

AIM: Numerous reports have described differences in the distribution of orbitofrontal cortex (OFC) sulcogyral patterns between patients with schizophrenia (SZ patients) and healthy controls (HC). Alterations in OFC morphology are also observed in those at high risk for developing SZ and in first-episode SZ, suggesting that genetic associations may be extant in determining OFC sulcogyral patterns. We investigated the association between single nucleotide polymorphisms (SNP) in NRG1 and OFC sulcogyral patterns. METHODS: A total of 59 Japanese patients diagnosed with SZ and 60 HC were scanned on a 1.5-T magnet. Patients were also assessed clinically. OFC sulcogyral patterns were evaluated for each participant, and genotyping was performed for four SNP in NRG1 (SNP8NRG243177, SNP8NRG221533, SNP8NRG241930, and rs1081062). RESULTS: There were significant differences in the distribution of OFC sulcogyral patterns between SZ patients and HC (χ(2) = 6.52, P = 0.038). SZ patients showed an increase in the frequency of Type III expression, which was associated with an earlier age of disease onset (ß = -0.302, F = 4.948, P = 0.030). Although no difference was found in genotype frequencies between SZ patients and HC, an NRG1 SNP, SNP8NRG243177, was associated with Type II expression in SZ patients (ß = 0.237, F = 4.120, P = 0.047). CONCLUSION: Our results suggest that OFC sulcogyral pattern formation in schizophrenia may be associated with NRG1 allele frequency, which is closely related to neurodevelopment.

Involvement of histaminergic inputs in the jaw-closing reflex arc.

Histamine receptors are densely expressed in the mesencephalic trigeminal nucleus (MesV) and trigeminal motor nucleus. However, little is known about the functional roles of neuronal histamine in controlling oral-motor activity. Thus, using the whole-cell recording technique in brainstem slice preparations from Wistar rats aged between postnatal days 7 and 13, we investigated the effects of histamine on the MesV neurons innervating the masseter muscle spindles and masseter motoneurons (MMNs) that form a reflex arc for the jaw-closing reflex. Bath application of histamine (100 µM) induced membrane depolarization in both MesV neurons and MMNs in the presence of tetrodotoxin, whereas histamine decreased and increased the input resistance in MesV neurons and MMNs, respectively. The effects of histamine on MesV neurons and MMNs were mimicked by an H1 receptor agonist, 2-pyridylethylamine (100 µM). The effects of an H2 receptor agonist, dimaprit (100 µM), on MesV neurons were inconsistent, whereas MMNs were depolarized without changes in the input resistance. An H3 receptor agonist, immethridine (100 µM), also depolarized both MesV neurons and MMNs without changing the input resistance. Histamine reduced the peak amplitude of postsynaptic currents (PSCs) in MMNs evoked by stimulation of the trigeminal motor nerve (5N), which was mimicked by 2-pyridylethylamine but not by dimaprit or immethridine. Moreover, 2-pyridylethylamine increased the failure rate of PSCs evoked by minimal stimulation and the paired-pulse ratio. These results suggest that histaminergic inputs to MesV neurons through H1 receptors are involved in the suppression of the jaw-closing reflex although histamine depolarizes MesV neurons and/or MMNs.

p38 phosphorylation in medullary microglia mediates ectopic orofacial inflammatory pain in rats.

BACKGROUND: Orofacial inflammatory pain is likely to accompany referred pain in uninflamed orofacial structures. The ectopic pain precludes precise diagnosis and makes treatment problematic, because the underlying mechanism is not well understood. Using the established ectopic orofacial pain model induced by complete Freund's adjuvant (CFA) injection into trapezius muscle, we analyzed the possible role of p38 phosphorylation in activated microglia in ectopic orofacial pain. RESULTS: Mechanical allodynia in the lateral facial skin was induced following trapezius muscle inflammation, which accompanied microglial activation with p38 phosphorylation and hyperexcitability of wide dynamic range (WDR) neurons in the trigeminal spinal subnucleus caudalis (Vc). Intra-cisterna successive administration of a p38 mitogen-activated protein kinase selective inhibitor, SB203580, suppressed microglial activation and its phosphorylation of p38. Moreover, SB203580 administration completely suppressed mechanical allodynia in the lateral facial skin and enhanced WDR neuronal excitability in Vc. Microglial interleukin-1ß over-expression in Vc was induced by trapezius muscle inflammation, which was significantly suppressed by SB203580 administration. CONCLUSIONS: These findings indicate that microglia, activated via p38 phosphorylation, play a pivotal role in WDR neuronal hyperexcitability, which accounts for the mechanical hypersensitivity in the lateral facial skin associated with trapezius muscle inflammation.