Computed tomography referral guidelines adherence in Europe: insights from a seven-country audit.

BACKGROUND: Ensuring appropriate computed tomography (CT) utilization optimizes patient care while minimizing radiation exposure. Decision support tools show promise for standardizing appropriateness. OBJECTIVES: In the current study, we aimed to assess CT appropriateness rates using the European Society of Radiology (ESR) iGuide criteria across seven European countries. Additional objectives were to identify factors associated with appropriateness variability and examine recommended alternative exams. METHODS: As part of the European Commission-funded EU-JUST-CT project, 6734 anonymized CT referrals were audited across 125 centers in Belgium, Denmark, Estonia, Finland, Greece, Hungary, and Slovenia. In each country, two blinded radiologists independently scored each exam's appropriateness using the ESR iGuide and noted any recommended alternatives based on presented indications. Arbitration was used in case auditors disagreed. Associations between appropriateness rate and institution type, patient's age and sex, inpatient/outpatient patient status, anatomical area, and referring physician's specialty were statistically examined within each country. RESULTS: The average appropriateness rate was 75%, ranging from 58% in Greece to 86% in Denmark. Higher rates were associated with public hospitals, inpatient settings, and referrals from specialists. Variability in appropriateness existed by country and anatomical area, patient age, and gender. Common alternative exam recommendations included magnetic resonance imaging, X-ray, and ultrasound. CONCLUSION: This multi-country evaluation found that even when using a standardized imaging guideline, significant variations in CT appropriateness persist, ranging from 58% to 86% across the participating countries. The study provided valuable insights into real-world utilization patterns and identified opportunities to optimize practices and reduce clinical and demographic disparities in CT use. KEY POINTS: Question Largest multinational study (7 EU countries, 6734 CT referrals) assessed real-world CT appropriateness using ESR iGuide, enabling cross-system comparisons. Findings Significant variability in appropriateness rates across institution type, patient status, age, gender, exam area, and physician specialty, highlighted the opportunities to optimize practices based on local factors. Clinical relevance International collaboration on imaging guidelines and decision support can maximize CT benefits while optimizing radiation exposure; ongoing research is crucial for refining evidence-based guidelines globally.

Real-time influence of intracellular acidification and Na+ /H+ exchanger inhibition on in-cell pyruvate metabolism in the perfused mouse heart: A 31 P-NMR and hyperpolarized 13 C-NMR study.

Disruption of acid-base balance is linked to various diseases and conditions. In the heart, intracellular acidification is associated with heart failure, maladaptive cardiac hypertrophy, and myocardial ischemia. Previously, we have reported that the ratio of the in-cell lactate dehydrogenase (LDH) to pyruvate dehydrogenase (PDH) activities is correlated with cardiac pH. To further characterize the basis for this correlation, these in-cell activities were investigated under induced intracellular acidification without and with Na+ /H+ exchanger (NHE1) inhibition by zoniporide. Male mouse hearts (n = 30) were isolated and perfused retrogradely. Intracellular acidification was performed in two ways: (1) with the NH4 Cl prepulse methodology; and (2) by combining the NH4 Cl prepulse with zoniporide. 31 P NMR spectroscopy was used to determine the intracellular cardiac pH and to quantify the adenosine triphosphate and phosphocreatine content. Hyperpolarized [1-13 C]pyruvate was obtained using dissolution dynamic nuclear polarization. 13 C NMR spectroscopy was used to monitor hyperpolarized [1-13 C]pyruvate metabolism and determine enzyme activities in real time at a temporal resolution of a few seconds using the product-selective saturating excitation approach. The intracellular acidification induced by the NH4 Cl prepulse led to reduced LDH and PDH activities (-16% and -39%, respectively). This finding is in line with previous evidence of reduced myocardial contraction and therefore reduced metabolic activity upon intracellular acidification. Concomitantly, the LDH/PDH activity ratio increased with the reduction in pH, as previously reported. Combining the NH4 Cl prepulse with zoniporide led to a greater reduction in LDH activity (-29%) and to increased PDH activity (+40%). These changes resulted in a surprising decrease in the LDH/PDH ratio, as opposed to previous predictions. Zoniporide alone (without intracellular acidification) did not change these enzyme activities. A possible explanation for the enzymatic changes observed during the combination of the NH4 Cl prepulse and NHE1 inhibition may be related to mitochondrial NHE1 inhibition, which likely negates the mitochondrial matrix acidification. This effect, combined with the increased acidity in the cytosol, would result in an enhanced H+ gradient across the mitochondrial membrane and a temporarily higher pyruvate transport into the mitochondria, thereby increasing the PDH activity at the expense of the cytosolic LDH activity. These findings demonstrate the complexity of in-cell cardiac metabolism and its dependence on intracellular acidification. This study demonstrates the capabilities and limitations of hyperpolarized [1-13 C]pyruvate in the characterization of intracellular acidification as regards cardiac pathologies.

Follow-up of liver metastases: a comparison of deep learning and RECIST 1.1.

OBJECTIVES: To compare liver metastases changes in CT assessed by radiologists using RECIST 1.1 and with aided simultaneous deep learning-based volumetric lesion changes analysis. METHODS: A total of 86 abdominal CT studies from 43 patients (prior and current scans) of abdominal CT scans of patients with 1041 liver metastases (mean = 12.1, std = 11.9, range 1-49) were analyzed. Two radiologists performed readings of all pairs; conventional with RECIST 1.1 and with computer-aided assessment. For computer-aided reading, we used a novel simultaneous multi-channel 3D R2U-Net classifier trained and validated on other scans. The reference was established by having an expert radiologist validate the computed lesion detection and segmentation. The results were then verified and modified as needed by another independent radiologist. The primary outcome measure was the disease status assessment with the conventional and the computer-aided readings with respect to the reference. RESULTS: For conventional and computer-aided reading, there was a difference in disease status classification in 40 out of 86 (46.51%) and 10 out of 86 (27.9%) CT studies with respect to the reference, respectively. Computer-aided reading improved conventional reading in 30 CT studies by 34.5% for two readers (23.2% and 46.51%) with respect to the reference standard. The main reason for the difference between the two readings was lesion volume differences (p = 0.01). CONCLUSIONS: AI-based computer-aided analysis of liver metastases may improve the accuracy of the evaluation of neoplastic liver disease status. CLINICAL RELEVANCE STATEMENT: AI may aid radiologists to improve the accuracy of evaluating changes over time in metastasis of the liver. KEY POINTS: • Classification of liver metastasis changes improved significantly in one-third of the cases with an automatically generated comprehensive lesion and lesion changes report. • Simultaneous deep learning changes detection and volumetric assessment may improve the evaluation of liver metastases temporal changes potentially improving disease management.

Deep learning for detection and 3D segmentation of maxillofacial bone lesions in cone beam CT.

OBJECTIVES: To develop an automated deep-learning algorithm for detection and 3D segmentation of incidental bone lesions in maxillofacial CBCT scans. METHODS: The dataset included 82 cone beam CT (CBCT) scans, 41 with histologically confirmed benign bone lesions (BL) and 41 control scans (without lesions), obtained using three CBCT devices with diverse imaging protocols. Lesions were marked in all axial slices by experienced maxillofacial radiologists. All cases were divided into sub-datasets: training (20,214 axial images), validation (4530 axial images), and testing (6795 axial images). A Mask-RCNN algorithm segmented the bone lesions in each axial slice. Analysis of sequential slices was used for improving the Mask-RCNN performance and classifying each CBCT scan as containing bone lesions or not. Finally, the algorithm generated 3D segmentations of the lesions and calculated their volumes. RESULTS: The algorithm correctly classified all CBCT cases as containing bone lesions or not, with an accuracy of 100%. The algorithm detected the bone lesion in axial images with high sensitivity (95.9%) and high precision (98.9%) with an average dice coefficient of 83.5%. CONCLUSIONS: The developed algorithm detected and segmented bone lesions in CBCT scans with high accuracy and may serve as a computerized tool for detecting incidental bone lesions in CBCT imaging. CLINICAL RELEVANCE: Our novel deep-learning algorithm detects incidental hypodense bone lesions in cone beam CT scans, using various imaging devices and protocols. This algorithm may reduce patients' morbidity and mortality, particularly since currently, cone beam CT interpretation is not always preformed. KEY POINTS: • A deep learning algorithm was developed for automatic detection and 3D segmentation of various maxillofacial bone lesions in CBCT scans, irrespective of the CBCT device or the scanning protocol. • The developed algorithm can detect incidental jaw lesions with high accuracy, generates a 3D segmentation of the lesion, and calculates the lesion volume.

Accumulation of 3-aminopropylphosphonate in the ex vivo brain observed by phosphorus-31 nuclear magnetic resonance.

3-aminopropylphosphonate (3-APP) is known for its use as an exogenous indicator of extracellular volume and pH in phosphorus-31 nuclear magnetic resonance (31 P NMR) studies. We used 3-APP for estimating the extracellular volume in NMR studies of several ex vivo preparations including retrograde perfused mouse heart (n = 4), mouse liver slices (n = 2), xenograft breast cancer tumors (n = 7, MCF7), and rat brain slices (n = 4). In the former three preparations, the 3-APP signal was stable in lineshape and intensity for hours and the chemical shift of the signal in the presence of the biological sample was the same as in the perfusion medium without the biological sample. However, in studies of brain slices, the 3-APP signal appeared split into two, with an upfield component (0.7 ± 0.1 ppm to the left) increasing with time and showing a wider linewidth (66.7 ± 12.6 vs. 39.1 ± 7.6 Hz, the latter is of the perfusion medium signal). This finding suggests that 3-APP inadvertently accumulated in brain slices, most likely as a membrane bound form. This observation limits the use of 3-APP as an inert biochemical indicator in brain preparations and should be taken into account when using 3-APP in vivo.

Clinical decision support system recommendations: how often do radiologists and clinicians accept them?

OBJECTIVE: To assess the acceptance and reliability of clinical decision support system (CDSS) imaging referral scores (ESR iGuide). METHODS: A pilot study was conducted in a tertiary hospital. Four different experts were invited to rate 40 simulated clinical cases on a 5-level scale, for the level of agreement with the ESR iGuide's recommended procedures. In cases of disagreement, physicians were asked to indicate the reason. Descriptive measures were calculated for the level of agreement. We also explored the degree of agreement between four different specialists, and examined the cases in which clinicians disagreed with ESR iGuide best practice recommendations. RESULTS: The mean rating of the four experts for the 40 clinical simulated cases was 4.17 ± 0.65, median 4.25 (on a scale of 1-5). All four raters totally agreed with the system recommendation in 75% of cases. No significant relationship was found between the degree of agreement and the number of indications and the patient's age or gender. In an optimistic scenario, using a binary agree/disagree variable, the Overall Percentage Agreement for the rating of the 40 simulated cases between the four experts was 77.28%. There were a total of 20 disagreements out of 160 cases with the ESR iGuide, of which 7 were among the two radiologists. CONCLUSIONS: CDSS can be an effective tool for guiding the selection of appropriate imaging examinations, thus cutting costs due to unnecessary imaging scans. Since this is a pilot study, further research on a larger scale, preferably at national level, is required. KEY POINTS: • The average of the mean rating of the four experts was 4.17 ± 0.65, median 4.25, on a scale of 1-5 where 5 represents total agreement with the CDSS tool. • In an optimistic scenario, using a binary agree/disagree variable, the Overall Percentage Agreement between the four experts was 77.28%. • Radiologists had fewer disagreements with the recommendations of the CDSS tool than other physicians, indicating a better fit of the support system to radiology experts' perspective.

Parenchymal echotexture changes as a predictor of viability in testicular torsion.

INTRODUCTION: Preoperative test that can predict the salvageability of the torsed testis may add essential information to the surgeon managing testicular torsion (TT), this can assist with patients' and parents' expectations, particularly with nonviable testes. We aimed to examine if parenchymal echotexture changes in preoperative ultrasound can predict irreversible hemorrhagic necrosis. MATERIALS AND METHODS: Preoperative ultrasound studies of 154 patients with TT were reviewed by 3 raters (2 radiologists and 1 urologist). The raters were asked to categorize the affected testicular parenchymal echotexture into one of the following categories: (1) normal (identical to the contra-lateral testis), (2) homogenous hypoechoic, or (3) focal heterogeneous echotexture. Testis non-viability was defined macroscopically during surgical exploration and correlated with the US results. Sensitivity, specificity, and positive and negative predicting values of the proposed diagnostic test were calculated. Cohen's kappa coefficient was used to determine inter-rater agreement. RESULTS: A total of 54/154 patients had a nonviable testis. Mean of 59.5% cases was classified as category 1, 27.3% cases as category 2, and 13.2% cases as category 3. Testicular necrosis was 12%, 34%, and 92% in each category, respectively. Category 3 classified non-viability with a mean specificity of 99.3% and with a high inter-rater agreement level (Cohen's kappa coefficient of 0.830). Mean positive predictive value of 97% and mean negative predictive value of 74.3%. The mean sensitivity of this test however was low 39.7%. CONCLUSION: Ultrasound finding of focal parenchymal echotexture heterogeneous changes is highly specific although not sensitive, for nonviable testis. The presence of this finding reassures non-viability in over 99%.

Feasibility and Accuracy of a Novel Hands-Free Robotic System for Percutaneous Needle Insertion and Steering.

PURPOSE: To assess the performance and accuracy of CT-guided needle insertion for clinical biopsies using a novel, hands-free robotic system that balances accuracy with the duration of the procedure and radiation dose. MATERIALS AND METHODS: A prospective, multi-center study was conducted on 60 clinically indicated biopsies of abdominal lesions at two centers (Center 1, n=26; Center 2, n=34). CT datasets were obtained for planning and controlled placement of 17g and 18g needles using a patient-mounted, CT-guided robotic system with 5 degrees of freedom. Planning included target selection, skin entry point, and predetermined checkpoints where additional imaging was performed to permit stepwise correction of the needle trajectory. Success rate, needle tip-to-target distance, number of checkpoints used, number of trajectory corrections, procedure duration, and effective radiation dose were recorded and compared between centers. RESULTS: In 55 of 60 procedures (91.7%), the robot positioned the trocar needle successfully on target. In the remaining 5 patients, the procedure was manually performed by the operator due to technical failure (n=3) or patient-related factors (n=2). The average lesion size was 2.8 ± 1.7cm with a lesion depth from the skin of 8.7 ± 2.6cm, and there was no difference between centers. The overall accuracy (needle tip-to-target distance) was 1.71 ± 1.49 (range 0.05-7.20mm), with an accuracy of 2.06 ± 1.45 mm at Center 1 and 1.45 ± 1.52 mm at Center 2 (p=0.1358). Center 1 used significantly more checkpoints (4.96 ± 1.08) and performed target adjustments in 20 of 24 (83%) cases compared to Center 2 (2.77 ± 0.6 checkpoints and target adjustments in 13 of 31 cases, 42%) (p=0.0024). Accordingly, the steering duration from skin entry to the target varied between Centers 1 and 2; 13.1min ± 4.25min vs. 5.7min ± 2.7min, respectively (p <0.001). The average DLP for the entire procedure was 1147 ± 820 mGycm, with a slightly lower average at Center 2 (1031 ± 724 mGycm) compared to Center 1 (1297 ± 925 mGycm) (p=0.236). CONCLUSION: Accurate needle-targeting within an error of 2mm can be achieved in patients using a CT-guided robotic system. The variation in the number of checkpoints did not affect system accuracy but was related to shorter steering times and may contribute to a lower radiation dose. Accurate needle insertion using a hands-free CT-guided robotic system may facilitate difficult needle placement and enhance the performance of less-experienced interventionalists.

The metabolic representation of ischemia in rat brain slices: A hyperpolarized 13 C magnetic resonance study.

The ischemic penumbra in stroke is not clearly defined by today's available imaging tools. This study aimed to develop a model system and noninvasive biomarkers of ischemic brain tissue for an examination that might potentially be performed in humans, very quickly, in the course of stroke triage. Perfused rat brain slices were used as a model system and 31 P spectroscopy verified that the slices were able to recover from an ischemic insult of about 3.5 min of perfusion arrest. This was indicated as a return to physiological pH and adenosine triphosphate levels. Instantaneous changes in lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) activities were monitored and quantified by the metabolic conversions of hyperpolarized [1-13 C]pyruvate to [1-13 C]lactate and [13 C]bicarbonate, respectively, using 13 C spectroscopy. In a control group (n = 8), hyperpolarized [1-13 C]pyruvate was administered during continuous perfusion of the slices. In the ischemia group (n = 5), the perfusion was arrested 30 s prior to administration of hyperpolarized [1-13 C]pyruvate and perfusion was not resumed throughout the measurement time (approximately 3.5 min). Following about 110 s of the ischemic insult, LDH activity increased by 80.4 ± 13.5% and PDH activity decreased by 47.8 ± 25.3%. In the control group, the mean LDH/PDH ratio was 16.6 ± 3.3, and in the ischemia group, the LDH/PDH ratio reached an average value of 38.7 ± 16.9. The results suggest that monitoring the activity of LDH and PDH, and their relative activities, using hyperpolarized [1-13 C]pyruvate, could serve as an imaging biomarker to characterize the changes in the ischemic penumbra.

Correlation between lactate dehydrogenase/pyruvate dehydrogenase activities ratio and tissue pH in the perfused mouse heart: A potential noninvasive indicator of cardiac pH provided by hyperpolarized magnetic resonance.

Cardiovascular diseases account for more than 30% of all deaths worldwide and many could be ameliorated with early diagnosis. Current cardiac imaging modalities can assess blood flow, heart anatomy and mechanical function. However, for early diagnosis and improved treatment, further functional biomarkers are needed. One such functional biomarker could be the myocardium pH. Although tissue pH is already determinable via MR techniques, and has been since the early 1990s, it remains elusive to use practically. The objective of this study was to explore the possibility to evaluate cardiac pH noninvasively, using in-cell enzymatic rates of hyperpolarized [1-13 C]pyruvate metabolism (ie, moles of product produced per unit time) determined directly in real time using magnetic resonance spectroscopy in a perfused mouse heart model. As a gold standard for tissue pH we used 31 P spectroscopy and the chemical shift of the inorganic phosphate (Pi) signal. The nonhomogenous pH distribution of the perfused heart was analyzed using a multi-parametric analysis of this signal, thus taking into account the heterogeneous nature of this characteristic. As opposed to the signal ratio of hyperpolarized [13 C]bicarbonate to [13 CO2 ], which has shown correlation to pH in other studies, we investigated here the ratio of two intracellular enzymatic rates: lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), by way of determining the production rates of [1-13 C]lactate and [13 C]bicarbonate, respectively. The enzyme activities determined here are intracellular, while the pH determined using the Pi signal may contain an extracellular component, which could not be ruled out. Nevertheless, we report a strong correlation between the tissue pH and the LDH/PDH activities ratio. This work may pave the way for using the LDH/PDH activities ratio as an indicator of cardiac intracellular pH in vivo, in an MRI examination.

An international expert opinion statement on the utility of PET/MR for imaging of skeletal metastases.

BACKGROUND: MR is an important imaging modality for evaluating musculoskeletal malignancies owing to its high soft tissue contrast and its ability to acquire multiparametric information. PET provides quantitative molecular and physiologic information and is a critical tool in the diagnosis and staging of several malignancies. PET/MR, which can take advantage of its constituent modalities, is uniquely suited for evaluating skeletal metastases. We reviewed the current evidence of PET/MR in assessing for skeletal metastases and provided recommendations for its use. METHODS: We searched for the peer reviewed literature related to the usage of PET/MR in the settings of osseous metastases. In addition, expert opinions, practices, and protocols of major research institutions performing research on PET/MR of skeletal metastases were considered. RESULTS: Peer-reviewed published literature was included. Nuclear medicine and radiology experts, including those from 13 major PET/MR centers, shared the gained expertise on PET/MR use for evaluating skeletal metastases and contributed to a consensus expert opinion statement. [18F]-FDG and non [18F]-FDG PET/MR may provide key advantages over PET/CT in the evaluation for osseous metastases in several primary malignancies. CONCLUSION: PET/MR should be considered for staging of malignancies where there is a high likelihood of osseous metastatic disease based on the characteristics of the primary malignancy, hight clinical suspicious and in case, where the presence of osseous metastases will have an impact on patient management. Appropriate choice of tumor-specific radiopharmaceuticals, as well as stringent adherence to PET and MR protocols, should be employed.

CT severity indices derived from low monoenergetic images at dual-energy CT may improve prediction of outcome in acute pancreatitis.

OBJECTIVES: To determine whether imaging features and severity indices using low monoenergetic DECT images improve diagnostic conspicuity and outcome prediction in acute pancreatitis compared to conventional images. METHODS: A retrospective study of patients with clinical and radiographic signs of acute pancreatitis who underwent 50 contrast-enhanced CT exams conducted on a single-source DECT was performed. Representative conventional and 50 keV-monoenergetic images were randomized and presented to four abdominal radiologists to determine preferred imaging for detecting fat stranding and parenchymal inflammation. Contrast and signal-to-noise ratios were constructed for necrotic, hypoattenuated, inflamed, and healthy parenchyma. These parameters and the CT severity index (CTSI) were compared between conventional and low monoenergetic images using paired t tests and correlated to clinical outcome. RESULTS: Although preference for conventional images was noted for subtle peri-pancreatic fat stranding (169/200 (85%) reads), there was clear preference for low monoenergetic images among all readers for pancreatic inflammation evaluation (188/200 (94%) reads). Moreover, identification of small, hypoattenuating inflammatory foci on monoenergetic images alone in 13/50 (26%) cases resulted in upstaged CTSI from mild to moderate in 7/50 (14%), associated with longer hospitalization (16 ± 17 days vs. 5 ± 2 days; p < 0.05), ICU admission, and drainage. Quantitatively, a twofold difference between normal and inflamed parenchyma attenuation was identified for monoenergetic (44.8 ± 27.6) vs. conventional (25.1 ± 14.7) images (p < 0.05). Significant increases were seen in the monoenergetic SNR and CNR compared to the conventional images (p < 0.05). CONCLUSIONS: DECT low monoenergetic images afford better tissue assessment and demarcation of inflamed pancreatic parenchyma. Additionally, they provide improved characterization of the extent parenchymal necrosis, enabling better classification that may better predict severe clinical outcomes. KEY POINTS: • DECT low monoenergetic images afford better tissue assessment and demarcation of inflamed pancreatic parenchyma and provide improved characterization of the extent parenchymal necrosis. • Qualitatively, low monoenergetic images were preferred over conventional DECT images for the evaluation of pancreatic inflammation; and quantitatively, there is a twofold difference between normal and inflamed parenchyma attenuation, SNR, and CNR between monoenergetic vs. conventional images. • Monoenergetic imaging identified additional small, hypoattenuating inflammatory foci in 26% resulting in an upstaged CT severity index in 14% associated with longer hospitalization, ICU admission, and drainage, thereby enabling better classification and better prediction of severe clinical outcomes.

An International Survey of Quality and Safety Programs in Radiology.

PURPOSE: The aim of this study was to determine the status of radiology quality improvement programs in a variety of selected nations worldwide. METHODS: A survey was developed by select members of the International Economics Committee of the American College of Radiology on quality programs and was distributed to committee members. Members responded on behalf of their country. The 51-question survey asked about 12 different quality initiatives which were grouped into 4 themes: departments, users, equipment, and outcomes. Respondents reported whether a designated type of quality initiative was used in their country and answered subsequent questions further characterizing it. RESULTS: The response rate was 100% and represented Australia, Canada, China, England, France, Germany, India, Israel, Japan, the Netherlands, Russia, and the United States. The most frequently reported quality initiatives were imaging appropriateness (91.7%) and disease registries (91.7%), followed by key performance indicators (83.3%) and morbidity and mortality rounds (83.3%). Peer review, equipment accreditation, radiation dose monitoring, and structured reporting were reported by 75.0% of respondents, followed by 58.3% of respondents for quality audits and critical incident reporting. The least frequently reported initiatives included Lean/Kaizen exercises and physician performance assessments, implemented by 25.0% of respondents. CONCLUSION: There is considerable diversity in the quality programs used throughout the world, despite some influence by national and international organizations, from whom further guidance could increase uniformity and optimize patient care in radiology.

Hyperpolarized product selective saturating-excitations for determination of changes in metabolic reaction rates in real-time.

Investigation of hyperpolarized substrate metabolism has been showing utility in real-time determination of in-cell and in vivo enzymatic activities. Intracellular reaction rates may vary during the course of a measurement, even on the very short time scales of visibility on hyperpolarized MR, due to many factors such as the availability of the substrate and co-factors in the intracellular space. Despite this potential variation, the kinetic analysis of hyperpolarized signals typically assumes that the same rate constant (and in many cases, the same rate) applies throughout the course of the reaction as observed via the build-up and decay of the hyperpolarized signals. We demonstrate here an acquisition approach that can null the need for such an assumption and enable the detection of instantaneous changes in the rate of the reaction during an ex vivo hyperpolarized investigation, (i.e. in the course of the decay of one hyperpolarized substrate dose administered to a viable tissue sample ex vivo). This approach utilizes hyperpolarized product selective saturating-excitation pulses. Similar pulses have been previously utilized in vivo for spectroscopic imaging. However, we show here favorable consequences to kinetic rate determinations in the preparations used. We implement this acquisition strategy for studies on perfused tissue slices and develop a theory that explains why this particular approach enables the determination of changes in enzymatic rates that are monitored via the chemical conversions of hyperpolarized substrates. Real-time changes in intracellular reaction rates are demonstrated in perfused brain, liver, and xenograft breast cancer tissue slices and provide another potential differentiation parameter for tissue characterization.

The Effect of Gadolinium Doping in [13 C6 ,2 H7 ]Glucose Formulations on 13 C Dynamic Nuclear Polarization at 3.35†T.

The promise of hyperpolarized glucose as a non-radioactive imaging agent capable of reporting on multiple metabolic routes has led to recent advances in its dissolution-DNP (dDNP) driven polarization using UV-light induced radicals and trityl radicals at high field (6.7 T) and 1.1 K. However, most preclinical dDNP polarizers operate at the field of 3.35 T and 1.4-1.5 K. Minute amounts of Gd3+ complexes have shown large improvements in solid-state polarization, which can be translated to improved hyperpolarization in solution. However, this Gd3+ effect seems to depend on magnetic field strength, metal ion concentration, and sample formulation. The effect of varying Gd3+ concentrations at 3.35 T has been described for 13 C-labeled pyruvic acid and acetate. However, it has not been studied for other compounds at this field. The results presented here suggest that Gd3+ doping can lead to various concentration and temperature dependent effects on the polarization of [13 C6 ,2 H7 ]glucose, not necessarily similar to the effects observed in pyruvic acid or acetate in size or direction. The maximal polarization for [13 C6 ,2 H7 ]glucose appears to be at a Gd3+ concentration of 2 mM, when irradiating for more than 2 h at the negative maximum of the DNP intensity profile. Surprisingly, for shorter irradiation times, higher polarization levels were determined at 1.50 K compared to 1.45 K, at a [Gd3+ ]=1.3 mM. This was explained by the build-up time constant and maximum at these temperatures.

Clinical and Radiologic Characteristics of Intra-Abdominal Fistulizing Crohn's Disease.

BACKGROUND: Few studies describe the radiological and laboratory characteristics of patients with Crohn's disease (CD) with intra-abdominal fistulae. OBJECTIVES: We aimed to describe a cohort of CD patients with intra-abdominal fistulae and determine characteristics associated with complex fistulae. METHODS: Data were gathered from medical records and imaging studies of patients. Evaluation included type of fistula, number of fistulae, and radiological characteristics. RESULTS: A total of 205 fistulae in 132 patients were identified with an average patient age of 31 (±12) years. The average time from CD diagnosis to fistula development was 7 years. The most common type of fistula was entero-enteric (53%). Patients with an extra-intestinal fistula presented with an average of 1.96 fistulae, compared with an average of 1.28 fistulae for those with a fistula limited to the bowel (p =0.01). Except for the number of fistula no other significant differences were observed in radiological characteristics of patients who were diagnosed with a fistula at time of CD diagnosis compared to those diagnosed with a fistula later. CONCLUSIONS: The most common CD-associated intra-abdominal fistulae are entero-enteric and entero-colonic fistulae. An extra-intestinal fistula and diagnosis of a fistula subsequent to diagnosis of CD were associated with an increased number of fistulae per patient.

Real-time ALT and LDH activities determined in viable precision-cut mouse liver slices using hyperpolarized [1-13 C]pyruvate-Implications for studies on biopsied liver tissues.

Precision-cut liver slices (PCLS) are widely used in liver research as they provide a liver model with all liver cell types in their natural architecture. The purpose of this study was to demonstrate the use of PCLS for hyperpolarized metabolic investigation in a mouse model, for potential future application in liver biopsy cores. Fresh normal liver was harvested from six mice. 500 µm PCLS were prepared and placed in a 10 mm NMR tube in an NMR spectrometer and perfused continuously. 31 P spectra were acquired to evaluate the presence of adenosine triphosphate (ATP) and validate viability in all samples. Hyperpolarized [1-13 C]pyruvate was flushed into the NMR tube in the spectrometer. Consecutive 13 C NMR spectra were acquired immediately after the injection using both non-selective (five injections, two livers) and selective RF excitation (six injections, three livers). The 31 P spectra showed the characteristic signals of ATP, confirming the viability of the PCLS for more than 2.5 h in the spectrometer. After each of the [1-13 C]pyruvate injections, both [1-13 C]lactate and [1-13 C]alanine signals were detected. Selective RF excitation aimed at both [1-13 C]lactate and [1-13 C]alanine enabled better visualization and quantification of the metabolic activity. Using this acquisition approach only the newly formed metabolites are observed upon excitation, and their intensities relative to those of hyperpolarized pyruvate enable quantification of metabolite production rates. This rate of lactate and alanine production appeared to be constant throughout the measurement time, with alanine production about 2.3 times higher than lactate. In summary, the viability of PCLS in an NMR spectrometer was demonstrated and hyperpolarized [1-13 C]pyruvate metabolism was recorded. This study opens up the possibility of evaluating alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities in human liver biopsies, while preserving the tissue architecture and viability. In healthy, well-perfused liver slices the ratio of ALT to LDH activity is about 2.3.

In-cell determination of Lactate Dehydrogenase Activity in a Luminal Breast Cancer Model ⁻ ex vivo Investigation of Excised Xenograft Tumor Slices Using dDNP Hyperpolarized [1-13C]pyruvate.

[1-13C]pyruvate, the most widely used compound in dissolution-dynamic nuclear polarization (dDNP) magnetic resonance (MR), enables the visualization of lactate dehydrogenase (LDH) activity. This activity had been demonstrated in a wide variety of cancer models, ranging from cultured cells, to xenograft models, to human tumors in situ. Here we quantified the LDH activity in precision cut tumor slices (PCTS) of breast cancer xenografts. The Michigan Cancer Foundation-7 (MCF7) cell-line was chosen as a model for the luminal breast cancer type which is hormone responsive and is highly prevalent. The LDH activity, which was manifested as [1-13C]lactate production in the tumor slices, ranged between 3.8 and 6.1 nmole/nmole adenosine tri-phosphate (ATP) in 1 min (average 4.6 ± 1.0) on three different experimental set-ups consisting of arrested vs. continuous perfusion and non-selective and selective RF pulsation schemes and combinations thereof. This rate was converted to an expected LDH activity in a mass ranging between 3.3 and 5.2 µmole/g in 1 min, using the ATP level of these tumors. This indicated the likely utility of this approach in clinical dDNP of the human breast and may be useful as guidance for treatment response assessment in a large number of tumor types and therapies ex vivo.

Long-lived 15 N Hyperpolarization and Rapid Relaxation as a Potential Basis for Repeated First Pass Perfusion Imaging - Marked Effects of Deuteration and Temperature.

Deuteration of the exchangeable hydrogens of [15 N2 ]urea was found to prolong the T1 of the 15 N sites to more than 3 min at physiological temperatures. This significant increase in the lifetime of the hyperpolarized state of [15 N2 ]urea, compared to [13 C]urea - a pre-clinically proven perfusion agent, makes [15 N2 ]urea a promising perfusion agent. The molecular parameters that may lead to this profound effect were assessed by investigating small molecules with different molecular structures containing 15 N sites bound to labile protons and determining the hyperpolarized 15 N T1 in H2 O and D2 O. Dissolution in D2 O led to marked prolongation for all of the selected sites. In whole human blood, the T1 of [15 N2 ]urea was shortened. We present a general strategy for exploiting the markedly longer T1 outside the body and the quick decay in blood for performing multiple hyperpolarized perfusion measurements with a single hyperpolarized dose. Improved storage of the generated [15 N2 ]urea polarization prior to the contact with the blood is demonstrated using higher temperatures due to further T1 prolongation.