Increase In Apparent Diffusion Coefficient Research Articles

Normal Brain and Brain Tumor ADC: Changes Resulting From Variation of Diffusion Time and/or Echo Time in Pulsed-Gradient Spin Echo Diffusion Imaging.

Increasing gradient performance on modern magnetic resonance imaging scanners has profoundly reduced the attainable diffusion and echo times for clinically available pulsed-gradient spin echo (PGSE) sequences. This study investigated how this may impact the measured apparent diffusion coefficient (ADC), which is considered an important diagnostic marker for differentiation between normal and abnormal brain tissue and for therapeutic follow-up. Diffusion time and echo time dependence of the ADC were evaluated on a high-performance 3 T magnetic resonance imaging scanner. Diffusion PGSE brain scans were performed in 10 healthy volunteers and in 10 brain tumor patients using diffusion times of 16, 40, and 70 ms, echo times of 60, 75, and 104 ms at 3 b-values (0, 100, and 1000 s/mm 2 ), and a maximum gradient amplitude of 68 mT/m. A low gradient performance system was also emulated by reducing the diffusion encoding gradient amplitude to 19 mT/m. In healthy subjects, the ADC was measured in 6 deep gray matter regions and in 6 white matter regions. In patients, the ADC was measured in the solid part of the tumor. With increasing diffusion time, a small but significant ADC increase of up to 2.5% was observed for 6 aggregate deep gray matter structures. With increasing echo time or reduced gradient performance, a small but significant ADC decrease of up to 2.6% was observed for 6 aggregate white matter structures. In tumors, diffusion time-related ADC changes were inconsistent without clear trend. For tumors with diffusivity above 1.0 μm 2 /ms, with prolonged echo time, there was a pronounced ADC increase of up to 12%. Meanwhile, for tumors with diffusivity at or below 1.0 μm 2 /ms, no change or a reduction was observed. Similar results were observed for gradient performance reduction, with an increase of up to 21%. The coefficient of variation determined in repeat experiments was 2.4%. For PGSE and the explored parameter range, normal tissue ADC changes seem negligible. Meanwhile, observed tumor ADC changes can be relevant if ADC is used as a quantitative biomarker and not merely assessed by visual inspection. This highlights the importance of reporting all pertinent timing parameters in ADC studies and of considering these effects when building scan protocols for use in multicenter investigations.

Engeletin alleviates depressive-like behaviours by modulating microglial polarization via the LCN2/CXCL10 signalling pathway.

Microglial polarization and associated inflammatory activity are the key mediators of depression pathogenesis. The natural Smilax glabra rhizomilax derivative engeletin has been reported to exhibit robust anti-inflammatory activity, but no studies to date have examined the mechanisms through which it can treat depressive symptoms. We showed that treatment for 21 days with engeletin significantly alleviated depressive-like behaviours in chronic stress social defeat stress (CSDS) model mice. T1-weighted imaging (T1WI), T2-weighted imaging (T2WI) imaging revealed no significant differences between groups, but the bilateral prefrontal cortex of CSDS mice exhibited significant increases in apparent diffusion coefficient and T2 values relative to normal control mice, with a corresponding reduction in fractional anisotropy, while engeletin reversed all of these changes. CSDS resulted in higher levels of IL-1β, IL-6, and TNF-a production, enhanced microglial activation, and greater M1 polarization with a concomitant decrease in M2 polarization in the mPFC, whereas engeletin treatment effectively abrogated these CSDS-related pathological changes. Engeletin was further found to suppress the LCN2/C-X-C motif chemokine ligand 10 (CXCL10) signalling axis such that adeno-associated virus-induced LCN2 overexpression ablated the antidepressant effects of engeletin and reversed its beneficial effects on the M1/M2 polarization of microglia. In conclusion, engeletin can alleviate CSDS-induced depressive-like behaviours by regulating the LCN2/CXCL10 pathway and thereby altering the polarization of microglia. These data suggest that the antidepressant effects of engeletin are correlated with the polarization of microglia, highlighting a potential avenue for future design of antidepressant strategies that specifically target the microglia.

Abstract A098: Quantitative MRI metrics capture pancreatic cancer and stroma responses to novel KRAS inhibitor

Abstract Introduction Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer with limited treatment options. Oncogene KRAS mutations found in majority of PDA patients with KRAS(G12D) mutation being the most common. A new KRAS(G12D) specific inhibitor, MRTX1133 has been shown to induce rapid tumor regression in PDA models while the effect on stroma is only revealed by postmortem analyses of tumor specimens, making it hard to assess the dynamics of stroma remodeling. Furthermore, in clinical testing of KRAS(G12C) inhibitor, only ~50% of patients responded to the treatment despite the presence of correct genetic mutation in biopsy specimens, therefore, early and accurate assessment of the drug-target engagement is important in clinical setting. Our study was designed to test the hypothesis that multimetric MRI captures early responses to KRAS(G12D) inhibitor beyond the change of tumor size in a PDA model. Especially, changes in apparent diffusion coefficient (ADC) from diffusion weighted (DW) MRI, Ktrans from dynamic contrast enhanced (DCE) MRI, and magnetization transfer ratio (MTR). Methods A genetically engineered model of PDA bearing KRAS(G12D) and Trp53 mutation referred to as KPC was used. Male and female mice were enrolled to receive MRTX1133 at 30mg/kg BID or PBS via i.p injection. Murine PDA cells bearing KRAS(G12C) mutation were inoculated in the flank of C57BL/6 mice to grow subcutaneous tumors. In vivo DW- and DCE-MRI were obtained on a 9.4T Bruker system employing pulse sequences insensitive to respiratory motion. Results In KPC mice, striking increase of tumor ADC were detected as early as 48h after treatment initiation and was confirmed by statistical analyses at 48h and day7 accompanied by decrease of tumor size, in contrast to a trend of increased tumor size and decreased ADC in PBS-treated mice. H&E section revealed gross necrosis and extensive cell death. A clear increase of Ktrans suggesting an increase of capillary permeability and/or perfusion was detected at 48h, persisting to day7; while CD31 did not change significantly, capillary lumen area appeared enlarged at 48h, consistent with reduced interstitial fluid pressure resulted from clearance of stromal hyaluronic acid. A remarkable reduction of MTR at 48h clearly captured the stromal effect of MRTX1133 whereas no change observed in PBS-treated mice. Consistently, Sirius red (SR) staining for collagen revealed a high degree of heterogeneity where regions of depletion versus dense SR staining coexist. Lack of tumor regression and ADC change in KRAS(G12C) tumors confirmed the specificity of MRTX1133 to G12D however, a reduction of MTR was revealed, suggesting stromal impact as off-target effect of MRTX1133. Conclusion To our knowledge, this represents the first MRI study of the new KRAS inhibitor. The multimetric MRI approach is novel and significant because it captured MRTX1133-induced cancer cell death and stroma change over time. With further validation, these translatable imaging metrics can provide biological mechanism underneath tumor size change in the clinical setting. Citation Format: Mamta Gupta, Hoon Choi, Emma E. Furth, Miguel Joaquim, Stephen Pickup, Cynthia Clendenin, Margo Orlen, Thomas Karasic, Hee Kwon Song, Yong Fan, Peter O’Dwyer, Robert H. Vonderheide, Mark Rosen, Ben Z. Stanger, Rong Zhou. Quantitative MRI metrics capture pancreatic cancer and stroma responses to novel KRAS inhibitor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A098.

Diffusion-weighted imaging for determining response to neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis

ObjectivesTo determine the role of diffusion-weighted imaging (DWI) for predicting response to neoadjuvant therapy (NAT) in pancreatic cancer.Materials and methodsMEDLINE, EMBASE, and Cochrane Library databases were searched for studies evaluating the performance of apparent diffusion coefficient (ADC) to assess response to NAT. Data extracted included ADC pre- and post-NAT, for predicting response as defined by imaging, histopathology, or clinical reference standards. ADC values were compared with standardized mean differences. Risk of bias was assessed using the Quality Assessment of Diagnostic Studies (QUADAS-2).ResultsOf 337 studies, 7 were included in the analysis (161 patients). ADC values reported for the pre- and post-NAT assessments overlapped between responders and non-responders. One study reported inability of ADC increase after NAT for distinguishing responders and non-responders. A correlation with histopathological response was reported for pre- and post-NAT ADC in 4 studies. DWI’s diagnostic performance was reported to be high in three studies, with a 91.6–100% sensitivity and 62.5–94.7% specificity. Finally, heterogeneity and high risk of bias were identified across studies, affecting the domains of patient selection, index test, reference standard, and flow and timing.ConclusionDWI might be useful for determining response to NAT in pancreatic cancer. However, there are still too few studies on this matter, which are also heterogeneous and at high risk for bias. Further studies with standardized procedures for data acquisition and accurate reference standards are needed.Clinical relevance statementDiffusion-weighted MRI might be useful for assessing response to neoadjuvant therapy in pancreatic cancer. However, further studies with robust data are needed to provide specific recommendations for clinical practice.Key Points•The role of DWI with ADC measurements for assessing response to neoadjuvant therapy in pancreatic cancer is still unclear.•Pre- and post-neoadjuvant therapy ADC values overlap between responders and non-responders.•DWI has a reported high diagnostic performance for determining response when using histopathological or clinical reference standards; however, studies are still few and at high risk for bias.

MRI features of neuronal intranuclear inclusion disease, combining visual and quantitative imaging investigations

ObjectiveTo observe the radiological characteristics of Neuronal Intranuclear Inclusion Disease (NIID) on lesion locations and diffusion property using quantitative imaging analysis. MethodsVisual inspection and quantitative analyses were performed on MRI data from 31 retrospectively included patients with NIID. Frequency heatmaps of lesion locations on T2WI and DWI were generated using voxel-wise analysis. Gray matter volume (GMV), white matter volume (WMV) and diffusion property of apparent diffusion coefficient (ADC) values of patients were voxel-wisely compared with healthy controls. Moreover, the ADC values within the DWI-detected lesion were compared with those within the adjacent cortical gray matter and white matter. Voxel-based lesion symptom mapping (VLSM) techniques, were used to determine the relationship between DWI lesion location and disease durations. ResultsBy visual inspection on the imaging findings, we proposed an “cockscomb flower sign” for describing the radiological feature of DWI hyperintensity within the corticomedullary junction. A “T2WI-DWI mismatch of spatial distribution” pattern was also revealed with visual inspection and frequency heatmaps, for describing the feature of a wider lesion distribution covering white matter shown on T2WI than that on DWI. Voxel-based morphometry comparison revealed that wildly reduced GMV and WMV, both the lesion areas detected by DWI and T2WI demonstrated ADC increase in patients. Furthermore, the ADC values within the DWI-detected lesion were intermediate between the adjacent cortex and the deep white matter with highest ADC. VLSM analysis revealed that frontal lobe, parietal lobe and internal capsule damage were associated with higher NIID durations. ConclusionNIID features with “cockscomb flower-like” DWI hyperintensity in area of corticomedullary junction, based on a “T2WI-DWI mismatch of spatial distribution” of lesion locations. The pathological substrate of corticomedullary junction hyperintensity on DWI, can not be explained as diffusion restriction. These typical radiological features of brain MRI would be helpful for diagnosis of NIID.

Hyperpolarised xenon-129 diffusion-weighted magnetic resonance imaging for assessing lung microstructure in idiopathic pulmonary fibrosis.

Hyperpolarised 129-xenon (129Xe) magnetic resonance imaging (MRI) shows promise in monitoring the progression of idiopathic pulmonary fibrosis (IPF) due to the lack of ionising radiation and the ability to quantify functional impairment. Diffusion-weighted (DW)-MRI with hyperpolarised gases can provide information about lung microstructure. The aims were to compare 129Xe DW-MRI measurements with pulmonary function tests (PFTs), and to assess whether they can detect early signs of disease progression in patients with newly diagnosed IPF. This is a prospective, single-centre, observational imaging study of patients presenting with IPF to Northern General Hospital (Sheffield, UK). Hyperpolarised 129Xe DW-MRI was performed at 1.5 T on a whole-body General Electric HDx scanner and PFTs were performed on the same day as the MRI scan. There was an increase in global 129Xe apparent diffusion coefficient (ADC) between the baseline and 12-month visits (mean 0.043 cm2·s-1, 95% CI 0.040-0.047 cm2·s-1 versus mean 0.045 cm2·s-1, 95% CI 0.040-0.049 cm2·s-1; p=0.044; n=20), with no significant change in PFTs over the same time period. There was also an increase in 129Xe ADC in the lower zone (p=0.027), and an increase in 129Xe mean acinar dimension in the lower zone (p=0.033) between the baseline and 12-month visits. 129Xe DW-MRI measurements correlated strongly with diffusing capacity of the lung for carbon monoxide (% predicted), transfer coefficient of the lung for carbon monoxide (KCO) and KCO (% predicted). 129Xe DW-MRI measurements appear to be sensitive to early changes of microstructural disease that are consistent with progression in IPF at 12 months. As new drug treatments are developed, the ability to quantify subtle changes using 129Xe DW-MRI could be particularly valuable.

Optimal time for early therapeutic response prediction in nasopharyngeal carcinoma with functional magnetic resonance imaging.

Physiological changes in tumour occur much earlier than morphological changes. They can potentially be used as biomarkers for therapeutic response prediction. This study aimed to investigate the optimal time for early therapeutic response prediction with multi-parametric magnetic resonance imaging (MRI) in patients with nasopharyngeal carcinoma (NPC) receiving concurrent chemo-radiotherapy (CCRT). Twenty-seven NPC patients were divided into the responder (N=23) and the poor-responder (N=4) groups by their primary tumour post-treatment shrinkages. Single-voxel proton MR spectroscopy (1H-MRS), diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI were scanned at baseline, weekly during CCRT and post-CCRT. The median choline peak in 1H-MRS, the median apparent diffusion coefficient (ADC) in DW-MRI, the median influx rate constant (Ktrans), reflux rate constant (Kep), volume of extravascular-extracellular space per unit volume (Ve), and initial area under the time-intensity curve for the first 60s (iAUC60) in DCE-MRI were compared between the two groups with the Mann-Whitney tests for any significant difference at different time points. In DW-MRI, the percentage increase in ADC from baseline to week-1 for the responders (median=11.39%, IQR=18.13%) was higher than the poor-responders (median=4.91%, IQR=7.86%) (p=0.027). In DCE-MRI, the iAUC60 on week-2 was found significantly higher in the poor-responders (median=0.398, IQR=0.051) than the responders (median=0.192, IQR=0.111) (p=0.012). No significant difference was found in median choline peaks in 1H-MRS at all time points. Early perfusion and diffusion changes occurred in primary tumours of NPC patients treated with CCRT. The DW-MRI on week-1 and the DCE-MRI on week-2 were the optimal time points for early therapeutic response prediction.

Greater increases in intratumoral apparent diffusion coefficients after chemoradiotherapy predict better overall survival of patients with cervical cancer.

To evaluate whether 1) the intratumoral apparent diffusion coefficients (ADCs) change during cervical cancer treatment and 2) the pretreatment ADC values or their change after treatment predict the treatment outcome or overall survival of patients with cervical cancer. We retrospectively enrolled 52 patients with inoperable cervical cancer treated with chemoradiotherapy, who had undergone diffusion weighted MRI before treatment and post external beam radiotherapy (EBRT) and concurrent chemotherapy. A subgroup of patients (n = 28) underwent altogether six consecutive diffusion weighted MRIs; 1) pretreatment, 2) post-EBRT and concurrent chemotherapy; 3-5) during image-guided brachytherapy (IGBT) and 6) after completing the whole treatment course. To assess interobserver and intertechnique reproducibility two observers independently measured the ADCs by drawing freehand a large region of interest (L-ROI) covering the whole tumor and three small ROIs (S-ROIs) in areas with most restricted diffusion. Reproducibility was equally good for L-ROIs and S-ROIs. The pretreatment ADCs were higher in L-ROIs (883 mm2/s) than in S-ROIs (687 mm2/s, P < 0.001). The ADCs increased significantly between the pretreatment and post-EBRT scans (L-ROI: P < 0.001; S-ROI: P = 0.001). The ADCs remained significantly higher than pretreatment values during the whole IGBT. Using S-ROIs, greater increases in ADCs between pretreatment and post-EBRT MRI predicted better overall survival (P = 0.018). ADC values significantly increase during cervical cancer treatment. Greater increases in ADC values between pretreatment and post-EBRT predicted better overall survival using S-ROIs. Standardized methods for timing and delineation of ADC measurements are advocated in future studies.

Incremental value of diffusion weighted imaging over conventional MRI for the diagnosis of osteomyelitis of extremities.

To determine the incremental value of diffusion weighted imaging (DWI) over conventional MR imaging in diagnosing extremity osteomyelitis (OM). In this cross-sectional study, three experienced musculoskeletal radiologists evaluated clinically suspected cases of extremity OM in two rounds-first on conventional MR imaging, and then conventional MR imaging combined with DWI 4-6 weeks later. The readers recorded a result of the presence or absence of OM and their diagnostic confidence on a 1-5 scale. Mean and minimum apparent diffusion coefficient (ADC) were measured. Pathology diagnosis served as the reference standard. Statistical analysis utilized intraclass correlation (ICC) and Conger's kappa. A total of 213 scans of suspected OM were reviewed by three musculoskeletal radiologists with no significant changes in sensitivity (0.97, 0.97), specificity (0.97, 0.94), positive predictive value (0.91, 0.87), or negative predictive value (0.98, 0.98) between conventional MR imaging and MR imaging combined with DWI, respectively. Reader confidence did not significantly change with the addition of DWI (4.55 and 4.70, respectively). A high inter-reader agreement was observed for the diagnosis of OM, soft tissue abscess, and intraosseous abscess in both rounds. A higher mean (1.46+/-0.43 × 10-3 mm2/s > 0.64+/-0.47 × 10-3mm2/s) and minimum (1.18+/-0.45 × 10-3mm2/s > 0.37+/-0.44 × 10-3mm2/s) ADC value was associated with OM (p-value < 0.0001) with odds ratios of 1.34 and 1.31, respectively, for mean and minimum ADC of the involved bone. DWI-derived ADC increase is associated with OM. The use of DWI slightly increases reader confidence in the diagnosis of OM; however, no significant incremental value over conventional MR imaging is seen for the final diagnosis of OM.

Prospective validation of diffusion-weighted MRI as a biomarker of tumor response and oncologic outcomes in head and neck cancer: Results from an observational biomarker pre-qualification study

PurposeTo determine DWI parameters associated with tumor response and oncologic outcomes in head and neck (HNC) patients treated with radiotherapy (RT). MethodsHNC patients in a prospective study were included. Patients had MRIs pre-, mid-, and post-RT completion. We used T2-weighted sequences for tumor segmentation which were co-registered to respective DWIs for extraction of apparent diffusion coefficient (ADC) measurements. Treatment response was assessed at mid- and post-RT and was defined as: complete response (CR) vs. non-complete response (non-CR). The Mann-Whitney U test was used to compare ADC between CR and non-CR. Recursive partitioning analysis (RPA) was performed to identify ADC threshold associated with relapse. Cox proportional hazards models were done for clinical vs. clinical and imaging parameters and internal validation was done using bootstrapping technique. ResultsEighty-one patients were included. Median follow-up was 31 months. For patients with post-RT CR, there was a significant increase in mean ADC at mid-RT compared to baseline ((1.8 ± 0.29) × 10–3 mm2/s vs. (1.37 ± 0.22) × 10–3 mm2/s, p < 0.0001), while patients with non-CR had no significant increase (p > 0.05). RPA identified GTV-P delta (Δ)ADCmean < 7% at mid-RT as the most significant parameter associated with worse LC and RFS (p = 0.01). Uni- and multi-variable analysis showed that GTV-P ΔADCmean at mid-RT ≥ 7% was significantly associated with better LC and RFS. The addition of ΔADCmean significantly improved the c-indices of LC and RFS models compared with standard clinical variables (0.85 vs. 0.77 and 0.74 vs. 0.68 for LC and RFS, respectively, p < 0.0001 for both). ConclusionΔADCmean at mid-RT is a strong predictor of oncologic outcomes in HNC. Patients with no significant increase of primary tumor ADC at mid-RT are at high risk of disease relapse.

Evaluating drug distribution in children and young adults with diffuse midline glioma of the pons (DIPG) treated with convection-enhanced drug delivery.

To determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED. 13 children diagnosed with DIPG received between 3.8 and 5.7 ml of infusate, through two pairs of catheters to encompass tumor volume on day 1 of cycle one of treatment. Volumetric T2-weighted (T2W) and diffusion-weighted MRI imaging (DWI) were performed before and after day 1 of CED. Apparent diffusion coefficient (ADC) maps were calculated. The tumor volume pre and post CED was automatically segmented on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were aligned and subtracted to visualize the infusate distribution. There was a significant increase (p < 0.001) in mean ADC and T2W signal intensity (SI) ratio and a significant (p < 0.001) increase in mean tumor volume defined by ADC and T2W SI post infusion (mean ADC volume pre: 19.8 ml, post: 24.4 ml; mean T2W volume pre: 19.4 ml, post: 23.4 ml). A significant correlation (p < 0.001) between infusate volume and difference in ADC/T2W SI defined tumor volume was observed (ADC, r = 0.76; T2W, r = 0.70). Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion demonstrated a volume of high signal intensity, presumed infusate distribution. ADC and T2W MRI are proposed as a combined parameter method for evaluation of CED infusate distribution in brainstem tumors in future clinical trials.

Nerve abnormalities in lumbar disc herniation: A systematic review and meta-analysis of diffusion tensor imaging.

The purpose of this study was to examine the values of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in diffusion tensor imaging (DTI) for diagnosing patients with nerve impairment due to lumbar disc herniation (LDH). A literature search of databases (PubMed, Web of Science, Cochrane Library and Embase) was systematically performed to identify articles published before September 2021 that were relevant to this study. FA and ADC estimates of compressed nerve roots due to LDH and healthy controls in the same segment were compared, with either fixed or random effects models selected according to I2 heterogeneity. Additionally, subgroup analysis, sensitivity analysis, potential publication bias analysis and meta-regression analysis were also performed. A total of 369 patients with LDH from 11 publications were included in this meta-analysis. The results showed significantly lower FA values (Weighted Mean Difference (WMD): -0.08, 95% confidence interval (CI): -0.09 to -0.07, P ≤ 0.001, I2 = 87.6%) and significantly higher ADC values (WMD: 0.25, 95% CI: 0.20 to 0.30, P ≤ 0.001, I2 = 71.4%) of the nerve on the compressed side due to LDH compared to the healthy side. Subgroup analysis indicated that different countries and magnetic field strengths may be associated with higher heterogeneity. Furthermore, meta-regression analysis further revealed that segment and field strength did not have a significant effect on the results, regardless of the FA or ADC values. Contrastingly, in FA, the year of publication, country, b value and directions showed an effect on the results. This meta-analysis showed a significant decrease in FA and a significant increase in ADC in patients with nerve damage due to LDH. The results favourably support the presence of nerve impairment in patients with LDH.

Evaluation of lesion and overlying articular cartilage in patients with juvenile osteochondritis dissecans of the knee using quantitative diffusion MRI.

Current clinical MRI of patients with juvenile osteochondritis dissecans (JOCD) is limited by the low reproducibility of lesion instability evaluation and inability to predict which lesions will heal after nonoperative treatment and which will later require surgery. The aim of this study is to verify the ability of apparent diffusion coefficient (ADC) to detect differences in lesion microstructure between different JOCD stages, treatment groups, and healthy, unaffected contralateral knees. Pediatric patients with JOCD received quantitative diffusion MRI between January 2016 and September 2020 in this prospective research study. A disease stage (I-IV) and stability of each JOCD lesion was evaluated. ADCs were calculated in progeny lesion, interface, parent bone, cartilage overlying lesion, control bone, and control cartilage regions. ADC differences were evaluated using linear mixed models with Bonferroni correction. Evaluated were 30 patients (mean age, 13 years; 21 males), with 40 JOCD-affected and 12 healthy knees. Nine patients received surgical treatment after MRI. Negative Spearman rank correlations were found between ADCs and JOCD stage in the progeny lesion (ρ = -0.572; p < 0.001), interface (ρ = -0.324; p = 0.041), and parent bone (ρ = -0.610; p < 0.001), demonstrating the sensitivity of ADC to microstructural differences in lesions at different JOCD stages. We observed a significant increase in the interface ADCs (p = 0.007) between operative (mean [95%CI] = 1.79 [1.56-2.01] × 10-3 mm2 /s)and nonoperative group (1.27 [0.98-1.57] × 10-3 mm2 /s). Quantitative diffusion MRI detects microstructural differences in lesions at different stages of JOCD progression towards healing and reveals differences between patients assigned for operative versus nonoperative treatment.

Apparent Diffusion Coefficient (ADC) as an Early Biomarker for Tumor Response to Radiation Therapy, a Meta-Analysis

<h3>Purpose/Objective(s)</h3> MRI equipped linear accelerators are increasing the routine ability to acquire daily diffusion weight imaging (DWI) during a course of radiation therapy (RT). Multiple small series have examined DWI and apparent diffusion coefficient (ADC) as an early biomarker of tumor response to RT. We sought to comprehensively evaluate ADC change (ΔADC) by conducting a meta-analysis of published data. We hypothesized that quantifiable changes in ADC occur early after initiation of treatment and that a certain magnitude in ΔADC changes would be associated with response to RT. <h3>Materials/Methods</h3> A search was conducted for studies with ADC values acquired during and following RT. Studies were included that published mean ADC values of tumors prior to treatment (baseline), 1 and/or 2 weeks into treatment, and included therapeutic response data or progression reported in follow up. The mean percentage changes between studies were combined using the inverse variance weighted method, where variances were estimated from the study reported standard deviations, using a random effects model, to accommodate potential between study heterogeneity. A single estimate of percentage change in ADC, along with the standard deviation and sample size corresponding to estimate was used as the summary statistic of interest from each study, for the response and non-response groups separately. These were combined using the inverse variance weighting method to obtain an overall estimate of percentage ADC change for the two groups of interest, where the square of the reported standard deviation served as the variance estimate. The overall estimate was computed using the random-effects meta-analysis technique. <h3>Results</h3> Data from eight published studies were analyzed totaling 207 patients undergoing RT for brain metastases (n=66), esophageal (n=50), head-and-neck (n=34), cervical (n=33), and rectal (n=24) cancer. One week after the induction of RT, there was no significant change in ADC from baseline in non-responding lesions, +3.32%, 95% CI [-2.25, +8.89], or responding lesions, +6.61%, 95% CI [-0.27, +13.49]. Two weeks after induction, however, the ADC in responding lesions increased by an average of 16.60%, 95% CI [4.86, 28.34], while non-responding lesions remained unchanged from baseline with a mean ΔADC of +4.36%, 95% CI [-8.38, +17.10]. ADC was significantly increased from baseline at two weeks, but not at one week, and lesions with less than 4.86% increase in ADC from baseline at two weeks were unlikely to be responding to the current therapeutic regimen. <h3>Conclusion</h3> From this relatively small meta-analysis it was demonstrated that significant increases in mean ADC for responding lesions were observed as early as two weeks after the initiation of RT. No significant change from baseline ADC was observed in tumors that did not respond to therapy. These data suggest a strong potential role for ΔADC as an early universal biomarker should be investigated in prospective clinical trials as a method to personalize RT dose.

Prospective Assessment of Diffusion-Weighted-MRI as a Biomarker of Treatment Response and Disease Control in Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> To determine diffusion-weighted MRI (DWI) parameters associated with tumor response and local control (LC) in head and neck (HNC) patients treated with definitive radiation therapy (RT). <h3>Materials/Methods</h3> Eighty-seven HNC patients enrolled in an active prospective imaging study at MD Anderson Cancer Center were included in the analysis. Patients had MRIs prior to, at mid-RT, and post-treatment completion. Inclusion criteria include adult with histologic evidence of malignant head and neck neoplasm indicated for curative-intent treatment with RT with/without chemotherapy; good performance status (ECOG score 0-2); and with no contraindications to MRI. Patients were scanned using a full-body MRI scanner with two large four-channel flex phased-array coils. We used fat-suppressed T2-weighted turbo spin echo for tumor segmentation which was co-registered to respective DWIs for extraction of apparent diffusion coefficient (ADC) measurements. Sequence parameters were (TR/TE (ms); pixel size/slice thickness (mm); b-values (s/mm2)): T2-weighted (5280/80; 0.5/2; N/A), BLADE (5900/50; 2/4; 0 & 800), RESOLVE (9380/63; 2/4; 0 & 800). Treatment response was assessed at mid-RT and at 8-12 weeks post-RT using RECIST 1.1 criteria and was defined as: complete response (CR) vs non-complete response (non-CR). Pre-RT ADC was correlated with RT response (CR vs non-CR) at mid- and post-RT time points. Mann-Whitney test was used to compare ADC values between the mid-treatment CR group and the non-CR group. Recursive partitioning analysis (RPA) was done to identify ADC threshold associated with relapse. <h3>Results</h3> Fifty-nine patients with grossly visible primary tumor volume prior to RT start were included in this analysis. Patients' disease and treatment criteria are shown in Table 1. Pre-treatment ADC was not correlated with tumor response or oncologic outcomes (P>0.05). For patients with CR at the end of RT, there was a significant increase in mean ADC at mid-RT compared to baseline ((1.8 ± 0.29) × 10^–3 mm²/s <i>vs</i> (1.37 ± 0.22) × 10^–3 mm²/s, <i>p</i> <0.0001). However, patients with no-CR had no statistically significant increase (p>0.05). Median follow-up was 32 months. Patients with ≤106% delta ADC at mid-RT had significantly worse local control at 2-year compared to patients with higher delta ADC (48% vs 96%, <i>p</i> <0.0001). <h3>Conclusion</h3> Delta ADC changes is a strong predictor of local recurrence in head and neck cancer patients. Multi-institutional data is needed for validation of our results.

A Simple Elimination of the Thermal Convection Effect in NMR Diffusiometry Experiments.

Thermal convection is always present when the temperature of an NMR experiment is different from the ambient one. Most often, it falsifies the value of the diffusion coefficient determined by NMR diffusiometry using a PGSE NMR experiment. In spite of common belief, it acts not only at higher temperatures but also at temperatures lower than in the laboratory. Sodium alkyl-sulfate monomers and micelles in D2O solvent were used as model molecules measured at T = 319 K in order to show that thermal convection sometimes remains hidden in experiments. In this paper, we demonstrate that the increase in apparent diffusion coefficient with increasing diffusion time is a definite indicator of thermal convection. Extrapolation to zero diffusion time can also be used to obtain the real diffusion coefficient, likewise applying the less sensitive pulse sequences designed for flow compensation or the expensive hardware, e.g., sapphire or Shigemi NMR tubes, to decrease the temperature gradient. Further, we show experiments illustrating the effect of a long diffusion time in which the periodic changes of the echo intensity with gradient strength appear as predicted by theories.

Microstructural changes of the vestibulocochlear nerve in patients with Ménière's disease using diffusion tensor imaging.

ObjectiveTo evaluate the microstructural changes of the vestibulocochlear nerve in patients with Ménière's disease.MethodsA total of 26 subjects, 13 patients with MD and 13 healthy controls, underwent diffusion tensor imaging (DTI) on a 3T scanner. The independent sample t-test was used to compare the differences in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) between the two groups. A Pearson correlation was used between DTI and the dizziness handicap inventory (DHI) scores.ResultsThere was a significant decrease in FA and an increase in ADC of the vestibulocochlear nerve in MD patients compared with healthy controls (P = 0.04, P = 0.001). FA had negative correlations with the DHI score (r = −0.62, P = 0.02) and DHI-functional score (r = −0.64, P = 0.02).ConclusionThese results are the first evidence of possible changes in the microstructure of the vestibulocochlear nerves in patients with MD. DTI is a potential technique for evaluating the vestibulocochlear nerve in patients with MD.

DIPG-18. Evaluating drug distribution in children with diffuse intrinsic pontine glioma (DIPG) treated with convection-enhanced drug delivery

BACKGROUND: There is currently no method for evaluating drug distribution and tumour coverage using the convection-enhanced drug delivery (CED) technique in diffuse midline glioma of the pons (previous DIPG). AIMS: To determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED of carboplatin and sodium valproate. METHODS: 12 children with DIPG received between 4–18ml of infusate, through 2 pairs of catheters to encompass tumour volume on 2 days. Volumetric T2W and Diffusion Weighted Imaging (DWI) MRI sequences were performed before and after the first cycle of CED therapy and Apparent Diffusion Coefficient (ADC) maps were calculated. The tumour volume pre and post CED was automatically segmented (ITKSnap) on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were registered and subtracted (FSL) to visualize the infusate distribution. RESULTS: ADC and T2W demonstrated a significant (<0.001) change in mean tumour volume post-infusion (mean ADC volume pre: 19.8ml, post 24.4ml; mean T2W volume pre 19.4ml, post 23.4ml). A significant correlation (p<0.001) was observed for the difference in tumour volume and the actual infused volume (ADC, r=0.76, T2W, r=0.70). There was a significant increase (p<0.001) in mean ADC and mean T2W signal intensity ratio post-infusion, no significant correlation with infusion volume. Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion visually demonstrated high signal intensity, presumed infusate coverage of the tumour. CONCLUSIONS: Our study provides the preliminary evidence that measurement of change in tumour ADC and T2W MR sequences, has a potential value for quantifying the distribution of infusate delivered by the intermittent CED, which will facilitate the use of CED in future clinical trials.

Radiotherapy and olaptesed pegol (NOX-A12) in partially resected or biopsy-only MGMT-unmethylated glioblastoma: Interim data from the German multicenter phase 1/2 GLORIA trial.

2050 Background: Pre-clinical studies consistently demonstrate that inhibition of the CXCL12/CXCR4/CXCR7 axis abrogates recruitment of pro-vasculogenic bone marrow-derived cells after radiotherapy (RT) of glioblastoma (GBM) and promotes T cell exclusion from the tumor microenvironment (TME). The German multicenter phase 1/2 trial GLORIA (NCT04121455) assesses safety of RT plus escalating dose levels (DL) of the CXCL12-neutralizing RNA-Spiegelmer Olaptesed pegol (OLA; NOX-A12) in patients with chemotherapy-resistant GBM. Methods: Until now, GLORIA enrolled 10 patients newly diagnosed with incompletely resected (n = 8) or biopsied (n = 2) GBM with ECOG≤2, age ≥18 and without MGMT promoter hypermethylation. All patients receive standard RT (60 Gy in 30 fractions or 40.05 Gy in 15 fractions) and continuous (24/7) i.v. infusions of either 200 mg (DL1; n = 3), 400 mg (DL2; n = 3) or 600 mg (DL3; n = 4) per week of OLA for 26 weeks. The primary endpoint (EP) is safety as per incidence of treatment-related adverse events (AE). Secondary EPs include radiographic response as per mRANO criteria, dynamic susceptibility contrast perfusion (DSC) and the fraction of highly-perfused tumor (FTBhigh) as well as the apparent diffusion coefficient (ADC). Target lesions (TL) and non-target lesions (NTL, i.e. in-field satellite lesions) are analyzed separately. Tumor tissue is assessed by high-plex immunofluorescence imaging (co-detection by indexing; CODEX). Matched reference cohorts serve as controls for MRI (n = 14) and CODEX (n = 8) data. Results: Combination of RT and OLA was well-tolerated and safe. Of all G ≥ 2 AEs (n = 77), 3 (4%) were deemed to be solely OLA-related, including 1 grade 3 AE at DL3. There were no dose limiting toxicities and no treatment-related deaths. In total, eight of the nine patients (89%) with TLs at baseline showed a TL response during OLA therapy, with four (40%) reaching partial remission (PR) as per radiologic mRANO criteria (n = 2 at DL1 and n = 2 at DL3). All three patients treated at DL1 and all four of DL3 reached PR of one or more NTLs. In three cases (n = 2 at DL1; n = 1 at DL3), at least one NTL completely disappeared. Under OLA, radiographic responses of NTL were best at the highest DL (DL1 +49.5/DL2 +488.3/DL3 -59%), as was the increase in diffusion (mean ADC increase +46.4/+28.2/+56.7%) and the decrease in FTBhigh (mean -33.5/-32.8/-47.7%). Matched pre-/post-surgery CODEX of a confirmed pseudoprogression revealed intralesional clusters of proliferating cytotoxic T cells. Analysis of tissue from a non-responding patient showed T-cell encapsulation by M2-polarized macrophages in an immune-cell enriched TME. Additional follow-up is ongoing. Conclusions: Interim data from the ongoing GLORIA trial demonstrates safety of RT plus OLA and suggests promising clinical efficacy of a new class of drugs targeting CXCL12 in GBM. Clinical trial information: NCT04121455.

Age-related topographic map of magnetic resonance diffusion metrics in neonatal brains.

Accelerated maturation of brain parenchyma close to term‐equivalent age leads to rapid changes in diffusion‐weighted imaging (DWI) and diffusion tensor imaging (DTI) metrics of neonatal brains, which can complicate the evaluation and interpretation of these scans. In this study, we characterized the topography of age‐related evolution of diffusion metrics in neonatal brains. We included 565 neonates who had MRI between 0 and 3 months of age, with no structural or signal abnormality—including 162 who had DTI scans. We analyzed the age‐related changes of apparent diffusion coefficient (ADC) values throughout brain and DTI metrics (fractional anisotropy [FA] and mean diffusivity [MD]) along white matter (WM) tracts. Rate of change in ADC, FA, and MD values across 5 mm cubic voxels was calculated. There was significant reduction of ADC and MD values and increase of FA with increasing gestational age (GA) throughout neonates' brain, with the highest temporal rates in subcortical WM, corticospinal tract, cerebellar WM, and vermis. GA at birth had significant effect on ADC values in convexity cortex and corpus callosum as well as FA/MD values in corpus callosum, after correcting for GA at scan. We developed online interactive atlases depicting age‐specific normative values of ADC (ages 34–46 weeks), and FA/MD (35–41 weeks). Our results show a rapid decrease in diffusivity metrics of cerebral/cerebellar WM and vermis in the first few weeks of neonatal age, likely attributable to myelination. In addition, prematurity and low GA at birth may result in lasting delay in corpus callosum myelination and cerebral cortex cellularity.