The use of ferumoxytol for high-resolution vascular imaging and troubleshooting for abdominal allografts.

Ferumoxytol is an ultrasmall superparamagnetic iron oxide which has been used as an off-label intravenous contrast agent for MRI. Unlike gadolinium-based contrast agents, ferumoxytol remains in the intravascular space with a long half-life of 14-21 h. During the first several hours, it acts as a blood-pool agent and has minimal parenchymal enhancement. Studies have shown adequate intravascular signal for up to 72 h after initial contrast bolus. Ferumoxytol has been shown to be safe, even in patients with renal failure. Ferumoxytol has shown promise in a variety of clinical settings. The exquisite resolution enabled by the long intravascular times and lack of background parenchymal enhancement is of particular interest in the vascular imaging of solid organ allografts. Ferumoxytol magnetic resonance angiography (MRA) may identify clinically actionable findings months before ultrasound, CT angiography, or Gadolinium-enhanced MRA. Ferumoxytol MRA is of particular benefit as a troubleshooting tool in the setting of equivocal ultrasound and CT imaging. In the following review, we highlight the use of ferumoxytol for high-resolution MR vascular imaging for abdominal solid organ allografts, with representative cases.

MRI in Adult Patients with Active and Inactive Implanted MR-conditional, MR-nonconditional, and Other Devices.

Active implanted medical devices (AIMDs) enable therapy and patient monitoring by way of electrical activity and typically have a battery and electrical leads. The most common types of AIMDs include cardiac implantable electronic devices (CIEDs), spinal cord stimulators, deep brain stimulators, bone growth or fusion stimulators, other neurostimulators, and drug infusion pumps. As more patients with AIMDs undergo MRI, it is important to consider the safety of patients who have these implanted devices during MRI. The authors review the physics concepts related to MRI safety, such as peak spatial gradient magnetic field, specific absorption rate, root mean square value of the effective magnetic component of the transmitted RF pulse, and gradient slew rate, as well as the parameters necessary to remain within safety limits. The roles of MRI safety personnel, as set forth by the International Society of Magnetic Resonance in Medicine, are emphasized. In addition, the relevant information provided in vendor manuals is reviewed, with a focus on how to obtain relevant up-to-date information. The radiologist should be able to modify protocols to meet safety requirements, address possible alternatives to MRI, and weigh the potential benefits of MRI against the potential risks. A few more advanced topics, such as fractured or abandoned device leads and patients with multiple implanted medical devices, also are addressed. Recommended workflows for MRI in patients with implanted medical devices are outlined. It is important to implement an algorithmic MRI safety process, including a review of the MRI safety information; patient screening; optimal imaging; and monitoring patients before, during, and after the examination. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. See the invited commentary by Shetty et al in this issue.

A Gene Panel for Early Identification of Future Responders to Immune Checkpoint Blockade.

Immune checkpoint blockade (ICB), therapies that target the PD-1 pathway, CTLA-4 pathway, and other checkpoint pathways, lead to durable responses in many cancer types. Since only a minority of patients respond to ICB, it may be useful to identify the future responders early in the course of treatment. In this study we evaluated a small (15 genes) biologically motivated panel, consisting of genes involved in immune activation and checkpoint pathways, for early identification of future responders to ICB. The panel passed consistency check, pathological and in-silico validations, and was an excellent predictor (area under ROC curve >0.95) of eventual response to ICB, both CTLA-4 and PD-1 blockade, when applied to metastatic melanoma patients undergoing ICB (i.e., "on-treatment") in a publicly available dataset. These results suggest that this small biologically motivated panel may be useful for early identification of future responders to ICB.

The Magnet Is Sometimes "Off"-Practical Strategies for Optimizing Challenging Musculoskeletal MR Imaging.

To describe practical solutions to the unique technical challenges of musculoskeletal magnetic resonance imaging, including off-isocenter imaging, artifacts from motion and metal prostheses, small field-of-view imaging, and non-conventional scan angles and slice positioning. Unique challenges of musculoskeletal magnetic resonance imaging require a collaborative approach involving radiologists, physicists, and technologists utilizing optimized magnetic resonance protocols, specialized coils, and unique patient positioning, in order to reliably diagnose critical musculoskeletal MR image findings.

Gene Expression in Barrett's Esophagus Cell Lines Resemble Esophageal Squamous Cell Carcinoma Instead of Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) is strongly associated with Barrett's esophagus (BE), a pre-malignant condition resulting from gastric reflux. Esophageal squamous cell carcinoma (ESCC), the other major subtype of esophageal cancer, shows strong association with smoking and alcohol intake and no association with gastric reflux. In this study, we constructed and validated gene expression signatures of EAC vs. ESCC tumors using publicly available datasets, and subsequently assessed the enrichment levels of these signatures in commonly used EAC and ESCC cell lines, normal esophageal tissues and normal esophageal cell lines, and primary BE tissues and BE cell lines. We found that unlike ESCC cell lines which were quite similar to primary ESCC tumors, EAC cell lines were considerably different from primary EAC tumors but still more similar to EAC tumors than ESCC tumors, as the genes up in EAC vs. ESCC (EAChi) had considerably lower expression in EAC cell lines than EAC tumors. However, more surprisingly, unlike various normal cell lines (EPC2, Het-1A) which were very similar to various tissues from normal esophagus, BE cell lines (BAR-T, CP-A) were extremely different from primary BE tissues, as BE cell lines had substantially lower levels of EAChi and substantially higher levels of ESCChi gene expression. This ESCC-like profile of the BAR-T remained unaltered even after prolonged exposure to an acidic bile mixture in vitro resulting in malignant transformation of this cell line. However, primary BE tissues had EAC-like gene expression profiles as expected. Only one EAC case from the Cancer Genome Atlas resembled BE cell lines, and while it had the clinical profile and some mutational features of EAC, it had some mutational features, the copy number alteration profile, and the gene expression profile of ESCC instead. These incomprehensible changes in gene expression patterns may result in ambiguous changes in the phenotype and warrants careful evaluation to inform selection of appropriate in vitro tools for future studies on esophageal adenocarcinoma.

Barrett's Epithelium to Esophageal Adenocarcinoma: Is There a "Point of No Return"?

Background: Esophageal adenocarcinoma (EA) arises from Barrett's epithelium (BE), and chronic gastroesophageal reflux disease is considered the strongest risk factor for disease progression. All BE patients undergo acid suppressive therapy, surveillance, and BE removal by surgery or endoscopic ablation, yet the incidence of EAC continues to increase. Despite the known side effects and mortality, the one-size-fits-all approach is the standard clinical management as there are no reliable methods for risk stratification. Methods: Paired-end Illumina NextSeq500 RNA sequencing was performed on total RNA extracted from 20-week intervals (0, 20, 40, and 60 W) of an in vitro BE carcinogenesis (BEC) model to construct time series global gene expression patterns (GEPs). The cells from two strategic time points (20 and 40 W) based on the GEPs were grown for another 20 weeks, with and without further acid and bile salt (ABS) stimulation, and the recurrent neoplastic cell phenotypes were evaluated. Results: Hierarchical clustering of 866 genes with ≥ twofold change in transcript levels across the four time points revealed maximum variation between the BEC20W and BEC40W cells. Enrichment analysis confirmed that the genes altered ≥ twofold during this window period associated with carcinogenesis and malignancy. Intriguingly, the BEC20W cells required further ABS exposure to gain neoplastic changes, but the BEC40W cells progressed to malignant transformation after 20 weeks even in the absence of additional ABS. Discussion: The transcriptomic gene expression patterns in the BEC model demonstrate evidence of a clear threshold in the progression of BE to malignancy. Catastrophic transcriptomic changes during a window period culminate in the commitment of the BE cells to a "point of no return," and removal of ABS is not effective in preventing their malignant transformation. Discerning this "point of no return" during BE surveillance by tracking the GEPs has the potential to evaluate risk of BE progression and enable personalized clinical management.

SMAD4 is critical in suppression of BRAF-V600E serrated tumorigenesis.

BRAF-driven colorectal cancer is among the poorest prognosis subtypes of colon cancer. Previous studies suggest that BRAF-mutant serrated cancers frequently exhibit Microsatellite Instability (MSI) and elevated levels of WNT signaling. The loss of tumor-suppressor Smad4 in oncogenic BRAF-V600E mouse models promotes rapid serrated tumor development and progression, and SMAD4 mutations co-occur in human patient tumors with BRAF-V600E mutations. This study assesses the role of SMAD4 in early-stage serrated tumorigenesis. SMAD4 loss promotes microsatellite stable (MSS) serrated tumors in an oncogenic BRAF-V600E context, providing a model for MSS serrated cancers. Inactivation of Msh2 in these mice accelerated tumor formation, and whole-exome sequencing of both MSS and MSI serrated tumors derived from these mouse models revealed that all serrated tumors developed oncogenic WNT mutations, predominantly in the WNT-effector gene Ctnnb1 (ß-catenin). Mouse models mimicking the oncogenic ß-catenin mutation show that the combination of three oncogenic mutations (Ctnnb1, Braf, and Smad4) are critical to drive rapid serrated dysplasia formation. Re-analysis of human tumor data reveals BRAF-V600E mutations co-occur with oncogenic mutations in both WNT and SMAD4/TGFß pathways. These findings identify SMAD4 as a critical factor in early-stage serrated cancers and helps broaden the knowledge of this rare but aggressive subset of colorectal cancer.

Genomic and Immunologic Correlates of Indoleamine 2,3-Dioxygenase Pathway Expression in Cancer.

Immune checkpoint blockade leads to unprecedented responses in many cancer types. An alternative method of unleashing anti-tumor immune response is to target immunosuppressive metabolic pathways like the indoleamine 2,3-dioxygenase (IDO) pathway. Despite promising results in Phase I/II clinical trials, an IDO-1 inhibitor did not show clinical benefit in a Phase III clinical trial. Since, a treatment can be quite effective in a specific subset without being effective in the whole cancer type, it is important to identify the subsets of cancers that may benefit from IDO-1 inhibitors. In this study, we looked for the genomic and immunologic correlates of IDO pathway expression in cancer using the Cancer Genome Atlas (TCGA) dataset. Strong CD8+ T-cell infiltration, high mutation burden, and expression of exogenous viruses [Epstein-Barr virus (EBV), Human papilloma virus (HPV), and Hepatitis C virus (HCV)] or endogenous retrovirus (ERV3-2) were associated with over-expression of IDO-1 in most cancer types, IDO-2 in many cancer types, and TDO-2 in a few cancer types. High mutation burden in ER+ HER2- breast cancer, and ERV3-2 expression in ER- HER2- and HER2+ breast, colon, and endometrial cancers were associated with over-expression of all three genes. These results may have important implications for guiding development clinical trials of IDO-1 inhibitors.

Recurring Translocations in Barrett's Esophageal Adenocarcinoma.

Barrett's esophagus (BE) is a premalignant metaplasia in patients with chronic gastroesophageal reflux disease (GERD). BE can progress to esophageal adenocarcinoma (EA) with less than 15% 5-year survival. Chromosomal aneuploidy, deletions, and duplication are early events in BE progression to EA, but reliable diagnostic assays to detect chromosomal markers in premalignant stages of EA arising from BE are lacking. Previously, we investigated chromosomal changes in an in vitro model of acid and bile exposure-induced Barrett's epithelial carcinogenesis (BEC). In addition to detecting changes already known to occur in BE and EA, we also reported a novel recurring chromosomal translocation t(10:16) in the BE cells at an earlier time point before they undergo malignant transformation. In this study, we refine the chromosomal event with the help of fluorescence microscopy techniques as a three-way translocation between chromosomes 2, 10, and 16, t(2:10;16) (p22;q22;q22). We also designed an exclusive fluorescent in situ hybridization for esophageal adenocarcinoma (FISH-EA) assay that detects these chromosomal breakpoints and fusions. We validate the feasibility of the FISH-EA assay to objectively detect these chromosome events in primary tissues by confirming the presence of one of the fusions in paraffin-embedded formalin-fixed human EA tumors. Clinical validation in a larger cohort of BE progressors and non-progressors will confirm the specificity and sensitivity of the FISH-EA assay in identifying malignant potential in the early stages of EA.

Contrast-enhanced Mammography: How Does It Work?

Contrast-enhanced mammography (CEM) is an imaging technique that uses iodinated contrast medium to improve visualization of breast lesions and assessment of tumor neovascularity. Through modifications in x-ray energy, high- and low-energy images of the breast are combined to highlight areas of contrast medium pooling. The use of contrast material introduces different workflows, artifacts, and risks related to the contrast medium dose. In addition, the need to acquire multiple images in each view introduces different workflows, artifacts, and risks associated with the radiation dose. Although CEM and conventional mammography share many underlying principles, it is important to understand how these two mammographic examinations differ and the mechanisms that facilitate image contrast at CEM. ©RSNA, 2021.

Genomic and immunologic correlates of LAG-3 expression in cancer.

Immune checkpoint blockade leads to unprecedented responses in many cancers. Although currently available agents mostly target the PD-1 and CTLA-4 pathways, agents targeting the immune checkpoint protein LAG-3 are under active clinical development, and early clinical data show that LAG-3 expression is a biomarker of response to LAG-3 blockade. To determine which cancers may benefit most from LAG-3 blockade, we performed a pan-cancer analysis of The Cancer Genome Atlas dataset to identify genomic and immunologic correlates of LAG-3 expression. High mutation burden, and expression of exogenous virus (EBV, HPV) or endogenous retrovirus (ERV3-2), were associated with overexpression of LAG-3 in multiple cancers. Although CD8+ T-cell marker (CD8A) and LAG-3 were strongly co-expressed with each other and with PD-L1 in most cancers, there were three notable exceptions: HPV+ head-neck squamous cell cancer, renal cell cancer, and glioblastoma. These results may have important implications for guiding development clinical trials of LAG-3 blockade.

DNA hypomethylation promotes transposable element expression and activation of immune signaling in renal cell cancer.

Recently, we reported that expression of endogenous retroviruses (ERVs) is associated with response to immune checkpoint blockade (ICB) in renal cell carcinoma (RCC). We show that decitabine, a DNA hypomethylating agent, activates transposable element (TE) expression (LINE1 and ERVs ERV3-2 and ERV4700) and antiviral signaling to potentially enhance response to ICB in kidney cancer cell lines and primary cells. KO of RIGI and MDA5 dsRNA sensors attenuated activation of antiviral signaling associated with DNA hypomethylation, and RIGI and MDA5 IPs showed increased ERV binding with decitabine treatment. Bioinformatic analyses showed the decitabine-induced signature could be associated with increased immune infiltration and response to ICB. Cytokine secretion induced by decitabine could modestly improve T cell activation and robustly enhanced T cell migration. In a small retrospective cohort of metastatic clear cell RCC (ccRCC) patients treated with anti-PD1/PDL1 blockade, activation of some antiviral genes was significantly higher in responders. Thus, we identified a potential strategy to induce TE expression through inhibition of DNA methylation in modulating T cell action via regulation of the innate antiviral pathway.

Tissue- and development-stage-specific mRNA and heterogeneous CNV signatures of human ribosomal proteins in normal and cancer samples.

We give results from a detailed analysis of human Ribosomal Protein (RP) levels in normal and cancer samples and cell lines from large mRNA, copy number variation and ribosome profiling datasets. After normalizing total RP mRNA levels per sample, we find highly consistent tissue specific RP mRNA signatures in normal and tumor samples. Multiple RP mRNA-subtypes exist in several cancers, with significant survival and genomic differences. Some RP mRNA variations among subtypes correlate with copy number loss of RP genes. In kidney cancer, RP subtypes map to molecular subtypes related to cell-of-origin. Pan-cancer analysis of TCGA data showed widespread single/double copy loss of RP genes, without significantly affecting survival. In several cancer cell lines, CRISPR-Cas9 knockout of RP genes did not affect cell viability. Matched RP ribosome profiling and mRNA data in humans and rodents stratified by tissue and development stage and were strongly correlated, showing that RP translation rates were proportional to mRNA levels. In a small dataset of human adult and fetal tissues, RP protein levels showed development stage and tissue specific heterogeneity of RP levels. Our results suggest that heterogeneous RP levels play a significant functional role in cellular physiology, in both normal and disease states.

Nanocomposite Hydrogel with Tantalum Microparticles for Rapid Endovascular Hemostasis.

Endovascular embolization to treat vascular hemorrhage involves pushing coil-shaped metal wires into the artery repeatedly until they are densely packed to slow the blood flow and clot. However, coil embolization is associated with high rebleeding rates, unpredictable economics and, most importantly, they rely on the patient's ability to make a clot. These issues are exacerbated when the patient is anticoagulated or coagulopathic. A novel bioengineered tantalum-loaded nanocomposite hydrogel for gel embolic material (Ta-GEM) that can be rapidly delivered using clinical catheters for instant hemostasis regardless of the coagulopathic state is reported. Ta-GEM formulation is visible by most of the clinically available imaging modalities including ultrasound, computed tomography, magnetic resonance imaging, and fluoroscopy without significant artifact. In addition, Ta-GEM can be retrieved, allowing temporary vascular occlusion, and it can be used to rescue cases of failed coil embolization. Ta-GEM occlusion of first-order arteries such as the renal artery and iliac artery in a swine model is found to be safe and durable; by 28 days, 75% of the injected Ta-GEM in the arterial lumen is replaced by dense connective tissue. Altogether, this study demonstrates that Ta-GEM has many advantages over the current technologies and has potential applications in clinical practice.

MRI in acute pancreatitis.

Computed tomography (CT) is the most commonly performed imaging test for acute pancreatitis. Nevertheless, magnetic resonance (MRI) imaging is useful in many specific situations. These include evaluating patients with acute pancreatitis who cannot receive iodinated CT contrast, elucidating the underlying cause of acute pancreatitis, assessing ductal disconnection and for guiding intervention of necrotic collections. Non-contrast MRI is superior to non-contrast CT and MRI for the diagnosis of acute pancreatitis. We discuss these specific uses of MRI in acute pancreatitis. We highlight the future advances in MRI including faster, free-breathing scans that allow MRI to be completed within 10 min.

Sample content of kinesthetic educational training: Reducing scattered X-ray exposures to interventional physician operators of fluoroscopy.

Content used by Medical Physicists for fluoroscopy safety training to staff is deliverable via several formats, that is, online content or a live audience slide presentations. Here, we share one example of a kinesthetic (live, hands-on simulation) educational program in use at our facility for some time (~10 years). In this example, the format and content specifically target methods of reducing physician operator exposures from scattered x rays. A kinesthetic format identifies and promotes the adoption of exposure-reducing behaviors. Key kinesthetic elements of this type of training include: physician hands-on measurements of radiation levels at locations specific to their standing positions (e.g., primary arterial access points) in the room using handheld exposure rate meters, measurement of exposure rate reduction to physicians provided by using personal protective equipment, that is, wearable aprons, hanging lead drapes, and pull-down shields. Physician choice of procedure-specific tableside selectable controls affecting exposure rate from optional fluoroscopy, Cine or digital subtraction angiography (DSA), along with comparative measured contribution to physician exposure is demonstrated. The inverse square exposure rate reduction to physicians when stepping back from the table during DSA is a key observation. Kinesthetic simulations in the rooms used by physicians have been found to provide the highest level of understanding giving rise to adoption of practices that are impactful for physicians. Specific training scripts are in place for physician sub-specialization in interventional radiology, cardiology, neurosurgery, vascular surgery, and gastroenterology. This training is used for new physician staff while classroom presentations (whose content mimics in room training) are used with staff who have had previously had in room training.

Safety and Image Quality of 1.5-T Endorectal Coil Multiparametric MRI of the Prostate or Prostatectomy Fossa for Patients With Pacemaker or Implantable Cardioverter-Defibrillator.

OBJECTIVE: The purpose of this study is to report the patient safety and image quality of 1.5-T multiparametric MRI of the prostate in patients with cardiac implantable electronic devices (CIEDs). MATERIALS AND METHODS: In this retrospective study, a database was searched to identify prostate multiparametric 1.5-T MRI examinations performed with endorectal coils for patients with CIEDs from 2012 to 2016 (study group) and matched patients without CIEDs (control group). Clinical safety in the study group was reviewed. The specific absorption rate (SAR) and signal-to-noise ratio (SNR) were measured in both groups. Imaging quality and artifact on T2-weighted images, DW images, and dynamic contrast-enhanced images were rated on a 5-point scale by two independent readers. RESULTS: The study group consisted of total 28 multiparametric MRI examinations in 25 patients. There were no serious device-related adverse effects observed (0/28; 0%), and the estimated whole-body SAR in the study group was never greater than 1.5 W/kg. The SNR values tended to be lower in the study group than in the control group. However, overall perceived image preferences and influences of artifacts on image quality for the study group were not significantly different from those for the control group (p > 0.05), which were rated above average (rating 3) by both readers 1 and 2. CONCLUSION: Multiparametric 1.5-T MRI examination of the prostate can be safely performed in selected patients with CIEDs under controlled conditions with applicable image quality while maintaining a SAR less than 1.5 W/kg.