Comparative study of experienced vs non-experienced radiologists in assessing parametric CT images of the response of the prostate gland to radiotherapy.

Functional CT can demonstrate acute quantitative increases in perfusion, permeability and fractional vascular volume in the prostate gland of patients with prostate cancer following radiotherapy (RT). We hypothesize that these quantitative changes can also be demonstrated visually by presenting them as colour parametric maps using custom software. 21 patients with prostate cancer were studied before, and 1-2 weeks after, RT. Repeated CT scans through a single section of the prostate was performed following contrast injection. Capillary permeability, fractional vascular volume and tissue perfusion were calculated and converted to colour maps using a customized Matlab imaging programme. Five "expert" and five "novice" radiologists scored pairs of randomized prostate images as an "increase", "decrease" or "no change" in intensity following RT. Kappa (kappa) statistics was used to assess the concordance of opinions. Significant quantitative increases in all indices occurred after RT, and almost all of the parametric images were scored as an increase in intensity following RT (perfusion = 95%, permeability = 88%, volume = 84%). There was substantial agreement between the experts and novices (kappa: perfusion = 0.93, permeability = 0.80, volume = 0.90), as well as within the expert (kappa: perfusion = 1, permeability = 0.86, volume = 1) and novice (kappa: perfusion = 0.82, permeability = 0.78, volume = 0.78) groups. Functional colour maps of the prostate can reliably portray the hyperaemic response following RT in a group with quantitative increases in perfusion, permeability and fractional vascular volume, and provides a potentially accessible and convenient method for image analysis by radiologists of varying experience.

Can contrast-enhanced ultrasonography characterize focal liver lesions and differentiate between benign and malignant, thus providing a one-stop imaging service for patients?().

PURPOSE: Contrast-enhanced ultrasonography (CEUS) displays high sensitivity and specificity in characterizing focal liver lesions (FLLs). We attempted to determine how often CEUS provides an unequivocal diagnosis of FLLs that does not require additional imaging studies. MATERIALS AND METHODS: Seventy-three patients with 146 FLLs were scanned with B-mode, Doppler, and contrast-enhanced US (2 × 2.4 ml SonoVue, low MI, 4-6 MHz curved array transducer, Toshiba Aplio/Siemens-Acuson Sequoia). Data were digitally stored and transferred to a work station with the GE PACS system. Images were reviewed by a consultant radiologist experienced in CEUS and interpreted in accordance with the criteria for characterizing FLLs published by the European Federation of Societies for Ultrasound in Medicine and Biology. Diagnoses were compared with those based on computed tomography (CT) and/or magnetic resonance (MR) findings if these were available. However, our aim was to assess the frequency with which CEUS provided diagnoses that were considered reliable enough to exclude the need for other imaging studies. Therefore, the CEUS diagnoses were not necessarily confirmed by other methods. RESULTS: Based on CEUS findings alone, 130/146 (89.0%) FLLs could be classified as benign or malignant, and in 118/146 (80.8%) cases, the lesion could be specifically identified. The other 28/146 (19.2%) FLLs could not be characterized based on CEUS data alone. In 58 (80.8%) of the 73 patients with multiple FLLs, CEUS findings were sufficient to establish the benign vs. malignant nature of all the patient's lesions; in 51/73 (69.9%) patients, all the lesions could also be characterized with CEUS. In the remaining cases, at least one lesion required additional imaging to determine whether it was malignant (14/73, 19.2%) or to establish its identity (22/73, 30.1%). In 4/73 (5.5%) patients, CEUS revealed additional lesions not detected on B-mode US. CONCLUSIONS: CEUS alone was sufficient to classify 89.0% of the FLLs as benign or malignant, and in 80.8% it was also regarded as sufficient to identify the lesion. It served as a one-stop diagnostic test for 80.8% of the patients, reducing the need for CT-MR scans and providing savings in terms of radiation exposure, time, and money.

Ultrasonographic and radiographic results from a two-year controlled trial of immediate or one-year-delayed addition of infliximab to ongoing methotrexate therapy in patients with erosive early rheumatoid arthritis.

OBJECTIVE: To compare the impact of immediate and delayed introduction of anti-tumor necrosis factor therapy on inflammation and structural damage in methotrexate (MTX)-treated patients with early rheumatoid arthritis (RA). METHODS: Twenty-four patients with erosive early RA (duration < 3 years) who were receiving MTX were randomized to receive infliximab 5 mg/kg or placebo infusions at weeks 0, 2, and 6, and then every 8 weeks through week 46. Beginning at week 54 and thereafter, all patients received infliximab 5 mg/kg. Metacarpophalangeal joints were scanned using high-frequency ultrasonography and power Doppler imaging. Radiographs were evaluated using the modified Sharp/van der Heijde scoring system. RESULTS: From baseline to week 54, total synovial thickness was significantly improved in the infliximab + MTX group compared with the placebo + MTX group (median reduction 95.8% versus 37.5%; P = 0.005), as was the total color Doppler area (CDA; vascularity assessment) (median reduction 100% and 47.1%, respectively; P = 0.025). From week 0 to week 110, no significant between-group difference was observed in the change from baseline for total synovial thickening or the total CDA. At week 54, greater progression in the Sharp/van der Heijde score was apparent in patients receiving placebo + MTX compared with those receiving infliximab + MTX. Although radiographic progression in the placebo + MTX group was greatly reduced in the second year (after initiation of infliximab therapy), marked differences were observed between the infliximab + MTX group (median change in the Sharp/van der Heijde score 4.0) and the placebo + MTX group (median change 14.5) from baseline to week 110 (P = 0.076). CONCLUSION: The results indicate that the efficacy of 2 years of combination therapy with infliximab + MTX for inhibiting cumulative structural damage was superior to that of 1 year of treatment with MTX alone followed by the addition of infliximab.

Hepatic vein transit times using a microbubble agent can predict disease severity non-invasively in patients with hepatitis C.

BACKGROUND AND AIMS: A reliable non-invasive assessment of the severity of diffuse liver disease is much needed. We investigated the utility of hepatic vein transit times (HVTT) for grading and staging diffuse liver disease in a cohort of patients with hepatitis C virus (HCV) infection using an ultrasound microbubble contrast agent as a tracer. MATERIALS AND METHODS: Eighty five untreated patients with biopsy proven HCV induced liver disease were studied prospectively. All were HCV RNA positive on polymerase chain reaction testing. Based on their histological fibrosis (F) and necroinflammatory (NI) scores, untreated patients were divided into mild hepatitis (F < or =2/6, NI < or =3/18), moderate/severe hepatitis (3 < or =F <6 or NI > or =4), and cirrhosis (F=6/6) groups. In addition, 20 age matched healthy volunteers were studied. After an overnight fast, a bolus of contrast agent (Levovist) was injected into an antecubital vein and spectral Doppler signals were recorded from both the right and middle hepatic veins for analysis. HVTTs were calculated as the time from injection to a sustained rise in Doppler signal >10% above baseline. The Doppler signals from the carotid artery were also measured in 60 patients and carotid delay times (CDT) calculated as the difference between carotid and hepatic vein arrival times. The earliest HVTT in each patient was used for analysis. RESULTS: Mean (SEM) HVTT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis groups showed a monotonic decrease of 38.1 (2.8), 38.8 (2.4), 26.0 (2.4), and 15.8 (0.8) seconds, respectively. Mean (SEM) CDT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis patients again showed progressive shortening of 30.3 (2.6), 25.9 (2.6), 14.8 (2.1), and 5.6 (1.2) seconds, respectively. There were significant differences between the groups for HVTT (ANOVA, p<0.001) and CDT (ANOVA, p<0.001). There was 100% sensitivity and 80% specificity for diagnosing cirrhosis and 95% sensitivity and 86% specificity for differentiating mild hepatitis from more severe liver disease. CONCLUSION: We have shown, for the first time, that HVTT using an ultrasound microbubble contrast agent can assess HCV related liver disease with clear differentiation between mild hepatitis and cirrhosis. There were significant differences between these two groups and the moderate/severe hepatitis group. CDT offers no additional benefit or greater differentiation than HVTT and can be omitted, thus simplifying this technique. HVTT may complement liver biopsy and may also be a useful alternative for assessment of liver disease in patients who have contraindications to biopsy.

Transdermal estradiol improves bone density when used as single agent therapy for prostate cancer.

PURPOSE: Current androgen deprivation therapies for men with prostate cancer cause accelerated osteoporosis and a significant risk of osteoporotic fracture. We have recently shown that transdermal estradiol is an effective alternative for such patients. Here we report the impact of transdermal estradiol therapy on the bone mineral density of men with prostate cancer. MATERIALS AND METHODS: A total of 20 patients with newly diagnosed locally advanced or metastatic prostate cancer were treated with transdermal estradiol patches. Bone mineral density of the lumbar spine and the proximal femur was measured with dual-energy x-ray absorptiometry, and correlated with computerized tomography and isotope bone scan findings at 6-month intervals. RESULTS: In all measured regions bone mineral density increased with time. By 1 year mean bone mineral density +/- SEM had increased by 3.60% +/- 1.6% in the lumbar spine (p = 0.055), 2.19% +/- 1.03% in the femoral neck (p = 0.055), 3.76% +/- 1.35% in the Ward's region (p = 0.008) and 1.90% +/- 0.85% in the total hip (p = 0.031), respectively. Of 12 osteoporotic sites 4 had improvement based on World Health Organization grading. All other sites improved toward a better classification. CONCLUSIONS: Transdermal estradiol protects against bone loss in men with prostate cancer and may improve bone density in those at risk for osteoporotic fracture.

Comparison of ultrasonographic assessment of synovitis and joint vascularity with radiographic evaluation in a randomized, placebo-controlled study of infliximab therapy in early rheumatoid arthritis.

OBJECTIVE: To investigate sensitive ultrasonographic imaging methods for detection of synovial thickness and vascularity to discriminate between patients with early rheumatoid arthritis (RA) receiving infliximab + methotrexate (MTX) versus placebo + MTX over 18 weeks, and to compare the relationship between synovial thickening and vascularity at baseline and radiologic damage to joints of the hands and feet at 54 weeks. METHODS: Patients with early RA (duration <3 years) receiving stable dosages of MTX were randomly assigned to receive blinded infusions of 5 mg/kg infliximab (n = 12) or placebo (n = 12) at weeks 0, 2, 6, and then every 8 weeks until week 46. At baseline and week 18, clinical assessments were performed, and metacarpophalangeal joints were assessed by high-frequency ultrasonography and power Doppler ultrasonography measurements. Radiographs of the hands and feet taken at baseline and at 54 weeks were evaluated using the van der Heijde modification of the Sharp method (vdH-Sharp score). RESULTS: Using changes in the total vdH-Sharp score over 54 weeks and changes in synovial thickening and joint vascularity at 18 weeks, we were able to distinguish those patients receiving infusions of infliximab + MTX from those receiving placebo + MTX. Sonographic measurements of synovial thickening and vascularity at baseline in the placebo + MTX group demonstrated clear relationships with the magnitude of radiologic joint damage at week 54. Infliximab + MTX treatment abolished these relationships. CONCLUSION: The delay or reversal of inflammatory and joint-destructive mechanisms in patients with early RA was already apparent following 18 weeks of treatment with infliximab + MTX and was reflected in radiologic changes at 54 weeks.

Liver microbubble transit time compared with histology and Child-Pugh score in diffuse liver disease: a cross sectional study.

BACKGROUND: A previous pilot study showed that early arrival time of a microbubble in a hepatic vein is a sensitive indicator of cirrhosis. AIM: To see if this index can also grade diffuse liver disease. PATIENTS: Thirty nine fasted patients with histologically characterised disease were studied prospectively. Nine patients had no evidence of liver fibrosis, 10 had fibrosis without cirrhosis, and 20 had cirrhosis (five Child's A, seven Child's B, and eight Child's C). METHODS: Bolus injections of a microbubble (Levovist; Schering, Berlin) were given intravenously, followed by a saline flush. Time intensity curves of hepatic vein and carotid artery spectral Doppler signals were analysed. Hepatic vein transit time (HVTT) was calculated as the time after injection at which a sustained signal increase >10% of baseline was seen. Carotid delay time (CDT) was calculated as the difference between carotid and hepatic vein enhancement. RESULTS: Diagnostic studies were achieved in 38/39 subjects. Both HVTT and CDT became consistently shorter with worsening disease, as follows (means (SD)): HVTT: no fibrosis 44 (25) s, fibrosis 26 (8) s, Child's A 21 (1) s, Child's B 16 (3) s, and Child's C 16 (2) s; CDT: no fibrosis 31 (29) s, fibrosis 14 (6) s, Child's A 8 (1) s, Child's B 4 (4) s, and Child's C 3 (3) s. These differences were highly significant (p<0.001, ANOVA comparison). A HVTT <24 s and a CDT <10 s were 100% sensitive for cirrhosis (20/20 and 18/18, respectively) but not completely specific: 2/8 subjects with fibrosis had CDT values <10 s and 3/9 had HVTT <24 s. CONCLUSION: This minimally invasive test shows promise not only in diagnosing cirrhosis but also in assessing disease severity.

Microbubble ultrasound improves the efficiency of gene transduction in skeletal muscle in vivo with reduced tissue damage.

Intramuscular injection of naked plasmid DNA is a safe approach to the systemic delivery of therapeutic gene products, but with limited efficiency. We have investigated the use of microbubble ultrasound to augment naked plasmid DNA delivery by direct injection into mouse skeletal muscle in vivo, in both young (4 weeks) and older (6 months) mice. We observed that the albumin-coated microbubble, Optison (licensed for echocardiography in patients), significantly improves the transfection efficiency even in the absence of ultrasound. The increase in transgene expression is age related as Optison improves transgene expression less efficiently in older mice than in younger mice. More importantly, Optison markedly reduces muscle damage associated with naked plasmid DNA and the presence of cationic polymer PEI 25000. Ultrasound at moderate power (3 W/cm2 1 MHz, 60 s exposure, duty cycle 20%), combined with Optison, increases transfection efficiency in older, but not in young, mice. The safe clinical use of microbubbles and therapeutic ultrasound and, particularly, the protective effect of the microbubbles against tissue damage provide a highly promising approach for gene delivery in muscle in vivo.

The role of ultrasound in molecular imaging.

Ultrasound has received less attention than other imaging modalities for molecular imaging, but has a number of potential advantages. It is cheap, widely available and portable. Using Doppler methods, flow information can be obtained easily and non-invasively. It is arguably the most physiological modality, able to image structure and function with less sedation than other modalities. This means that function is minimally disturbed, and multiple repeat studies or the effect of interventions can easily be assessed. High frame rates of over 200 frames a second are achievable on current commercial systems, allowing for convenient cardiac studies in small animals. It can be used to guide interventional or invasive studies, such as needle placement. Ultrasound is also unique in being both an imaging and therapeutic tool and its value in gene therapy has received much recent interest. Ultrasound biomicroscopy has been used for in utero imaging and can guide injection of virus and cells. Ultrahigh frequency ultrasound can be used to determine cell mechanical properties. The development of microbubble contrast agents has opened many new opportunities, including new functional imaging methods, the ability to image capillary flow and the possibility of molecular targeting using labelled microbubbles.

Functional ultrasound methods in oncological imaging.

The real time nature of ultrasound and functional methods such as Doppler ultrasound mean that ultrasound can claim to have always been a functional imaging method, but recent developments in quantitation, dramatic improvement in Doppler performance and now microbubbles have created many exciting new applications. These include methods for assessing the neovascularity of tumours, for following the effects of therapy and for predicting the likelihood of development of metastatic disease at the staging of primary tumours.

Hepatocellular adenoma: diagnostic difficulties and novel imaging techniques.

We report the case of a 30-year-old eastern European female who presented with right upper quadrant pain. Clinical examination was unremarkable and liver function tests were normal. CT identified a 5 cm lesion in segment V of the liver, which was of homogeneous low density with no calcification or significant enhancement. MRI showed the lesion to be hypointense to liver on T(1) weighted sequences and isointense on T(2) weighted sequences. Rapid arterial enhancement with gadolinium-DTPA faded without leaving a definite central scar. Ultrasound showed the lesion to be echogenic with minimal vascularity. Administration of a liver-specific microbubble contrast agent showed low uptake relative to the surrounding liver. Phosphorus-31 MR spectroscopy, localized to the lesion itself, revealed a markedly increased phosphomonoester resonance with a decreased phosphodiester resonance, compatible with increased cell turnover. Biopsy confirmed the lesion to be a hepatocellular adenoma. The diagnosis of a hepatic adenoma is difficult with tissue diagnosis the gold standard, but it may be suggested by a combination of imaging modalities. We have described two new imaging techniques not previously described in characterization of hepatic adenomata, namely ultrasound with contrast agent and MR spectroscopy.

Does the presence of distant and local malignancy alter parenchymal perfusion in apparently disease-free areas of the liver?

Our objective was to investigate if hepatic arterial (HAP) and portal venous perfusion (PVP) in apparently normal areas of liver, as measured by functional CT, are affected by the presence of extra- and intrahepatic malignancy Three patient groups were compared: A, controls with no malignancy (N = 10); B, extrahepatic malignancy without liver involvement (N = 12); and C, subjects with metastases elsewhere in the liver (N = 13). HAP, PVP, and a CT hepatic perfusion index (CT-HPI) calculated as HAP/(HAP + PVP) were calculated on a section free of metastatic disease, using a previously published method. Figures for PVP were (median and interquartile range) in group A were 1.06 (0.9-1.30), in B 1.03 (0.81-1.09), and in C 0.75 (0.54-1.02) ml/min/ml; for HAP group A values were 0.07 (0.052-0.078), in B 0.07 (0.053-0.147), and in C 0.12 (0.091-0.146) ml/min/ml and for CT-HPI Group A values were 4.9% (4.8-6.6%), in B 5.6% (3.8-13.6%), and in C 14.3% (10.4-15.4%). Significant differences in all indices were seen between groups A and C. A significant difference (P = 0.017) was seen between groups B and C in the CT-HPI values. In conclusion, patients with liver metastases show abnormal blood flow in apparently normal liver compared to controls. This difference was not seen in subjects with malignancy without liver metastases. Possible explanations would be either the unmasking of occult metastatic disease or vasoactive or mechanical effects due to liver malignancy.

Do different types of liver lesions differ in their uptake of the microbubble contrast agent SH U 508A in the late liver phase? Early experience.

PURPOSE: To compare the uptake of SH U 508A in different types of liver lesions by using stimulated acoustic emission. MATERIALS AND METHODS: Thirty-seven patients with characterized lesions (metastasis, n = 17; hepatocellular carcinoma, n = 4; hemangioma, n = 9; focal nodular hyperplasia, n = 7) received 2.5 g SH U 508A. After 5 minutes, stimulated acoustic emission was elicited by using a previously described method. Liver and/or lesional differences were assessed with videodensitometry (objective conspicuity score), and two observers assessed each lesion by using a six-point scale (subjective conspicuity score). RESULTS: Metastases and hepatocellular carcinoma had low stimulated acoustic emission; median objective conspicuity scores were 70% and 68% (all scores were > or =43%), respectively, and subjective conspicuity scores were 2 or higher for both observers. Hemangiomas had reduced stimulated acoustic emission, with more variability; the median objective conspicuity score was 41% (range, 9%-72%), and the median subjective conspicuity scores were 2 (range, 1-4) and 3.5 (range, 1-5) for observers 1 and 2, respectively. Focal nodular hyperplasia had stimulated acoustic emission comparable to that of the liver in all cases; the median objective conspicuity score was -4.7% (all scores were <6%), and the subjective conspicuity score was 1 or lower for both observers. This finding completely separated focal nodular hyperplasia and malignancies. Significant differences were seen between focal nodular hyperplasia and all other lesion types (P < .05). CONCLUSION: Strong late-phase lesional uptake of SH U 508A is characteristic of focal nodular hyperplasia, is seen in some hemangiomas, and was not observed in malignancies.

Developments in ultrasound contrast media.

Ultrasound microbubble contrast agents are effective and safe echo enhancers. An ingenious array of methods are employed to achieve stability and provide a clinically useful enhancement period. Microbubbles enhance ultrasound signals by up to 25 dB (greater than 300-fold increase) due to resonant behaviour. This is used to rescue failed Doppler studies and may be extended to image the microcirculation of tumours and the myocardium using non-linear modes. Functional studies open up a whole range of applications by using a variety of active and passive quantitation techniques to derive indices from the transit of contrast through a tissue of interest. This has been especially successful in the detection of liver metastases and cirrhosis and shows great promise as a clinical tool. It also has great potential in measuring microcirculatory flow velocity. The demonstration that some microbubbles are not just pure blood pool agents but have a hepatosplenic specific phase has extended the versatility of ultrasound. Imaging of this stationary phase with non-linear modes such as phase inversion and stimulated acoustic emission, has improved the sensitivity and specificity of ultrasound in the detection and characterisation of focal liver lesions to rival that of CT and MR.

Functional CT imaging of the acute hyperemic response to radiation therapy of the prostate gland: early experience.

PURPOSE: Functional CT can measure perfusion and permeability. We hypothesized that acute changes could be measured in these indexes following radiation therapy (RT) to the prostate gland. METHOD: Twenty-two patients with prostatic cancer were studied before and 1-2 and 6-12 weeks after RT. A single section through the prostate was repeatedly scanned after contrast medium bolus injection. Contrast agent clearance per unit volume (alpha/V) and fractional vascular volume (fvv) were calculated using Patlak graphical analysis. Perfusion was calculated as the ratio between maximal rate of tissue enhancement and peak arterial enhancement. RESULTS: Significant increases in all indexes occurred after RT. Mean perfusion rose from 0.122 to 0.263 ml/min/ml at 1-2 weeks, mean alpha/V increased from 0.0012 to 0.0016 ml/min/ml at 1-2 weeks, and mean fvv increased from 13.7 to 21% at 1-2 weeks. All three indexes remained elevated at 6-12 weeks after the start of RT. CONCLUSION: Functional CT demonstrated an acute hyperemic response following RT to the prostate gland.

Determination of glomerular filtration rate per unit renal volume using computerized tomography: correlation with conventional measures of total and divided renal function.

PURPOSE: Previous studies suggest that functional computerized tomography (CT) can measure glomerular filtration rate (GFR) per unit renal volume. We compared this index with conventionally determined GFR measurements. MATERIALS AND METHODS: A total of 16 men and 8 women 63.3 +/- 14.9 years old (range 31 to 88) were studied using with contrast enhanced CT. A single slice of kidney was scanned sequentially after bolus injection (0.5 to 1.0 ml. per second(-1)) of 20 ml. iopamidol (300 mg. iodine per ml.(-1)). GFR per volume of kidney was calculated using a Patlak graphical analysis, and this index was multiplied by renal volume on CT to yield global GFR (ml. per minute(-1)). Divided function was also calculated. GFR and divided renal function were calculated in all cases from radioisotope renography with 99m diethylenetetraminepentaacetic acid. In 12 subjects in whom 24-hour urine collection was possible GFR was also calculated from creatinine clearance. RESULTS: A strong correlation was observed between divided renal function, expressed with respect to the right kidney calculated from CT (52.7 +/- 14.8%, range 19.9% to 97.4%) and by radioisotope renography (51.7 +/- 14.6%, range 18.9% to 92.6%, r = 0.97, p <0.0001). A strong correlation (r = 0.92, p <0.0001) was also seen between global GFR determined by CT (80.1 +/- 43.9 ml. per minute(-1), range 38.2 to 197.9) and creatinine clearance (72.4 +/- 47.5, range 14.6 to 168.5), and was stronger than the correlation between the radioisotope and creatinine clearance method (r = 0.67, p = 0.02) in the same patients. CONCLUSION: Functional CT using nonionic contrast material can measure GFR normalized to renal volume and is an accurate alternative to conventional methods of renal function evaluation.