Serial Magnetic Resonance Imaging Research Articles

Multimodal In Vivo Tracking of Chimeric Antigen Receptor T Cells in Preclinical Glioblastoma Models.

Iron oxide nanoparticles have been used to track the accumulation of chimeric antigen receptor (CAR) T cells with magnetic resonance imaging (MRI). However, the only nanoparticle available for clinical applications to date, ferumoxytol, has caused rare but severe anaphylactic reactions. MegaPro nanoparticles (MegaPro-NPs) provide an improved safety profile. We evaluated whether MegaPro-NPs can be applied for in vivo tracking of CAR T cells in a mouse model of glioblastoma multiforme. We labeled tumor-targeted CD70CAR (8R-70CAR) T cells and non-tumor-targeted controls with MegaPro-NPs, followed by inductively coupled plasma optical emission spectroscopy, Prussian blue staining, and cell viability assays. Next, we treated 42 NRG mice bearing U87-MG/eGFP-fLuc glioblastoma multiforme xenografts with MegaPro-NP-labeled/unlabeled CAR T cells or labeled untargeted T cells and performed serial MRI, magnetic particle imaging, and histology studies. The Kruskal-Wallis test was conducted to evaluate overall group differences, and the Mann-Whitney U test was applied to compare the pairs of groups. MegaPro-NP-labeled CAR T cells demonstrated significantly increased iron uptake compared with unlabeled controls ( P < 0.01). Cell viability, activation, and exhaustion markers were not significantly different between the 2 groups ( P > 0.05). In vivo, tumor T2* relaxation times were significantly lower after treatment with MegaPro-NP-labeled CAR T cells compared with untargeted T cells ( P < 0.01). There is no significant difference in tumor growth inhibition between mice injected with labeled and unlabeled CAR T cells. MegaPro-NPs can be used for in vivo tracking of CAR T cells. Because MegaPro-NPs recently completed phase II clinical trial investigation as an MRI contrast agent, MegaPro-NP is expected to be applied to track CAR T cells in cancer immunotherapy trials in the near future.

Novel Cardiokine GDF3 Predicts Adverse Fibrotic Remodeling After Myocardial Infarction.

Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery by promoting the development of noncontractile fibrotic areas. The mechanisms that lead to cardiac fibrosis are diverse and incompletely characterized. We explored whether the expansion of cardiac fibroblasts after MI can be regulated through a paracrine action of cardiac stromal cells. We performed a bioinformatic secretome analysis of cardiac stromal PW1+ cells isolated from normal and post-MI mouse hearts to identify novel secreted proteins. Functional assays were used to screen secreted proteins that promote fibroblast proliferation. The expressions of candidates were subsequently analyzed in mouse and human hearts and plasmas. The relationship between levels of circulating protein candidates and adverse post-MI cardiac remodeling was examined in a cohort of 80 patients with a first ST-segment-elevation MI and serial cardiac magnetic resonance imaging evaluations. Cardiac stromal PW1+ cells undergo a change in paracrine behavior after MI, and the conditioned media from these cells induced a significant increase in the proliferation of fibroblasts. We identified a total of 12 candidates as secreted proteins overexpressed by cardiac PW1+ cells after MI. Among these factors, GDF3 (growth differentiation factor 3), a member of the TGF-β (transforming growth factor-β) family, was markedly upregulated in the ischemic hearts. Conditioned media specifically enriched with GDF3 induced fibroblast proliferation at a high level by stimulation of activin-receptor-like kinases. In line with the secretory nature of this protein, we next found that GDF3 can be detected in mice and human plasma samples, with a significant increase in the days after MI. In humans, higher GDF3 circulating levels (measured in the plasma at day 4 after MI) were significantly associated with an increased risk of adverse remodeling 6 months after MI (adjusted odds ratio, 1.76 [1.03-3.00]; P=0.037), including lower left ventricular ejection fraction and a higher proportion of akinetic segments. Our findings define a mechanism for the profibrotic action of cardiac stromal cells through secreted cardiokines, such as GDF3, a candidate marker of adverse fibrotic remodeling after MI. URL: https://www. gov; Unique identifier: NCT01113268.

AAV8-mediated sVEGFR2 and sVEGFR3 gene therapy combined with chemotherapy reduces the growth and microvasculature of human ovarian cancer and prolongs the survival in mice.

Vascular endothelial growth factors (VEGFs) are major regulators of intratumoral angiogenesis in ovarian cancer (OVCA). Overexpression of VEGFs is associated with increased tumor growth and metastatic tendency and VEGF-targeting therapies are thus considered as potential treatments for OVCA. Here, we examined the antiangiogenic and antitumoral effects on OVCA of adeno-associated virus 8 (AAV8)-mediated expression of soluble VEGF receptors (sVEGFRs) sVEGFR2 and sVEGFR3 together with paclitaxel and carboplatin chemotherapy. Immunodeficient mice were inoculated with human OVCA cell line SKOV-3m. Development of tumors was confirmed with magnetic resonance imaging (MRI) and mice were treated with gene therapy and paclitaxel and carboplatin chemotherapy. The study groups included (I) non-treated control group, (II) blank control vector AAV8-CMV, (III) AAV8-CMV with chemotherapy, (IV) AAV8-sVEGFR2, (V) AAV8-sVEGFR3, (VI) AAV8-sVEGFR2 and AAV8-sVEGFR3, and (VII) AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy. Antiangiogenic and antitumoral effects were evaluated with immunohistochemical stainings and serial MRI. Reduced intratumoral angiogenesis was observed in all antiangiogenic gene therapy groups. The combined use of AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy suppressed ascites fluid formation and tumor growth, thus improving the overall survival of mice. Antitumoral effect was mainly caused by AAV8-sVEGFR2 while the benefits of AAV8-sVEGFR3 and chemotherapy were less prominent. Combined use of the AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy reduces intratumoral angiogenesis and tumor growth in OVCA mouse model. Results provide preclinical proof-of-concept for the use of soluble decoy VEGFRs and especially the AAV8-sVEGFR2 in the treatment of OVCA.

Serial magnetic resonance imaging of splenomegaly in the Trypanosoma brucei infected mouse.

Splenomegaly, an enlargement of the spleen, is a known clinical sign of the parasitic disease, human African trypanosomiasis. This study follows the development of splenomegaly in a group of mice over multiple infection points, using a non-invasive imaging modality, magnetic resonance imaging (MRI). CD-1 mice infected with GVR35 T.b. brucei demonstrated a significant increase in spleen size from day 7 post-infection, with changes in the spleen tracked in individual animals over five time points. At the final time point, the mean spleen weight calculated using the spleen volume from the MR images was compared with the post-mortem gross spleen weight. No significant difference was detected between the two methods (1.62 ± 0.06g using MRI and 1.51 ± 0.04g gross weight, p = 0.554). Haematology and histological analysis were also performed, giving additional insight into splenomegaly for the GVR35 strain of infection. The study demonstrates that MRI is a useful tool when examining changes in organ volume throughout HAT infection and may be applicable in the investigation of a range of conditions where changes in organ volume occur and MRI has not been used previously.

Standard deviations of MR signal intensities show a consistent trend during imaging follow-ups for glioblastoma patients when corrected for non-biological heterogeneity due to hardware and software variation

IntroductionGlioblastoma multiforme (GBM) has a poor prognosis in spite of advanced MRI guided treatments today. Routine MRI using conventional T1 or advanced permeability based MRI of GBM often does not adequately represent changing tumor phases or overall survival. In this work, region of interest (ROI) based tissue MR standard deviation (SD) is demonstrated as an important MRI variable that could be a potential biomarker of GBM heterogeneity and radioresistance. Materials and methodsMRI characterization is often qualitative and lacks reproducibility. Using standardized MRI phantoms we have normalized retrospective records of 12 radioresistant GBM patients that underwent radiation therapy (RT) with concomitant and adjuvant temozolomide (TMZ) chemotherapy followed by serial MR imaging with gadolinium contrast. Results and discussionWe have identified key variables like hardware, software and protocol variation and have standardized those using test phantoms at five MR systems. We suggest GBM growth during the treatment period can be linked to normalized MRI signal and its fluctuations from session to session and from magnet to magnet by using an ROI derived standard deviation that corresponds to heterogeneity of the tumor MRI signal and changes in magnetic susceptibility. The time period observed in our patient group for peak standard deviations is approximately halfway through the tumor course and may correspond to a growth of more aggressive MES subtype of cells. To model the GBM heterogeneity we performed in vitro T1 weighted inversion recovery MRI experiments at 3 T for porous media of silicate particles in 1% aq solution of Gadavist and linked SD with particle size and local gadolinium volume within porous media. Such in vitro models mimic the increased SD in radioresistant GBM and as a novel contribution suggest that finer texture with high surface area might arise approximately halfway through the overall survival duration in GBM. ConclusionStandard deviation as a measure of magnetic susceptibility may be collectively linked to the changes in texture, cell fractions (biological) and trapped contrast media (vascular as well as artifactual consequences) and should be evaluated as a potential biomarker of GBM aggressiveness than the overall MRI signal intensity from a GBM.

Abstract B015: MRI features can identify DCIS patients who can be managed with endocrine therapy alone

Abstract Background: Ductal carcinoma in situ (DCIS) represents almost a quarter of newly diagnosed breast cancers in the US. It is currently treated like a stage 1 cancer, with surgical excision, radiation, and endocrine therapy (ET). Not all cases will progress to invasive cancer and thus we may be overtreating some lesions. Using a cohort of women who participated in an Active Surveillance (AS) with neoadjuvant ET and serial MR imaging, we aimed to identify features on MRI that could stratify DCIS lesions with low- and high-risk of progressing to invasive cancer. Materials/Methods: This was an IRB-approved retrospective study of women with DCIS who chose AS for treatment and were enrolled in MR imaging studies between 2002 and 2020. All women in this study had at least 2 breast MRI scans, which consisted of normal sequences with two post-contrast timepoints. Two radiologists, who were blinded to outcomes, analyzed MRI sequences for each patient at each timepoint for features that may be indicative of risk. Baseline imaging features collected were utilized in an RPART recursive partitioning algorithm that created a classification tree based on a DCIS lesions likelihood to progress to invasive cancer. Our final cohort consisted of 63 cases of DCIS (62 women, 1 with bilateral disease) with a mean age of 58.3 years (range of 29.8-78.8 years). All 62 patients (63 cases, 100%, 63/63) agreed to take hormone therapy for their DCIS. Results: The RPART algorithm showed two baseline features that were important in predicting risk: 1) the presence of a lesion that is distinct from the surrounding tissue and 2) background parenchymal enhancement (BPE). It separated our cohort into three sub-groups based on risk of progression: A (n=32) with the lowest-risk, B (n=17) with the second lowest-risk, and C (n=14) with the highest-risk. In A and B, 6 cases of DCIS progressed to invasive cancer (12.2%, 6/49). These groups had an enrichment of mild, moderate, and marked BPE. Group A (12.5%, 4/32 progressed to IDC) did not have any lesions that were distinct above BPE. All cases in B (11.8%, 2/17 progressed to IDC) had lesions that were distinct above BPE initially but reduced in response to endocrine therapy. In C, 10 cases of DCIS progressed to invasive cancer (71.4%, 10/14). In this group, the combination of minimal BPE and a distinct lesion above BPE was enriched (78.6%, 11/14). Conclusion: Our results suggest that imaging features, such as BPE, lesion distinctness and change in BPE and lesion provide information about risk for invasive cancer. MRI features provide insight as to whether risk is diffuse or focal, and which women can safely undergo AS with hormone treatment and avoid surgery, and which women are at higher-risk and have focal lesions better treated with surgical excision. We plan to validate the use of these features to triage patients in an upcoming prospective multisite trial to stratify DCIS patients for active surveillance vs. surgical resection. Citation Format: Cristian K. Maldonado Rodas, Heather Greenwood, Rita Freimanis, Alexander D. Borowsky, Gillian Hirst, Nola Hylton, Laura Esserman, Amrita Basu. MRI features can identify DCIS patients who can be managed with endocrine therapy alone [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B015.

A coarse-to-fine and automatic algorithm for breast diagnosis on multi-series MRI images

IntroductionEarly breast carcinomas can be effectively diagnosed and controlled. However, it demands extra work and radiologist in China often suffer from overtime working due to too many patients, even experienced ones could make mistakes after overloaded work. To improve the efficiency and reduce the rate of misdiagnosis, automatic breast diagnosis on Magnetic Resonance Imaging (MRI) images is vital yet challenging for breast disease screening and successful treatment planning. There are some obstacles that hinder the development of automatic approaches, such as class-imbalance of samples, hard mimics of lesions, etc. In this paper, we propose a coarse-to-fine algorithm to address those problems of automatic breast diagnosis on multi-series MRI images. The algorithm utilizes deep learning techniques to provide breast segmentation, tumor segmentation and tumor classification functions, thus supporting doctors' decisions in clinical practice.MethodsIn proposed algorithm, a DenseUNet is firstly employed to extract breast-related regions by removing irrelevant parts in the thoracic cavity. Then, by taking advantage of the attention mechanism and the focal loss, a novel network named Attention Dense UNet (ADUNet) is designed for the tumor segmentation. Particularly, the focal loss in ADUNet addresses class-imbalance and model overwhelmed problems. Finally, a customized network is developed for the tumor classification. Besides, while most approaches only consider one or two series, the proposed algorithm takes in account multiple series of MRI images.ResultsExtensive experiments are carried out to evaluate its performance on 435 multi-series MRI volumes from 87 patients collected from Tongji Hospital. In the dataset, all cases are with benign, malignant, or both type of tumors, the category of which covers carcinoma, fibroadenoma, cyst and abscess. The ground truths of tumors are labeled by two radiologists with 3 years of experience on breast MRI reporting by drawing contours of tumor slice by slice. ADUNet is compared with other prevalent deep-learning methods on the tumor segmentation and quantitative results, and achieves the best performance on both Case Dice Score and Global Dice Score by 0.748 and 0.801 respectively. Moreover, the customized classification network outperforms two CNN-M based models and achieves tumor-level and case-level AUC by 0.831 and 0.918 respectively.DiscussionAll data in this paper are collected from the same MRI device, thus it is reasonable to assume that they are from the same domain and independent identically distributed. Whether the proposed algorithm is robust enough in a multi-source case still remains an open question. Each stage of the proposed algorithm is trained separately, which makes each stage more robust and converge faster. Such training strategy considers each stage as a separate task and does not take into account the relationships between tasks.

RADT-40. RADIATION-INDUCED CONTRAST ENHANCEMENT FOLLOWING PROTON RADIOTHERAPY FOR LOW-GRADE GLIOMA DEPENDS ON TUMOR CHARACTERISTICS AND IS RARER IN CHILDREN THAN ADULTS

Abstract Proton beam radiotherapy (PRT) is used in the treatment of low-grade glioma (LGG) to mitigate long-term sequelae. Following PRT, increased rates of radiation-induced contrast enhancements (RICE) are suspected but poorly understood. We analyzed consecutive 227 patients (42 children and 185 adults) treated with PRT (54Gy RBE) for LGG from 2010 to 2020 and followed with serial clinical exams and magnetic resonance imaging for in median 5.6 years. Tumors were graded WHO 1 in a minority (n = 22, 12%) of adults, but a majority of children (n = 29, 69%). In contrast, tumors were graded WHO 2 in the majority (n = 160, 87%) of adults and a minority of children (n = 10, 24%). Five-year overall survival following PRT was 81% in adults and 91% in children. The risk of RICE was 5-fold more frequent in adults (25%) versus children (5%) (p = 0.0043). Also, within the adult cohort, RICE risk increases with age (p = 0,00128). In children and adults, RICE were symptomatic in 50% and 55% (n = 1 and 26) of cases with CTCAE grade 0 in 47% (n = 23), grade 1 in 25% (n = 12), 0% grade 2 (n = 0) and 29% grade 3 (n = 14), respectively. In adults, RICE risk was associated to WHO grading (8% in WHO grade 1 vs. 24% in WHO grade 2, p = 0.026), independent of age (p = 0.44) and irradiation dose (p = 0.005), but not independent of IDH mutational status. These data demonstrate effectiveness of PRT for LGG in both children and adults. The RICE risk is lower in children which are a main target group for PRT and differs with WHO grading.

RADT-15. 18F-DOPA PET/CT SURVEILLANCE FOR GLIOBLASTOMA: A RADIOMIC MODEL FROM A PROSPECTIVE PHASE II CLINICAL TRIAL PREDICTING SURVIVAL IN IDH-WILDTYPE, MGMT-UNMETHYLATED PATIENTS

Abstract BACKGROUND Interpretation of serial magnetic resonance imaging (MRI) for glioblastoma following radiation therapy (RT) is complicated by difficulty differentiating tumor from treatment-related changes, even using updated RANO criteria. The incorporation of novel imaging such as 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) PET/CT to post-treatment serial imaging may improve prognostication and better facilitate future treatment decisions. METHODS The secondary analysis of a recent phase II prospective clinical trial of 18F-DOPA PET/CT-directed dose-escalated RT included patients with IDH-wildtype, MGMT-unmethylated glioblastoma who underwent post-treatment serial 18F-DOPA PET/CT surveillance. Quantitative features were extracted from pre-RT and post-RT serial PET/CT images, and robust prognostic features were selected using an in-house workflow. Both an automated machine learning (ML) algorithm and an interpretable ML algorithm were utilized to correlate surveillance PET image features with subsequent survival of greater than 12 months versus less than 12 months from the surveillance timepoint. Changes from pre-RT to post-RT PET/CT (delta model) were also assessed for association with post-RT survival and validated with a separate cohort. RESULTS Thirty-five patients with IDH-wildtype, MGMT-unmethylated glioblastoma who had at least one available (range: 1-14) post-treatment 18F-DOPA PET/CT were included. Twenty-four were used for model training, while 11 were used for validation. Ultimately, a five-feature post-RT model utilizing two shape, two texture, and one first-order radiomic feature was selected. For the delta model, five texture, two shape, and one first order radiomic feature were selected. The models show 90% accuracy in predicting survival &amp;lt; 12 months post-surveillance on the training set, and 68%-73% accuracy (AUC 0.64-0.73) for the validation cohort. Delta features were significantly associated with overall survival (p &amp;lt; 0.05). CONCLUSIONS Post-RT serial 18F-DOPA PET/CT imaging can help distinguish true tumor progression in patients with glioblastoma using a radiomics model. Tumor response evaluated for changes from pre-RT to post-RT 18F-DOPA PET/CT also predicted subsequent overall survival.

NCMP-02. RENAL CELL CARCINOMA WITH METASTASIS TO THE CHOROID PLEXUS

Abstract BACKGROUND Intraventricular brain tumors make up only 0.9–4.5% of all cases of metastatic brain cancer.1 Involvement of the choroid plexus (CP) is even rarer with only a handful of documented cases. 2,3 Here we describe a case of bilateral multifocal metastasis to the choroid plexus appearing 10 years after nephrectomy in a male with stage IV renal cell carcinoma (RCC). CASE PRESENTATION: Our patient is a 74-year-old male with stage IV RCC diagnosed in 2006 and treated with radical nephrectomy and immunotherapy in 2011. In 2020, he presented to the emergency department with altered mental status. Brain magnetic resonance imaging (MRI) revealed an enhancing hemorrhagic lesion in the trigone of the right lateral ventricle (LV) and nodular thickening in the center of the right LV and trigone of the left LV, suggestive of metastatic disease. In 2021, the patient developed refractory seizures, and serial MRIs showed disease progression. He underwent several craniotomies with pathology confirming metastatic clear cell carcinoma, consistent with a renal primary. In 2022, the patient again presented with altered mental status. MRI revealed new avidly enhancing subcentimeter solid nodules in the CP of both LVs consistent with metastatic disease. Per the wishes of the family, palliative measures were pursued, and the patient was discharged home. CONCLUSION RCC can reappear several years after nephrectomy. 4 Metastatic RCC appears to have a unique propensity to spread to the ventricular system and the CP, which indicates late progression of disease. 1,5,6 While surgery may be viable if tumor burden is low, therapeutic options are limited in the advanced disease stages, as in our patient. Palliative care should be offered early to maximize remaining quality of life.

Automated Registration and Color Labeling of Serial 3D Double Inversion Recovery MR Imaging for Detection of Lesion Progression in Multiple Sclerosis.

Automated co-registration and subtraction techniques have been shown to be useful in the assessment of longitudinal changes in multiple sclerosis (MS) lesion burden, but the majority depend on T2-fluid-attenuated inversion recovery sequences. We aimed to investigate the use of a novel automated temporal color complement imaging (CCI) map overlapped on 3D double inversion recovery (DIR), and to assess its diagnostic performance for detecting disease progression in patients with multiple sclerosis (MS) as compared to standard review of serial 3D DIR images. We developed a fully automated system that co-registers and compares baseline to follow-up 3D DIR images and outputs a pseudo-color RGB map in which red pixels indicate increased intensity values in the follow-up image (i.e., progression; new/enlarging lesion), blue-green pixels represent decreased intensity values (i.e., disappearing/shrinking lesion), and gray-scale pixels reflect unchanged intensity values. Three neuroradiologists blinded to clinical information independently reviewed each patient using standard DIR images alone and using CCI maps based on DIR images at two separate exams. Seventy-six follow-up examinations from 60 consecutive MS patients who underwent standard 3T MR brain MS protocol that included 3D DIR were included. Median cohort age was 38.5years, with 46 women, 59 relapsing-remitting type MS, and median follow-up interval of 250days (interquartile range: 196-394days). Lesion progression was detected in 67.1% of cases using CCI review versus 22.4% using standard review, with a total of 182 new or enlarged lesions using CCI review versus 28 using standard review. There was a statistically significant difference between the two methods in the rate of all progressive lesions (P < 0.001, McNemar's test) as well as cortical progressive lesions (P < 0.001). Automated CCI maps using co-registered serial 3D DIR, compared to standard review of 3D DIR alone, increased detection rate of MS lesion progression in patients undergoing clinical brain MRI exam.

13-year Old Male Child Patient with a known Case of Necrotizing Encephalopathy

ANCE (Acute necrotizing encephalopathy of childhood) is a disease that affects children with a high fever, a respiratory or gastrointestinal infection, rapid changes in awareness, and seizures. Almost all Asian newborns and children who were previously in good health are affected by this illness. According to serial magnetic resonance imaging studies, the thalami, cerebellum, brainstem, and white matter all showed symmetric lesions in this disease. The condition has a poor prognosis with high morbidity and mortality rates. Amir Kola Children's Hospital is evaluating an A.N.E.C. in a 22-month-old kid Missense mutations were also detected in the gene that codes for the nuclear pore protein- Ran Binding Protein 2 (RANBP2). Though the clinical course and prognosis of ANE differ, the characteristic of neuro radiology manifestation of ANE is multifocal symmetric brain lesions visible on computed tomography (C.T.) or magnetic resonance imaging (M.R.I.).The treatment of ANCE is still under particular observation. We provide the most up-to-date information on ANCE, emphasizing early detection and successful consultation and treatment of this rare but deadly disease.

Features of metabolic syndrome and inflammation independently affect left ventricular function early after first myocardial infarction

BackgroundA high body mass index (BMI) is often associated with metabolic syndrome, which is accompanied by systemic low-grade chronic inflammation. Here, we analyzed whether BMI, other components of metabolic syndrome, and/or inflammatory markers correlate with left ventricular geometry, function, and infarct size as assessed by serial cardiac magnetic resonance imaging (MRI) after a first (clinically evident) ST-elevation MI (STEMI). MethodsWithin the Etiology, Titre-Course, and effect on Survival (ETiCS) study, cardiac MRI conducted 7–9 days and 12 months after MI enabled longitudinal characterization of patients with a first STEMI along with serial routine blood counts and multiplex cytokine measurements. ResultsOf 91 locally included STEMI patients, 47% were overweight (25 kg/m2 < BMI < 30 kg/m2) and 24% were obese (BMI ≥ 30 kg/m2). No patient died during 12 months of follow-up. Left ventricular ejection fraction (LVEF), measured 7–9 days after STEMI, was significantly lower in overweight (49.5 ± 7.1%) and obese (45.8 ± 12.0%) patients than in the normal weight group (56.2 ± 7.7%). Along with BMI (T = -3.8; p < 0.001), hemoglobin A1c (HbA1c; T = -3.1; p = 0.004) and peak C-reactive protein (T = -2.6; p = 0.013) emerged as independent predictors of worse LVEF 7–9 days post MI (R2 = 0.45). Only peak C-reactive protein (T = -4.4; p < 0.001), but not parameters of the metabolic syndrome, predicted worse LVEF 12 months after STEMI (R2 = 0.20). ConclusionBoth BMI and HbA1c correlated negatively with LVEF only early, but not late after STEMI. Peak CRP evolved as strongest predictor of cardiac function at all time points independent of the metabolic syndrome.

Leveraging Serial MRI Radiomics and Machine Learning to Predict Risk of Radiation Necrosis in Patients with Brain Metastases Managed with Stereotactic Radiation and Immunotherapy

<h3>Purpose/Objective(s)</h3> Radiation necrosis (RN) is the primary dose-limiting toxicity of stereotactic radiotherapy (SRT) for brain metastases (BMs), especially in patients also receiving immunotherapy (IO). We investigated the utility of serial magnetic resonance imaging (MRI) radiomic features to develop predictive quantitative imaging biomarkers of brain metastases response to SRT and IO. <h3>Materials/Methods</h3> Using an IRB-approved single-institution database, we retrospectively identified adult patients with brain metastases managed with SRT and IO between 2006 and 2021. We collected per-lesion outcomes measures of RN (radiographic and/or symptomatic), progressive disease (PD), or neither (NA). Routine pre- and post-SRT contrast-enhanced T1-weighted MRIs were pushed to MIM Software (Beachwood, OH), where individual BMs were manually contoured. A total of 1061 radiomics features were extracted per lesion using a digital gene expression panel. They were selected from the following categories: shape, intensity, neighborhood intensity difference (NID), grey-level co-occurrence matrix (GLCM), and grey-level run-length matrix (GLRLM). Feature reduction followed using Spearman's correlation coefficient (0.3 cut-off). Features with non-significantly different mean ranks pre- and post-SRT (p<0.01) per Wilcoxon signed-rank test were also excluded. Simple then multiple nominal logistic regressions (SLR and MLR) with Bonferroni correction were used to model the risk of RN, PD, or NA based on pre- and post-SRT, and delta-radiomic ([post-pre]/pre) features. 95% CI of ROC AUC was obtained by 10,000 bootstrapping. Statistical analysis was performed using software. <h3>Results</h3> Our dataset encompassed 301 BMs from 92 patients with NSCLC, melanoma, and renal cell carcinoma, all treated with brain SRT and IO. 74 (24.6%), 75 (24.9%), and 152 developed RN, PD, or NA, respectively. The final radiomic feature set included 39 features that significantly changed post-SRT (p<0.01). MLR resulted in a 3-radiomic feature model that predicted risk of RN (ROC AUC 0.71). The model included post-SRT BM surface area and texture (GLCM 3D Homogeneity) and pre-RT BM roundness. Interestingly, another 5-radiomic feature MLR model predicted RN and PD (ROC AUC 0.71) based on pre-SRT GLCM 3D texture feature, 3 post-SRT shape features (surface area, mean breadth, and roundness), in addition to delta-volume. <h3>Conclusion</h3> Our analysis showed that static and serial MR radiomic features could potentially predict BMs response to SRT and IO. Model external validation, combination with clinical variables, and integration of other MRI sequences are warranted before the large-scale adoption of this novel diagnostic approach.

Default-Mode Network Connectivity Changes During the Progression Toward Alzheimer's Dementia: A Longitudinal Functional Magnetic Resonance Imaging Study.

Background/Purpose: Brain function changes with Alzheimer's disease (AD) progression. Evaluating those changes longitudinally is important to understand the complex relationships between brain pathologies and cognition. We aimed (1) to identify longitudinal changes in functional connectivity in patients with mild cognitive impairment (MCI) characterized for amyloid-β (Aβ) status and (2) to relate these functional changes to clinical progression. Methods: Forty-four patients with MCI were followed using serial functional magnetic resonance imaging (fMRI) over 1.2 years (three sessions) and cognitive testing over 3.1 years (five sessions). Intra and inter-network connectivities were computed to assess changes in brain connectivity using a network atlas adapted for late adulthood. Sixteen low-Aβ clinically normal older adults underwent a single fMRI session for group comparisons at baseline. Linear mixed-effects models with random intercept and slope were used to predict changes in connectivity based on Aβ status and progression to dementia. Results: At baseline, intra and inter-network resting-state fMRI connectivities did not differ by baseline clinical diagnosis, Aβ status, or clinical progression to dementia. At the final imaging session, progressive MCI had significantly higher connectivity compared with stable MCI, specifically within the default-mode network (DMN). Longitudinally, progressive MCI had increasing intra-DMN connectivity over time compared with stable MCI, and the rate of changes in connectivity was significantly associated with the rate of cognitive decline. Conclusions: Intra-DMN connectivity increases in MCI patients progressing toward dementia, suggesting aberrant synchronization in the symptomatic stages of AD. Impact statement Changes in functional connectivity occur in the course of Alzheimer's disease. We observed a progressive increase over time in resting-state functional connectivity within the default-mode network in patients with mild cognitive impairment who progressed to dementia. The rate of connectivity increase was significantly associated with the rate of cognitive decline. The observation of increased functional connectivity during the progression to dementia, and not only in the pre-clinical stage, is interpreted as an aberrant synchronization rather than a compensation mechanism.

Rate of Change of Liver Iron Content by MR Imaging Methods: A Comparison Study.

Objective: Magnetic resonance imaging (MRI) can accurately quantify liver iron concentration (LIC), eliminating the need for an invasive liver biopsy. Currently, the most widely used relaxometry methods for iron quantification are R2 and R2*, which are based on T2 and T2* acquisition sequences, respectively. We compared the rate of change of LIC as measured by the R2-based, FDA-approved commercially available third-party software with the rate of change of LIC measured by in-house analysis using R2*-relaxometry-based MR imaging in patients undergoing follow-up MRI scans for liver iron estimation. Methods: We retrospectively included patients who had undergone serial MRIs for liver iron estimation. The MR studies were performed on a 1.5T scanner; standard multi-slice, multi-echo T2- and T2*-based sequences were acquired, and LIC was estimated. The comparison between the rate of change of LIC by R2 and R2* values was performed via correlation coefficients and Bland–Altman difference plots. Results: One hundred and eighty-nine MR abdomen studies for liver iron evaluation from 81 patients (male: 38; female: 43) were included in the study. Fifty-nine patients had two serial scans, eighteen patients had three serial scans, three patients had four serial scans, and one patient had five serial scans. The average time interval between the first and last scans for each patient was 13.3 months. The average rates of change of LIC via R2 and R2* methods were −0.0043 ± 0.0214 and −0.0047 ± 0.012 mg/g per month, respectively. There was no significant difference in the rate of change of LIC observed between the two methods. Linearity between the rate of change of LIC measured by R2 (LIC R2) and R2* (LIC R2*) was strong, showing a correlation coefficient of r = 0.72, p < 0.01. A Bland–Altman plot between the rate of change of the two methods showed that the majority of the plotted variables were between two standard deviations. Conclusion: There was no significant difference in the rate of change of LIC detected between the R2 method and the R2* method that uses a gradient echo (GRE) sequence acquired with breath-hold. Since R2* is relatively faster and less prone to motion artifacts, R2*-derived LIC is recommended for iron homeostasis follow-up in patients with liver iron overload.

Therapeutic value of tafamidis in patients with wild-type transthyretin amyloidosis (ATTRwt) with cardiomyopathy based on cardiovascular magnetic resonance (CMR) imaging

Abstract Background Tafamidis was approved in Europe for the treatment of cardiomyopathy (CM) in patients with transthyretin amyloidosis (ATTR) in April 2020. So far, real-world data addressing the therapeutic value of tafamidis for the treatment of ATTR-CM are scarce. The purpose of this study was to carefully analyse the therapeutic benefit of tafamidis in patients with wild-type ATTR (ATTRwt) and CM (ATTRwt-CM) after one year of therapy based on serial multi-parametric cardiovascular magnetic resonance (CMR) imaging. Purpose The purpose of this study was to carefully analyse the therapeutic benefit of tafamidis in patients with wild-type transthyretin amyloidosis (ATTRwt) and cardiomyopathy (ATTRwt-CM) after one year of therapy based on serial multi-parametric cardiovascular magnetic resonance (CMR) imaging. Methods The present study comprised N=40 patients with ATTRwt-CM who underwent two serial multi-parametric CMR studies within a follow-up period of 12±3 months. Baseline (BL) clinical parameters, serum biomarkers and CMR findings were compared to follow-up (FU) values in patients with treated “with” tafamidis 61mg daily (n=20, group A) and those “without” tafamidis therapy (n=16, group B). CMR studies were performed on a 1.5-T system and comprised (amongst others) cine-imaging for assessment of cardiac anatomy and function including 3D longitudinal strain assessment. In addition, a modified Look-Locker inversion recovery (MOLLI) T1-mapping sequence was performed for measurement of pre- and post-contrast myocardial T1-values with additional calculation of extracellular volume fraction (ECV)-values. Results While left ventricular ejection fraction (LV-EF), left ventricular mass index (LVMi), left ventricular wall thickness (LVWT), native T1- and ECV-values remained unchanged in the tafamidis group A, a slight reduction in LV-EF (p=0.003) as well as a subtle increase in LVMi (p=0.034), in LVWT (p=0.001), in native T1- (p=0.038) and ECV-values (p=0.017) were observed in the untreated group B. Serum NT-proBNP levels showed an overall increase in both groups, however, with the untreated group B showing a relatively higher increase compared to the treated group A. Assessment of NYHA class did not result in significant intra-group differences when BL were compared with FU, but a trend to improvement in the treated group A compared to a worsening trend in the untreated group B (Δp=0.005). Conclusion Tafamidis does not improve cardiac phenotype in patients with ATTRwt-CM after one year of therapy. However, tafamidis seems to slow down cardiac disease progression in patients with ATTRwt-CM compared to those without tafamidis therapy based on multi-parametric CMR data already after one year of therapy. Funding Acknowledgement Type of funding sources: None.

Herpes simplex virus and rates of cognitive decline or whole brain atrophy in the Dominantly Inherited Alzheimer Network.

To investigate whether herpes simplex virus type 1 (HSV-1) infection was associated with rates of cognitive decline or whole brain atrophy among individuals from the Dominantly Inherited Alzheimer Network (DIAN). Among two subsets of the DIAN cohort (age range 19.6-66.6 years; median follow-up 3.0 years) we examined (i) rate of cognitive decline (N = 164) using change in mini-mental state examination (MMSE) score, (ii) rate of whole brain atrophy (N = 149), derived from serial MR imaging, calculated using the boundary shift integral (BSI) method. HSV-1 antibodies were assayed in baseline sera collected from 2009-2015. Linear mixed-effects models were used to compare outcomes by HSV-1 seropositivity and high HSV-1 IgG titres/IgM status. There was no association between baseline HSV-1 seropositivity and rates of cognitive decline or whole brain atrophy. Having high HSV-1 IgG titres/IgM was associated with a slightly greater decline in MMSE points per year (difference in slope - 0.365, 95% CI: -0.958 to -0.072), but not with rate of whole brain atrophy. Symptomatic mutation carriers declined fastest on both MMSE and BSI measures, however, this was not influenced by HSV-1. Among asymptomatic mutation carriers, rates of decline on MMSE and BSI were slightly greater among those who were HSV-1 seronegative. Among mutation-negative individuals, no differences were seen by HSV-1. Stratifying by APOE4 status yielded inconsistent results. We found no evidence for a major role of HSV-1, measured by serum antibodies, in cognitive decline or whole brain atrophy among individuals at high risk of early-onset AD.

Administration of a human recombinant apyrase (AZD3366) limits myocardial tissue injury and improves cardiac function in a pig model of STEMI assessed by serial CMR

Abstract Background Mitigating myocardial tissue injury (MTI) remains an unmet clinical need in the reperfusion era. Stimulating adenosine synthesis through the breakdown of adenosine triphosphate (ATP) by apyrase (CD39), an endothelial ADPase, has emerged as a potential new avenue in the reduction of MTI. Purpose In this study we examined whether the intravenous administration of a recombinant soluble form of human apyrase (AZD3366) prior to reperfusion limits MTI and improves cardiac function in a pig model of STEMI as assessed by serial cardiac magnetic resonance (CMR) imaging. Methods Pigs (n=16) were subjected to STEMI induction (1.5h closed-chest complete LAD coronary balloon occlusion). Immediately prior to reperfusion, pigs were randomized to intravenously receive one single dose of 3 mg/kg AZD3366 (n=8) or vehicle (n=8). Serial-CMR imaging was performed at baseline, 3 days, and 42 days post-MI for the assessment of structural and functional readouts at rest and during dobutamine stress. Light transmittance aggregometry (LTA; challenged by 5, 10 and 20 μM ADP) and ear bleeding time were monitored pre-MI, post-MI and at day 3. Results AZD3366 significantly reduced MTI by limiting (around 60%) oedema formation (21.3±6.7 vs. 12.3±6.7 g LV) and infarct size (14.3±6.1 vs. 8.4±3.4 g LV) and preventing microvascular obstruction (2.3±0.9 vs. 0.5±0.5 g LV) at 3 days post-MI, compared to vehicle-administered STEMI pigs (p&amp;lt;0.05). At a functional level, LVEDV and LVESV showed less deterioration in AZD3366 treated animal as compared to vehicle 3 days post-MI (p&amp;lt;0.05) and less numerical decrease of LVEF. Furthermore, AZD3366-treated animals showed no deterioration in LVEF upon dobutamine stress in contrast to vehicle-infused animals, (p&amp;lt;0.05). AZD3366 treatment nearly abolished LTA at all tested ADP doses early post-STEMI, an effect that remained up to 3 days post-infusion but did not affect ear bleeding time at any of the tested time points. No additional effects were seen at 42 days. Conclusion Infusion of one single dose of the soluble recombinant apyrase AZD3366 prior to reperfusion exerts cardioprotection by reducing oedema formation, microvascular obstruction and necrosis and improving cardiac performance at rest and after dobutamine stress during the acute post-MI period. Administration of AZD3366 as an adjunctive therapy to standard of care for STEMI patients undergoing primary PCI may reduce myocardial tissue injury. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): AstraZeneca, Gothenburg, Sweden

Radiologic Characteristics of Spinal Hemangioblastomas in von Hippel Lindau Disease as Guidance in Clinical Interventions

Hemangioblastomas in the central nervous system are the most common manifestation of von Hippel-Lindau (VHL) disease. Because the growth rate of hemangioblastomas is unpredictable, regular follow-up is mandatory, focusing on clinical symptoms and imaging of the central nervous system. However, clinical symptoms may be subtle and nonspecific, and data about the relationship between the radiologic findings and clinical symptoms are sparse. This study aims to evaluate if and how findings of magnetic resonance imaging (MRI) regarding spinal hemangioblastomas are associated with symptoms of VHL disease, with special attention to peritumoral edema and spinal cysts. Serial spinal MRI scans of 43 genetically or clinically established VHL patients with at least 2 years of follow-up were reevaluated to examine the volume, growth rate, and location of spinal hemangioblastomas and the presence, size, and growth rate of peritumoral edema and cysts. Findings were compared with clinical symptoms using the Fisher exact test. We observed a total of 77 spinal hemangioblastomas in 28 patients. Eight of the 28 patients showed peritumoral edema and spinal cysts, and 1 patient showed peritumoral edema without cyst formation; 6 of these 9 patients showed clinical symptoms. Both peritumoral edema and spinal cysts were associated with clinical symptoms (P= 0.023 and P= 0.011, respectively). The presence of peritumoral edema and/or spinal cysts shown on MRI in VHL patients with spinal hemangioblastomas is associated with symptoms in more than half of the patients and may alert the clinician to intensify clinical and radiologic surveillance.