SONOTHROMBOLYSIS: An EFFECTIVE STROKE TREATMENT ?

Abstract

New therapeutic strategies under development aim to improve recanalization rates and clinical outcomes after ischemic stroke. One such approach is ultrasound (US)-enhanced thrombolysis, or sonothrombolysis, which can improve thrombolytic drug actions and even intrinsic fibrinolysis. Although the mechanisms are not fully understood, it is postulated that thrombolysis enhancement is related to nonthermal mechanical effects of US. Recent results indicate that US with or without microbubbles may be effective in clot lysis of ischemic stroke even without additional thrombolytic drugs. Sonothrombolysis is a promising tool for treating acute ischemic stroke, but its efficacy, safety, and technical details have not been elucidated and proved yet in stroke treatment.

Acute cerebral artery occlusion leads to ischemic brain tissue damage, which is time dependent. If the artery is not opened quickly, the ischemic process worsens, leading to tissue death and cerebral infarction. These factors are the most important determinants of the quality of life and life expectancy of stroke survivors.1

Currently, the only approved treatment for acute ischemic stroke is intravenous (IV) recombinant tissue plasminogen activator (tPA) administered during the first 3 hours after symptom onset.2,3 In Europe, this time window has been extended to 4.5 hours according to recommendations from the European Cooperative Acute Stroke Study III.4

When given IV, tPA can initiate intracranial thrombus dissolution within minutes. This early and very often partial recanalization can lead to ischemic tissue rescue and subsequent recovery. However, less than 5% of patients with ischemic stroke receive IV tPA. Furthermore, only 30% to 40% of treated patients achieve early recanalization, and the recanalization is complete and sustained in only 18%.5–7

Carotid and transcranial sonography in acute stroke allows early recognition of the stroke subtype, etiology, and clinical prognosis at the bedside.8,9 Furthermore, during tPA treatment, continuous transcranial Doppler monitoring can be performed easily with a fixed head frame directed to the occluded cerebral artery. With this procedure, information about vessel patency can be obtained in real time, allowing better selection of patients who could benefit from more aggressive endovascular reperfusion therapies.10

Sonothrombolysis in Stroke Treatment

New therapeutic strategies under development aim to improve recanalization rates and clinical outcomes after ischemic stroke. One such approach is ultrasound (US)-enhanced thrombolysis, or sonothrombolysis, which can improve drug actions and even intrinsic fibrinolysis. The ability of US energy to increase enzymatic thrombolysis was first described in 1976,11 and several experimental studies have confirmed this finding.12–14 Although the mechanisms are not fully understood, it is postulated that thrombolysis enhancement is related to nonthermal mechanical effects of US.15

Negative-pressure US waves inside blood vessels create fluid motion, or microstreaming, and radiation forces, which can promote tPA circulation and increase the thrombus surface in contact with the enzyme.16 Furthermore, in vitro studies have shown that US insonation on a clot leads to reversible disaggregation of cross-linked fibrin fibers.17 Ultrasound can also increase the exposed plasmin-binding sites and the penetration of fibrinolytic enzymes into the clot.18 Acoustic cavitation, which is the ability of US to create microbubbles from gases dissolved in a liquid medium, may also play a role in sonothrombolysis by direct harm to the clot surface or an increase in tPA permeation inside the thrombus.19

Several US frequencies and intensities have been tested in vitro and in animal models.13,18,20–22 The negative US pressure is directly related to the US intensity and inversely related to the frequency.22 Higher US frequencies lead to greater energy attenuation through the skull (up to 90% of energy is lost at 1–2 MHz). On the other hand, an increase in the thermal effects of US is associated with higher intensities.23,24 Therefore, most initial in vitro and animal models for sonothrombolysis were developed with low US frequencies (kilohertz range) and low intensities (0.2–2 W/cm²).24 However, a clinical trial of low-frequency US showed harm from symptomatic bleeding into the brain.25 For that reason, clinical trials at the present time are restricted to higher-frequency, low-intensity US, similar to that used for diagnostic purposes. Frequencies of 1 to 2 MHz have been shown to be safe and effective in experimental models as well as phase 1 and 2 clinical trials. These frequencies also provide information about vessel patency in real time.7

One of the first clinical trials on sonothrombolysis in acute ischemic stroke used low frequencies delivered by pulsed US at 300 ± 1.5 kHz with a spatial-peak temporal-average intensity of 700 mW/cm².15 A special device was designed for the study, which emitted US waves from 4 diamond-shaped transducers exposing the middle cerebral artery from the contralateral temporal bone surface.25 The Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia trial included acute stroke patients presenting within a 6-hour time window from stroke onset with a baseline stroke severity score of greater than 4 points on the National Institutes of Health (NIH) Stroke Scale at admission and with evidence of proximal intracranial occlusion on brain magnetic resonance angiography.

Patients were randomized to either IV tPA alone (control treatment arm) or IV tPA in conjunction with 90 minutes of low-frequency US insonation (active treatment arm). The study was prematurely stopped because of a significant increase in intracerebral hemorrhage rates in the target group treated with IV tPA and low-frequency US (36% in the active treatment arm versus 0% in the control treatment arm). There were no differences in the recanalization rates or long-term outcomes between the groups. Some of the intracranial hemorrhages in the target group occurred in atypical areas for patients with stroke (subarachnoid, intraventricular, and contralateral hemorrhages). Subsequent experiments suggested that low-frequency US may cause “hot spots” due to summation of US waves when the pulse repetition frequency remains relatively high. In addition, beam propagation and reflections would be different in the human skull than in the small craniums of animal models,25 and a large brain area insonated with the 4-element transducer would increase the amount of potential tissue exposed to US, where low-frequency US could cause disruptions of small arterioles or the blood-brain barrier due to longer wavelengths.26

The safety and efficacy of higher frequencies (2 MHz) was studied at low-intensity (<700 cm="" mw="" span="">²) diagnostic US settings in the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic tPA trial.7 This randomized international study tested the combination of 0.9-mg/kg IV tPA administered during a 3-hour window including 2 hours of continuous monitoring with conventional diagnostic transcranial Doppler imaging. After the occlusion was detected on transcranial Doppler imaging, a head frame was placed, which allowed hand-free continuous insonation during 2 hours in the target group with placebo monitoring in controls (1:1 randomization). The prespecified safety end point was symptomatic intracranial hemorrhage, causing worsening of the neurologic deficit by 4 points or more on the NIH Stroke Scale. The primary combined activity end point was complete recanalization on transcranial Doppler imaging or a dramatic clinical recovery, defined as a total NIH Stroke Scale score of 3 points or less or improvement in the score by at least 10 points within 2 hours after the tPA bolus. The clinical investigators were blinded to the group assignment (active or sham monitoring) made by the sonographers. One hundred twenty-six patients were included in the study, and after adjusting for potential confounders, 49% of the target group achieved the combined efficacy end point, compared to 30% of the controls (P = .03). The symptomatic intracranial hemorrhage rate was 4.8% in both groups, and there was a trend toward a better functional outcome in the target group.27

Recently, the results of a small randomized trial with transcranial color-coded US have been reported.28 Transcranial color-coded US transducers have a wider footprint than the 1-cm diameter of transcranial Doppler probes. Transcranial color-coded US generates multiple small beams at dual emission frequencies: ie, one for Doppler imaging (1.8 MHz) and one for grayscale imaging (4 MHz). Patients with less than 3 hours of acute proximal middle cerebral artery occlusion treated with conventional IV tPA were randomized by a coin toss to 1-hour handheld US monitoring of the occluded artery or diagnostic transcranial color-coded US every 20 minutes  for 1 hour with a “refresh” mode (grayscale and color-coded imaging of the vessel) every 7 seconds to confirm the location of the pulsed Doppler insonation on the sphenoid segment of the middle cerebral artery. Thirty-seven patients were included, 19 of whom were in the target group. Partial or complete recanalization was achieved in 57% of the patients in the target group (22.2% in controls; P = .045), with better early clinical evolution and a significantly higher rate of Barthel Index values of 95 or greater at 3 months (8 of 19; P = .003). However, the rate of symptomatic intracranial hemorrhage in the patients who received continuous transcranial color-coded US monitoring tended to be higher than in the controls (15.8% versus 5.6%, respectively; P = .60). The small numbers of the study preclude definitive conclusions, but the higher hemorrhage rate compared to the transcranial Doppler studies could be related to increased brain tissue insonation (as in the Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia trial). Furthermore, the dual frequencies of the transcranial color-coded US transducers and their higher mechanical indices could increase the hemorrhagic risk. Another problem with transcranial color-coded sonothrombolysis is the absence of head frames, which forces a handheld approach and probably would prevent generalization of the treatment.29

Use of Microbubbles in Sonothrombolysis

Experimental and in vivo studies have shown that US by itself and, especially, enhanced by microbubbles can induce clot lysis without a fibrinolytic drug.30–32 This effect would probably be related to an increase in the intrinsic fibrinolytic activity, although mechanical thrombus damage by US energy can be detected in experimental models.

In human stroke, a small study tested application of US without fibrinolytic drugs in patients with contraindications to or ineligibility for IV tPA treatment.33 Fifteen patients with proximal middle cerebral artery occlusion and contraindications to tPA were randomized to 1 hour of continuous transcranial color-coded US monitoring or a placebo. The target group achieved a higher recanalization rate and an earlier clinical outcome, but these promising results need to be confirmed in larger studies.

Microbubbles, or microspheres, are gas- or air-filled lipid shell bubbles in the micrometer size range that have been used for a long time as diagnostic US echo contrast agents.30 In the last few years, some experimental data have suggested that microbubbles can also increase the effect of US in sonothrombolysis.19,31 When microbubbles pass through the US energy field, they undergo translations and size oscillations (static cavitation), which generate harmonic signals that are able to increase the acoustic impedance mismatch between the blood and surrounding tissue, improving the diagnostic value of vascular US. These harmonic emissions also release energy and agitate the fluid where the spheres are dissolved, improving tPA delivery and penetration inside a clot.32 If the negative US pressure is increased, the bubble collapses (inertial cavitation), leading to intense localized stresses and microjets, which can cause mechanical fragmentation of the thrombus.34 Therefore, microbubbles act as nuclei for acoustic cavitation, lowering the US intensity threshold for this acoustic phenomenon, which probably cannot be achieved without microbubbles with the low-intensity US emissions permitted in human practice.19

In human stroke, the largest study of microbubble-enhanced sonothrombolysis published to date tested the synergic effect of 3 bolus injections of air-filled galactose-based microbubbles (Levovist; Schering AG, Berlin, Germany) associated with 2 hours of continuous high-frequency, low-intensity diagnostic transcranial Doppler monitoring and IV tPA.35 This pilot study was nonrandomized, included patients with acute middle cerebral artery occlusion within a 3-hour window, and compared the protocol described in the US + tPA group and the tPA-alone group from the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic tPA trial. Thirty-eight patients were treated with microbubbles, and the investigators showed that 2 hours after the tPA bolus, the tPA + transcranial Doppler US + Levovist group achieved a 55% sustained recanalization rate compared to 40% and 23% in the tPA + transcranial Doppler US and tPA-alone groups. The rate of intracranial hemorrhage in the target group was 23%, with only 3% symptomatic intracranial hemorrhage, probably reflecting a higher recanalization rate, according to the authors.

The same microbubble type was tested with transcranial color-coded US in patients with acute middle cerebral artery occlusion of less than 3 hours who were randomized to conventional IV tPA alone or tPA and 1 hour of handheld transcranial color-coded US monitoring and a continuous infusion of Levovist during the same period. Complete recanalization in the target group was achieved in 48% of cases, but the study was stopped with only 9 patients included because of an unexpected increase in the intracranial hemorrhage rate (78%). However, none of the hemorrhages were symptomatic, which made the decision of stopping the study controversial. It was also unclear whether the hemorrhage increase could be related to the synergistic effect of the microbubbles or the transcranial color-coded US monitoring (which has been suggested previously), and this issue may not be resolved in the absence of a non-US group.36

On the basis of these promising results, a multicenter international dose escalation phase 1 and 2 single-blinded trial (Transcranial Ultrasound in Clinical Sonothrombolysis) was designed.37 Patients with acute intracranial artery occlusion detected by transcranial Doppler imaging were randomized 2:1 to IV tPA plus continuous infusion of lipid-coated microbubbles containing C3F8 (perflutren) (MRX-801; ImaRx Therapeutics, Inc, Tucson, AZ) plus transcranial Doppler monitoring during 90 minutes or conventional IV tPA. The primary safety outcome was the presence of symptomatic intracranial hemorrhage, and activity outcomes were the complete recanalization rate and functional outcome. Thirty-five patients were included: 23 in the target group (cohort 1, 1.4 mL of microbubbles, 12 patients; cohort 2, 2.8 mL of microbubbles, 11 patients). Twelve control patients received 0.9-mg/kg IV tPA and brief transcranial Doppler assessments. There was no symptomatic hemorrhage in the first cohort and controls, but there were 3 in cohort 2 (27%), of which 2 were fatal, so the study was stopped by the sponsor. The recanalization tended to be faster and higher in both treatment groups (67% and 46% of complete recanalization in cohorts 1 and 2, respectively, compared to 33% in controls), and there was a trend toward a better functional outcome after 3 months in the patients who received the microbubbles. The authors suggested that the increased symptomatic intracranial hemorrhage in cohort 2 may have been influenced by imbalances between the groups. Cohort 2 had a higher baseline NIH Stroke Scale score, a longer interval between tPA and microbubble (MRX-801) infusion, and, probably most important, a higher systolic blood pressure with blood pressure control protocol violations. Therefore, a safe dose of 1.4 mL has been identified as having a trend toward an increased recanalization rate and better functional outcomes; thus, additional larger studies with extended enrollment and further experiments are needed to determine the mechanisms by which microbubbles and US interact with tissue, particularly ischemic stroke tissue.

Safety and Efficacy of Sonothrombolysis

A meta-analysis of randomized and nonrandomized studies on the safety and efficacy of sonothrombolysis38 identified and analyzed all studies of US-enhanced thrombolysis in acute ischemic stroke. Recanalization rates and symptomatic intracranial hemorrhage were compared between tPA, tPA + transcranial Doppler US ± microbubbles, tPA + transcranial color-coded US ± microbubbles, and tPA + low-frequency US.

A total of 6 randomized (n = 224) and 3 nonrandomized (n = 192) studies were identified. The rates of symptomatic intracranial hemorrhage in randomized studies were as follows: tPA + transcranial Doppler US, 3.8% (95% confidence interval [CI], 0%–11.2%); tPA + transcranial color-coded US, 11.1% (95% CI, 0%–28.9%); tPA + low-frequency US, 35.7% (95% CI, 16.2%–61.4%); and tPA alone, 2.9% (95% CI, 0%–8.4%). Complete recanalization rates were higher in patients receiving a combination of transcranial Doppler with tPA compared to patients treated with tPA alone: 37.2% (95% CI, 26.5%–47.9%) versus 17.2% (95% CI, 9.5%–24.9%), respectively.

In 8 trials of high-frequency (transcranial Doppler/transcranial color-coded US) US-enhanced thrombolysis, tPA + transcranial Doppler/transcranial color-coded US ± microbubbles was associated with a higher likelihood of complete recanalization (pooled odds ratio, 2.99; 95% CI, 1.70–5.25; P = .0001) compared to tPA alone. High-frequency sonothrombolysis was not associated with an increased risk of symptomatic intracerebral hemorrhage (pooled odds ratio, 1.26; 95% CI, 0.44–3.60; P = .67). The conclusion of this extensive meta-analysis was that sonothrombolysis with high-frequency diagnostic US appears to be safe, leading to higher rates of complete recanalization compared to systemic thrombolysis.38

To date, no studies of the thrombolytic effects of microbubbles and US alone, without tPA, have been done in human stroke patients.39 Combined therapy with US and microbubbles without tPA was successfully used for lysis of thrombosed dialysis grafts in 22 humans. No adverse events were encountered, and the microbubble clearing of the thrombosed grafts was similar to the effect of tPA alone.40

Recent results suggest that US and microbubbles may be effective for clot lysis in ischemic stroke even without additional thrombolytic drugs. Although improved clinical thrombolysis with microbubbles in combination with US with or without thrombolytic drugs shows great promise in stroke treatment, the optimal techniques and application protocols, indications, and contraindications have to be defined. On the other hand, the optimal microbubble dosage, mode of delivery, thrombolytic drug dosage, and US characteristics (frequency, duration, and mode of insonation) all remain uncertain and need clarification.39,41

Novel Developments in Sonothrombolysis

Novel developments combine nanotechnology with microbubbles for drug delivery (like glycoprotein IIb/IIIa inhibitors). Entrapment of tPA in liposomes can also improve the efficacy of thrombolysis by clot cavitation and acoustic radiation force. Targeting of clot-dissolving therapeutic agents could potentially decrease the frequency of complications while simultaneously increasing treatment effectiveness by concentrating the available drug at the desired site, thus permitting a lower systemic dose of a thrombolytic drug.39 Recent data also suggest that US and microbubbles with or without thrombolytic drugs can also improve flow in the cerebral microcirculation, which may provide new concepts for stroke treatment.39

The complex effect of US on acceleration of thrombus lysis has not been completely elucidated yet. It is assumed that US waves accelerate enzymatic fibrinolysis primarily by nonthermal mechanisms. Other mechanical effects of US, such as temporary peripheral vasodilatation caused by increased production of dinitrogen oxide in the endothelium, radiation forces, and acoustic cavitation, have been noted in the peripheral circulation.15,24

A recently published article by Bardoň et al42 assessed the effect of continuous 1-hour insonation (sonolysis) of the middle cerebral artery in 15 healthy volunteers using a 2-MHz diagnostic transcranial probe. Measurements of blood flow parameters were performed at 2-minute intervals, and during the second session, a flow curve was recorded for 10 seconds at 2-minute intervals. Although irregular changes were recorded in the measured parameters (peak systolic velocity, end-diastolic velocity, mean flow velocity, pulsatility index, and resistive index) during both measurements, there were no significant differences between the two measurements. As opposed to sonolysis of the radial artery, sonolysis of the middle cerebral artery using a diagnostic 2-MHz frequency in healthy volunteers did not lead to significant changes in the cerebral hemodynamic parameters (peak systolic velocity, end-diastolic velocity, pulsatility index, and resistive index) or peripheral vasodilatation. This finding implied that exposure to US energy in the range used for sonolysis is unlikely to cause a primary alteration in cerebral hemodynamic parameters or vasodilatation. However, a synergistic effect during the release of bioactive compounds, enzymes, and proteins cannot be excluded.

The different results seen for the effects of US on peripheral arteries (radial arteries) and cerebral arteries (middle cerebral arteries) can at least in part be explained by the influence of autoregulation in cerebral arteries, which prevents strong vasodilatation caused by US. This factor could be one of the important explanations for the huge differences in recanalization and reocclusion rates, symptomatic intracranial hemorrhage rates, and outcomes for different US frequencies and modes of application of sonothrombolysis in acute ischemic stroke treatment published until now.

In conclusion, sonothrombolysis could become an effective, safe, standardized, and highly recommended treatment of acute ischemic stroke, but further studies are needed to elucidate its complex mechanisms of action and to identify subgroups of patients with ischemic stroke who would have the highest benefit from this kind of therapy.

Abbreviations

CI=confidence interval, IV=intravenous, NIH=National Institutes of Health, tPA=tissue plasminogen activator, US=ultrasound

© 2013 by the American Institute of Ultrasound in Medicine

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Ultrasound Helps Spot Early Liver Cancer

Reuters Health Information

Biannual Ultrasound Helps Spot Early Liver Cancer

Jun 26, 2013

By David Douglas

NEW YORK (Reuters Health) Jun 26 - In cirrhotic patients, biannual ultrasonography may have advantages over annual computed tomography for detecting early hepatoma, researchers suggest.

Whether early detection will reduce mortality is another question, however.

"No appropriately designed study has ever shown a mortality benefit" of screening for early hepatocellular carcinoma (HCC), said study coauthor Dr. Christine Pocha, of Minneapolis VAHCS System, Minnesota, in email to Reuters Health.

"More importantly," she continued, "surveillance programs must recognize the limitations in HCC surveillance tests and treatment efficacy in specific patient populations."

Still, she added, ultrasound screening has been recommended for more than a decade. Alpha-fetoprotein (AFP) levels were used until recently as well, although that marker has now been dropped officially because of a lack of sensitivity.

There's no consensus on screening intervals, however, and now some providers have started to use computed tomography (CT), as Dr. Pocha's team points out in a June 10 online paper in Alimentary Pharmacology and Therapeutics.

In the current study, the researchers sought to evaluate CT screening, thinking it would detect smaller tumors at lower overall cost.

They randomized 163 Veterans Health Administration patients with compensated cirrhosis to biannual ultrasonography (US) or yearly triple-phase-contrast CT. In addition, patients had AFP testing twice per year.

The HCC incidence was 6.6% per year. Nine HCCs were detected by US and eight by CT. Sensitivity and specificity rates, respectively, were 71.4% and 97.5% with US vs 66.7% and 94.4% with CT.

The biannual AFP testing added little to overall HCC detection, the investigators say. They add, however, that its cost was low, and one patient was identified by increasing AFP level, although initial imaging was negative.

But while 58.8% of HCCs were detected at an early stage, only 23.5% of patients received potentially curative treatment, and only one patient received a liver transplant. HCC-related mortality was 70.5% and overall mortality was 82.3%, suggesting that most patients died of their cancer.

The researchers conclude that biannual US was marginally more sensitive and less costly than annual CT for detecting early HCC. Because of the costs and the risks involved in CT, they say it "should not be used as screening tool for a population at risk for HCC."

Advances in screening technologies and HCC treatments "may provide further incremental improvements in the cost/effectiveness equation," Dr. Pocha told Reuters Health.

But in the meantime, her team concludes in its paper, "The overall efficacy of HCC surveillance in a cirrhotic population in the United States has yet to be demonstrated, and further research is needed."

SOURCE: http://bit.ly/1afuQLP

Aliment Pharmacol Ther 2013.

Summary

Background

Guidelines recommend screening for hepatocellular cancer (HCC) with ultrasonography. The performance of ultrasonography varies widely. Computed tomography (CT) is less operator dependent.

Aim

To compare the performance and cost of twice-a-year ultrasonography to once-a-year triple-phase-contrast CT for HCC screening in veterans. We hypothesised that CT detects smaller HCCs at lower overall cost.

Method

One hundred and sixty-three subjects with compensated cirrhosis were randomised to biannual ultrasonography or yearly CT. Twice-a-year alpha-feto protein testing was performed in all patients. Contingency table analysis using chi-squared tests was used to determine differences in sensitivity and specificity of screening arms, survival analysis with Kaplan–Meier method to determine cumulative cancer rates. Multivariate logistic regression models were used to examine predictive factors.

Results

Hepatocellular cancer incidence rate was 6.6% per year. Nine HCCs were detected by ultrasonography and eight by CT. Sensitivity and specificity were 71.4% and 97.5%, respectively, for ultrasonography vs. 66.7% and 94.4%, respectively, for CT. Although 58.8% of screen-detected HCC were early stage (Barcelona Clinic Liver Cancer stage A), only 23.5% received potentially curative treatment despite all treatment options being available. HCC-related and overall mortality were 70.5% and 82.3%, respectively, in patients with screen-detected tumour. Overall costs were less for biannual ultrasonography than annual CT.

Conclusions

Biannual ultrasonography was marginally more sensitive and less costly for detection of early HCC compared with annual CT. Despite early detection, HCC-related mortality was high. These data support the use of biannual ultrasonography for HCC surveillance in a US patient population (NCT01350167).

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Ultrasound and Osteoporosis

www.portableultrasoundmachines.net/ultr...

There is an insidious nature to osteoporosis. It is a gradual loss of bone tissue that is so slow that it is usually not noticed until there is a traumatic event like a fracture. Screens exist that can predict osteoporosis and allow treatment to begin early, and one of the best screens is ultrasound based.

Quantitative ultrasound (QUS) measures the speed of sound and broad band ultrasonic attenuation of the ultrasound beam as it passes between two ultrasound transducers. QUS can become a screen that may be predict future fractures in peri-menopausal and immediate post-menopausal women, and senior citizens of both genders. Those who have low QUS values for the ankle bone, the most common bone screened, are referred for further testing, like measurements of the spine.

QUS works by measuring how the ultrasound machine beam changes as it passes through the bone. The name for this type of ultrasound is Broad Band Ultrasonic Attenuation, or BUA. QUS can also measure how quickly the ultrasound beam passes through the patient’s bone; the name for this is Speed of Sound, abbreviated as SOS.

These two readings when taken together can tell us about how bones are structured, whether or not they are elastic, and how strong they are—in short, measures of the quality of the bone. That can be compared to the bone density. Taken together, these two assessments can help doctors predict each patient’s risk of suffering a bone fracture.

The bones of the foot are used because just like the lumbar spine, as we age these bones change. Spinal changes cause the majority problems in patients with osteoporosis. In addition, QUS is a simple process, the equipment is portable, and for the patient there is no radiation exposure.

In the three-year multicenter study, 6,174 women age 70 to 85 with no previous formal diagnosis of osteoporosis were screened with heel-bone quantitative ultrasound (QUS), a diagnostic test used to assess bone density. QUS was used to calculate the stiffness index, which is an indicator of bone strength, at the heel. Researchers added in risk factors such as age, history of fractures or a recent fall to the results of the heel-bone ultrasound to develop a predictive rule to estimate the risk of fractures. The results showed that 1,464 women (23.7 percent) were considered lower risk and 4,710 (76.3 percent) were considered higher risk.
Study participants where mailed questionnaires every six months for up to 32 months to record any changes in medical conditions, including illness, changes in medications or any fracture. If a fracture had occurred, the patients were asked to specify the fracture's precise location and trauma level and to include a medical report from the physician in charge.
In the group of higher risk women, 290 (6.1 percent) developed fractures whereas only 27 (1.8 percent) of the women in the lower risk group developed fractures. Among the 66 women who developed a hip fracture, 60 (90 percent) were in the higher risk group.
The results show that heel QUS is not only effective at identifying high-risk patients who should receive further testing, but also may be helpful in identifying patients for whom further testing can be avoided.
"Heel QUS in conjunction with clinical risk factors can be used to identify a population at a very low fracture probability in which no further diagnostic evaluation may be necessary".

 Studies have shown that a combination of QUS and an inquiry about personal and familial risk factors would detect more cases of osteoporosis and had slightly better chance to predict fractures than the risk factors inquiry alone. It has also been discovered that ultrasound test alone have much better predictive value than risk factors alone. It is, however, still good clinical practice to do an overall assessment of risk for osteoporosis rather than QUS alone.

Ultrasound machine scanning, therefore, is a simple, quick, safe, portable, and inexpensive clinical test. It can provide physicians an opportunity to improve on the current method of identifying patients at risk for osteoporosis and the associated fractures.

THYROID NODULES: ROLE of CORE-NEEDLE BIOPSY

Abstract

Purpose: To evaluate the role of core-needle biopsy (CNB) in thyroid nodules with nondiagnostic results at previous fine-needle aspiration (FNA).

Materials and Methods: From October 2008 to July 2011, 155 nodules from 155 patients (37 men, 118 women) with a mean age of 51.8 years (age range, 22–76 years) with nondiagnostic results at previous FNA were reviewed retrospectively. The Bethesda system for reporting thyroid cytopathologic results was used to assign FNA and CNB findings. Malignant nodules (n = 37) were diagnosed after surgery. Benign nodules (n = 79) were diagnosed either after surgery, with benign findings after FNA and/or CNB that had been repeated at least twice, or after benign cytology findings at FNA or CNB with a stable size at follow-up. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of ultrasonographically guided CNB were evaluated.

Results: At CNB, two nodules (1.3%) showed nondiagnostic results, and 135 nodules (87.1%) had conclusive diagnoses. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of core biopsies for the detection of malignancy were 94.6% (35 of 37), 100% (79 of 79), 100% (35 of 35), 97.5% (79 of 81), and 98.3% (114 of 116), respectively. For 28 nodules, nondiagnostic results were found after two or more FNA procedures; however, diagnostic surgery was performed in only one patient.

Conclusion: CNB of the thyroid nodule demonstrates high rates of conclusive and accurate diagnoses in patients for whom previous FNA results were nondiagnostic, thereby reducing the need for unnecessary diagnostic surgery.

© RSNA, 2013

NHÂN CA PSEUDOMYXOMA PERITONEI ở MEDIC

Xem Appendiceal Mucocele: US Findings
Xem Nhân ca u nhày ruột thừa gây lồng ruột tại Medic 
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Pseudomyxoma peritonei (PMP) usually begins as a slow-growing tumour in the appendix, called a Low-Grade Mucinous Appendiceal Neoplasm (LAMN). Rarely, PMP starts in other parts of the bowel, ovary or bladder.

Over time, the tumour produces a jelly-like substance called mucin. This can cause the appendix to swell up like a balloon. The tumour can then break through the wall of the appendix and spread tumour cells into the lining of the tummy (the peritoneum).

The tumour cells and mucin build up in the lining of the tummy, putting pressure on the bowel and causing symptoms. It can be many years before symptoms become obvious. Unlike other cancers, PMP rarely spreads via the lymphatic system or the bloodstream. It usually remains inside the tummy, spreading along its internal surfaces.

Causes of pseudomyxoma peritonei

The cause of PMP is unknown.

Signs and symptoms of pseudomyxoma peritonei

Most people don't have any symptoms for a long time. When symptoms occur they may include any of the following:

• slow increase in waist size
• hernia (a swelling on the abdomen)
• loss of appetite
• unexplained weight gain
• abdominal or pelvic pain
• changes in bowel habits
• appendicitis.

Most people with these symptoms won't have PMP, but it's important to have any symptoms checked by your doctor.

How pseudomyxoma peritonei is diagnosed

PMP can be difficult to diagnose. It may be found during investigations into abdominal symptoms, or it may be discovered during an operation for another problem.

CT (computerised tomography) scan

A CT scan takes a series of x-rays that build up a three-dimensional picture of the inside of the body. The scan is painless. It can help to find where the tumour started and check whether it has spread within the abdomen. It usually takes 10-30 minutes. CT scans use a small amount of radiation, which is very unlikely to harm you and won't harm anyone you come into contact with. You will be asked not to eat or drink for at least four hours before the scan.

You may be given a drink or injection of a dye, which allows particular areas to be seen more clearly. For a few minutes, this may make you feel hot all over. If you are allergic to iodine or have asthma you could have a more serious reaction to the injection, so it's important to let your doctor know beforehand.

Sometimes the pictures from the CT scan are enough to make the diagnosis, but sometimes biopsies or an operation are needed to be sure of the diagnosis of PMP.

Treatment

The treatment of PMP depends on a number of factors. These include how far the tumour has spread and your general health. Some of the standard cancer treatments, such as radiotherapy, aren't suitable for treating PMP. This is because PMP cells aren't sensitive to radiotherapy and they are often spread over too large an area for this treatment.

Surgery

You may be offered surgery| to treat this kind of cancer. There are two types of surgery:

• Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).
• Debulking surgery.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC)

This may be an option for some people. It‘s an intensive treatment that aims to remove the tumour to try to cure PMP. It is also known as the Sugarbaker technique (named after the surgeon who first developed it). It involves removing the lining of the abdomen or organs such as the bowel, omentum (fatty tissue in the tummy) and gallbladder. In women, the womb (uterus) and ovaries may also be removed. About half (50%) of people who have a Sugarbaker operation will need a stoma (colostomy). Most of the stomas are temporary and will be reversed after about six months.

Once the surgeon has removed all or most of the tumour, a heated chemotherapy drug is put in the tummy (hyperthermic intraperitoneal chemotherapy) for 90 minutes during the operation. The combination of the chemotherapy drug and heat aims to kill any tumour cells that are left behind.

This is a major operation and may take up to 10 hours. Afterwards, you’ll be nursed in a critical care unit for several days and will stay in hospital for about 2 weeks. This operation has potentially serious complications and the surgeon will discuss these with you.

The National Institute for Health and Clinical Excellence (NICE)| is an organisation that currently advises doctors on treatments for all types of illness. It has produced guidelines about this type of surgery with intraperitoneal chemotherapy. You can read the guidelines on the NICE website.

It's very important to discuss this operation with specialist doctors, as the Sugarbaker technique is a very complicated procedure and isn't suitable for everyone. It should only be carried out at a specialist centre. There are two in the UK:

• The Basingstoke and North Hampshire Hospital
• The Christie Hospital – Manchester.

Debulking surgery

This is done when it’s not possible to have cytoreductive surgery. It aims to remove as much of the tumour as possible to reduce the symptoms of the cancer. This may involve removing the omentum (fatty tissue in the tummy) and part of the bowel. In women, the womb (uterus) and ovaries may also be removed.

Unfortunately, this surgery will not take away all the tumour cells and the PMP is likely to grow back. Further debulking operations may be needed. However, each operation becomes more difficult to do, with less benefit and more risks of complications each time.

Sometimes, a permanent stoma is needed after debulking surgery. It can help to prevent the bowel from becoming blocked (obstructed). Your specialist nurse can give you more information about looking after a stoma.

Chemotherapy

Chemotherapy| can be used to treat PMP. Some people who can’t have surgery may benefit from chemotherapy. It does not cure the cancer but can be used to slow it down. Research into other treatments for PMP is ongoing and advances are being made. Cancer specialists use clinical trials| to assess new treatments. You may be asked to take part in a clinical trial. Your doctor must discuss the treatment with you so that you have a full understanding of the trial and what it means to take part.

Watchful waiting

For some people, the risks of treatment may outweigh the potential benefits, especially as this can be a slow-growing cancer. If you're in this situation, your specialist may suggest watchful waiting. This involves being monitored closely with regular check-ups. Only if the PMP begins to cause you problems will your specialist discuss starting treatment.

Reviewing information is just one of the ways you could help when you join our Cancer Voices network|.

Content last reviewed: 1 February 2013

Ultrasound Helps Diagnose Lung Congestion in Dialysis Patients

 

 

Asymptomatic lung congestion has been shown to increase dialysis patients’ risks of dying prematurely or experiencing myocardial infarctions or other cardiac events, according to recent research.

The findings also revealed that utilizing lung ultrasound to identify this congestion aids in diagnosing patients at risk. Italian investigators recently measured the degree of lung congestion in 392 dialysis patients by using a very simple and inexpensive technique – lung ultrasound.

Lung congestion due to fluid accumulation is very common among kidney failure patients on dialysis, but it frequently does not cause any symptoms. To see whether such asymptomatic congestion affects dialysis patients’ health, Carmine Zoccali, MD, from Ospedali Riuniti (Reggio Calabria, Italy; www.rc.ibim.cnr.it) and his colleagues published their study findings February 28, 2013, in the  Journal of the American Society of Nephrology (JASN).

Among the major findings (1) Lung ultrasound revealed very severe congestion in 14% of patients and moderate-to-severe lung congestion in 45% of patients. (2) Among those with moderate-to-severe lung congestion, 71% were asymptomatic. (3) Compared with those having slight or no congestion, those with very severe congestion had a 4.2-fold increased risk of dying and a 3.2-fold increased risk of experiencing heart attacks or other cardiac events over a two-year follow-up period. (4) Lastly, asymptomatic lung congestion identified by lung ultrasound was a better predictor of patients’ risk of dying prematurely or experiencing cardiac events than symptoms of heart failure.

By evaluating subclinical pulmonary edema can help better establish dialysis patients’ prognoses, according to the findings.The researchers will soon initiate a clinical trial that will integrate lung fluid measurements by ultrasound and will examine whether dialysis intensification in patients with asymptomatic lung congestion can reduce the risk of heart failure and cardiac events and prevent premature death.

From MII, June 2013

 Background

Advancement in dialysis technology and new drug therapies of uremic complications are major achievements of modern nephrology. As a result of progress in the care of ESRD, a continuous increase in survival of dialysis 4 patients has been documented over the last 13 years in the European Renal Association-European Dialysis Transplant Association (ERA-EDTA) registry (1). Adequate control of fluid balance is a primary goal of dialysis treatment and experience in centres applying strict volume control policies documented a remarkable reduction in mortality in comparison with average mortality rate in well matched cohorts in the USRDS and in the ERA-EDTA Registry (2). Even though specific recommendations in past and current guidelines emphasise the risk of volume overload, the problem still remains pervasive in the dialysis population (3). Unsatisfactory control of volume expansion depends on various reasons encompassing both medical and non-medical factors such as reimbursement of the cost of extra or longer dialyses and other organizational and logistic factors. As to the medical factors, it is widely agreed that the high prevalence of patients with LV dysfunction and heart failure and the lack of simple, non-expensive, bedside techniques that may serve to estimate and monitor parameters of central hemodynamics for guiding the prescription of ultrafiltration (UF) and drug treatment  is a factor of major clinical relevance.

Extra-vascular lung water (LW), a fundamental component of body fluids volume, represents the water content of the lung interstitium which is strictly dependent on the filling pressure of the left ventricle (4; 5). Chest ultrasound (US) has recently emerged as a reliable technique for detecting LW in intensive care patients (6) and in patients with heart failure (7). The basic principle of this technique is that in the presence of excessive LW, the ultrasound beam is efflected by subpleural thickened interlobular septa, a low impedance structure surrounded by air with a high acoustic mismatch. US reflection generates hyperechoic reverberation artefacts between thickened septa and the overlying pleura which are defined “lung comets” (8). These artefacts are easily detected with standard US probes and chest US has been formally validated as a reliable technique to estimate LW in patients with heart diseases (9). This method captures changes in LW which occur across dialysis and the feasibility and repeatability of chest US studies in hemodialysis patients has been recently described (10). However the clinical usefulness of this technique in the everyday care in ESRD patients is still untested and it remains unknown whether systematic application of chest US may translate into better clinical outcomes in these patients. With this background in mind the European Renal and Cardiovascular Medicine (EURECA-m) working group of the ERA-EDTA designed a randomised, multicenter, clinical trial investigating whether a treatment policy based on LW monitoring in haemodialysis patients by chest US is more effective than standard clinical monitoring for reducing death, decompensated heart failure and myocardial infarction and prevent the evolution of LVH and LV dysfunction in patients with myocardial ischemia or heart failure over a 2-year follow-up.

 

This trial will be the first which formally tests a biomarker as a guide the optimize volume control and drug treatment in high risk dialysis patients. Other promising indicators of fluid volume in dialysis patients - such as body impedance analysis (BIA) or cardiac natriuretic peptides - have never been tested into a clinical trial, which is a basic requirement for recommending systematic use of biomarkers in clinical practice.