Dematerialisation of patient's informed consent in radiology: insights on current status and radiologists' opinion from an Italian online survey.

PURPOSE: To assess the current status of patient's informed consent (PIC) management at radiological centres and the overall opinion of radiologist active members of the Italian Society of Medical Radiology (SIRM) about PIC dematerialisation through an online survey. METHODS AND MATERIALS: All members were invited to join the survey as an initiative by the Imaging Informatics Chapter of SIRM. The survey consisted of 11 multiple-choice questions about participants' demographics, current local modalities of PIC acquisition and storage, perceived advantages and disadvantages of PIC dematerialisation over conventional paper-based PIC, and overall opinion about PIC dematerialisation. RESULTS: A total of 1791 radiologists (amounting to 17.4% of active SIRM members for the year 2016) joined the survey. Perceived advantages of PIC dematerialisation were easier and faster PIC recovery (96.5%), safer storage and conservation (94.5%), and reduced costs (90.7%). Conversely, the need to create dedicated areas for PIC acquisition inside each radiological unit (64.0%) and to gain preliminary approval for the use of advanced digital signature tools from patients (51.8%) were seen as potential disadvantages. Overall, 94.5% of respondents had a positive opinion about PIC dematerialisation. CONCLUSION: Radiologists were mostly favourable to PIC dematerialisation. However, concerns were raised that its practical implementation might face hurdles due to its complexity in current real life working conditions.

Coronary computed tomography angiography using model-based iterative reconstruction algorithms in the detection of significant coronary stenosis: how the plaque type influences the diagnostic performance.

PURPOSE: To evaluate the ability of coronary computed tomography angiography (CCTA) with model-based iterative reconstruction (MBIR) algorithm in detecting significant coronary artery stenosis compared with invasive coronary angiography (ICA). MATERIAL AND METHODS: We retrospectively identified 55 patients who underwent CCTA using the MBIR algorithm with evidence of at least one significant stenosis (≥ 50%) and an ICA within three months. Patients were stratified based on calcium score; stenoses were classified by type and by coronary segment involved. Dose-length-product was compared with the literature data obtained with previous reconstruction algorithms. Coronary artery stenosis was estimated on ICAs based on a qualitative method. RESULTS: CCTA data were confirmed by ICA in 89% of subjects, and in 73% and 94% of patients with CS < 400 and ≥ 400, respectively. ICA confirmed 81% of calcific stenoses, 91% of mixed, and 67% of soft plaques. Both the dose exposure of patients with prospective acquisition (34) and the exposure of the whole population were significantly lower than the standard of reference (p < 0.001 and p = 0.007). CONCLUSIONS: CCTA with MBIR is valuable in detecting significant coronary artery stenosis with a solid reduction of radiation dose. Diagnostic performance was influenced by plaque composition, being lower compared with ICA for patients with lower CAC score and soft plaques; the visualisation of an intraluminal hypodensity could cause false positives, particularly in D1 and MO segments.

An unusual presentation of anomalous left coronary artery from the pulmonary artery (ALCAPA) syndrome in a 70-year-old man: a case report.

BACKGROUND: We present a rare case of anomalous origin of the left coronary artery from the pulmonary artery syndrome in an elderly man, and we describe coronary computed tomographic angiographic imaging findings to improve diagnostic confidence for the evaluation of this uncommon coronary artery anomaly. CASE PRESENTATION: A 70-year-old Caucasian man came to our hospital with slight limitation of physical activity (New York Heart Association class II). He was asymptomatic for angina, syncope, and palpitations. Cardiac magnetic resonance imaging was performed after echocardiography because a hypertrophic cardiomyopathy was suspected; a plausible coronary artery anomaly was demonstrated as collateral evidence. Subsequently, coronary computed tomographic angiography showed the anomalous origin of left coronary artery from the pulmonary artery; the coronary vessels appeared markedly dilated and tortuous. Dilated intercoronary vessels along the epicardial surface of the heart and dilated bronchial arteries, corresponding to collateral pathways, were observed. Left ventricular hypertrophy, delayed subendocardial enhancement, and mitral insufficiency were better evaluated on magnetic resonance images. Invasive coronary angiography confirmed the main findings. Given the patient's age and clinical performance, surveillance with medical management was considered appropriate, and surgical repair was avoided. CONCLUSIONS: Confidence with the anatomic pattern and clinical significance of this anomalous condition is necessary to improve cardiac imaging evaluation ability. In our patient, coronary computed tomographic angiography proved to be a reliable imaging approach, superior to invasive coronary angiography in terms of diagnostic performance and patient safety.

Left ventricle remodeling in patients with ß-thalassemia major. An emerging differential diagnosis with left ventricle noncompaction disease.

To differentiate left ventricle non-compaction (LVNC) from hypertrabeculated myocardium due to LV remodeling in ß-thalassemia major (ß-TM) patients, cardiac magnetic resonance (CMR) images of 38 ß-TM patients and 10 LVNC patients were compared using 3 diagnostic criteria: ratio of diastolic segmental non-compacted to compacted myocardium (NC/C ratio) >2.5, percentage of non-compacted LV mass (NC-LVM%) >20% and >25% of global LV mass. Specificity of NC/C ratio of >2.5 was the lowest (58%) and of NC-LVM% of >25% the highest (93%). A NC-LVM% >20% showed sensitivity 100% and specificity 87%. Disease differentiation depends on the selected CMR criterion and is better with NC-LVM%.

Computed tomographic colonography in the evaluation of a case of giant colonic diverticulum.

The aim of this article was to present our experience with CT-colonography evaluation of a case of giant colonic diverticulum. Despite the high prevalence of diverticular disease in the Western world, giant colonic diverticula are rare entities, with fewer than 200 cases reported in literature.

Primary septic arthritis of the manubriosternal joint in an immunocompetent young patient: A case report.

The aim of this article was to illustrate a case of primary septic arthritis of the manubriosternal joint, due to Staphylococcus aureus infection, in an immunocompetent 28-year-old male patient. The manubriosternal joint can be rarely involved in inflammatory processes, but pyarthrosis is even more unusual in an otherwise healthy adult. Although rare, pyarthrosis could be associated with significant morbidity and mortality, first of all because of spreading to mediastinal structures. Diagnosis is generally made thanks to imaging findings after clinical suspicion in a patient with anterior chest pain and swelling, fever, and raised inflammatory markers, especially when any risk factors are known. Management is generally aggressive because intravenous antibiotics and surgical debridement are necessary.

Comparative assessment of image quality for coronary CT angiography with iobitridol and two contrast agents with higher iodine concentrations: iopromide and iomeprol. A multicentre randomized double-blind trial.

OBJECTIVES: To demonstrate non-inferiority of iobitridol 350 for coronary CT angiography (CTA) compared to higher iodine content contrast media regarding rate of patients evaluable for the presence of coronary artery stenoses. METHODS: In this multicentre trial, 452 patients were randomized to receive iobitridol 350, iopromide 370 or iomeprol 400 and underwent coronary CTA using CT systems with 64-detector rows or more. Two core lab readers assessed 18 coronary segments per patient regarding image quality (score 0 = non diagnostic to 4 = excellent quality), vascular attenuation, signal and contrast to noise ratio (SNR, CNR). Patients were considered evaluable if no segment had a score of 0. RESULTS: Per-patient, the rate of fully evaluable CT scans was 92.1, 95.4 and 94.6 % for iobitridol, iopromide and iomeprol, respectively. Non-inferiority of iobitridol over the best comparator was demonstrated with a 95 % CI of the difference of [-8.8 to 2.1], with a pre-specified non-inferiority margin of -10 %. Although average attenuation increased with higher iodine concentrations, average SNR and CNR did not differ between groups. CONCLUSIONS: With current CT technology, iobitridol 350 mg iodine/ml is not inferior to contrast media with higher iodine concentrations in terms of image quality for coronary stenosis assessment. KEY POINTS: • Iodine concentration is an important parameter for image quality in coronary CTA. • Contrast enhancement must be balanced against the amount of iodine injected. • Iobitridol 350 is non-inferior compared to CM with higher iodine concentrations. • Higher attenuation with higher iodine concentrations, but no SNR or CNR differences.

Cardiac resynchronization therapy guided by multimodality cardiac imaging.

AIMS: Up to 30-45% of implanted patients are non-responders to CRT. We evaluated the role of a 'CRT team' using cardiac magnetic resonance (CMR) and longitudinal myocardial strain to identify the target area defined as the most delayed and viable region for LV pacing. METHODS AND RESULTS: A total of 100 heart failure patients candidates for CRT divided into two groups were enrolled. Group 1 consisted of 50 consecutive patients scheduled for CRT and prospectively included. Group 2 (control) consisted of 50 patients with a CRT device implanted according to standard clinical practice and matched for age, sex, and LVEF with group 1. Patients were evaluated at baseline and at 6-month follow-up. In group 1, patients underwent two-dimensional speckle-tracking assessment of longitudinal myocardial strain and CMR imaging to identify the target area for LV lead pacing. A positive response to CRT was defined as a reduction of ≥15% of the LV end-systolic volume at 6-month follow-up. A total of 39 (78%) patients of group 1 were classified as responders to CRT whilst in group 2, only 28 (56%) were responders (P = 0.019). The 'CRT team' identified as target for LV pacing the lateral area in 30 (60%) patients, and the anterolateral or posterolateral areas in 12 (24%) patients. In 8 (16%) patients, the target was far from the lateral area, in the anterior or posterior areas. The patients with concordant position exhibited the highest positive response (93.1%) to CRT. CONCLUSIONS: Multimodality cardiac imaging as a guide for CRT implantation is useful to increase response rate.

Emphysema- and airway-dominant COPD phenotypes defined by standardised quantitative computed tomography.

EvA (Emphysema versus Airway disease) is a multicentre project to study mechanisms and identify biomarkers of emphysema and airway disease in chronic obstructive pulmonary disease (COPD). The objective of this study was to delineate objectively imaging-based emphysema-dominant and airway disease-dominant phenotypes using quantitative computed tomography (QCT) indices, standardised with a novel phantom-based approach.441 subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-3) were assessed in terms of clinical and physiological measurements, laboratory testing and standardised QCT indices of emphysema and airway wall geometry.QCT indices were influenced by scanner non-conformity, but standardisation significantly reduced variability (p<0.001) and led to more robust phenotypes. Four imaging-derived phenotypes were identified, reflecting "emphysema-dominant", "airway disease-dominant", "mixed" disease and "mild" disease. The emphysema-dominant group had significantly higher lung volumes, lower gas transfer coefficient, lower oxygen (PO2 ) and carbon dioxide (PCO2 ) tensions, higher haemoglobin and higher blood leukocyte numbers than the airway disease-dominant group.The utility of QCT for phenotyping in the setting of an international multicentre study is improved by standardisation. QCT indices of emphysema and airway disease can delineate within a population of patients with COPD, phenotypic groups that have typical clinical features known to be associated with emphysema-dominant and airway-dominant disease.

Polar plot maps by parametric strain echocardiography allow accurate evaluation of non-viable transmural scar tissue in ischaemic heart disease.

AIMS: Assessment of left ventricular (LV) transmural scar tissue in clinical practice is still challenging because magnetic resonance imaging (MRI) and nuclear techniques have limited access and cannot be performed extensively. The aim of this study was to verify whether parametric two-dimensional speckle-tracking echocardiography (2D-STE) can more accurately localize and quantify LV transmural scar tissue in patients with healed myocardial infarct (MI) in comparison with MRI. METHODS AND RESULTS: Thirty-one consecutive patients (age 56 ± 32 years, 29 males) with MRI and echocardiography performed after at least 6 months from an acute MI were studied. Apical LV longitudinal strain images by 2D-STE and short-axis contrast images by MRI were analysed to generate parametric bull's eye maps showing the distribution of the LV transmural scar tissue, whose extension was measured by planimetry and expressed as a percentage of the total myocardial area. Twelve patients also had early 2D-STE and MRI examinations after the acute MI. 2D-STE accurately quantified the extent of transmural scar tissue vs. MRI (r = 0.86; limits of agreement 10.0 and -9.5%). Concordance between 2D-STE and MRI for transmural scar tissue localization was high, with only 3.6% of discordant segments using an LV 16-segment model. Lin coefficients, intra-class correlation coefficients, and Bland-Altman analysis showed very good intra- and inter-observer reproducibility for 2D-STE evaluations. The transmural scar tissue area at 6 months could be predicted by early 2D-STE evaluation. CONCLUSION: 2D-STE polar plots of LV longitudinal strain characterize transmural scar tissue accurately compared with MRI and may facilitate its assessment in clinical practice.

Waiting time prioritisation for specialist services in Italy: the homogeneous waiting time groups approach.

The demand for referrals and diagnostic procedures in Italy has been rising constantly in recent years, making access to diagnostic services increasingly difficult with significant waiting times. A number of Health Authorities (known as Local Health Units) have responded by implementing formalised waiting-time prioritisation tools, giving rise to what are known as Homogeneous Waiting Groups (HWGs). The study describes the implementation of the HWG approach in Italy. This represents a promising tool for improving the prioritisation of patients waiting to see a specialist or to receive a diagnostic test. The study of the Italian HWG experience provides useful insights to improve the outpatient referral process for those countries where the demand prioritisation policies have focused more on inpatient care than outpatient specialist care and diagnostic services.

Trans-arterial chemoembolization of metastatic colorectal carcinoma to the liver adopting DC Bead®, drug-eluting bead loaded with irinotecan: results of a phase II clinical study.

UNLABELLED: Trans-arterial chemoembolization (TACE) is a promising locoregional therapy for the treatment of primary hepatic tumors and liver metastases. The aim of the study was to define the activity and outcome of using DC Bead, drug-eluting bead, a spherical embolic device capable of being loaded with irinotecan. PATIENTS AND METHODS: We conducted a double institutional, single arm, phase II clinical study to evaluate TACE adopting this device in 82 patients presenting with metastatic colorectal carcinoma to the liver after failing chemotherapy. The primary endpoints were tumor shrinkage, safety, feasibility, compliance, and overall survival. RECIST criteria were used to assess responses. Quality of life (QoL) was addressed using Edmonton SAS improvement scale. RESULTS: Out of 103 patients considered, 82 were enrolled and underwent a total of 185 treatments of TACE. The median number of TACE was 2.2 (1-4). A post-embolization syndrome was frequently observed. Adverse observed effects were: right upper quadrant pain (40%), fever (80%), nausea (27%) and increased transaminases (70%). The median follow-up was 29 months. Within one month after treatment, each patient received a computed tomograpic scan. It showed reduction of metastatic contrast enhancement in all patients. Responses were 78% at 3 months. After the first treatment, 75 out 82 patients declared an improvement of their well being lasting more than 18 weeks. The median duration of response was 6 (range 3-10) months; the median follow up was 29 (range 7-48) months. The median survival was 25 (range 6-34) months, with progression free survival at 8 (range 4-16) months. CONCLUSION: We suggest that TACE adopting DC Bead®, drug-eluting bead loaded with irinotecan could be proposed as palliative therapy for unresectable and chemotherapy resistant liver metastases from CRC.

High-resolution MRI of carotid plaque with a neurovascular coil and contrast-enhanced MR angiography: one-stop shopping for the comprehensive assessment of carotid atherosclerosis.

OBJECTIVE: The objective of our study was to assess a protocol of study of carotid atherosclerosis coupling vascular wall imaging and luminal imaging in the same examination and to evaluate the accuracy of high-resolution MRI with a neurovascular coil in carotid plaque characterization. SUBJECTS AND METHODS: Thirty-two consecutive patients with 34 carotid artery stenoses were prospectively enrolled. MRI was performed on a 1.5-T unit. Plaque assessment was performed starting with a diffusion-weighted sequence and followed by a fat-suppressed T1-weighted sequence; after contrast-enhanced MR angiography (CE-MRA), all patients were evaluated with a T1-weighted 3D high-resolution sequence. Carotid plaques were classified as type A, having a large lipid-necrotic core; type B, being a complex fibrotic-calcified plaque with soft content (mixed plaque); or type C, being a fibrotic-calcified plaque (hard). Additional features indicative of vulnerable plaque such as intraplaque hemorrhage (IPH), ulceration, and severe stenosis were registered. MR findings were compared with surgical specimens. RESULTS: MRI correctly identified 11 of 13 type A, eight of 11 type B, and eight of 10 type C plaques (sensitivity, 84.6%, 72.7%, and 80%, respectively). In the identification of lipid-necrotic core plaque, MRI showed a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 84.6%, 100%, 100%, and 91.3%, respectively (κ = 0.87). For reordering all plaques in two groups (i.e., soft vs nonsoft) in the identification of soft plaques, MRI had a sensitivity, specificity, PPV, and NPV of 83.3%, 80%, 90.9%, and 66.7%, respectively (κ = 0.59). IPH, ulcers, and severe stenosis were detected in eight of eight, 11 of 13, and 25 of 25 cases, respectively. CONCLUSION: In patients with carotid atherosclerosis, ongoing CE-MRA with a neurovascular coil for the simultaneous detection of unstable plaques is feasible. Our MR protocol accurately identifies the major features of vulnerable plaque.

Coronary artery anomalies presenting with ST-segment elevation myocardial infarction.

ST-segment elevation MI (STEMI) is a rare presentation in patients with coronary artery anomalies. In these patients, the identification of the culprit lesion and its treatment may be difficult, particularly in the emergency setting of primary percutaneous coronary intervention (PCI). From January 2008 to April 2011, 1015 STEMI patients received coronary artery angiography and primary PCI in our centre. Of these, 5 (0.4%) patients showed a coronary artery anomaly. In this paper we reported two rare cases: i) the first is a single coronary artery originating from right sinus of Valsalva; ii) the second is a separate origin of 3 coronary arteries originating from the right sinus of Valsalva. In conclusion, coronary artery anomalies presenting with STEMI are really uncommon, but often are a challenge. The integration between traditional coronary artery angiography and multidetector computerized tomography is crucial to optimize the interventional and medical management of these patients.

Long-lasting response with metronomic capecitabine in advanced hepatocellular carcinoma.

Effective and safe systemic treatment for advanced hepatocellular carcinoma (HCC) with severe underlying cirrhosis is not yet available. Sorafenib, an oral multikinase inhibitor, has proved to be effective in the treatment of patients affected by HCC with Child-Pugh class A liver function. For patients with cirrhosis-associated HCC having Child-Pugh class B and C liver function, no systemic treatments of documented efficacy and safety exist. We report a case of metastatic HCC associated with Child-Pugh class B cirrhosis that was treated with low, "metronomic" doses of capecitabine (1000 mg/day continuously). This treatment was effective and well tolerated and the response was maintained for 18 months. Metronomic capecitabine may represent a possible alternative in the treatment of those patients with advanced cirrhosis-associated HCC who cannot be treated with sorafenib.

Intra-arterial hepatic chemoembolization (TACE) of liver metastases from ocular melanoma with slow-release irinotecan-eluting beads. Early results of a phase II clinical study.

BACKGROUND: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and the liver is the predominant site of metastases (LM). If metastases appear, none of the systemic treatments established for cutaneous melanoma so far have any significant impact. Several authors have adopted transarterial chemoembolization (TACE) as palliation. TACE combines hepatic artery embolization with infusion of concentrated doses of chemotherapeutic drugs. DC Beads are new embolic products that can be loaded with irinotecan (IRI). The beads consist of polyvinyl alcohol microspheres modified with sulfonic acid groups and are available at different size ranges from 100 to 900 microns in diameter. The use of IRI as drug-eluting beads seems to optimize TACE in UM. OBJECTIVE: Our purpose was to assess the safety and efficacy of this new kind of TACE in a phase II clinical study. PATIENTS AND METHODS: Ten patients with LM from UM were treated with TACE-containing beads preloaded with IRI (100 mg). RESULTS: All patients had an objective response, three presented a very good partial response and seven obtained a partial response. The median follow-up time from the beginning of therapy was 6.5 months (range 4-9 months). Eight patients are alive at the time of this analysis. The most important adverse event was abdominal pain during the procedure. Adequate supportive treatment with antibiotic and antiemetic prophylaxis, desametazone and intravenous hydration is strictly necessary until stabilization of serum levels of transaminases and to prevent infections. A major analgesic such as morphine must be used before and after the procedure. CONCLUSION: TACE containing beads preloaded with IRI is effective in the treatment of LM from UM. This approach seems to have better efficacy than previous TACE regimens adopted.

Chemoembolization (TACE) of unresectable intrahepatic cholangiocarcinoma with slow-release doxorubicin-eluting beads: preliminary results.

The purpose of this study was to evaluate the safety and efficacy of TACE with microspheres preloaded with doxorubicin in unresectable intrahepatic cholangiocarcinoma (UCH). Twenty patients with UCH were observed; 9 refused, preferring other palliative care or chemotherapy, and 11 agreed to be treated with one or more cycles of DC beads loaded with doxorubicin (100-150 mg) in a TACE procedure between February 2006 and September 2007. A total of 29 individual TACE procedures were performed. Follow-up imaging was performed on all patients before, immediately after, and 4 weeks after each TACE procedure to evaluate the response and need for further treatment. Each patient received i.v hydration, antibiotics, and medications against nausea and pain before TACE. Survival rate was calculated using Kaplan-Meier survival curve. A response rate of 100% followed RECIST criteria was observed. Eight of eleven patients are alive, with a median survival of 13 months. TACE was well tolerated by all patients. One patient developed hepatic abscess requiring antibiotic therapy. No evidence of marrow toxicity has been reported. Only one of nine patients treated with chemotherapy or palliative care is alive (with a median survival of 7 months in this group of patients). In conclusion, we suggest that doxorubicin-eluting beads TACE is a feasible and effective treatment in patients with UCH. Survival seems to be clearly prolonged in the treated group with respect to the palliative group. We consider that doxorubicin-eluting beads TACE of 100-150 mg may be an appropriate palliative therapy for these patients. Further studies are warranted to confirm these interesting preliminary data.

Not all acute lower back pain is benign--paravertebral abscess and colonic cancer.

Low back pain with sciatica is one of the most common complaints of patients presenting to the ED, and it is usually managed on an outpatient basis. However, acute lower back pain not always derives from a benign cause. We report here the case of a 63-year-old diabetic man who presented to the ED complaining of acute low back pain with sciatica and fever. The cause was a large paravertebral abscess by Streptococcus milleri, and this was the first presenting sign of an unknown underlying colonic cancer.

Renal artery stenosis evaluation: diagnostic performance of gadobenate dimeglumine-enhanced MR angiography--comparison with DSA.

PURPOSE: To prospectively determine diagnostic performance and safety of contrast material-enhanced (CE) magnetic resonance (MR) angiography with 0.1 mmol per kilogram of body weight gadobenate dimeglumine for depiction of significant steno-occlusive disease (> or =51% stenosis) of renal arteries, with digital subtraction angiography (DSA) as reference standard. MATERIALS AND METHODS: This multicenter study was approved by local institutional review boards; all patients provided written informed consent. Patient enrollment and examination at centers in the United States complied with HIPAA. Two hundred ninety-three patients (154 men, 139 women; mean age, 61.0 years) with severe hypertension (82.2%), progressive renal failure (11.3%), and suspected renal artery stenosis (6.5%) underwent CE MR angiography with three-dimensional spoiled gradient-echo sequences after administration of 0.1 mmol/kg gadobenate dimeglumine at 2 mL/sec. Anteroposterior and oblique DSA was performed in 268 (91.5%) patients. Three independent blinded reviewers evaluated CE MR angiographic images. Sensitivity, specificity, and accuracy of CE MR angiography for detection of significant steno-occlusive disease (> or =51% vessel lumen narrowing) were determined at segment (main renal artery) and patient levels. Positive and negative predictive values and positive and negative likelihood ratios were determined. Interobserver agreement was analyzed with generalized kappa statistics. A safety evaluation (clinical examination, electrocardiogram, blood and urine analysis, monitoring for adverse events) was performed. RESULTS: Of 268 patients, 178 who were evaluated with MR angiography and DSA had significant steno-occlusive disease of renal arteries at DSA. Sensitivity, specificity, and accuracy of CE MR angiography for detection of 51% or greater stenosis or occlusion were 60.1%-84.1%, 89.4%-94.7%, and 80.4%-86.9%, respectively, at segment level. Similar values were obtained for predictive values and for patient-level analyses. Few CE MR angiographic examinations (1.9%-2.8%) were technically inadequate. Interobserver agreement for detection of significant steno-occlusive disease was good (79.9% agreement; kappa = 0.69). No safety concerns were noted. CONCLUSION: CE MR angiography performed with 0.1 mmol/kg gadobenate dimeglumine, compared with DSA, is safe and provides good sensitivity, specificity, and accuracy for detection of significant renal artery steno-occlusive disease.