Molecular imaging of large vessel vasculitis.

Large vessel vasculitis (LVV) affects mainly large arteries with giant cell arteritis (GCA) and Takayasu arteritis (TAK) being the two most frequent forms. Clinical symptoms can be non-specific, including headache, fatigue, weight loss, and change in vision. Untreated, LVV may also lead to serious complications such as blindness, aortic aneurysm and dissection. Therefore, rapid recognition of the disease leading to accurate diagnosis and appropriate treatment is essential. FDG-PET/CT imaging has emerged as a sensitive marker of active vascular inflammation and its use in the management of LVV is now integrated in guidelines. In this article, we will discuss the role of FDG-PET/CT for the diagnosis of LVV and monitoring of therapy, as well as review technical and interpretation parameters.

Differential Detection of Hepatic Metastases on 68 Ga-DOTATATE PET/CT and 177 Lu-DOTATATE SPECT/CT.

ABSTRACT: 68 Ga-DOTATATE PET/CT is indicated for selecting patients for peptide receptor radionuclide therapy (PRRT). Although highly sensitive, the detectability of smaller lesions, particularly in the liver, is lower. We present the case of a 58-year-old man with metastatic well-differentiated pancreatic neuroendocrine tumor whose MRI revealed progression of hepatic metastases. 68 Ga-DOTATATE PET/CT performed to determine eligibility for PRRT did not demonstrate DOTATATE-avid disease within the liver. 18 F-FDG PET/CT was also negative at the liver and the patient proceeded to 177 Lu-DOTATATE PRRT, where multi-time point posttherapy planar imaging and SPECT/CT showed intense uptake in the known liver metastases.

Comparing digital to analog prostate-specific membrane antigen-targeted piflufolastat 18 F PET/CT in prostate cancer patients in early biochemical failure.

PURPOSE: Prostate-specific membrane antigen (PSMA) positron emission tomography/computer tomography (PET/CT) in prostate cancer patients with biochemical failure(BCF) showslimited sensitivity when the prostate-specific antigen(PSA) <0.5 ng/mL. The development of digital PET/CT has greatly improved smaller lesion detection. This study's goal was to compare the performance and clinical value of PSMA-targeted piflufolastat PET/CT for prostate cancer BCF with digital versus analog PET/CT. METHODS: In this retrospective study, all piflufolastat PET/CT scans in subjects with PSA ≤ 3.0 ng/mL who were referred for prostate cancer BCF were included. The performance characteristics of 171 analog PET/CT studies in 155 subjects from May 2017 to January 2020 and 106 digital PET/CT studies in 103 subjects from February 2020 to December 2020 were compared. Lesions were considered malignant if they did not match the known physiological distribution of piflufolastat and did not represent uptake in benign lesions. PSMA PET/CT studies were considered positive if at least one malignant lesion was detected and negative if none were detected. RESULTS: Digital piflufolastat PET/CT outperformed analog piflufolastat PET/CT in subjects with PSA < 0.5 ng/mL with a positivity rate of 69% versus 37%, respectively. In patients with PSA ≥ 0.5 ng/mL, both technologies performed similarly. There was no statistically significant difference between the number or size of piflufolastat-avid lesions detected per PET/CT study. CONCLUSION: In prostate cancer patients with BCF and PSA < 0.5 ng/mL, digital piflufolastat PET/CT has a higher detection rate of malignant lesions than analog piflufolastat PET/CT.

Hybrid imaging of Diabetic Foot Infections.

Diabetic foot infections, a common but diagnostically challenging clinical presentation, requires the difficult differentiation between soft tissue-only infection, diabetic neuropathic osteoarthropathy, osteomyelitis or a combination of these pathological processes. While there are clinical predictors for osteomyelitis and simple bedside tests available, imaging is often required for accurate diagnosis. A variety of anatomic and molecular imaging tests are in clinical use, each with its advantages and disadvantages. This review will provide an overview of the different available imaging modalities and their diagnostic criteria, emphasizing the role of hybrid imaging for the accurate diagnosis of osteomyelitis.

Intra-individual comparison of 18F-sodium fluoride PET-CT and 99mTc bone scintigraphy with SPECT in patients with prostate cancer or breast cancer at high risk for skeletal metastases (MITNEC-A1): a multicentre, phase 3 trial.

BACKGROUND: Detection of skeletal metastases in patients with prostate cancer or breast cancer remains a major clinical challenge. We aimed to compare the diagnostic performance of 99mTc-methylene diphosphonate (99mTc-MDP) single-photon emission CT (SPECT) and 18F-sodium fluoride (18F-NaF) PET-CT for the detection of osseous metastases in patients with high-risk prostate or breast cancer. METHODS: MITNEC-A1 was a prospective, multicentre, single-cohort, phase 3 trial conducted in ten hospitals across Canada. Patients aged 18 years or older with breast or prostate cancer with a WHO performance status of 0-2 and with high risk or clinical suspicion for bone metastasis, but without previously documented bone involvement, were eligible. 18F-NaF PET-CT and 99mTc-MDP SPECT were done within 14 days of each other for each participant. Two independent reviewers interpreted each modality without knowledge of other imaging findings. The primary endpoint was the overall accuracy of 99mTc-MDP SPECT and 18F-NaF PET-CT scans for the detection of bone metastases in the per-protocol population. A combination of histopathological, clinical, and imaging follow-up for up to 24 months was used as the reference standard to assess the imaging results. Safety was assessed in all enrolled participants. This study is registered with ClinicalTrials.gov, NCT01930812, and is complete. FINDINGS: Between July 11, 2014, and March 3, 2017, 290 patients were screened, 288 of whom were enrolled (64 participants with breast cancer and 224 with prostate cancer). 261 participants underwent both 18F-NaF PET-CT and 99mTc-MDP SPECT and completed the required follow-up for statistical analysis. Median follow-up was 735 days (IQR 727-750). Based on the reference methods used, 109 (42%) of 261 patients had bone metastases. In the patient-based analysis, 18F-NaF PET-CT was more accurate than 99mTc-MDP SPECT (84·3% [95% CI 79·9-88·7] vs 77·4% [72·3-82·5], difference 6·9% [95% CI 1·3-12·5]; p=0·016). No adverse events were reported for the 288 patients recruited. INTERPRETATION: 18F-NaF has the potential to displace 99mTc-MDP as the bone imaging radiopharmaceutical of choice in patients with high-risk prostate or breast cancer. FUNDING: Canadian Institutes of Health Research.

[18F]FDG-PET CT for the evaluation of native valve endocarditis.

BACKGROUND: We examined the use of [18F]FDG-PET/CT for the diagnosis of native valve endocarditis (NVE). METHODS: PET/CT images in patients with suspected NVE were retrospectively reviewed independently by two experienced physicians blinded to all clinical information. The gold standard consisted of surgical findings, when available, or the modified Duke criteria. RESULTS: Fifty four subjects were included, 31 (57%) with a diagnosis of NVE. [18F]FDG-PET/CT correctly identified 21/31 (67.7%) subjects, yielding a sensitivity and specificity of 68% (95% CI 49-83%) and 100% (95% CI 85-100%), respectively. The sensitivity and specificity of the modified Duke criteria were 48% and 74%, respectively. Positive and negative predictive values of PET were 100% (95% CI 84-100%) and 70% (95% CI 51-84%), respectively. Modifying the Duke criteria to include [18F]FDG-PET positivity as a major criterion increased sensitivity to 77% without affecting specificity and led to the correct reclassification of 8/18 (44.4%) subjects from Possible IE to Definite IE. CONCLUSION: The addition of a positive [18F]FDG-PET/CT as a major criterion in the modified Duke Criteria improved performance of the criteria for the diagnosis of NVE, particularly in those subjects with Possible IE.

Incidental Skeletal Findings on Sodium-fluoride Positron Emission Tomography: A Collection of Benign Tumors

Sodium-fluoride (NaF) positron emission tomography (PET) is a sensitive method to detect altered bone mineralization. Its increasing use in routine clinical practice for metastatic bone disease has also resulted in the detection or characterization of incidental benign bone lesions. A spectrum of NaF PET scan cases with benign bone tumors are presented in this article, including whole body PET bone scan and selected PET/computed tomography (CT), CT, or magnetic resonance imaging (MRI) of the region of interest. The reader will be able to improve their knowledge related to the clinical presentation of these entities, some are rare and recognize based on NaF PET and CT/MRI patterns by reviewing these cases.

Sarcopenia in cardiac surgery: Dual X-ray absorptiometry study from the McGill frailty registry.

BACKGROUND: To determine the prevalence and prognostic value of sarcopenia measured by dual x-ray absorptiometry (DXA) and physical performance tests in patients undergoing coronary artery bypass surgery or heart valve procedures. METHODS: Adults undergoing cardiac surgery were prospectively enrolled and completed a questionnaire, physical performance battery, and a DXA scan (GE Lunar) to measure appendicular muscle mass indexed to height2 (AMMI). Patients were categorized as sarcopenic based on European Working Group 2 guidelines if they had low AMMI defined as <7 kg/m2 for men or <5.5 kg/m2 for women, and low muscle strength defined as 5 chair rise time ≥15 seconds. Cox proportional hazards regression was used to test the association between sarcopenia and all-cause mortality over a median follow-up of 4.3 years. RESULTS: The cohort consisted of 141 patients with a mean age of 69.7 ± 10.0 years and 21% females. The prevalence rates of low AMMI, slow chair rise time, and sarcopenia (low AMMI and slow chair rise time) were 24%, 57%, 13%, respectively. The 4-year survival rate was 79% in the non-sarcopenic group as compared to 56% in the sarcopenic group (Log-rank P = 0.01). In the multivariable model, each standard deviation of decreasing AMMI and increasing chair rise time was associated with a hazard ratio for all-cause mortality of 1.84 (95% CI 1.18, 2.86) and 1.79 (95% CI 1.26, 2.54), respectively. CONCLUSION: Lower-extremity muscle strength and DXA-based muscle mass are objective indicators of sarcopenia that are independently predictive of all-cause mortality in older cardiac surgery patients.

Magnetic Resonance Imaging Based Radiomic Models of Prostate Cancer: A Narrative Review.

The management of prostate cancer (PCa) is dependent on biomarkers of biological aggression. This includes an invasive biopsy to facilitate a histopathological assessment of the tumor's grade. This review explores the technical processes of applying magnetic resonance imaging based radiomic models to the evaluation of PCa. By exploring how a deep radiomics approach further optimizes the prediction of a PCa's grade group, it will be clear how this integration of artificial intelligence mitigates existing major technological challenges faced by a traditional radiomic model: image acquisition, small data sets, image processing, labeling/segmentation, informative features, predicting molecular features and incorporating predictive models. Other potential impacts of artificial intelligence on the personalized treatment of PCa will also be discussed. The role of deep radiomics analysis-a deep texture analysis, which extracts features from convolutional neural networks layers, will be highlighted. Existing clinical work and upcoming clinical trials will be reviewed, directing investigators to pertinent future directions in the field. For future progress to result in clinical translation, the field will likely require multi-institutional collaboration in producing prospectively populated and expertly labeled imaging libraries.

Physiologic prostate-specific membrane antigen-targeted 18F-DCFPyL uptake in the epididymis head newly appreciated on digital PET/CT.

PURPOSE: The published physiological distribution of prostate specific membrane antigen (PSMA) PET ligands includes normal uptake in the lacrimal glands, salivary glands, bowel, liver, spleen, kidneys and parasympathetic ganglia but does not include the epididymis. METHODS: Retrospective review of 134 PSMA-targeted 2-(3-(1-carboxy-5-[(6-[18F]fluoropyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL) PET/CT scans performed on a latest generation digital scanner for radiotracer uptake in the epididymal head region was correlated with multiple clinical and laboratory factors. RESULTS: Physiologic PSMA radiotracer uptake in the epididymal head region was present in 57% of all subjects, including 29% in those with a total serum testosterone ≤ 5 nmol/L and 65% of patients with serum testosterone > 5 nmol/L, odds ratio of 0.21 (P < 0.01). CONCLUSION: Epididymal head uptake is physiologic and very common on digital PSMA PET/CT and is more frequent in patients with higher serum testosterone levels. The enhanced small structure detection of digital PET/CT is the most likely explanation for the novel visualization of this normal variant.

Diagnostic performance of 18F-DCFPyL positron emission tomography/computed tomography for biochemically recurrent prostate cancer and change-of-management analysis.

INTRODUCTION: Conventional imaging (CI) performs poorly to identify sites of disease in biochemically recurrent prostate cancer. 68Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) is most studied but has a very short half-life. This study reports the diagnostic performance of the novel prostate-specific membrane antigen (PSMA) radiotracer 18F-DCFPyL using real-life data and tumor board simulation to estimate the impact of 18F-DCFPyL PET on patient management. METHODS: Ninety-three 18F-DCFPyL PET/CT scans performed for patients previously treated for prostate cancer with a rising prostate-specific antigen (PSA) were retrospectively compared to contemporary CI and clinical imaging and PSA followups. A chart review was performed to document prior imaging, pathology results, serial serum PSA measurements, and other pertinent clinical data. Clinical utility of 18F-DCFPyL PET was measured using a simulated tumor board formed by three physicians with extensive prostate cancer experience deciding on management with and without knowledge of PET/CT results. RESULTS: At median PSA 2.27 (interquartile rage [IQR] 5.27], 82% of 18F-DCFPyL PET/CT demonstrated at least one site of disease: non-regional lymph nodes (37% of scans), regional lymph node metastases (28%), local recurrence (27%), and bone metastases (20%), with higher PET positivity at higher PSA. Compared to 18F-DCFPyL PET/CT, CI showed overall poor performance, with accuracy below 20% for all extent of disease. PET/CT changed management in 44% of cases. The most frequent scenario was a radical change from initiating androgen deprivation therapy (ADT) to stereotactic body radiotherapy (SBRT) of oligo-lesional disease. In univariate and multivariate analysis, no patient characteristic could predict change of management by PET/CT results. CONCLUSIONS: 18F-DCFPyL significantly outperforms CI in recurring prostate cancer and is likely to impact management.

Detection of Native and Prosthetic Valve Endocarditis: Incremental Attributes of Functional FDG PET/CT over Morphologic Imaging.

PURPOSE OF REVIEW: The clinical and incremental value of functional imaging with 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG PET/CT) for the diagnosis and management of patients with suspected native and prosthetic valve infective endocarditis (IE). RECENT FINDINGS: The diagnosis of IE is challenging because of the highly variable clinical presentations, especially in the case of prosthetic valve endocarditis (PVE). FDG PET/CT has been shown to play an important role for the diagnosis of PVE as a major Duke criterion. Whether FDG PET/CT could play a similar role in patients with suspected native valve endocarditis (NVE) is less well established. It is increasingly recognized that IE is a multisystem disorder, and identification of extra-cardiac manifestations on whole-body FDG PET/CT impacts management and prognosis of patients with IE. Finally, FDG PET/CT provides incremental prognostic value over other clinical and para-clinical parameters, enabling prediction of in-hospital mortality, IE recurrence, hospitalization, and new onset heart failure and embolic events. FDG PET/CT plays a key role in the investigation of patients with suspected IE, enabling detection of valvular infection and extra-cardiac manifestations of the infection which has important prognostic implications.

Ureteral Metastasis From Prostate Cancer: A PSMA PET Pitfall.

A 72-year-old man with a history of prostate adenocarcinoma initially managed by radical prostatectomy and salvage radiation therapy underwent resection of a left vas deferens recurrence identified on PSMA PET. Despite an initial response, PSA failed to fall below 3.5 ng/L, prompting re-evaluation with PSMA PET/CT: a left distal hydroureter with presumed physiologic urine activity remains despite diuretic administration. Upon scrutiny of the prior PSMA PET/CT and diagnostic CTs, the distal ureteral uptake matched a subtle circumferential area of enhancing mild ureteral thickening. Pathological review after left uretectomy confirmed metastatic prostate cancer.

Tc-99m-pyrophosphate scintigraphy for the diagnosis of ATTR cardiac amyloidosis: Comparison of quantitative and semi-quantitative approaches.

BACKGROUND: ATTR cardiac amyloidosis (CA) can be diagnosed with Tc-99m-PYP scintigraphy. There are two recommended interpretative approaches: the quantitative heart-to-contralateral lung ratio (H/CL) at 1 hour and the semi-quantitative visual system at 3 hours. This study's aim was to compare both approaches and to apply the semi-quantitative method at 1 hour. METHODS: Tc-99m-PYP scans of 122 consecutive subjects were reviewed using both approaches. On 1 hour planar images, regions of interest were drawn over the heart and contralateral chest to determine H/CL. Myocardial uptake was graded on 1 and 3 hour SPECT images according to the semi-quantitative method. Concordance was examined using kappa statistics. RESULTS: 31, 10, and 81 studies were positive, negative, and equivocal, respectively, for ATTR-CA using the H/CL approach. Using the grading system, 35, 77, and 10 scans were positive, negative, and equivocal, respectively. The quantitative approach led to a significantly higher proportion of equivocal studies compared to the semi-quantitative approach (P < .0001). These approaches yielded discordant results in 2 subjects; biopsy results were concordant with SPECT grade. 1 and 3 hour SPECT grades provided concordant result in 99% of cases. CONCLUSIONS: The H/CL approach resulted in a high proportion of equivocal studies. Using SPECT imaging, the semi-quantitative approach minimized this proportion and showed high concordance at 1 and 3 hours.

Incidental Hydroxyapatite Ocular Implant Uptake on Bone Scan Done for Prostate Cancer Staging: Case Report and Brief Review

A 74-year-old man recently diagnosed with high-risk prostate cancer with high serum prostate specific antigen was referred to nuclear medicine for a technetium-99m-methylene diphosphonate (Tc-99m MDP) bone scan. On delayed three-hour anterior planar image, an unexpected round focus of intense uptake was found overlying the right orbit. Single-photon emission computed tomography/computed tomography localized the uptake to an ocular prosthesis. The hydroxyapatite composition of the ocular implant can be recognized by its bone-like density and its intense accumulation of Tc-99m MDP. Review of the patient's history revealed remote right eye evisceration secondary to a complication of cataract surgery, consistent with the findings.

18F-fluorodeoxyglucose positron emission tomography/computed tomography in extensive bland portal vein thrombosis from retroperitoneal adenocarcinoma.

A 73-year-old woman undergoing hormone therapy for previously treated localized breast cancer presented at oncology follow-up 4 years after mastectomy/radiation therapy with weight loss, night sweats, and abdominal pain. Contrast computed tomography (CT) abdomen revealed a soft-tissue mass posterior to the pancreas, several enlarged retroperitoneal lymph nodes, and a dilated portal vein. On 18F-fluorodeoxyglucose positron emission tomography/CT, metabolic activity extended along the portal vein, outlining most of the liver venous system. This "tree-like" appearance was diagnostic of recent portal vein thrombosis by vascular compression from the retroperitoneal mass. Biopsy of the mass later confirmed undifferentiated adenocarcinoma without breast cancer marker expression.

Molecular Imaging of Cardiac Amyloidosis.

PURPOSE OF REVIEW: The aim of this review is to give an update on the molecular imaging tools currently available as well as to discuss the potential roles and limitations of molecular imaging in cardiac amyloidosis. RECENT FINDINGS: Molecular imaging plays a central role in the evaluation of patients with suspected cardiac amyloidosis. It can be used to diagnose and distinguish between the different types of cardiac amyloidosis. The diagnostic properties of bone scintigraphy are such that it allows reliable diagnosis of transthyretin cardiac amyloidosis without the need of endomyocardial biopsy in a significant proportion of patients. Furthermore, molecular tracers assessing amyloid plaque burden and sympathetic innervation may be useful for the non-invasive evaluation diagnosis and risk stratification of patients with suspected cardiac amyloidosis. Cardiac amyloidosis is an under-recognized cause of left ventricular hypertrophy and heart failure in the elderly. The role of molecular imaging in cardiac amyloidosis is expected to grow considering the arrival of new therapies and molecular imaging probes.

18F-FDG PET/CT versus conventional investigations for cancer screening in autoimmune inflammatory myopathy in the era of novel myopathy classifications.

BACKGROUND: To compare the performance of fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) and conventional tests for cancer screening in autoimmune inflammatory myopathy (AIM) patients. PATIENTS AND METHODS: We carried out a retrospective cohort study of AIM patients from one academic center in Montreal, Canada, classified using myositis-specific antibodies, who underwent F-FDG PET/CT between April 2005 and February 2018 and were followed up on average 3.5±2.4 years. Patients were excluded if follow-up was insufficient, AIM diagnosis was indeterminate, and/or malignancy was diagnosed before an F-FDG PET/CT scan. Demographic/clinical data, F-FDG PET/CT results, and available conventional screening tests results were retrieved from electronic and paper medical records. RESULTS: 100 F-FDG PET/CT studies in 63 unique patients [31/63 dermatomyositis (DM), 25/63 overlap myositis, 1/63 inclusion body myositis, 1/63 polymyositis, 1/63 orbital myositis and 4/63 unspecified myositis] were evaluated. Three patients, all classified as DM, were diagnosed with cancer during follow-up with conventional cancer screening tests: breast cancer detected by mammography; squamous cell carcinoma of the skin detected by physical examination; and multiple myeloma detected by blood work. F-FDG PET/CT did not detect any malignancy and led to more additional biopsies than conventional screening (8 vs. 5). CONCLUSION: F-FDG PET/CT does not appear to be useful in cancer screening for AIM patients compared with conventional screening and carries potential harms associated with follow-up investigations. The risk of cancer in AIM differs by myositis-specific antibodies-defined subsets and cancer screening is likely to be indicated only in high-risk patients, particularly DM. These results, replicated in larger, multicentered studies, may carry significant consequences for optimal management of AIM and health resource utilization.

Splenic Hemangioma as a Potential Pitfall on PSMA-Targeted 18F-DCFPyL PET/CT.

A 69-year-old man with biochemical recurrence after radical prostatectomy underwent 6 months of androgen deprivation therapy. Upon discontinuation of androgen deprivation therapy, serum prostate-specific antigen rose again to 0.69 ng/mL, and F-DCFPyL PET/CT was performed to identify the site of recurrence. However, only an intense focus of uptake in the spleen could be found. Subsequent contrast-enhanced MRI findings were pathognomonic for splenic hemangioma.

Serial imaging after pulmonary embolism and correlation with functional limitation at 12 months: Results of the ELOPE Study.

INTRODUCTION: Risk factors for exercise limitation after acute pulmonary embolism (PE) are unknown. As a planned sub-study of the prospective, multicenter ELOPE (Evaluation of Long-term Outcomes after PE) Study, we aimed to describe the results of serial imaging by computed tomography pulmonary angiography (CTPA) and perfusion scan during 1 year after a first episode of acute pulmonary embolism, and to assess the association between imaging parameters and exercise limitation at 1 year. METHODS: In a prospective cohort study, 100 patients were recruited between June 2010 and February 2013 at five Canadian university-affiliated hospitals. CT pulmonary angiography was performed at baseline and 12 months, perfusion scan at 6 and 12 months, and cardio-pulmonary exercise testing at 1 and 12 months. Imaging parameters included: on CT pulmonary angiography, CT obstruction index (CTO) (% clot burden in the pulmonary vasculature), and on perfusion scan, pulmonary vascular obstruction (PVO) (% perfusion defect). Abnormal cardio-pulmonary exercise test (primary outcome) was defined as percent of predicted peak oxygen uptake (VO2) <80%. RESULTS: Mean (median; SD) CT obstruction index was 28.1% (27.5%; 18.3%) at baseline, 1.2% (0%; 4.3%) at 12 months. Mean (median; SD) pulmonary vascular obstruction was 6.0% (0%; 9.6%) at 6 months, 5.6% (0%; 9.8%) at 12 months. Eighty-six patients had exercise testing at 12 months, and 46.5% had VO2 < 80% predicted. Mean (median; SD) CT obstruction index at 1 year was similar in patients with percent-predicted VO2 peak <80% vs >80% on 1-year cardio-pulmonary exercise testing (1.4% [0%; 5.7%] vs 1.0% [0%; 2.4%]; P = .70). Mean (SD) pulmonary vascular obstruction at 6 and at 12 months was similar in patients with percent-predicted VO2 peak <80% vs >80% (6 months: 5.9% [0%; 10.4%] vs 6.2% [4.5%; 9.0%]; P = .91; 12 months: 5.1% [0%; 10.2%] vs 6.0% [0%; 9.7%]; P = .71). CONCLUSIONS: Imaging findings after pulmonary embolism did not predict exercise limitation. Residual thrombus does not appear to explain long-term functional limitation after pulmonary embolism.