Exploratory clinical trial to evaluate the efficacy and safety of carbon dioxide paste in healthy people.

INTRODUCTION: Scarring and pain are postoperative complications in patients after head and neck cancer treatment; however, there is no effective treatment. These complications are affected by local blood flow disorders, and it is well known that the transcutaneous application of carbon dioxide (CO2) improves local blood flow. Previously, we have shown that the transcutaneous application of carbon dioxide causes absorption of CO2 and increase the oxygen (O2) pressure in the treated tissue; it is expected that the application of CO2 may reduce scarring and pain caused by cancer treatment. We newly introduced the CO2 paste as a new CO2 application method, which does not need to use CO2 gas directly. In this study, we aimed to apply of CO2 paste to healthy people and to investigate its usefulness, safety and feasibility by analysing the increase in blood flow and frequency of adverse events. METHODS: We applied carbon dioxide paste to skin over the sternocleidomastoid and gastrocnemius muscles of eight healthy volunteers. The changes in blood flow before and after the CO2 paste application using dynamic MRI, and changes in the vital signs were evaluated. RESULTS: In the neck area and middle layer of the lower leg, the signal intensity (SI) significantly increased 60 seconds after application. In the surface layer of the lower leg, the SI was significantly increased 60 and 300 seconds after paste application. Although mild heat was noted after the paste application, no obvious adverse events occurred. CONCLUSION: We demonstrated the increase in SI by dynamic MRI at the site of the carbon dioxide paste application, which indicates the paste application is effective in improving the blood flow.

Glioma cells require one-carbon metabolism to survive glutamine starvation.

Cancer cells optimize nutrient utilization to supply energetic and biosynthetic pathways. This metabolic process also includes redox maintenance and epigenetic regulation through nucleic acid and protein methylation, which enhance tumorigenicity and clinical resistance. However, less is known about how cancer cells exhibit metabolic flexibility to sustain cell growth and survival from nutrient starvation. Here, we find that serine and glycine levels were higher in low-nutrient regions of tumors in glioblastoma multiforme (GBM) patients than they were in other regions. Metabolic and functional studies in GBM cells demonstrated that serine availability and one-carbon metabolism support glioma cell survival following glutamine deprivation. Serine synthesis was mediated through autophagy rather than glycolysis. Gene expression analysis identified upregulation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate one-carbon metabolism. In clinical samples, MTHFD2 expression was highest in the nutrient-poor areas around "pseudopalisading necrosis." Genetic suppression of MTHFD2 and autophagy inhibition caused tumor cell death and growth inhibition of glioma cells upon glutamine deprivation. These results highlight a critical role for serine-dependent one-carbon metabolism in surviving glutamine starvation and suggest new therapeutic targets for glioma cells adapting to a low-nutrient microenvironment.

Lesion characteristics between cryoballoon ablation and radiofrequency ablation with a contact force-sensing catheter: Late-gadolinium enhancement magnetic resonance imaging assessment.

BACKGROUND: Pulmonary vein isolation (PVI) lesions after cryoballoon ablation (CBA) are characterized as a wider and more continuous than that after conventional radiofrequency catheter ablation (RFCA) without the contact force (CF)-sensing technology. However, the impact on the lesion characteristics of ablation with a CF-sensing catheter has not been well discussed. We sought to assess the lesions using late-gadolinium enhancement magnetic resonance imaging (LGE-MRI) and to compare the differences between the two groups (CB group vs. RF group). METHODS: A total of 30 consecutive patients who underwent PVI were enrolled (CB group, 18; RF group, 12). The RF applications were delivered with a target lesion size index (LSI) of 5. The PVI lesions were assessed by LGE-MRI 3 months after the PVI. The region around the PV was divided into eight segments: roof, anterior-superior, anterior carina, anterior inferior, bottom, posterior inferior, posterior carina, and posterior superior segment. The lesion width and visual gap of each segment were compared between the two groups. The visual gaps were defined as no-enhancement site of >4 mm. RESULTS: The mean LSI was 4.7 ± 0.7. The lesion width was significantly wider but the visual gaps were more frequently documented at the bottom segment of right PV in the CBA group (lesion width: 8.1 ± 2.2 vs. 6.3 ± 2.2 mm; p = .032; visual gap at the bottom segment or right PV: 39% vs. 0%; p = .016). CONCLUSIONS: The PVI lesion was wider after CBA, while the visual gaps were fewer after RFCA with a CF-sensing catheter.

Intraoperative 3-T Magnetic Resonance Spectroscopy for Detection of Proliferative Remnants of Glioma.

BACKGROUND: Few studies have examined the usefulness of intraoperative magnetic resonance spectroscopy (iMRS) for identifying abnormal signals at the resection margin during glioma surgery. The aim of this study was to assess the value of iMRS for detecting proliferative remnants of glioma at the resection margin. METHODS: Fifteen patients with newly diagnosed glioma underwent single-voxel 3-T iMRS concurrently with intraoperative magnetic resonance imaging-assisted surgery. Volumes of interest (VOIs) were placed at T2-hyperintense or contrast-enhancing lesions at the resection margin. In addition to technical verification, the correlation between the MIB-1 labeling index (a pathologic feature) and metabolites measured using iMRS (N-acetyl-L-aspartate [NAA], choline [Cho], and Cho/NAA ratio) was analyzed. RESULTS: iMRS was performed for 20 VOIs in 15 patients. Fourteen (70%) of these VOIs were confirmed to be MIB-1-positive. There was a significant positive correlation between the Cho/NAA ratio and MIB-1 index (r = 0.46, P = 0.04). Cho level (P = 0.003) and Cho/NAA ratio (P = 0.002) were significantly higher in VOIs that were MIB-1-positive than in those that were MIB-1-negative. Detection of a Cho level >1.074 mM and a Cho/NAA ratio >0.48 using iMRS resulted in high diagnostic accuracy for MIB-1-positive remnants (Cho level: sensitivity 86%, specificity 100%; Cho/NAA ratio: sensitivity 79%, specificity 100%). CONCLUSIONS: This study provides evidence that 3-T iMRS can detect proliferative remnants of glioma at the resection margin using the Cho level and Cho/NAA ratio, suggesting that intraoperative magnetic resonance imaging-assisted surgery with iMRS would be practicable in glioma.

Lesion distribution after cryoballoon ablation and hotballoon ablation: Late-gadolinium enhancement magnetic resonance imaging analysis.

INTRODUCTION: Pulmonary vein isolation (PVI) lesions after cryoballoon ablation (CBA) are wide and continuous, however, the distribution can depend on the pulmonary vein (PV) size. We sought to assess the relationship between the lesion distribution and PV size after CBA and hotballoon ablation (HBA). METHODS AND RESULTS: A total of 80 consecutive patients who underwent PVI were enrolled (40 with CBA). The lesions were visualized by late-gadolinium enhancement magnetic resonance imaging. The lesion width, lesion gaps, and distance from the PV ostium (PVos) to distal lesion edge (DLE) were assessed. If the DLE extended inside the PV, the value was expressed as a negative value. Although the lesion width was significantly wider in the CB group (7.8 ± 2.0 vs 4.9 ± 1.0 mm, P < .001), the number of lesion gaps was significantly less in the HB group (2.9 ± 2.4 vs 1.3 ± 1.4 gaps, P = .001). The distance from the PVos to DLE was a negative value in both groups, but the impact was significantly greater (-1.5 ± 1.8 vs -0.2 ± 1.2 mm, P < .001) and negatively correlated with PV size in the CB group, but not in HB group (r = -0.27, P = .007). The AF recurrence 12 months after the procedure did not differ (5 [12.5%] of 40 in the CB group vs 4 [10%] of 40 in the HB group, P = .695). CONCLUSIONS: The PVI lesions after HBA were characterized by (a) narrower, but (b) more continuous, (c) smaller lesion inside the PV, and (d) irrespective of PV size as compared to that after CBA.

Influence of arm position and respiration technique during liver examinations on the detectability of mammary lesions.

During liver computed tomography (CT), scanning is performed with the raised arm position and an inhalation technique. However, for liver magnetic resonance imaging (MRI), the arms are placed at the sides of the body and an exhalation technique is used. This study was aimed at evaluating the effect that the patient's arm position and respiration technique had on the ability to detect mammary glands in the scan range to discover unexpected mammary lesions during the liver MRI examination. Liver MRI and CT images were compared for 337 female patients. More than half of the mammary glands were included in 97.3% of MRI, but in 4.7% of CT. No mammary lesions were found during CT, whereas seven were found during MRI. The mammary lesions are more likely to be detected when the patient places her arms at the sides of the body and uses the exhalation technique during liver MRI.

Comparison of dosimetric parameters in the treatment planning of magnetic resonance imaging-based intracavitary image-guided adaptive brachytherapy with and without optimization using the central shielding technique.

This study aimed to compare dosimetric parameters between non-optimized and optimized treatment planning (NOP and OP, respectively) of magnetic resonance imaging (MRI) -based intracavitary (IC) image-guided adaptive brachytherapy (IGABT) using the central shielding (CS) technique for cervical cancer. Fifty-three patients treated with external beam radiotherapy using CS and MRI-based IGABT with the IC approach alone were evaluated. The total high-risk clinical target volume (HR-CTV) D90 was aimed at >70 Gy equivalent dose in 2 Gy fractions (EQD2). In the small HR-CTV group (≤30 cm3), the mean D90s for NOP/OP were 98.6/80.7 Gy. In the large (30.1-40 cm3) and extensive (>40 cm3) HR-CTV groups, the mean D90s were 81.9/77.5 and 71.1/73.6 Gy, respectively. The mean D2cc values for organs at risks (OARs) in OP were acceptable in all groups, despite the high bladder D2cc in the NOP. The correlation between HR-CTV at first brachytherapy (BT) and NOP D90 was stronger than that between HR-CTV at first BT and OP D90. The targeted HR-CTV D90 and dose constraints of D2cc for OARs were both achieved in 16 NOP/47 OP patients for the bladder, 39/50 for the rectum, and 47/50 for the sigmoid colon (P < 0.001, P = 0.007, and P = 0.34, respectively). For small tumors, the role of optimization was to reduce the D2cc for OARs while maintaining the targeted D90. However, optimization was of limited value for extensive tumors. Methods of optimization in IGABT with CS for cervical cancer should be standardized while considering its effectiveness and limitations.

Comparison of fat suppression capability for chest MR imaging with Dixon, SPAIR and STIR techniques at 3 Tesla MR system.

PURPOSE: To directly compare fat suppression efficacy of Dixon, spectral attenuated inversion recovery (SPAIR) and short tau inversion recovery (STIR) techniques for a 3T MR system. MATERIALS AND METHODS: Nineteen consecutive patients (11 men, 8 women; mean age 67.9years) underwent chest MR imaging. Contrast-noise ratio (CNR) between muscle and fat (CNRFat) was calculated by ROI measurement. Then, two radiologists used a five-point scale for visual assessment of image quality, fat suppression capability and lesion detection. Next, the quantitative calculations obtained with all three techniques were compared by means of Tukey's honest significant difference (HSD) test. Inter-observer agreements were assessed by kappa statistics and χ2 test. Fisher's least significant difference (LSD) test was used for comparison among all scores. RESULTS: CNRFat of SPAIR were significantly higher than those of Dixon and STIR (p<0.001). Inter-observer agreements were assessed as significantly moderate, substantial or almost perfect (0.51<κ<0.89, p<0.0001). Total image quality and fat suppression capability of Dixon and STIR were significantly higher than those of SPAIR (p<0.001). CONCLUSION: Dixon technique has better fat suppression capability on T2-weighted turbo SE imaging than SPAIR technique on chest MR imaging examined with a 3T MR system, although it can't substitute STIR technique on fat suppression and lesion visualization.

Myo-inositol concentration in MR spectroscopy for differentiating high grade glioma from primary central nervous system lymphoma.

It is sometimes difficult to distinguish gliomas from other tumors on routine imaging. In this study, we assessed whether 3-T magnetic resonance spectroscopy (MRS) with LCModel software might be useful for discriminating glioma from other brain tumors, such as primary central nervous system lymphomas (PCNSLs) and metastatic tumors. A total of 104 cases of brain tumor (66 gliomas, 20 PCNSLs, 6 metastatic tumors, 12 other tumors) were preoperatively investigated with short echo time (35 ms) single-voxel 3-T MRS. LCModel software was used to evaluate differences in the absolute concentrations of choline, N-acetylaspartate, N-acetylaspartylglutamate, glutamate + glutamine, myo-inositol (mIns), and lipid. mIns levels were significantly increased in high-grade glioma (HGG) compared with PCNSL (p < 0.001). In multivariate logistic regression analysis, mIns was the best marker for differentiating HGG from PCNSL (p < 0.0001, odds ratio 1.9927, 95% confidence interval 1.3628-3.2637). Conventional MRS detection of mIns resulted in a high diagnostic accuracy (sensitivity, 64%; specificity, 90%; area under the receiver operator curve, 0.80) for HGG. The expression of inositol 3-phosphate synthase (ISYNA1) was significantly higher in gliomas than in PCNSLs (p < 0.05), suggesting that the increased level of mIns in glioma is due to high expression of ISYNA1, the rate-limiting enzyme in the mIns-producing pathway. In conclusion, noninvasive analysis of mIns using single-voxel MRS may be useful in distinguishing gliomas from other brain tumors, particularly PCNSLs.

Value of three-dimensional T2-weighted turbo spin-echo imaging with tissue-specific variable refocusing flip angle for 3-T magnetic resonance imaging of prostate cancer: comparison with conventional two- and three-dimensional T2-weighted turbo spin-echo imaging.

PURPOSE: To investigate the impact of three-dimensional (3D) T2-weighted turbo spin-echo imaging (TSE-T2WI) with tissue-specific variable refocusing flip angle (TS-VRFA) on image quality and prostate cancer (PCa) detection and extraprostatic extension (EPE) evaluation compared to 2D TSE-T2WI and conventional 3D TSE-T2WI with volume isotropic TSE acquisition (VISTA). MATERIALS AND METHODS: Image data sets of 40 patients who underwent 3-T MRI before prostatectomy, including multiplane 2D T2WI, 3D T2WI with TS-VRFA and VISTA, and diffusion-weighted images were independently evaluated by two radiologists. The detectability of PCa and EPE of each sequence was assessed using areas by the receiver operating characteristic curve (AUC) analysis. Image quality measures and contrast ratios (CR) between cancerous lesions and non-cancerous regions for each T2WI were also evaluated. RESULTS: Overall image quality of TS-VRFA was better than that of VISTA and equivalent to 2D. The highest CR was obtained with TS-VRFA (P < 0.05). For both readers, no significances were observed in detectability for PCa detection between three sequences (P > 0.05). For both readers, there were no significant differences in AUC for EPE evaluation between three sequences (P > 0.05). CONCLUSION: 3D T2 WI using TS-VRFA could potentially replace multiplane 2D T2 WI for prostate cancer diagnosis with better image quality than VISTA.

Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma.

BACKGROUND: Mutations in the isocitrate dehydrogenase 1 (IDH1) gene that are frequently observed in low-grade glioma are strongly associated with the accumulation of 2-hydroxyglutarate (2HG), which is a valuable diagnostic and prognostic biomarker of IDH1 mutant glioma. However, conventional MR spectroscopy (MRS)-based noninvasive detection of 2HG is challenging. In this study, we aimed to determine the additional value of other metabolites in predicting IDH1 mutations with conventional MRS. METHODS: Forty-seven patients with glioma underwent conventional single voxel short echo time MRS prior to surgery. A stereotactic navigation-guided operation was performed to resect tumor tissues in the center of the MRS voxel. MRS-based measurements of metabolites were validated with gas chromatography-mass spectrometry. We also conducted integrated analyses of glioma cell lines and clinical samples to examine the other metabolite levels and molecular findings in IDH1 mutant gliomas. RESULTS: A metabolomic analysis demonstrated higher levels of 2HG in IDH1 mutant glioma cells and surgical tissues. Interestingly, glutamate levels were significantly decreased in IDH1 mutant gliomas. Through an analysis of metabolic enzyme genes in glutamine pathways, it was shown that the expressions of branched-chain amino acid transaminase 1 were reduced and glutamate dehydrogenase levels were elevated in IDH1 mutant gliomas. Conventional MRS detection of glutamate and 2HG resulted in a high diagnostic accuracy (sensitivity 72%, specificity 96%) for IDH1 mutant glioma. CONCLUSIONS: IDH1 mutations alter glutamate metabolism. Combining glutamate levels optimizes the 2HG-based monitoring of IDH1 mutations via MRS and represents a reliable clinical application for diagnosing IDH1 mutant gliomas.

Triexponential function analysis of diffusion-weighted MRI for diagnosing prostate cancer.

BACKGROUND: To evaluate more detailed information noninvasively through on diffusion and perfusion in prostate cancer (PCa) using triexponential analysis of diffusion-weighted imaging (DWI). METHODS: Sixty-three prostate cancer patients underwent preoperative 3.0 Tesla MRI including eight b-values DWI. Triexponential analysis was performed to obtain three diffusion coefficients (Dp , Df , Ds ), as well as fractions (Fp , Ff , Fs ). Each diffusion parameter for cancerous lesions and normal tissues was compared and the relationship between diffusion parameters and Gleason score (GS) was assessed. K(trans) , Ve , and the ratios of intracellular components measured in histopathological specimens were compared with diffusion parameters. RESULTS: Dp was significantly greater for cancerous lesions than normal peripheral zone (PZ) (P < 0.001), whereas Dp in transition zone (TZ) showed no significant difference (P = 0.74, 95% confidence interval (CI) = -4.69-6.48). Ds was significantly smaller for each cancerous lesions in PZ and TZ (P < 0.001, respectively). There was no significant difference in Df between cancerous lesions and normal tissues in PZ and TZ (P = 0.07, 95% CI = -0.29-0.12 and P = 0.53, 95% CI = -3.51-2.29, respectively). D obtained with biexponential analysis were significantly smaller in cancerous lesions than in normal tissue in PZ and TZ (P < 0.001 for both), while D* in PZ and TZ showed no significant difference (P = 0.14, 95% CI = -1.60-0.24 and P = 0.31, 95% CI = -3.43-1.16, respectively). Dp in PZ and TZ showed significant correlation with K(trans) (R = 0.85, P < 0.001; R = 0.81, P < 0.001, respectively), while D(*) in PZ obtained with biexponential analysis showed no such correlation (P = 0.08, 95% CI = -0.14-0.30). Fs was significantly correlated with intracellular space fraction evaluated in histopathological specimens in PZ and TZ cancer (R = 0.41, P < 0.05; R = 0.59, P < 0.001, respectively). Ff and Fs correlated significantly with GS in PZ and TZ cancer (PZ: R = -0.44, P < 0.05; R = 0.37, P < 0.05, TZ: R = -0.59, P < 0.05; R = 0.57, P < 0.05, respectively). CONCLUSION: Triexponential analysis is a noninvasive approach that can provide more detailed information regarding diffusion and perfusion of PCa than biexponential analysis.

Dynamic Blood Oxygen Level-dependent MR Imaging of Muscle: Comparison of Postocclusive Reactive Hyperemia in Young Smokers and Nonsmokers.

PURPOSE: The role of early stage functional assessment of muscle blood flow response (MFR) by dynamic muscle blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging is unknown. We investigated the effect of smoking on vascular function according to MFR derived from dynamic muscle BOLD MR imaging during postocclusive reactive hyperemia in young smokers and nonsmokers. METHODS: Sixteen healthy male volunteers (8 smokers, 8 nonsmokers; mean age, 30.4 ± 4.6 years) underwent BOLD MR imaging of the left calf muscle. During reactive hyperemia provoked by a cuff-compression technique, we measured muscle BOLD (mB) using a 3-tesla single-shot multi-echo gradient-echo echo-planar imaging sequence. The 2 key mB variables in the reactive hyperemic phase that we studied were times to half hyperemic peak (T(1/2peak)) and peak (TTP), each measured from cuff deflation. We used the Welch test to assess differences in these between smokers and nonsmokers. RESULTS: T(1/2peak) and TTP were significantly longer in smokers (P < 0.05) in reactive hyperemia. T(1/2peak) was 13.8 ± 5.4 s in smokers and 7.6 ± 1.5 s in nonsmokers, and TTP was 67.5 ± 18.8 s in smokers and 45.4 ± 7.1 s in nonsmokers. CONCLUSION: Dynamic BOLD MR imaging of calf muscle during postocclusive reactive hyperemia demonstrated statistically significant differences in T(1/2peak) and TTP between young smokers and nonsmokers, indicating the presence of early stage smoking-related deterioration in MFR.

Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment.

The mechanistic target of rapamycin (mTOR) is hyperactivated in many types of cancer, rendering it a compelling drug target; however, the impact of mTOR inhibition on metabolic reprogramming in cancer is incompletely understood. Here, by integrating metabolic and functional studies in glioblastoma multiforme (GBM) cell lines, preclinical models, and clinical samples, we demonstrate that the compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors. Metabolomic studies in GBM cells revealed that glutaminase (GLS) and glutamate levels are elevated following mTOR kinase inhibitor treatment. Moreover, these mTOR inhibitor-dependent metabolic alterations were confirmed in a GBM xenograft model. Expression of GLS following mTOR inhibitor treatment promoted GBM survival in an α-ketoglutarate-dependent (αKG-dependent) manner. Combined genetic and/or pharmacological inhibition of mTOR kinase and GLS resulted in massive synergistic tumor cell death and growth inhibition in tumor-bearing mice. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance and suggest that rational combination therapy has the potential to suppress resistance.