The Role of 89Zr-Immuno-PET in Navigating and Derisking the Development of Biopharmaceuticals.

The identification of molecular drivers of disease and the compelling rise of biotherapeutics have impacted clinical care but have also come with challenges. Such therapeutics include peptides, monoclonal antibodies, antibody fragments and nontraditional binding scaffolds, activatable antibodies, bispecific antibodies, immunocytokines, antibody-drug conjugates, enzymes, polynucleotides, and therapeutic cells, as well as alternative drug carriers such as nanoparticles. Drug development is expensive, attrition rates are high, and efficacy rates are lower than desired. Almost all these drugs, which in general have a long residence time in the body, can stably be labeled with 89Zr for whole-body PET imaging and quantification. Although not restricted to monoclonal antibodies, this approach is called 89Zr-immuno-PET. This review summarizes the state of the art of the technical aspects of 89Zr-immuno-PET and illustrates why it has potential for steering the design, development, and application of biologic drugs. Appealing showcases are discussed to illustrate what can be learned with this emerging technology during preclinical and especially clinical studies about biologic drug formats and disease targets. In addition, an overview of ongoing and completed clinical trials is provided. Although 89Zr-immuno-PET is a young tool in drug development, its application is rapidly expanding, with first clinical experiences giving insight on why certain drug-target combinations might have better perspectives than others.

Incremental prognostic value of hybrid [15O]H2O positron emission tomography-computed tomography: combining myocardial blood flow, coronary stenosis severity, and high-risk plaque morphology.

AIMS: This study sought to determine the prognostic value of combined functional testing using positron emission tomography (PET) perfusion imaging and anatomical testing using coronary computed tomography angiography (CCTA)-derived stenosis severity and plaque morphology in patients with suspected coronary artery disease (CAD). METHODS AND RESULTS: In this retrospective study, 539 patients referred for hybrid [15O]H2O PET-CT imaging because of suspected CAD were investigated. PET was used to determine myocardial blood flow (MBF), whereas CCTA images were evaluated for obstructive stenoses and high-risk plaque (HRP) morphology. Patients were followed up for the occurrence of all-cause death and non-fatal myocardial infarction (MI). During a median follow-up of 6.8 (interquartile range 4.8-7.8) years, 42 (7.8%) patients experienced events, including 23 (4.3%) deaths, and 19 (3.5%) MIs. Annualized event rates for normal vs. abnormal results of PET MBF, CCTA-derived stenosis, and HRP morphology were 0.6 vs. 2.1%, 0.4 vs. 2.1%, and 0.8 vs. 2.8%, respectively (P < 0.001 for all). Cox regression analysis demonstrated prognostic values of PET perfusion imaging [hazard ratio (HR) 3.75 (1.84-7.63), P < 0.001], CCTA-derived stenosis [HR 5.61 (2.36-13.34), P < 0.001], and HRPs [HR 3.37 (1.83-6.18), P < 0.001] for the occurrence of death or MI. However, only stenosis severity [HR 3.01 (1.06-8.54), P = 0.039] and HRPs [HR 1.93 (1.00-3.71), P = 0.049] remained independently associated. CONCLUSION: PET-derived MBF, CCTA-derived stenosis severity, and HRP morphology were univariably associated with death and MI, whereas only stenosis severity and HRP morphology provided independent prognostic value.

Diagnostic Value of Transluminal Attenuation Gradient for the Presence of Ischemia as Defined by Fractional Flow Reserve and Quantitative Positron Emission Tomography.

OBJECTIVES: The aim of this study was to investigate the incremental diagnostic value of transluminal attenuation gradient (TAG), TAG with corrected contrast opacification (TAG-CCO), and transluminal diameter gradient (TDG) over coronary computed tomography angiography (CTA)-derived diameter stenosis alone for the identification of ischemia as defined by both the invasive reference standard fractional flow reserve (FFR) and the noninvasive reference standard quantitative positron emission tomography (PET). BACKGROUND: In addition to anatomic information obtained by coronary CTA, several functional CT parameters have been proposed to identify hemodynamically significant lesions more accurately, such as TAG, TAG-CCO, and more recently TDG. However, clinical validation studies have reported conflicting results, and a recent study has suggested that TAG may be affected by changes in vessel diameter. METHODS: Patients with suspected coronary artery disease underwent coronary CTA and [15O]H2O PET followed by invasive coronary angiography with FFR of all major coronary arteries. TAG, TAG-CCO, and TDG were assessed, and the incremental diagnostic value of these parameters over coronary CTA-derived diameter stenosis alone for ischemia as defined by PET (hyperemic myocardial blood flow ≤2.30 ml/min/g) and FFR (≤0.80) was determined. RESULTS: A total of 557 (91.9%) coronary arteries of 201 patients were included for analysis. TAG, TAG-CCO, and TDG did not discriminate between vessels with or without ischemia as defined by either PET or FFR. Furthermore, these parameters did not have incremental diagnostic accuracy over coronary CTA alone for the presence of ischemia as defined by PET and FFR. There was a significant correlation between TDG and TAG (r = 0.47; p < 0.001) and between TDG and TAG-CCO (r = 0.37; p < 0.001). CONCLUSIONS: TAG, TAG-CCO, and TDG do not provide incremental diagnostic value over coronary CTA alone for the presence of ischemia as defined by [15O]H2O PET and/or FFR. The lack of diagnostic value of contrast enhancement-based flow estimations appears related to coronary luminal dimension variability.

Predictive value of targeted proteomics for coronary plaque morphology in patients with suspected coronary artery disease.

BACKGROUND: Risk stratification is crucial to improve tailored therapy in patients with suspected coronary artery disease (CAD). This study investigated the ability of targeted proteomics to predict presence of high-risk plaque or absence of coronary atherosclerosis in patients with suspected CAD, defined by coronary computed tomography angiography (CCTA). METHODS: Patients with suspected CAD (n = 203) underwent CCTA. Plasma levels of 358 proteins were used to generate machine learning models for the presence of CCTA-defined high-risk plaques or complete absence of coronary atherosclerosis. Performance was tested against a clinical model containing generally available clinical characteristics and conventional biomarkers. FINDINGS: A total of 196 patients with analyzable protein levels (n = 332) was included for analysis. A subset of 35 proteins was identified predicting the presence of high-risk plaques. The developed machine learning model had fair diagnostic performance with an area under the curve (AUC) of 0·79 ±â€¯0·01, outperforming prediction with generally available clinical characteristics (AUC = 0·65 ±â€¯0·04, p < 0·05). Conversely, a different subset of 34 proteins was predictive for the absence of CAD (AUC = 0·85 ±â€¯0·05), again outperforming prediction with generally available characteristics (AUC = 0·70 ±â€¯0·04, p < 0·05). INTERPRETATION: Using machine learning models, trained on targeted proteomics, we defined two complementary protein signatures: one for identification of patients with high-risk plaques and one for identification of patients with absence of CAD. Both biomarker subsets were superior to generally available clinical characteristics and conventional biomarkers in predicting presence of high-risk plaque or absence of coronary atherosclerosis. These promising findings warrant external validation of the value of targeted proteomics to identify cardiovascular risk in outcome studies. FUND: This study was supported by an unrestricted research grant from HeartFlow Inc. and partly supported by a European Research Area Network on Cardiovascular Diseases (ERA-CVD) grant (ERA CVD JTC2017, OPERATION). Funders had no influence on trial design, data evaluation, and interpretation.

Comparison of Coronary CT Angiography, SPECT, PET, and Hybrid Imaging for Diagnosis of Ischemic Heart Disease Determined by Fractional Flow Reserve.

Importance: At present, the choice of noninvasive testing for a diagnosis of significant coronary artery disease (CAD) is ambiguous, but nuclear myocardial perfusion imaging with single-photon emission tomography (SPECT) or positron emission tomography (PET) and coronary computed tomography angiography (CCTA) is predominantly used for this purpose. However, to date, prospective head-to-head studies are lacking regarding the diagnostic accuracy of these imaging modalities. Furthermore, the combination of anatomical and functional assessments configuring a hybrid approach may yield improved accuracy. Objectives: To establish the diagnostic accuracy of CCTA, SPECT, and PET and explore the incremental value of hybrid imaging compared with fractional flow reserve. Design, Setting, and Participants: A prospective clinical study involving 208 patients with suspected CAD who underwent CCTA, technetium 99m/tetrofosmin-labeled SPECT, and [15O]H2O PET with examination of all coronary arteries by fractional flow reserve was performed from January 23, 2012, to October 25, 2014. Scans were interpreted by core laboratories on an intention-to-diagnose basis. Hybrid images were generated in case of abnormal noninvasive anatomical or functional test results. Main Outcomes and Measures: Hemodynamically significant stenosis in at least 1 coronary artery as indicated by a fractional flow reserve of 0.80 or less and relative diagnostic accuracy of SPECT, PET, and CCTA in detecting hemodynamically significant CAD. Results: Of the 208 patients in the study (76 women and 132 men; mean [SD] age, 58 [9] years), 92 (44.2%) had significant CAD (fractional flow reserve ≤0.80). Sensitivity was 90% (95% CI, 82%-95%) for CCTA, 57% (95% CI, 46%-67%) for SPECT, and 87% (95% CI, 78%-93%) for PET, whereas specificity was 60% (95% CI, 51%-69%) for CCTA, 94% (95% CI, 88%-98%) for SPECT, and 84% (95% CI, 75%-89%) for PET. Single-photon emission tomography was found to be noninferior to PET in terms of specificity (P < .001) but not in terms of sensitivity (P > .99) using the predefined absolute margin of 10%. Diagnostic accuracy was highest for PET (85%; 95% CI, 80%-90%) compared with that of CCTA (74%; 95% CI, 67%-79%; P = .003) and SPECT (77%; 95% CI, 71%-83%; P = .02). Diagnostic accuracy was not enhanced by either hybrid SPECT and CCTA (76%; 95% CI, 70%-82%; P = .75) or by PET and CCTA (84%; 95% CI, 79%-89%; P = .82), but resulted in an increase in specificity (P = .004) at the cost of a decrease in sensitivity (P = .001). Conclusions and Relevance: This controlled clinical head-to-head comparative study revealed PET to exhibit the highest accuracy for diagnosis of myocardial ischemia. Furthermore, a combined anatomical and functional assessment does not add incremental diagnostic value but guides clinical decision-making in an unsalutary fashion.

MR and CT imaging characteristics and ablation zone volumetry of locally advanced pancreatic cancer treated with irreversible electroporation.

OBJECTIVES: To assess specific imaging characteristics after irreversible electroporation (IRE) for locally advanced pancreatic carcinoma (LAPC) with contrast-enhanced (ce)MRI and ceCT, and to explore the correlation of these characteristics with the development of recurrence. METHODS: Qualitative and quantitative analyses of imaging data were performed on 25 patients treated with percutaneous IRE for LAPC. Imaging characteristics of the ablation zone on ceCT and ceMRI were assessed over a 6-month follow-up period. Contrast ratio scores between pre- and post-treatment were compared. To detect early imaging markers for treatment failure, attenuation characteristics at 6 weeks were linked to the area of recurrence within 6 months. RESULTS: Post-IRE, diffusion-weighted imaging (DWI)-b800 signal intensities decreased in all cases (p < 0.05). Both ceMRI and ceCT revealed absent or decreased contrast enhancement, with a hyperintense rim on ceMRI. Ablation zone volume increase was noted on both modalities in the first 6 weeks, followed by a decrease (p < 0.05). In the patients developing tumour recurrence (5/25), a focal DWI-b800 hyperintense spot at 6 weeks predated unequivocal recurrence on CT. CONCLUSION: The most remarkable signal alterations after pancreatic IRE were shown by DWI-b800 and ceMRI. These early imaging characteristics may be useful to establish technical success and predict treatment outcome. KEY POINTS: • This study describes imaging characteristics after irreversible electroporation (IRE) for pancreatic adenocarcinoma. • Familiarity with typical post-IRE imaging characteristics helps to interpret ablation zones. • Post-IRE, no central and variable rim enhancement are visible on contrast-enhanced imaging. • DWI-b800 may prove useful to predict early tumour recurrence. • Post-IRE examinations reveal an initial volume increase followed by a decrease.

Ablation of Locally Advanced Pancreatic Cancer with Percutaneous Irreversible Electroporation: Results of the Phase I/II PANFIRE Study.

Purpose To (a) investigate the safety of percutaneous irreversible electroporation (IRE) for locally advanced pancreatic cancer and (b) evaluate the quality of life (QOL), pain perception, and efficacy in terms of time to local progression, event-free survival, and overall survival (OS). Materials and Methods The study was approved by the local review board (NL42888.029.13). All patients provided written informed consent for study participation, the ablation procedure, and data usage. Between January 2014 and June 2015, 25 patients with histologically proved locally advanced pancreatic cancer 5 cm or smaller (13 women, 12 men; median age, 61 years; age range, 41-78 years) were prospectively included to undergo percutaneous computed tomographic-guided IRE. Patients with a metallic biliary Wallstent, epilepsy, or ventricular arrhythmias were excluded. Kaplan-Meier estimates were used to investigate time to local progression, event-free survival, and OS. Safety was assessed on the basis of adverse events, which were graded according to the Common Terminology Criteria for Adverse Events. Pain perception and QOL were evaluated by using specific questionnaires. Results All patients underwent IRE. The median largest tumor diameter was 4.0 cm (range, 3.3-5.0 cm). After a median follow-up of 12 months (interquartile range: 7-16 months), median event-free survival after IRE was 8 months (95% confidence interval [CI]: 4 months, 12 months); the median time to local progression after IRE was 12 months (95% CI: 8 months, 16 months). The median OS was 11 months from IRE (95% CI: 9 months, 13 months) and 17 months from diagnosis (95% CI: 10 months, 24 months). There were 12 minor complications (grade I or II) and 11 major complications (nine grade III, two grade IV) in 10 patients. There were no deaths within 90 days after IRE. Conclusion Percutaneous IRE for locally advanced pancreatic cancer is generally well tolerated, although major adverse events can occur. Preliminary survival data are encouraging and support the setup of larger phase II and III clinical trials to assess the efficacy of IRE plus chemotherapy in the neoadjuvant and adjuvant or second-line setting compared with more widely adopted regimens such as chemotherapy and/or radiation therapy. © RSNA, 2016 Online supplemental material is available for this article.

MWA Versus RFA for Perivascular and Peribiliary CRLM: A Retrospective Patient- and Lesion-Based Analysis of Two Historical Cohorts.

PURPOSE: To retrospectively analyse the safety and efficacy of radiofrequency ablation (RFA) versus microwave ablation (MWA) in the treatment of unresectable colorectal liver metastases (CRLM) in proximity to large vessels and/or major bile ducts. METHOD AND MATERIALS: A database search was performed to include patients with unresectable histologically proven and/or (18)F-FDG-PET avid CRLM who were treated with RFA or MWA between January 2001 and September 2014 in a single centre. All lesions that were considered to have a peribiliary and/or perivascular location were included. Univariate logistic regression analysis was performed to assess the distribution of patient, tumour and procedure characteristics. Multivariate logistic regression was used to correct for potential confounders. RESULTS: Two hundred and forty-three patients with 774 unresectable CRLM were ablated. One hundred and twenty-two patients (78 males; 44 females) had at least one perivascular or peribiliary lesion (n = 199). Primary efficacy rate of RFA was superior to MWA after 3 and 12 months of follow-up (P = 0.010 and P = 0.022); however, after multivariate analysis this difference was non-significant at 12 months (P = 0.078) and vanished after repeat ablations (P = 0.39). More CTCAE grade III complications occurred after MWA versus RFA (18.8 vs. 7.9 %; P = 0.094); biliary complications were especially common after peribiliary MWA (P = 0.002). CONCLUSION: For perivascular CRLM, RFA and MWA are both safe treatment options that appear equally effective. For peribiliary CRLM, MWA has a higher complication rate than RFA, with similar efficacy. Based on these results, it is advised to use RFA for lesions in the proximity of major bile ducts.

Colorectal liver metastatic disease: efficacy of irreversible electroporation--a single-arm phase II clinical trial (COLDFIRE-2 trial).

BACKGROUND: Irreversible electroporation (IRE) is a novel image-guided tumor ablation technique that has shown promise for the ablation of lesions in proximity to vital structures such as blood vessels and bile ducts. The primary aim of the COLDFIRE-2 trial is to investigate the efficacy of IRE for unresectable, centrally located colorectal liver metastases (CRLM). Secondary outcomes are safety, technical success, and the accuracy of contrast-enhanced (ce)CT and (18)F-FDG PET-CT in the detection of local tumor progression (LTP). METHODS/DESIGN: In this single-arm, multicenter phase II clinical trial, twenty-nine patients with (18)F-FDG PET-avid CRLM ≤ 3,5 cm will be prospectively included to undergo IRE of the respective lesion. All lesions must be unresectable and unsuitable for thermal ablation due to vicinity of vital structures. Technical success is based on ceMRI one day post-IRE. All complications related to the IRE procedure are registered. Follow-up consists of (18)F-FDG PET-CT and 4-phase liver CT at 3-monthly intervals during the first year of follow-up. Treatment efficacy is defined as the percentage of tumors successfully eradicated 12 months after the initial IRE procedure based on clinical follow-up using both imaging modalities, tumor marker and (if available) histopathology. To determine the accuracy of (18)F-FDG PET-CT and ceCT, both imaging modalities will be individually scored by two reviewers that are blinded for the final oncologic outcome. DISCUSSION: To date, patients with a central CRLM unsuitable for resection or thermal ablation have no curative treatment option and are given palliative chemotherapy. For these patients, IRE may prove a life-saving treatment option. The results of the proposed trial may represent an important step towards the implementation of IRE for central liver tumors in the clinical setting. TRIAL REGISTRATION NUMBER: NCT02082782.

Subclinical synovitis detected by macrophage PET, but not MRI, is related to short-term flare of clinical disease activity in early RA patients: an exploratory study.

INTRODUCTION: Residual subclinical synovitis can still be present in joints of rheumatoid arthritis (RA) patients despite clinical remission and has been linked to ongoing radiological damage. The aim of the present study was to assess subclinical synovitis by positron emission tomography (PET; macrophage tracer (11)C-(R)-PK11195) in early RA patients with minimal disease activity without clinically apparent synovitis (MDA); and its relationship with clinical outcome and magnetic resonance imaging (MRI), respectively. METHODS: Baseline PET and MRI of hands/wrists were performed in 25 early MDA RA patients (DAS 44 < 1.6; no tender/swollen joints) on combined DMARD therapy. PET tracer uptake (semi-quantitative score: 0-3) and MRI synovitis and bone marrow edema (OMERACT RAMRIS) were assessed in MCP, PIP and wrist joints (22 joints/patient; cumulative score). RESULTS: Eleven of 25 patients (44 %) showed enhanced tracer uptake in ≥ 1 joint. Fourteen of these 25 (56 %) patients developed a flare within 1 year: 8/11 (73 %) with a positive, and 6/14 (43 %) with a negative PET. In the latter, in 5/6 patients flare was located outside the scan region. Median cumulative PET scores of patients with a subsequent flare in the hands or wrists were significantly higher than those of patients without a flare (1.5 [IQR 0.8-5.3] vs 0.0 [IQR 0.0-1.0], p = 0.04); significance was lost when all flares were considered (1.0 [IQR 0.0-4.0] vs 0.0 [IQR 0.0-1.0], p = 0.10). No difference in cumulative MRI scores was observed between both groups. CONCLUSIONS: Positive PET scans were found in almost half of early RA patients with MDA. Patients with a subsequent flare in hand or wrist had higher cumulative PET scores but not MRI scores, suggesting that subclinical arthritis on PET may predict clinical flare in follow-up.

WARRIOR-trial - is routine radiography following the 2-week initial follow-up in trauma patients with wrist and ankle fractures necessary: study protocol for a randomized controlled trial.

BACKGROUND: Extremity fractures such as wrist and ankle fractures are a common and costly healthcare problem. The management of these fractures depends on fracture type and loss of congruity of the joint, resulting in cast immobilization or operative treatment. Loss of congruity or displacement leading to uneven joint loading, osteoarthritis and an increased probability of a poor functional outcome should be identified within the first 2 weeks post-trauma, based upon radiographs to determine optimal treatment. After this period, routine radiographs are scheduled for monitoring the bone-healing process. Current protocols describe imaging at 1, 2, 6 and 12 weeks post-trauma. However, it is questionable whether routine radiography following the initial follow-up ( 2-weeks post-trauma) is cost effective. The aim of this study is to determine whether a modification of the radiographic follow-up protocol can be conducted with no worse outcome and less cost than the current standard of care for patients with a wrist or ankle fracture. METHODS/DESIGN: In a multicenter randomized controlled trial, 697 patients aged 18 years or older will be included: 385 wrist fracture- and 312 ankle fracture patients. Patients will be randomized into two groups: Group 1 receives usual care, consisting of radiographs 1, 2, 6 and 12 weeks post-trauma; Group 2 receives radiographs beyond the initial follow-up only when clinically indicated. The primary outcome is the overall extremity-specific function. For wrist fractures, this includes the Disabilities of the Arm, Shoulder and Hand Score; for the ankle fractures, this includes the Olerud and Molander ankle score. Secondary outcomes include: healthcare cost, the specific function measured with the Patient Rated Wrist and Hand Evaluation for wrist fractures and American Academy of Orthopaedic Surgeons foot and ankle questionnaire for ankle fractures, pain-intensity, health-related quality of life, self-perceived recovery, and complications. Both groups will be monitored at 1, 2, and 6 weeks and 3, 6, and 12 months. DISCUSSION: This study will provide data on (cost) effectiveness of routine radiography in the follow-up of wrist and ankle fractures, and could pave the way for a change in (inter)national protocols. TRIAL REGISTRATION: Netherlands Trial Register NTR4610 , registration date 22 June 2014.

Detection of subclinical synovitis with macrophage targeting and positron emission tomography in patients with rheumatoid arthritis without clinical arthritis.

OBJECTIVE: To determine whether macrophage targeting by (R)-11C-PK11195 positron emission tomography (PET) can visualize subclinical joint inflammation in patients with rheumatoid arthritis (RA) without clinical arthritis during or after treatment, with flare as clinical outcome measure. METHODS: (R)-11C-PK11195 PET and contrast-enhanced magnetic resonance imaging (MRI) of hands/wrists were performed in 29 patients with RA without clinical arthritis. (R)-11C-PK11195 PET uptake (semiquantitative score 0-3) in metacarpophalangeal, proximal interphalangeal, and wrist joints (i.e., 22 joints per patient) was scored and summed to obtain a cumulative PET score (range 0-66). Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) was performed on similar joints. Synovitis and bone marrow edema scores (>1) were summed to obtain a cumulative MRI score (range 0-288). Occurrence of flare was determined during 3-year followup. RESULTS: Flare was observed in 17/29 patients (59%). (R)-11C-PK11195 PET showed enhanced tracer uptake in 16/29 patients (55%), of which 11 (69%) developed a flare. Highest cumulative PET scores (>6, n=3) corresponded with highest cumulative MRI scores (>39) and were related to development of flare in hands/wrists within 6 months. Cumulative PET scores of patients developing a flare were higher than those of patients without a flare [median (interquartile range) 2 (0-4.5) vs 0 (0-1), p<0.05]. In contrast, no significant differences were found between cumulative MRI scores of patients with and without a flare. CONCLUSION: (R)-11C-PK11195 PET showed enhanced uptake, pointing to presence of subclinical synovitis in over half of patients without clinical arthritis. (R)-11C-PK11195 PET may be of value for prediction of exacerbation of RA, since cumulative PET scores > 1 were associated with development of flare within 3 years.

Irreversible electroporation for nonthermal tumor ablation in the clinical setting: a systematic review of safety and efficacy.

PURPOSE: To provide an overview of current clinical results of irreversible electroporation (IRE), a novel, nonthermal tumor ablation technique that uses electric pulses to induce cell death, while preserving structural integrity of bile ducts and vessels. METHODS: All in-human literature on IRE reporting safety or efficacy or both was included. All adverse events were recorded. Tumor response on follow-up imaging from 3 months onward was evaluated. RESULTS: In 16 studies, 221 patients had 325 tumors treated in liver (n = 129), pancreas (n = 69), kidney (n = 14), lung (n = 6), lesser pelvis (n = 1), and lymph node (n = 2). No major adverse events during IRE were reported. IRE caused only minor complications in the liver; however, three major complications were reported in the pancreas (bile leak [n = 2], portal vein thrombosis [n = 1]). Complete response at 3 months was 67%-100% for hepatic tumors (93%-100% for tumors o 3 cm). Pancreatic IRE combined with surgery led to prolonged survival compared with control patients (20 mo vs 13 mo) and significant pain reduction. CONCLUSIONS: In cases where other techniques are unsuitable, IRE is a promising modality for the ablation of tumors near bile ducts and blood vessels. This articles gives an extensive overview of the available evidence, which is limited in terms of quality and quantity. With the limitations of the evidence in mind, IRE of central liver tumors seems relatively safe without major complications, whereas complications after pancreatic IRE appear more severe. The available limited results for tumor control are generally good. Overall, the future of IRE for difficult-to-reach tumors appears promising.

Additional value of transluminal attenuation gradient in CT angiography to predict hemodynamic significance of coronary artery stenosis.

OBJECTIVES: The current study evaluates the incremental value of transluminal attenuation gradient (TAG), TAG with corrected contrast opacification (CCO), and TAG with exclusion of calcified coronary segments (ExC) over coronary computed tomography angiogram (CTA) alone using fractional flow reserve (FFR) as the gold standard. BACKGROUND: TAG is defined as the contrast opacification gradient along the length of a coronary artery on a coronary CTA. Preliminary data suggest that TAG provides additional functional information. Interpretation of TAG is hampered by multiple heartbeat acquisition algorithms and coronary calcifications. Two correction models have been proposed based on either dephasing of contrast delivery by relating coronary density to corresponding descending aortic opacification (TAG-CCO) or excluding calcified coronary segments (TAG-ExC). METHODS: Eighty-five patients with intermediate probability of coronary artery disease were prospectively included. All patients underwent step-and-shoot 256-slice coronary CTA. TAG, TAG-CCO, and TAG-ExC analyses were performed followed by invasive coronary angiography in conjunction with FFR measurements of all major coronary branches. RESULTS: Thirty-four patients (40%) were diagnosed with hemodynamically-significant coronary artery disease (i.e., FFR ≤0.80). On a per-vessel basis (n = 253), 59 lesions (23%) were graded as hemodynamically significant, and the diagnostic accuracy of coronary CTA (diameter stenosis ≥50%) was 95%, 75%, 98%, and 54% for sensitivity, specificity, negative predictive value, and positive predictive value, respectively. TAG and TAG-ExC did not discriminate between vessels with or without hemodynamically significant lesions (-13.5 ± 17.1 HU [Hounsfield units] × 10 mm(-1) vs. -11.6 ± 13.3 HU × 10 mm(-1), p = 0.36; and 13.1 ± 15.9 HU × 10 mm(-1) vs. -11.4 ± 11.7 HU × 10 mm(-1), p = 0.77, respectively). TAG-CCO was lower in vessels with a hemodynamically-significant lesion (-0.050 ± 0.051 10 mm(-1) vs. -0.036 ± 0.034 10 mm(-1), p = 0.03) and TAG-ExC resulted in a slight improvement of the net reclassification index (0.021, p < 0.05). CONCLUSIONS: TAG did not provide incremental diagnostic value over 256-slice coronary CTA alone in assessing the hemodynamic consequences of a coronary stenosis. Correction for temporal nonuniformity of contrast delivery or exclusion of calcified coronary segments slightly enhanced the results.

Effect of cardiac hybrid ¹5O-water PET/CT imaging on downstream referral for invasive coronary angiography and revascularization rate.

AIMS: This study evaluates the impact of hybrid imaging on referral for invasive coronary angiography (ICA) and revascularization rates. METHODS AND RESULTS: A total of 375 patients underwent hybrid (15)O-water positron emission tomography (PET)/computed tomography (CT)-based coronary angiography (CTCA) imaging for the evaluation of coronary artery disease (CAD). Downstream treatment strategy within a 60-day period after hybrid PET/CTCA imaging for ICA referral and revascularization was assessed. CTCA examinations were classified as showing no (obstructive) CAD, equivocal (borderline test result), or obstructive CAD, while the PET perfusion images were classified into normal or abnormal. On the basis of CTCA imaging, 182 (49%) patients displayed no (obstructive) CAD. Only 10 (5%) patients who showed no (obstructive) CAD on CTCA were referred for ICA, which were all negative. An equivocal CT study was observed in 80 (21%) patients, among whom 56 (70%) showed normal myocardial perfusion imaging (MPI), resulting in referral rates for ICA of 18% for normal MPI and 71% for abnormal MPI, respectively. No revascularizations were performed in the presence of normal MPI, while 59% of those with abnormal MPI were revascularized. CTCA indentified obstructive CAD in 113 (30%) patients accompanied in 59 (52%) patients with abnormal MPI. Referral rate for ICA was 57% for normal MPI and 88% for those with abnormal MPI, resulting in revascularization rates of 26% and 72%, respectively. CONCLUSION: Hybrid (15)O-water PET/CTCA imaging impacts clinical decision-making with regard to referral for ICA and revascularization procedures. Particularly, in the presence of an equivocal or abnormal CTCA, MPI could guide in the decision to refer for ICA and revascularization.

Combined non-invasive functional and anatomical diagnostic work-up in clinical practice: the magnetic resonance and computed tomography in suspected coronary artery disease (MARCC) study.

AIMS: The combined use of cardiac computed tomography (CT) coronary angiography (CTCA) and myocardial perfusion imaging allows the non-invasive evaluation of coronary morphology and function. Cardiovascular magnetic resonance (CMR) imaging has several advantages: it can simultaneously assess myocardial perfusion, ventricular and valvular function, cardiomyopathy, and aortic disease and does not involve any additional ionizing radiation. We investigated the combined use of cardiac CT and CMR for the diagnostic evaluation of patients with suspected coronary artery disease (CAD) in clinical practice. METHODS AND RESULTS: A total of 192 patients with low or intermediate pre-test probability of CAD underwent CTCA and CMR. All patients with obstructive CAD on CTCA and/or myocardial ischaemia on CMR were referred for invasive coronary angiography (ICA). Fractional flow reserve was measured in case of intermediate lesions (30-70% diameter stenosis) on ICA. Additional cardiac and extra-cardiac findings by CTCA and CMR were registered. The combination of CTCA and CMR significantly improved specificity and overall accuracy (94 and 91%) for the detection of significant CAD compared with their use as a single technique (CTCA 39 and 57%, P < 0.0001; CMR 82 and 83%, P = 0.016). No events were recorded during follow-up (18 ± 6 months) in 104 patients who did not undergo ICA. Furthermore, the combined strategy provided an alternative diagnosis in 19 patients. CONCLUSION: The combined use of CTCA and CMR significantly improved specificity and overall diagnostic accuracy for the detection of significant CAD and allowed the detection of alternative (extra-)cardiac disease in patients without significant CAD.

Comparison of MR enteroclysis with video capsule endoscopy in the investigation of small-intestinal disease.

PURPOSE: To evaluate the diagnostic accuracy of MR enteroclysis and to compare it to video capsule endoscopy (VCE) in the analysis of suspected small-bowel disease. METHODS: We performed a retrospective analysis of 77 patients who underwent both MR enteroclysis and VCE and compared the findings of these studies with the findings of enteroscopy, surgery, or with the results of clinical follow-up lasting ≥2 years. RESULTS: Findings included malignant neoplasms (n = 13), benign neoplasms (n = 10), refractory celiac disease (n = 4), Crohn's disease (n = 2) and miscellaneous conditions (n = 10). Specificity of MR enteroclysis was higher than that of VCE (0.97 vs. 0.84, P = 0.047), whereas sensitivity was similar (0.79 vs. 0.74, P = 0.591). In 2/32 (6.3%) patients with both negative VCE and negative MR enteroclysis a positive diagnosis was established, compared to 5/11 (45.5%) patients in whom VCE was positive and MR enteroclysis was negative (likelihood ratio 8.1; P = 0.004), 9/11 (81.8%) patients in whom MR enteroclysis was positive and VCE was negative (likelihood ratio 23.5; P < 0.0001), and all 23 patients in whom both VCE and MR enteroclysis showed abnormalities (likelihood ratio 60.8; P < 0.0001). CONCLUSIONS: VCE and MR enteroclysis are complementary modalities. In our study-population, MR enteroclysis was more specific than VCE, while both produced the same sensitivity.

Hybrid imaging using quantitative H215O PET and CT-based coronary angiography for the detection of coronary artery disease.

UNLABELLED: Hybrid imaging using PET in conjunction with CT-based coronary angiography (PET/CTCA) enables near-simultaneous quantification of myocardial blood flow (MBF) and anatomical evaluation of coronary arteries. CTCA is an excellent imaging modality to rule out obstructive coronary artery disease (CAD), but functional assessment is warranted in the presence of a CTCA-observed stenosis because the specificity of CTCA is relatively low. Quantitative H(2)(15)O PET/CTCA may yield complementary information and enhance diagnostic accuracy. The purpose of this study was to evaluate the diagnostic accuracy of quantitative H(2)(15)O PET/CTCA in a clinical cohort of patients with suspected CAD who underwent both cardiac H(2)(15)O PET/CTCA and invasive coronary angiography (ICA). In addition, this study aimed to evaluate and compare the accuracy of hyperemic MBF versus coronary flow reserve (CFR). METHODS: Patients (n = 120; mean age ± SD, 61 ± 10 y; 77 men and 43 women) with a predominantly intermediate pretest likelihood for CAD underwent both quantitative H(2)(15)O PET/CTCA and ICA. A ≥50% stenosis at ICA or a fractional flow reserve ≤ 0.80 was considered significant. RESULTS: Obstructive CAD was diagnosed in 49 of 120 patients (41%). The diagnostic accuracy of hyperemic MBF was significantly higher than CFR (80% vs. 68%, respectively, P = 0.02), with optimal cutoff values of 1.86 mL/min/g and 2.30, respectively. On a per-patient basis, the sensitivity, specificity, negative predictive value, and positive predictive value of CTCA were 100%, 34%, 100%, and 51%, respectively, as compared with 76%, 83%, 83%, and 76%, respectively, for quantitative hyperemic MBF PET. Quantitative H(2)(15)O PET/CTCA reduced the number of false-positive CTCA studies from 47 to 6, although 12 of 49 true-positive CTCAs were incorrectly reclassified as false-negative hybrid scans on the basis of (presumably) sufficient hyperemic MBF. Compared with CTCA (61%) or H(2)(15)O PET (80%) alone (both P < 0.05), the hybrid approach significantly improved diagnostic accuracy (85%). CONCLUSION: The diagnostic accuracy of quantitative H(2)(15)O PET/CTCA is superior to either H(2)(15)O PET or CTCA alone for the detection of clinically significant CAD. Hyperemic MBF was more accurate than CFR, implying that a single measurement of MBF in diagnostic protocols may suffice.

Carotid artery intima-media thickness, but not coronary artery calcium, predicts coronary vascular resistance in patients evaluated for coronary artery disease.

AIMS: There is growing evidence that coronary artery disease (CAD) affects not only the conduit epicardial coronary arteries, but also the microvascular coronary bed. Moreover, coronary microvascular dysfunction (CMVD) often precedes the stage of clinically overt epicardial CAD. Coronary artery calcium (CAC) and carotid intima-media thickness (C-IMT) measured with computed tomography (CT) and ultrasound, respectively, are among the available techniques to non-invasively assess atherosclerotic burden. An increased CAC score and C-IMT have also been associated with CMVD. It is therefore of interest to explore and compare the potential of CAC against C-IMT to predict minimal coronary vascular resistance (CVR). METHODS AND RESULTS: We evaluated 120 patients (mean age 56 ± 9 years, 58 men) without a documented history of CAD in whom obstructive CAD was excluded. All patients underwent C-IMT measurements, CAC scoring, and vasodilator stress (15)O-water positron emission tomography (PET)/CT, during which the coronary flow reserve (CFR) and minimal CVR were analysed. Minimal CVR increased significantly with increasing tertiles of C-IMT (22 ± 6, 27 ± 11, and 28 ± 9 mmHg mL(-1)min(-1) g(-1), P < 0.01), whereas the CFR was comparable across all C-IMT groups (P = 0.50). Minimal CVR increased significantly with an increase in CAC score (23 ± 9, 27 ± 8, 32 ± 10, and 32 ± 7 mmHg mL(-1) min(-1) g(-1), P < 0.01), whereas the CFR did not show a significant decrease with higher CAC scores (P = 0.18). Multivariable regression analysis revealed that C-IMT (P = 0.03), but not CAC, was independently associated with minimal CVR. CONCLUSION: C-IMT, but not CAC score, independently predicts minimal CVR in patients with multiple cardiovascular risk factors and suspected of CAD.