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Recently, the hemodynamic assessments with 3D cine phase-contrast (PC) MRI (4D flow MRI) have attracted considerable attention from clinicians. Unlike 2D cine PC MRI, the technique allows for cardiac phase-resolved data acquisitions of flow velocity vectors within the entire FOV during a clinically viable period. Thus, the method has enabled retrospective flowmetry in the spatial and temporal axes, which are essential to derive hemodynamic parameters related to vascular homeostasis and those to the progression of the pathologies. Accelerations in imaging are critical for this technology to be clinically viable; however, a high SNR or velocity-to-noise ratio (VNR) is also vital for accurate flow measurements. In this chapter, the technologies enabling this difficult balance are discussed.

BACKGROUND: The haemodynamics determined by different approaches for studying fluid dynamics – i.e. computational fluid dynamics (CFD), particle image velocimetry (PIV), and phase-contrast magnetic resonance imaging (PC-MRI) – have rarely been thoroughly compared; nor have the factors that affect accuracy and precision in each method. As each method has its own advantages and limitations, this knowledge is important for future studies to be able to achieve valid analyses of fluid flows. OBJECTIVE: To gauge the capacity of these methods for analysing aneurysmal flows, we compared the haemodynamic behaviours determined by each method within a patient-specific aneurysm model. METHODS: An in vitro silicone aneurysm model was fabricated for PIV and PC-MRI, and an in silico aneurysm model with the same geometry was reconstructed for CFD. With the same fluid model prepared numerically and physically, CFD, PIV and PC-MRI were performed to study aneurysmal haemodynamics. RESULTS: 2D velocity vectors and magnitudes show good agreement between PIV and CFD, and 3D flow patterns show good similarity between PC-MRI and CFD. CONCLUSIONS: These findings give confidence to future haemodynamic studies using CFD technology. For the first time, the morphological inconsistency between the PCMRI model and others is found to affect the measurement of local flow patterns.

We explored regional functional connectivity alterations in intractable focal epilepsy brains using resting-state functional MRI. Distributions of the network parameters (corresponding to degree and eigenvector centrality) measured at each brain region for all 25 patients were significantly different from age- and sex-matched control data that were estimated by a healthy control dataset (n = 582, 18–84 years old). The number of abnormal regions whose parameters exceeded the mean + 2 SD of age- and sex-matched data for each patient were associated with various clinical parameters such as the duration of illness and seizure severity. Furthermore, abnormal regions for each patient tended to have functional connections with each other (mean ± SD = 58.6 ± 20.2%), the magnitude of which was negatively related to the quality of life. The abnormal regions distributed within the default mode network with significantly higher probability (p

PURPOSE To determine if parasagittal gastric cine magnetic resonance imaging (MRI) is able to measure gastric oscillatory contractions around 0.05 Hz and to determine its relationship with electrical activity as measured by electrogastrography (EGG). METHODS Assessment of the gastric motility is important for the research of the enteric nervous system and for the diagnosis of functional gastric disorders. Electrogastrography is a non-invasive method that can measure gastric oscillatory electrical activity around 0.05 Hz (slow wave) using electrodes on the abdominal skin, but its sensitivity and specificity of the slow wave detection is limited. We used parasagittal gastric cine MRI around the angular incisure to measure gastric oscillatory contraction around 0.05 Hz in 24 healthy volunteers. Cine MRI was acquired with time resolution of 1 s for 10 min while freely breathing participants were lying on the bed. The gastric area of the cross section was measured for each MR image and assessed its change over time. The results were compared with those for simultaneously recorded EGG. RESULTS The main frequency of the gastric area change for each participant ranged from 0.041 to 0.059 Hz (mean ± S.D. = 0.049 ± 0.004), which corresponds to the gastric slow wave frequency (mean ± S.D. = 0.049 ± 0.004) as measured by EGG (p = 7.9585 × 10 -8, Kendall 's tau test). Cross correlation analysis showed that 22 of 24 participants' gastric area changes were significantly (p

The aim of this study was to conduct a flow experiment using a cerebrovascular phantom and investigate whether magnetic resonance angiography (MRA) could replace three-dimensional rotational angiography (RA) and computed tomography angiography (CTA) to construct vascular models for computational fluid dynamics (CFD). We performed MRA and 3D cine phase-contrast (PC) MR imaging with a silicone cerebrovascular phantom of an internal carotid artery-posterior communicating artery aneurysm with blood-mimicking fluid, and controlled flow with a flowmeter. We also obtained RA and CTA data for the phantom. Four analysts constructed vascular models based on the three different modalities. These 12 constructed models used flow information based on 3D cine PC MR imaging for CFD. We compared RA-, CTA-, MRA-based CFD results using the micro-CT-based CFD result as the criterion standard to investigate whether MRA-based CFD was not inferior to RA- or CTA-based CFD. We also analyzed the inter-analyst variability. Wall shear stress (WSS) distributions and streamlines of RA- or MRA-based CFD and those of micro-CT-based CFD were similar, but the vascular models and WSS values were different. Accuracy in measurements of blood vessel diameter, cross-sectional maximum velocity, and spatially averaged WSS was the highest for RA-based CFD, followed by MRA-based and CTA-based CFD using micro-CT-based CFD result as the reference. Except maximum velocity from CTA, all other parameters had good inter-analyst agreement using different modalities. The results demonstrated that non-invasive MRA can be used for cerebrovascular CFD models with good inter-analyst agreements.

Background Interstitial lung disease (ILD) induced by anti‐programmed‐cell death‐1 (PD‐1) and anti‐PD‐ligand 1 (PD‐L1) is potentially life‐threatening and is a common reason of the discontinuation of therapy. In contrast, an enhancement in antitumor effects was reported in patients who developed immune‐related adverse events, including ILD. Although recent evidence suggests that radiologic patterns of ILD may reflect the severity of ILD and the antitumor immune responses to anti‐PD‐1/PD‐L1 therapies, the association between radiologic features and clinical outcomes remains unclear. Methods Patients with advanced non‐small‐cell lung cancer who were treated with 1st to 3rd line anti‐PD‐1 therapy from January 2016 through October 2017 were identified at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. ILD was diagnosed by the treating physicians, and chest computed tomography scans were independently reviewed to assess the radiologic features of ILD. Results A total of 231 patients who received anti‐PD‐1 therapy were enrolled. Thirty‐one patients (14%) developed ILD. Sixteen patients were classified as having ground glass opacities (GGO), 16 were classified as having cryptogenic organizing pneumonia (COP), and one was classified as having pneumonitis not otherwise specified. Patients with GGO had significantly worse overall survival time compared to patients with COP (7.8 months (95% CI: 2.2‐NE) versus not reached (95% CI: 13.2‐NE); P = 0.0175). Multivariate analysis of all 231 patients also revealed that PS = 1 and ≥2 and GGO were significant predictors of a worse overall survival. Conclusions This study demonstrated that patients who developed GGO exhibited worse outcomes among non‐small‐cell lung cancer patients receiving anti‐PD‐1 therapies., Interstitial lung disease (ILD) induced by anti‐programmed‐cell death‐1 (PD‐1) is potentially life‐threatening and radiologic patterns of ILD may reflect the severity of ILD and the antitumor immune responses to anti‐PD‐1 therapies. The current study demonstrated that patients who developed ground glass opacities exhibited worse outcomes among non‐small‐cell lung cancer patients treated with anti‐PD‐1 therapies.

ObjectivesAlthough immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs.MethodsWe retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors.ResultsOf 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) vs. not reached (95% CI: 22.4–NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) vs. not reached (95% CI: 8.4–NE); p = 0.031].ConclusionThe current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.

Objective To clarify the incidence, risk factors, and impact of malignancy in patients with PM/DM-associated interstitial lung disease (ILD). Methods This study used data from 497 patients with PM/DM-associated ILD enrolled in a multicentre, retrospective and prospective cohort of incident cases. Cancer-associated myositis (CAM) was defined as malignancy diagnosed within 3 years before or after PM/DM diagnosis. Demographic and clinical information was recorded at the time of diagnosis, and data about the occurrence of mortality and malignancy was collected. Results CAM was identified in 32 patients with PM/DM-associated ILD (6.4%). Patients with CAM were older (64 vs 55 years, P < 0.001), presented with arthritis less frequently (24% vs 49%, P = 0.01), and showed a lower level of serum Krebs von den Lungen-6 (687 vs 820 IU/l, P = 0.03) than those without CAM. The distribution of myositis-specific autoantibodies, including anti-melanoma differentiation–associated gene 5, anti-aminoacyl tRNA synthetase, and anti-transcriptional intermediary factor 1-γ antibodies, did not differ between the groups. Survival analysis demonstrated that CAM patients had a poorer survival than non-CAM patients (P = 0.006), primarily due to excess deaths by concomitant malignancy, while mortality due to ILD-related respiratory failure was similar between the groups (P = 0.51). Conclusion Concomitant malignancy can occur in patients with PM/DM-associated ILD, and has significant impact on mortality. Older age, lack of arthritis, and a lower level of serum Krebs von den Lungen-6 at diagnosis are predictors of concomitant malignancy.

Purpose The accuracy of flow velocity and three-directional velocity components are important for the precise visualization of hemodynamics by 3D cine phase-contrast MRI (3D cine PC MRI, also referred to as 4D-flow). The aim of this study was to verify the accuracy of these measurements of prototype or commercially available 3D cine PC MRI obtained by three different manufactures' MR scanners. Methods The verification of the accuracy of flow velocity in 3D cine PC MRI was performed by circulating blood mimicking fluid through a straight-tube phantom in a slanting position, such that the three-directional velocity components were simultaneously measurable, using three 3T MR scanners from different manufacturers. The data obtained were processed by phase correction, and the velocity and three-directional velocity components in the center of the tube on the central cross section of a slab were calculated. The velocity profile in each three directions and the composite velocity profiles were compared with the calculated reference values, using the Hagen-Poiseuille equation. In addition, velocity profiles and the spatially time-averaged velocity perpendicular to the tube were compared with the theoretical values and measured values by a flowmeter, respectively. Results An underestimation of the maximum velocity in the center of the tube and an overestimation of the velocity near the tube wall due to partial volume effects were observed in all three scanners. A roughening and flattening of profiles in the center of the tube were observed in one scanner, due, presumably, to the low signal-to-noise ratio. However, the spatially time-averaged velocities corresponded well with the measured values by the flowmeter in all three scanners. Conclusion In this study, we have demonstrated that the accuracy of flow velocity and three-directional velocity components in 3D cine PC MRI was satisfactory in all three MR scanners.

Background Although immune checkpoint inhibitors (ICIs) are effective for advanced non-small cell lung cancer (NSCLC), ICIs may cause interstitial lung disease (ILD), which results in treatment discontinuation and is sometimes fatal. Despite the high incidence of ICI-related ILD, there are few cancer treatment options for patients. This study aimed to evaluate the safety and efficacy of subsequent systemic cancer therapy in NSCLC patients with ICI-related ILD. Methods We retrospectively assessed NSCLC patients who received programmed cell death-1 (PD-1) inhibitors as first- to third-line therapy at participating institutions of the Niigata Lung Cancer Treatment Group from January 2016 to October 2017. Results This analysis included 231 patients, 32 (14%) of whom developed ICI-related ILD. Of these patients, 16 (7%) received subsequent systemic cancer treatments. The median overall survival (OS) tended to be longer in the systemic cancer therapy group than in the no systemic cancer therapy group [22.2 months (95% CI: 1-NE) vs. 4.5 months (95% CI: 1-NE); P=0.067]. ICI-related ILD recurred in half of the patients who received systemic cancer therapy, and the median OS tended to be shorter in patients with recurrent ICI-related ILD [22.0 months (95% CI: 1-NE) vs. 7.0 months (95% CI: 1-NE); P=0.3154]. Conclusions According to the current study, systemic cancer treatment is effective in patients with ICI-related ILD; however, its safety is uncertain because of the high risk of ICI-related ILD recurrence and poor survival outcome following ILD recurrence.

The features of pancreatic parenchyma that tend to progress towards pancreatic cancer (PC) are unknown. We performed volumetry of the pancreas in PC patients using computed tomography (CT) scans acquired before detection of PC, and investigated whether CT findings of pancreatic parenchyma could predict the future occurrence of PC. Between April 2009 and March 2017, a total of 3769 patients underwent abdominal contrast-enhanced CT, the scans of which were archived as digital images. Among them, 15 PC patients underwent abdominal CT 6–120 months before diagnosis of PC. This retrospective study compared the 15 PC patients (PC group) with 15 propensity score-matched subjects without PC (non-PC group). Pancreatic volumetry and radiological findings were compared between the two groups. There were significant differences between the PC and non-PC groups in the volume of the main pancreatic duct (MPD) plus any cystic lesion (P = 0.007), volume of the MPD plus any cystic lesion/body surface area (BSA; P = 0.009), MPD diameter (P = 0.011), and MPD diameter/BSA (P = 0.013). Univariate analysis revealed volume of MPD plus any cystic lesion/BSA ≥ 0.53 mL/m2 (odds ratio [OR] 38.50, P = 0.002), volume of pancreatic parenchyma/BSA

Brain functional connectivity in the resting-state represents intrinsic functional states and correlates with cognitive performance. In patients with schizophrenia, reports on the relationships between forms of functional disconnectivity in local areas and cognitive disability have used resting-state functional magnetic resonance imaging data. Meanwhile, cognitive deficits in relation to inter-network forms of functional connectivity on a large scale are not well understood. This study examines cognitive functions in relation to the number of resting-state inter-network forms of functional connectivity focusing on task-positive networks (fronto-parietal network [FPN] and cingulo-opercular network [CON]) and task-negative network (default mode network [DMN]). We compare patients with schizophrenia (SCH group) and healthy controls (HC group). We conducted a functional network analysis by applying graph theory and evaluated cognitive functions using the Brief Assessment of Cognition in Schizophrenia. The number of forms of functional connectivity between FPN and DMN and between CON and DMN were significantly higher in SCH group than in HC group, and those in SCH group were also weakly correlated with their attention scores. It is suggested that fewer than typical functional segregations between task-positive and task-negative networks in SCH group relate to inefficient distribution of cognitive resources and low attentional abilities.

Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1)., Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.)

Background 18F-fluorodeoxyglucose (18F-FDG) uptake in hepatocellular carcinoma (HCC) is significantly associated with early recurrence and survival after curative surgical resection. However, there are no reports regarding the relationship between 18F-FDG uptake and outcomes after radiofrequency ablation (RFA). A prospective cohort study was conducted to evaluate the prognostic value of 18F-FDG positron emission tomography (PET) in HCC patients after RFA. Methods A total of 121 consecutive patients with primary HCC (≤3 tumors, of diameter ≤ 3 cm) without vascular invasion on imaging were examined by 18F-FDG-PET computed tomography prior to RFA. An HCC with a component of 18F-FDG uptake visibly stronger than that of surrounding liver was defined as 18F-FDG-PET positive. Results The median follow-up period was 1267 days. There were 110 18F-FDG-PET negative and 11 positive tumors. The cumulative 1-year recurrence rates in the 18F-FDG negative and positive groups were 30 and 64% (P = 0.017), respectively, and cumulative 1-year metastatic recurrence rates were 6 and 36% (P < 0.001), respectively. The cumulative 5-year survival rates were 88 and 22% (P < 0.001), respectively. Multivariate analysis revealed 18F-FDG-PET positivity and tumor size as independent factors related to metastatic recurrence and survival after RFA. Conclusions 18F-FDG-PET positivity was significantly associated with outcomes after RFA. RFA should not be readily selected as the first-line treatment for small HCC that includes a component of visually strong 18F-FDG uptake.

Impulsivity is a neuropsychiatric feature of Parkinson’s disease (PD). We investigated the pathophysiology of impulsivity in PD using resting-state functional magnetic resonance imaging (rs-fMRI). We investigated 45 patients with idiopathic PD and 21 healthy controls. Based on Barratt Impulsiveness Scale (BIS-11) score, PD patients were classified as higher (PD-HI) or lower impulsivity (PD-LI). Functional connectivity (FC) between various large-scale brain networks were analysed using the CONN toolbox. FC between the right frontoparietal network (FPN) and medial visual network (MVN) was significantly higher in PD-HI patients than PD-LI patients (false discovery rate [FDR]-adjusted p = 0.0315). FC between the right FPN and MVN had a significant positive correlation with total BIS-11 score (FDR-adjusted p = 0.010) and the attentional impulsivity (FDR-adjusted p = 0.046) and non-planning impulsivity subscale scores (FDR-adjusted p = 0.018). On the other hand, motor impulsivity subscale score had a significant negative correlation with the FC between the default-mode and salience networks (right supramarginal gyrus, FDR-adjusted p = 0.018; anterior cingulate cortex, FDR-adjusted p = 0.027); this trend was observed in healthy controls. The attentional and non-planning impulsivity, regarded as ‘cognitive’ impulsivity, may be associated with dysfunction in integration of perceptual information and flexible cognitive control in PD.

The aim of this study was to conduct a flow experiment using a cerebrovascular phantom and investigate whether magnetic resonance angiography (MRA) could replace three-dimensional rotational angiography (RA) and computed tomography angiography (CTA) to construct vascular models for computational fluid dynamics (CFD). We performed MRA and 3D cine phase-contrast (PC) MR imaging with a silicone cerebrovascular phantom of an internal carotid artery-posterior communicating artery aneurysm with blood-mimicking fluid, and controlled flow with a flowmeter. We also obtained RA and CTA data for the phantom. Four analysts constructed vascular models based on the three different modalities. These 12 constructed models used flow information based on 3D cine PC MR imaging for CFD. We compared RA-, CTA-, MRA-based CFD results using the micro-CT-based CFD result as the criterion standard to investigate whether MRA-based CFD was not inferior to RA- or CTA-based CFD. We also analyzed the inter-analyst variability. Wall shear stress (WSS) distributions and streamlines of RA- or MRA-based CFD and those of micro-CT-based CFD were similar, but the vascular models and WSS values were different. Accuracy in measurements of blood vessel diameter, cross-sectional maximum velocity, and spatially averaged WSS was the highest for RA-based CFD, followed by MRA-based and CTA-based CFD using micro-CT-based CFD result as the reference. Except maximum velocity from CTA, all other parameters had good inter-analyst agreement using different modalities. The results demonstrated that non-invasive MRA can be used for cerebrovascular CFD models with good inter-analyst agreements.

Purpose 2D cine phase contrast (PC)-MRI is a standard velocimetry for the superior mesenteric artery (SMA); however, the optimal localization of the measurement plane has never been fully discussed previously. The purpose of this Institutional Review Board approved prospective and single arm study is to test whether flow velocimetry of the SMA with combined use of 2D cine PC-MRI and meal challenge is dependent on the localizations of the measurement planes and to seek optimal section for velocimetry. Methods Seven healthy volunteers underwent cardiac phase resolved ECG gated 2D cine PC-MRI pre- and 30 min post-meal challenge at three measurement planes: proximal, curved mid section and distal straight section of the SMA at 3T. 4D Flow using 3D cine PC-MRI with vastly undersampled isotropic projection imaging (PC VIPR) was also performed right after 2D cine PC-MRI to delineate the flow dynamics within the SMA using streamline analysis. Two radiologists measured flow velocities, and rated the appearances of the abnormal flow in the SMA on streamlines derived from the 4D Flow and the computational fluid dynamics (CFD). Results 2D cine PC-MRI measured increased temporally averaged flow velocity (mm/s) after the meal challenge only in the proximal (129.3 vs. 97.8, P = 0.0313) and distal section (166.9 vs. 96.2, P = 0.0313), not in the curved mid section (113.1 vs. 85.5, P = 0.0625). The average velocities were highest and their standard errors (8.5-26.5) were smallest at the distal straight section both before and after the meal challenge as compared with other sections. The streamline analysis depicted more frequent appearances of vertical or helical flow in the curved mid section both on 4D Flow and CFD (κ: 0.27-0.68). Conclusion SMA velocimetry with 2D cine PC-MRI was dependent on the localization of the measurement planes. Distal straight section, not in the curved mid section is recommended for MR velocimetry.

Postural control is an essential function of the human body that uses several senses and information from the body as input, processes the input and then provides output to the muscles for control. In this study, we examine a method wherein several matrix-shaped tactile stimuli (MSTS) located on the skin of the trunk are used to away subjects’ bodies. To clarify the relationship between body sway and the MSTS, the subjects were tracked using a high-speed camera, a foot pressure distribution measuring instrument, and two acceleration sensors. Owing to the nature of using human subjects, the resulting data had high variance; therefore, each trial data set exhibits different features. The effects of each MSTS on body sway and the dynamics of body sway are discussed and evaluated here. Additionally, we propose a single trial analysis method based on the clustering based Gaussian mixture model and smoothing filtering.

Summary Objective Elucidation of abnormal connections throughout the whole brain is necessary to understand temporal lobe epilepsy (TLE). We examined abnormalities in whole‐brain white matter integrity and their relationship with duration of illness in patients with TLE. Methods The subjects were 15 patients with TLE and 17 healthy controls. Mean duration of illness in the TLE group was 21.6 years. Tract‐based spatial statistics (TBSS) were used for diffusion tensor imaging (DTI) analysis. Four diffusion tensor metrics, that is, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and then examined for differences between the TLE and healthy control groups. We also examined for correlations between DTI parameters and duration of illness in the TLE group. Results In the TLE group, compared with the healthy control group, FA was reduced, and MD and RD were increased, not only in the limbic and temporal lobe regions and their directly connecting regions in both hemispheres, but also in remote white matter regions. Duration of illness showed a significant negative correlation with mean whole‐brain FA and a significant positive correlation with both mean whole‐brain MD and RD. Brain regions showing correlation between disease duration and DTI metrics also extended to the limbic area and its connecting regions, and to remote white matter regions. Significance The results of this study suggest that widespread abnormalities in white matter integrity in patients with TLE are associated with long‐term disease.

We developed a method of velocimetry based on an optical flow method using quantitative analyses of tagged magnetic resonance (MR) images (tagged MR-optical flow velocimetry, tMR-O velocimetry). The purpose of our study was to examine the accuracy of measurement of the proposed tMR-O velocimetry. We performed retrospective pseudo-electrocardiogram (ECG) gating tagged cine MR imaging on a rotating phantom. We optimized imaging parameters for tagged MR imaging, and validated the accuracy of tMR-O velocimetry. Our results indicated that the difference between the reference velocities and the computed velocities measured using optimal imaging parameters was less than 1%. In addition, we performed tMR-O velocimetry and echocardiography on 10 healthy volunteers, for four sections of the heart (apical, midventricular, and basal sections aligned with the short-axis, and a four-chamber section aligned with the long-axis), and obtained radial and longitudinal myocardial velocities in these sections. We compared the myocardial velocities obtained using tMR-O velocimetry with those obtained using echocardiography. Our results showed good agreement between tMR-O velocimetry and echocardiography in the radial myocardial velocities in three short-axial sections and longitudinal myocardial velocities on the midventricular portion of the four-chamber section in the long-axis. In the study conducted on the rotating phantom, tMR-O velocimetry showed high accuracy; moreover, in the healthy volunteers, the myocardial velocities obtained using tMR-O velocimetry were relatively similar to those obtained using echocardiography. In conclusion, tMR-O velocimetry is a potentially feasible method for analyzing myocardial motion in the human heart.

Although diffusion tensor imaging (DTI) have revealed brain abnormalities in bipolar disorder (BD) subjects, DTI methods might not detect disease-related abnormalities in the white matter (WM) where nerve fibers are crossing. We investigated BD myelin-related abnormal brain regions in both gray matter and WM for 29 BD and 33 healthy control (HC) participants using T1-weighted (T1w)/T2-weighted (T2w) ratio images that increase myelin-related contrast irrespective of nerve fiber orientation. To check effect of the brain volume, the results were compared with those of voxel-based morphometry (VBM). We found significantly lower T1w/T2w signal intensity in broad WM regions in BD subjects, including the corpus callosum, corona radiata, internal capsule, middle cerebellar peduncle and cerebellum. Regional volume reduction was found in the WM bilateral posterior thalami and retrolenticular part of the internal capsules of BD subjects. We also performed tract-based spatial statistics (TBSS) in 25 BD and 24 HC participants and compared those for the T1w/T2w ratio images. Both methods detected the BD corpus callosum abnormality. Further, the ratio images detected the corona radiata and the cerebellar abnormality in BD. These results suggest that T1w/T2w ratio image analysis could take a complementary role with the DTI method in elucidating myelin-related abnormalities in BD.

Background The efficacy and safety of bevacizumab in elderly patients with non-small cell lung cancer remain controversial. This study focused on both selecting fit elderly patients and overcoming interpatient variability with respect to pharmacodynamics. Methods Elderly (age: ≥70 years) patients with advanced non-squamous non-small cell lung cancer were enrolled. Patients with uncontrolled congestive heart failure and uncontrolled diabetes were excluded. The treatment regimen comprised carboplatin at an area under the curve of 5 mg/ml/min on day 1, paclitaxel at 90 mg/m2 on days 1 and 8, and bevacizumab at 15 mg/kg on day 1 every 21 days for up to 4 cycles, followed by maintenance bevacizumab. Dose reduction due to side effects was performed, with a wide range of doses of paclitaxel from 23 mg/m2/week to 60 mg/m2/week. Results Of the 36 patients entered, 38.9% required a dose reduction or cancellation of paclitaxel administration on day 8, and 75% patients were able to complete 4 cycles of triplet therapy. The response rate, primary endpoint, was 69.4% (95% confidence interval [CI]: 51.9–83.7). The median progression free survival and overall survival were 8.4 months and 29.2 months, respectively. The most common adverse events included neutropenia, hypertension, anemia, and infection. Although Grade ≥ 3 adverse events were observed in 24 patients (66.7%), there were no deaths due to toxicity. Conclusion Carboplatin plus weekly paclitaxel with bevacizumab is a feasible, effective first-line regimen for elderly non-small cell lung cancer patients. (UMIN00006622).

This study aimed to assess whether contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS), compared to multidetector-row computed tomography (MDCT) and magnetic resonance imaging (MRI), is useful for early diagnosis of small pancreatic cancer (PC). Between March 2010 and June 2018, all three imaging modalities and surgery were performed for patients with a pancreatic solid lesion measuring ≤20 mm; diagnostic ability was compared among modalities. Fifty-one of 60 patients were diagnosed with PC (PC size in 41 patients: 11−20 mm; 10 patients: ≤10 mm). The sensitivity, specificity, and accuracy of CH-EUS, MDCT, and MRI for PC (11−20 mm) detection were 95%/83%/94%, 78%/83%/79%, and 73%/33%/68%, respectively. The diagnostic ability of CH-EUS was significantly superior compared with MDCT and MRI (p = 0.002 and p = 0.007, respectively). The sensitivity, specificity, and accuracy of CH-EUS, MDCT, and MRI for PC (≤10 mm) detection were 70%/100%/77%, 20%/100%/38%, and 50%/100%/62%, respectively. The diagnostic ability of CH-EUS tended to be superior to that of MDCT (p = 0.025). The sensitivity of MDCT for PC (≤10 mm) detection was significantly lower than that for PC (11−20 mm) detection (20% vs. 78%; p = 0.001). CH-EUS, compared to MDCT and MRI, is useful for diagnosing small PCs.

Pre-operative prediction of histological response to neoadjuvant therapy aids decisions regarding surgical management of borderline resectable pancreatic cancer (BRPC). We elucidate correlation between pre-/post-treatment whole-tumor apparent diffusion coefficient (ADC) value and rate of tumor cell destruction. We newly verify whether post-treatment ADC value at the site of vascular contact predicts R0 resectability of BRPC. We prospectively reviewed 28 patients with BRPC who underwent diffusion-weighted magnetic resonance imaging before neoadjuvant chemotherapy and surgery. Correlation between the percentage of tumor cell destruction and various parameters was analyzed. Strong parameters were assessed for their ability to predict therapeutic histological response and R0 resectability. Pre-/post-treatment whole-tumor ADC value correlated with tumor cell destruction rate by all parameters (R = 0.630/0.714, P 50% was determined at 1.42 × 10−3 mm2/s. It predicts R0 with 88% sensitivity, 50% specificity, and 61% accuracy. For histological response, the post-treatment whole-tumor ADC cutoff value for discriminating between tumor destruction of ≤ 50% and tumor destruction of > 50% was determined at 1.40 × 10−3 mm2/s. It predicts histological response with 100% sensitivity, 81% specificity, and 89% accuracy. It predicts R0 with 88% sensitivity, 70% specificity, and 75% accuracy. Post-treatment whole-tumor ADC value may be a predictor of R0 resectability in patients with BRPC. Tumor cell destruction rate is indicated by the difference between pre-/post-treatment ADC values. This difference is strongly affected by the pre-treatment ADC value. The cutoff value of ADC at the site of vascular contact could not discriminate R0 resectability.

The cover image is based on the Original Research Microstructural abnormalities in callosal fibers and their relationship with cognitive function in schizophrenia: A tract‐specific analysis study by Yuji Ohoshi et al., DOI: 10.1002/brb3.1357. [Image: see text]

Background Although the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) patients has been demonstrated, their efficacy in EGFR-mutant NSCLCs with central nervous system (CNS) metastases and the role of radiotherapy remain unclear. This study aimed to determine if it is preferable to add upfront cranial radiotherapy to EGFR-TKIs in patients with EGFR-mutant NSCLC with newly diagnosed brain metastases. Methods We retrospectively analyzed the data of EGFR-mutant NSCLC patients with CNS metastases who received EGFR-TKIs as a first-line therapy. Results A total of 104 patients were enrolled and 39 patients received upfront brain radiotherapy, while 65 patients received first and second generation EGFR-TKIs first. The median time to treatment failure (TTF) was 7.8 months (95% confidence interval [CI]: 6.3-9.4). The median survival time (MST) was 24.0 months (95% CI: 20.1-30.1). The overall response rate of the CNS was 37%. The median CNS progression-free survival (PFS) was 13.2 months (95% CI: 10.0-16.2). Brain radiotherapy prior to EGFR-TKI prolonged TTF (11.2 vs. 6.8 months, P = 0.038) and tended to prolong CNS-PFS (15.6 vs. 11.1 months, P = 0.096) but was not significantly associated with overall survival (MST 26.1 vs. 24.0 months, P = 0.525). Univariate and multivariate analyses indicated that poor performance status and the presence of extracranial metastases were poor prognostic factors related to overall survival. Conclusion EGFR-TKI showed a favorable effect for EGFR-mutant NSCLC patients with CNS metastases. Prolonged TTF and CNS-PFS were observed with upfront brain radiotherapy.

Introduction The corpus callosum serves the essential role of relaying cognitive information between the homologous regions in the left and the right hemispheres of the brain. Cognitive impairment is a core dysfunction of schizophrenia, but much of its pathophysiology is unknown. The aim of this study was to elucidate the association between microstructural abnormalities of the corpus callosum and cognitive dysfunction in schizophrenia. Methods We examined stepwise multiple regression analysis to investigate the relationship of the fractional anisotropy (FA) of callosal fibers in each segment with z‐scores of each brief assessment of cognition in schizophrenia subtest and cognitive composite score in all subjects (19 patients with schizophrenia [SZ group] and 19 healthy controls [HC group]). Callosal fibers were separated into seven segments based on their cortical projection using tract‐specific analysis of diffusion tensor imaging. Results The FA of callosal fibers in the temporal segment was significantly associated with z‐scores of token motor test, Tower of London test, and the composite score. In the SZ group, the FA of callosal fibers in the temporal segment was significantly associated with the z‐score of the Tower of London test. In addition, the FA of callosal fibers in temporal segment showed significant negative association with the positive and negative syndrome scale negative score in the SZ group. Compared to the HC group, the FA in temporal segment was significantly decreased in the SZ group. Conclusion Our results suggest that microstructural abnormalities in the callosal white matter fibers connecting bilateral temporal lobe cortices contribute to poor executive function and severe negative symptom in patients with schizophrenia.

Automatic exposure control technology can reduce the radiation dose during CT. The purpose of this study is to reveal the important points regarding the usage of organ effective modulation (OEM), by evaluating the characteristics of OEM, an automatic exposure control technology. An analysis of the dosage profiles revealed that OEM may not work with the first rotation of the X-ray tube in the helical method and wide volume method. This phenomenon can be avoided by using the orbital synchronism helical method. This was also demonstrated upon measurement of the integrated absorption dose at the imaging start position. An analysis of standard deviation measurement revealed that with the combined use of OEM and x-y modulation, the reduction in dose may significantly vary depending on the presence or absence of the gantry tilt. Based on the above results, when using OEM to reduce the dose at the imaging start position, the combined use of x-y modulation should be avoided and the orbital synchronism helical method should be used.

The objective of the present study was to investigate the usefulness of the maximum standardized uptake value (SUVmax) of the primary tumor on preoperative 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography and computed tomography (PET/CT) as a prognostic indicator in patients with endometrial neoplasms. A total of 75 patients with endometrial cancer or uterine carcinosarcoma who underwent surgical treatment were included in the present study. All patients underwent preoperative PET/CT, and the correlation between the SUVmax of the primary tumor and clinical outcomes was analyzed. The SUVmax was significantly higher in patients with stage II/III disease, a histology of grade 3 endometrioid adenocarcinoma and carcinosarcoma, a positive lymph node (LN) status, positive lymph-vascular space involvement (LVSI), and deep (≥1/2) myometrial invasion. Receiver operating characteristic curve analysis revealed that the optimal cut-off values of SUVmax for predicting a positive LN, LVSI and deep myometrial invasion were 7.49, 6.45 and 6.45, respectively. The overall survival (OS) and progression-free survival (PFS) of patients with a high SUVmax were significantly lower compared with those of patients with a low SUVmax using the cut-off value of 7.30. However, no significant difference was observed in the OS or PFS between the high and low SUVmax groups when analyzed in carcinosarcoma patients alone. Finally, multivariate analyses demonstrated that the SUVmax of the primary tumor was an independent prognostic factor for impaired PFS in 55 endometrioid adenocarcinoma patients; however, not in all patients, including those with carcinosarcoma. The present findings demonstrated that the SUVmax of the primary tumor may be a useful biomarker for predicting clinical outcomes of patients with endometrial cancer, although its prognostic impact appears to be limited in patients with uterine carcinosarcoma.

The objective of the present study was to investigate the prognostic value of 18F-fluoro-2-deoxy-D-glucose (FDG) uptake by primary tumors on positron emission tomography/computed tomography (PET/CT) in surgically resectable cervical cancer. A total of 59 patients with stage IA2-IIB cervical cancer who underwent preoperative FDG-PET/CT, followed by radical hysterectomy and lymphadenectomy, were included in the study. The maximum standardized uptake value (SUVmax) of the primary tumor was measured, and the association between the SUVmax and clinicopathological factors or patient outcomes was analyzed. The SUVmax was significantly higher in patients with an advanced stage, lymph node metastasis, lymph-vascular space involvement and large tumors. The overall survival (OS) and progression-free survival (PFS) of patients with a high SUVmax were significantly lower compared with patients with a low SUVmax, using an optimal cut-off value of 7.36 for OS and 5.59 for PFS obtained from receiver operating characteristic curve analysis. Similarly, OS and PFS in patients with a high SUVmax were significantly lower in 39 patients with stage IB using a cut-off value of 7.90 and 6.69 for OS and PFS, respectively. Finally, multivariate analyses showed that the SUVmax of the primary tumor was an independent prognostic factor for impaired PFS in all patients and those with stage IB alone. These findings demonstrated that a high SUVmax on preoperative PET/CT was correlated with unfavorable clinical outcomes in patients receiving radical hysterectomy, suggesting that the SUVmax of the primary tumor may be a prognostic indicator for surgically-treated, early-stage invasive cervical cancer.

Purpose Institutional Review Board (IRB)-approved prospective study was conducted to test whether objective and quantitative hemodynamic markers wall shear stress (WSS) and oscillatory shear index (OSI) measured by three-dimensional (3D) cine phase-contrast (PC) can reflect pulmonary arterial hypertension (PAH). Patients and methods Seventeen consecutive patients of suspected secondary PAH were examined for pulmonary artery pressures (PAPs) with right heart catheterization (RHC) and three-dimensional (3D) cine PC MR. Based on the RHC data, patients were subdivided into two groups of 12 non-PAH (median age of 74.5 years) and 5 PAH (median age of 77 years) patients. Based on 3D cine PC magnetic resonance (MR), hemodynamic parameters including spatially averaged systolic WSS (sWSS), diastolic WSS (dWSS), mean WSS (mWSS), OSI and blood vessel section area (BVSA) at the pulmonary arterial trunk were calculated. Streamline images in the pulmonary arteries were also assessed. All the parameters were compared between non-PAH and PAH groups. Results sWSS (N/m(2)) and mWSS (N/m(2)) of PAH group was lower than that of non-PAH group (0.594 ± 0.067 vs. 0.961 ± 0.590, P = 0.001), (0.365 ± 0.035 vs. 0.489 ± 0.132, P = 0.027). OSI of PAH group was higher than that of non-PAH (0.214 ± 0.026 vs. 0.130 ± 0.046, P = 0.001). sWSS, mWSS, and dWSS were inversely correlated and OSI was positively correlated to mean PAP or systolic PAP with r values of -0.638 (P = 0.005), -0.643 (P = 0.005), -0.485 (P = 0.049), and 0.625 (P = 0.007); or -0.622 (P = 0.008), -0.629 (P = 0.007), -0.484 (P = 0.049), and 0.594 (P = 0.012), respectively. sWSS was also inversely correlated to BVSA with r value of -0.488 (P = 0.049), and OSI was correlated to BVSA with r value of 0.574 (P = 0.016). Vortex or helical flows were observed more frequently in PAH patients. Conclusions The low sWSS and mWSS as well as high OSI measured with 3D cine PC MR could be potential hemodynamic markers for the increased PAP in suspected secondary PAH patients.

Perinatal hypertensive disorder including pre-eclampsia is a systemic syndrome that occurs in 3-5% of pregnant women. It can result in various degrees of brain damage. A recent study suggested that even gestational hypertension without proteinuria can cause cardiovascular or cognitive impairments later in life. We hypothesized that perinatal hypertension affects the brain functional connectivity (FC) regardless of the clinical manifestation of brain functional impairment. In the present study, we analyzed regional global connectivity (rGC) strength (mean cross-correlation coefficient between a brain region and all other regions) using resting-state functional magnetic resonance imaging to clarify brain FC changes associated with perinatal blood pressure using data from 16 women with a normal pregnancy and 21 pregnant women with pre-eclampsia. The rGC values in the bilateral orbitofrontal gyri were negatively correlated with diastolic blood pressure (dBP), which could not be explained by other pre-eclampsia symptoms. The strength of FC seeding at the left orbitofrontal gyrus was negatively correlated with dBP in the anterior cingulate gyri and right middle frontal gyrus. These results suggest that dBP elevation during pregnancy can affect the brain FC. Since FC is known to be associated with various brain functions and diseases, our findings are important for elucidating the neural correlate of cognitive impairments related to hypertension in pregnancy.

Background Recent studies have reported that immune-checkpoint inhibitors (ICIs) cause various immune-related adverse events (irAEs) and irAEs are associated with antitumor effects of ICIs. However, it remains unclear whether the incidence of irAEs was associated with types of PD-1 inhibitors and treatment lines. Methods We retrospectively evaluated data of advanced or recurrent NSCLC patients treated in 1st to 3rd line with PD-1 inhibitors at Niigata Lung Cancer Treatment Group between January 2016 and October 2017. Results Of 231 patients who received anti-PD-1 therapies, 176 patients received nivolumab and 55 patients received pembrolizumab, and 63 patients (36%) developed irAEs in nivolumab therapy and 30 patients (55%) developed irAEs in pembrolizumab therapy. In the univariate analysis, male (Odd Ratio: OR 2.38, p = 0.01), smoker (OR 3.29, p = 0.002), squamous cell carcinoma (OR 2.99, p = 0.0001), pembrolizumab therapy (OR 2.15, p = 0.01), 1st line anti-PD-1 treatment (OR 2.07, p = 0.04), EGFR gene mutation negative (OR 8.77, p = 0.03) were significant predictors of irAEs. Multivariate analysis identified younger age ( Conclusion In the current study, pembrolizumab therapy and 1st line treatment were predictors of irAE onset in univariate analysis, but not in multivariate analysis.

Aim The present study aimed to evaluate pathological features of hepatocellular carcinomas (HCC) appearing hypointense on the apparent diffusion coefficient (ADC) map, and to elucidate the association between the signal intensity on the ADC map and metastatic recurrences after hepatectomy. Methods In total, 52 consecutive patients with initial hypervascular HCC (solitary lesion ≤5 cm in diameter) without vascular invasion on imaging were examined by diffusion-weighted magnetic resonance imaging before hepatectomy. The signal intensities of HCC on the ADC map were visually compared with the surrounding liver and categorized as hypointense or non-hypointense. Intrahepatic metastatic recurrence was defined as more than three intrahepatic recurrences. Results The 52 HCC were evaluated as 26 hypointense and 26 non-hypointense tumors. No significant differences between the hypointense and non-hypointense groups were seen for age, sex, etiology, tumor size and tumor marker levels. However, in resected specimens, significant differences between the two groups were noted for histological grade and microscopic portal invasion. The percentages of poorly differentiated HCC and microscopic portal invasion in the hypointense group were significantly higher than those in the non-hypointense group. The cumulative 3-year metastatic recurrence rates of the hypointense and non-hypointense groups on the ADC map were 56% and 13% (P = 0.001), respectively. Multivariate analyses indicated that hypointensity on the ADC map was the only independent factor related to metastatic recurrence. Conclusion Hypointense HCC on ADC mapping are characterized by poor histological differentiation and more frequent microscopic portal invasion, and are significantly associated with metastatic recurrences after hepatectomy.

Background The corpus callosum modulates interhemispheric communication and cognitive processes. It has been suggested that white matter abnormalities in the corpus callosum are related to the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). The aim of this study was to examine microstructural abnormalities in callosal fibers separated by their connection to functional brain regions and determine the relationship of these abnormalities with cognitive function in MDD and BD. Methods The subjects were 18 patients with MDD, 20 patients with BD, and 21 healthy controls. The callosal fibers were divided into 6 segments based on their cortical projection using tract-specific analysis of diffusion tensor imaging. We examined differences in the fractional anisotropy (FA) of callosal fibers in six segments among the three subject groups and examined the correlation between the FA in each segment and cognitive performance in the 3 groups. Results The FA of anterior callosal fibers were reduced significantly in the MDD and BD groups compared to those in the HC group, and the FA of anterior callosal fibers correlated significantly with the raw scores of the digit sequencing task and symbol coding in the MDD group. Limitations The patients were medicated at the time of scanning, and the MDD and BD groups were not matched for symptom severity. Conclusions Our results suggest that MDD and BD have similar microstructural abnormalities in anterior callosal fibers connecting bilateral frontal cortices, and these abnormalities may be related to impairment of working memory and attention in MDD.

Objective: Chemotherapy with irinotecan plus cisplatin has shown promise in chemo-naïve small-cell lung cancer (SCLC) patients. However, irinotecan treatment for relapsed or refractory SCLC has not been adequately evaluated. This phase II study evaluated the appropriate treatment schedule of irinotecan as a single agent. This study was designed to determine the antitumor activity, toxicity, and survival in previously treated SCLC patients. Methods: Previously treated SCLC patients with at least one platinum-based regimen received irinotecan (100 mg/m2) on days 1 and 8, every 3 weeks, until disease progression. The assessment of the response rate was the primary endpoint. Results: Thirty patients were enrolled, with an objective response rate of 41.3% (95% confidence interval [CI] 25.5–59.3), and a disease control rate of 69%. Median progression-free and overall survival was 4.1 months (95% CI, 2.2–5.4) and 10.4 months (95% CI, 8.1–14), respectively. The grade 3/4 hematological toxicities were neutropenia (36.7%), thrombocytopenia (3.3%), anemia (13.3%), and febrile neutropenia (6.6%). There were no grade 4 nonhematological toxicities. Frequent grade 3 nonhematological toxicities included diarrhea (10%), anorexia (6.6%), and hyponatremia (6.6%). Conclusions: This phase II study showed a high objective response rate and long survival. Irinotecan monotherapy schedule used was well tolerated, and could be an active treatment option for these patients.