Anatomic and Functional Imaging of Immunoglobulin G4-related Disease and Its Mimics.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated fibrosclerosing disease with tumefactive lesions infiltrated by IgG4-positive plasma cells. Initially described as autoimmune pancreatitis, IgG4-RD is now recognized as a discrete entity and is found to affect virtually any organ in the body. Common extrapancreatic sites include the biliary tree, salivary glands, periorbital tissue, lungs, kidneys, lymph nodes, aorta, retroperitoneum, and thyroid gland. Diagnosis-which relies on histopathologic, serologic, and radiologic features-can be challenging with the disease underdiagnosed, as IgG4-RD often mimics malignancy, infectious processes, or other immune-mediated conditions. Patients may present with signs of compression of nearby structures due to mass effect or with organ failure when the disease is left untreated. The clinical course is complex, with single- or multiorgan involvement and metachronous or synchronous occurrence of lesions. IgG4-RD responds well to glucocorticoid therapy, disease-modifying antirheumatic drugs, and B-cell-depleting biologic agents; prompt diagnosis is important to avoid delay in treatment and unnecessary pharmacologic or surgical intervention. While imaging features may not be specific for IgG4-RD, functional whole-body imaging with fluorine 18-fluorodeoxyglucose PET/CT is a useful adjunct for localizing extrapancreatic sites for biopsy, monitoring therapeutic response, and demonstrating disease relapse. The authors describe the pancreatic and extrapancreatic sites of involvement in IgG4-RD, with imaging features and patterns to aid in distinguishing IgG4-RD from its mimics through a multimodality approach with emphasis on functional imaging evaluation. ©RSNA, 2023 Quiz questions in the supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article.

Anti-Correlation between the Dynamics of the Active Site Loop and C-Terminal Tail in Relation to the Homodimer Asymmetry of the Mouse Erythroid 5-Aminolevulinate Synthase.

Biosynthesis of heme represents a complex process that involves multiple stages controlled by different enzymes. The first of these proteins is a pyridoxal 5'-phosphate (PLP)-dependent homodimeric enzyme, 5-aminolevulinate synthase (ALAS), that catalyzes the rate-limiting step in heme biosynthesis, the condensation of glycine with succinyl-CoA. Genetic mutations in human erythroid-specific ALAS (ALAS2) are associated with two inherited blood disorders, X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP). XLSA is caused by diminished ALAS2 activity leading to decreased ALA and heme syntheses and ultimately ineffective erythropoiesis, whereas XLPP results from "gain-of-function" ALAS2 mutations and consequent overproduction of protoporphyrin IX and increase in Zn2+-protoporphyrin levels. All XLPP-linked mutations affect the intrinsically disordered C-terminal tail of ALAS2. Our earlier molecular dynamics (MD) simulation-based analysis showed that the activity of ALAS2 could be regulated by the conformational flexibility of the active site loop whose structural features and dynamics could be changed due to mutations. We also revealed that the dynamic behavior of the two protomers of the ALAS2 dimer differed. However, how the structural dynamics of ALAS2 active site loop and C-terminal tail dynamics are related to each other and contribute to the homodimer asymmetry remained unanswered questions. In this study, we used bioinformatics and computational biology tools to evaluate the role(s) of the C-terminal tail dynamics in the structure and conformational dynamics of the murine ALAS2 homodimer active site loop. To assess the structural correlation between these two regions, we analyzed their structural displacements and determined their degree of correlation. Here, we report that the dynamics of ALAS2 active site loop is anti-correlated with the dynamics of the C-terminal tail and that this anti-correlation can represent a molecular basis for the functional and dynamic asymmetry of the ALAS2 homodimer.

Troponins, intrinsic disorder, and cardiomyopathy.

Cardiac troponin is a dynamic complex of troponin C, troponin I, and troponin T (TnC, TnI, and TnT, respectively) found in the myocyte thin filament where it plays an essential role in cardiac muscle contraction. Mutations in troponin subunits are found in inherited cardiomyopathies, such as hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). The highly dynamic nature of human cardiac troponin and presence of numerous flexible linkers in its subunits suggest that understanding of structural and functional properties of this important complex can benefit from the consideration of the protein intrinsic disorder phenomenon. We show here that mutations causing decrease in the disorder score in TnI and TnT are significantly more abundant in HCM and DCM than mutations leading to the increase in the disorder score. Identification and annotation of intrinsically disordered regions in each of the troponin subunits conducted in this study can help in better understanding of the roles of intrinsic disorder in regulation of interactomes and posttranslational modifications of these proteins. These observations suggest that disease-causing mutations leading to a decrease in the local flexibility of troponins can trigger a whole plethora of functional changes in the heart.

Multi-Site Benchmark Study for Standardized Relative Cerebral Blood Volume in Untreated Brain Metastases Using the DSC-MRI Consensus Acquisition Protocol.

BACKGROUND AND PURPOSE: A national consensus recommendation for the collection of DSC (dynamic susceptibility contrast) MRI perfusion data, used to create maps of relative cerebral blood volume (rCBV), has been recently established for primary and metastatic brain tumors. The goal was to reduce inter-site variability and improve ease of comparison across time and sites, fostering widespread use of this informative measure. To translate this goal into practice the prospective collection of consensus DSC-MRI data and characterization of derived rCBV maps in brain metastases is needed. The purpose of this multi-site study was to determine rCBV in untreated brain metastases in comparison to glioblastoma and normal appearing brain using the national consensus protocol. MATERIALS AND METHODS: Subjects from three sites with untreated enhancing brain metastases underwent DSC-MRI according to a recommended option that uses a mid-range flip angle, GRE-EPI acquisition and the administration of both a pre-load and 2nd DSC-MRI dose of 0.1 mmol/kg GBCA. Quantitative maps of standardized rCBV (sRCBV) were generated and enhancing lesion ROIs determined from post-contrast T1-weighted images alone or calibrated difference maps, termed delta T1 (dT1) maps. Mean sRCBV for metastases were compared to normal appearing white matter (NAWM) and glioblastoma (GBM) from a previous study. Comparisons were performed using either the Wilcoxon signed-rank test for paired comparisons or the Mann-Whitney nonparametric test for unpaired comparisons. RESULTS: 49 patients with a primary histology of lung (n=25), breast (n=6), squamous cell carcinoma (SCC) (n=1), melanoma (n=5), gastrointestinal (GI) (n=3) and genitourinary (GU) (n=9) were included in comparison to GBM (n=31). The mean sRCBV of all metastases (1.83+/-1.05) were significantly lower (p=0.0009) than mean sRCBV for GBM (2.67±1.34) with both statistically greater (p<0.0001) than NAWM (0.68 +/- 0.18). Histologically distinct metastases are each statistically greater than NAWM (p<0.0001) with lung (p=0.0002) and GU (p=.02) sRCBV being significantly different than GBM sRCBV. CONCLUSIONS: 49 patients with a primary histology of lung (n=25), breast (n=6), squamous cell carcinoma (SCC) (n=1), melanoma (n=5), gastrointestinal (GI) (n=3) and genitourinary (GU) (n=9) were included in comparison to GBM (n=31). The mean sRCBV of all metastases (1.83+/-1.05) were significantly lower (p=0.0009) than mean sRCBV for GBM (2.67+1.34) with both statistically greater (p<0.0001) than NAWM (0.68 +/- 0.18). Histologically distinct metastases are each statistically greater than NAWM (p<0.0001) with lung (p=0.0002) and GU (p=.02) sRCBV being significantly different than GBM sRCBV. ABBREVIATIONS: dT1=delta T1; GBCA=gadolinium-based contrast agent; NAWM=normal appearing white matter; normalized relative cerebral blood volume=nRCBV; relative cerebral blood volume=rCBV; standardized relative cerebral blood volume=sRCBV.

The Complementary Role of 68Ga-DOTATATE PET/CT in Diagnosis of Recurrent Meningioma.

Introduction: Contrast-enhanced brain MRI is the choice of imaging modality in diagnosis and posttreatment evaluation, its role is limited in distinguishing recurrent lesion from postoperative change. 68Ga-DOTATATE is a somatostatin analog PET tracer which has high affinity to meningioma expressing somatostatin receptor. Methods and subjects: In this case series review, we described 8 patients with brain MRI suspected of recurrent meningioma who underwent focused 68Ga-DOTATATE PET/CT scan for radiation treatment planning. Results: The combined brain MRI and PET/CT allowed improved conspicuity of the lesions and aided radiation treatment planning. The time from the initial surgery to PET/CT scans varied widely ranging from 1 year to 12 years. Three patients had PET/CT shortly after the initial surgery (1-3 years) and underwent targeted radiation therapy. Subsequent imaging showed no evidence of recurrence. Four patients had prolonged time between the PET/CT and the initial surgery (7-12 years) which showed extensive tumor burden. All four patients expired shortly after the last PET/CT scan. Conclusion: 68Ga-DOTATATE PET shows promising complementary role in detection and treatment planning of recurrent meningioma.

Single-Center Review of Celiac Plexus/Retrocrural Splanchnic Nerve Block for Non-Cancer Related Pain.

RATIONALE AND OBJECTIVES: Celiac plexus and retrocrural splanchnic nerve (CP/RSN) blocks are widely used for cancer-related abdominal pain, but there is limited literature on their efficacy for non-cancer related pain. Our aim was to determine the indications and effectiveness of CT-guided CP/RSN blocks performed on patients with abdominal pain from non-cancer related sources. MATERIALS AND METHODS: CT-guided CP/RSN blocks for non-cancer related abdominal pain from 2011-2020 were retrospectively reviewed for patient demographics, procedure details, duration of pain relief, and complications. Effective blocks were defined as patient-reported pain relief or decrease in opioid use lasting 2 or more days for temporary blocks and 14 or more days for permanent blocks. RESULTS: Of 72 CT-guided CP/RSN blocks for non-cancer related abdominal pain, 48 (67%) were effective for a mean of 51 days (median 14, range 2-700). Of the 18 permanent blocks, 9 (50%) were effective for a mean of 111 days (median 90, range 14-390). Of the 54 temporary blocks, 39 (72%) were effective for a mean of 37 days (median 9, range 2-700). Indications included postural orthostatic tachycardia syndrome/dysautonomia (77% effective, 20/26), pancreatitis (86% effective, 12/14), postsurgical pain (62% effective, 8/13), median arcuate ligament syndrome (70% effective, 7/10), chronic pain syndrome (20% effective, 1/5), gastroparesis (80% effective, 4/5), and renal cystic disease (33% effective, 1/3). For postural orthostatic tachycardia syndrome /dysautonomia, pancreatitis, post-surgical pain, and MALS, there were no statistically significant differences in effectiveness between celiac vs. splanchnic blocks in groups matched by indication and intended duration (temporary/permanent). CONCLUSIONS: CT-guided CP/RSN blocks can effectively manage non-cancer related abdominal pain, though there is discrepancy in efficacy between temporary and permanent blocks.