Quantitative and Qualitative Approach for Shear Wave Elastography in Superficial Lymph Nodes.

The diagnostic contribution of 2-D shear-wave elastography (SWE) in management of superficial lymph nodes (LNs) of any origin was evaluated in 222 patients referred for needle core biopsy. Each patient underwent conventional B-mode/Doppler ultrasound examinations (conventional ultrasound) and SWE. Quantitative SWE parameters and qualitative SWE map features were extracted. Carcinomas were found to be significantly stiffer than benign LNs (29.5 ± 32.3 kPa vs. 6.7 ± 12.3 kPa). Lymphomas exhibited intermediate stiffness (11.4 ± 5.2 kPa). Qualitative SWE analysis provided color patterns specific to histopathology (stiff rim, nodular and undetermined patterns related to malignancy and blue pattern to benignity). Adding SWE to conventional ultrasound improved the sensitivity of LN diagnosis (from 81.1% to 92.0%) but decreased its specificity (from 73.2% to 67.6%) because of the high prevalence of lymphomas compared with carcinomas. Inter-observer agreement for quantitative SWE was good (intra-class correlation coefficient = 0.82) as was inter-observer diagnostic agreement for qualitative SWE (κ = 0.65). LN location and histology type were found to influence the reported diagnostic performance of SWE.

Solitary Breast Metastasis From Thyroid Papillary Carcinoma Revealed on Whole-Body Radioactive 131I Scan.

Breast metastasis from thyroid papillary carcinoma is an exceptional situation. Here, we present the diagnostic approach and the management of a 19-year-old woman with single breast metastasis from thyroid carcinoma. There was no extra thyroidal extension, neoplastic emboli, or lymph node invasion. The metastasis was revealed by whole-body radioactive I scan, explored by a fine-needle aspiration, and confirmed by elevated thyroglobulin in situ.

18F-Fluorocholine PET/CT and Parathyroid 4D Computed Tomography for Primary Hyperparathyroidism: The Challenge of Reoperative Patients.

BACKGROUND: To evaluate FCH-PET/CT and parathyroid 4D-CT so as to guide surgery in patients with primary hyperparathyroidism (pHPT) and prior neck surgery. METHODS: Medical records of all patients referred for a FCH-PET/CT in our institution were systematically reviewed. Only patients with pHPT, a history of neck surgery (for pHPT or another reason) and an indication of reoperation were included. All patients had parathyroid ultrasound (US) and Tc-99m-sestaMIBI scintigraphy, and furthermore, some patients had 4D-CT. Gold standard was defined by pathological findings and/or US-guided fine-needle aspiration with PTH level measurement in the washing liquid. RESULTS: Twenty-nine patients were included in this retrospective study. FCH-PET/CT identified 34 abnormal foci including 19 ectopic localizations. 4D-CT, performed in 20 patients, detected 11 abnormal glands at first reading and 6 more under FCH-PET/CT guidance. US and Tc-99m-sestaMIBI found concordant foci in 8/29 patients. Gold standard was obtained for 32 abnormal FCH-PET/CT foci in 27 patients. On a per-lesion analysis, sensitivity, specificity, positive and negative predictive values were, respectively, 96%, 13%, 77% and 50% for FCH-PET/CT, 75%, 40%, 80% and 33% for 4D-CT. On a per-patient analysis, sensitivity was 85% for FCH-PET/CT and 63% for 4D-CT. FCH-PET/CT results made it possible to successfully remove an abnormal gland in 21 patients, including 12 with a negative or discordant US/Tc-99m-sestaMIBI scintigraphy result, with a global cure rate of 73%. CONCLUSION: FCH-PET/CT is a promising tool in the challenging population of reoperative patients with pHPT. Parathyroid 4D-CT appears as a confirmatory imaging modality.

Does motion affect liver stiffness estimates in shear wave elastography? Phantom and clinical study.

This study was undertaken to evaluate the impact of free-breathing (FB) vs. Apnea on Shear-wave elastography (SWE) measurements. Quantitative liver-stiffness measurements were obtained during FB and Apnea for 97 patients with various body-morphologies and liver textures. Quality indexes of FB and Apnea elasticity maps (percentage of non-filling (PNF), temporal (TV) and spatial (SV) variabilities) were computed. SWE measurements were also obtained from an homogeneous phantom at rest and during a mechanically-induced motion. Liver-stiffness values estimated from FB and Apnea acquisitions were correlated, particularly for homogeneous livers (r=0.76, P<0.001) and favorable body-morphologies (r=0.68, P<0.001). However FB values were consistently 20-25% lower than Apnea ones (P<0.001). FB also systematically resulted in degradation of TV (P<0.005) and PNF (P<0.001) compared to Apnea but had no impact on SV. With the phantom, no differences between SWE measurements at rest and during motion were observed. Apnea and FB measurements are highly correlated, although FB data quality is degraded compared to Apnea and estimated stiffness in FB is systematically lower than in Apnea. These discrepancies between rest and motion states were observed for patients but not for phantom data, suggesting that patient breath-holding impacts liver stiffness.

ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease.

Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amyloid precursor protein (APP) metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that inversely correlates with amyloid load in Alzheimer's disease brains. Accordingly, in vitro down- or up-regulation of ADAM30 expression triggered an increase/decrease in Aß peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30(mut)) did not affect Aß secretion. Proteomics/cell-based experiments showed that ADAM30-dependent regulation of APP metabolism required both cathepsin D (CTSD) activation and APP sorting to lysosomes. Accordingly, in Alzheimer-like transgenic mice, neuronal ADAM30 over-expression lowered Aß42 secretion in neuron primary cultures, soluble Aß42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation alterations. Our data thus indicate that lowering ADAM30 expression may favor Aß production, thereby contributing to Alzheimer's disease development.

Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis.

Encephalitis associated with antibodies against leucine-rich glioma-inactivated 1 (LGI1) protein is increasingly recognized as an auto-immune disorder associated with characteristic tonic-dystonic seizures. The cortical or subcortical origin of these motor events is not clear. Some patients also present with different epileptic seizures and with cognitive impairment. The frequency of these features and their timing during the natural history of this encephalitis have not been fully described. We therefore reviewed data from 34 patients harbouring antibodies against LGI1 protein (21-81 years, median age 64) referred to the French Reference Centre for Neurological Paraneoplastic Syndrome. Three types of evidence suggested tonic-dystonic seizures were of cortical origin: (i) a slow, unilateral, frontal electroencephalographic wave, of duration ∼580 ms and amplitude ∼71 µV, preceded the contralateral tonic-dystonic seizures in simultaneous electroencephalographic and myographic records from seven of seven patients tested; (ii) 18-Fluorodeoxyglucose imaging revealed a strong hypermetabolism in primary motor cortex, controlateral to the affected limb, during encephalitis for five patients tested, as compared with data from the same patients after remission or from 16 control subjects; and (iii) features of polymyographic records of tonic-dystonic seizure events pointed to a cortical origin. Myoclonic patterns with brief, rhythmic bursts were present in three of five patients tested and a premyoclonic potential was identified in the cortex of one patient. Initially during encephalitis, 11 of 34 patients exhibited tonic-dystonic seizures (32%). Distinct epileptic syndromes were evident in 13 patients (38%). They were typically simple, focal seizures from the temporal lobe, consisting of vegetative symptoms or fear. At later stages, 22 of 32 patients displayed tonic-dystonic seizures (68%) and 29 patients presented frequent seizures (91%) including status epilepticus. Cognitive impairment, either anterograde amnesia or confusion was evident in 30 of 34 patients (88%). Brain imaging was normal in patients with isolated tonic-dystonic seizures; in patients with limbic symptoms it revealed initially a hippocampal hyperintensity in 8 of 19 patients (42%) and 17 of 24 patients (70%) at later stages. Our data suggest that the major signs of LGI1-antibody encephalitis can be linked to involvement of motor cortex and hippocampus. They occur in parallel with striatum involvement. One of these cortical targets is involved, often unilaterally at disease onset. As the encephalitis progresses, in the absence of immunomodulatory treatment, the second cortical target is affected and effects become bilateral. Progression to the second cortical target occurs with a variable delay of days to several months.

Automatic assessment of shear wave elastography quality and measurement reliability in the liver.

A strategy is proposed that accesses the quality of individual shear wave elastography (SWE) exams and the reliability of elasticity measurements in clinical practice. For that purpose, a confidence index based on temporal stability and SWE filling was defined to provide an automatic estimation of each scan quality: high (HG) or low (LG) grade. With this index, the intra-observer acquisition variability assessed by comparing consecutive scans of the same patient was 17% and 32% for HG and LG clips, respectively. The measurement quantification variability assessed by comparing the measurements of a radiologist with those of a trained operator and of two automatic measurements on a same clip averaged 13% and 22% for HG and LG exams, respectively. It was found that SWE measurements depend greatly on the quality of the acquired data. The proposed quality index (HG or LG) provides objective input on the accuracy and diagnostic reliability of SWE measurements.

Preoperative localization of neck recurrences from thyroid cancer: charcoal tattooing under ultrasound guidance.

BACKGROUND: Reoperation for thyroid cancer recurrence is a surgical challenge in previously dissected necks, and there is a need for a reliable procedure for surgeon guidance. In this study, the usefulness of preoperative charcoal tattooing for surgical guidance was evaluated. METHODS: From July 2007 to May 2010, 53 patients (40 females; Mage=44 years, range 19-76 years) were prospectively included for preoperative localization of neck recurrences from differentiated (n=46) or medullary thyroid cancer (n=7). Preoperative cytological assessment was performed for at least one lesion in each patient. Ultrasound (US) imaging was performed with high-frequency probes (8-14 Mhz). Micronized peat charcoal (0.5-3 mL) was injected under US guidance using a 25 gauge needle, 0-15 days preoperatively. RESULTS: A total of 106 lesions were selected for charcoal tattooing. Of these, 101 had been tattooed, and 102 were removed (85 metastases, 17 benign on pathology). The tolerance of charcoal injection was good in all but three patients. A mean volume of 1 mL of charcoal was injected with a mean of two targets per patient. Charcoal labeling facilitated intraoperative detection in 56 "difficult" lesions (i.e., small size, dense fibrosis, anatomical pitfalls), and charcoal trace facilitated intraoperative guidance in 17 lesions. Feasibility and usefulness rates were 83% and 70.7% respectively. CONCLUSION: These findings suggest that charcoal tattooing under US guidance is an easy to implement, safe, and useful procedure for surgeon guidance in neck reoperation for thyroid cancer.

The ß-secretase-derived C-terminal fragment of ßAPP, C99, but not Aß, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus.

Triple-transgenic mice (3xTgAD) overexpressing Swedish-mutated ß-amyloid precursor protein (ßAPP(swe)), P310L-Tau (Tau(P301L)), and physiological levels of M146V-presenilin-1 (PS1(M146V)) display extracellular amyloid-ß peptides (Aß) deposits and Tau tangles. More disputed is the observation that these mice accumulate intraneuronal Aß that has been linked to synaptic dysfunction and cognitive deficits. Here, we provide immunohistological, genetic, and pharmacological evidences for early, age-dependent, and hippocampus-specific accumulation of the ß-secretase-derived ßAPP fragment C99 that is observed from 3 months of age and enhanced by pharmacological blockade of γ-secretase. Notably, intracellular Aß is only detectable several months later and appears, as is the case of C99, in enlarged cathepsin B-positive structures, while extracellular Aß deposits are detected ~12 months of age and beyond. Early C99 production occurs mainly in the CA1/subicular interchange area of the hippocampus corresponding to the first region exhibiting plaques and tangles in old mice. Furthermore, the comparison of 3xTgAD mice with double-transgenic mice bearing the ßAPP(swe) and Tau(P301L) mutations but expressing endogenous PS1 (2xTgAD) demonstrate that C99 accumulation is not accounted for by a loss of function triggered by PS1 mutation that would have prevented C99 secondary cleavage by γ-secretase. Together, our work identifies C99 as the earliest ßAPP catabolite and main contributor to the intracellular ßAPP-related immunoreactivity in 3xTgAD mice, suggesting its implication as an initiator of the neurodegenerative process and cognitive alterations taking place in this mouse model.

BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and ß-amyloid production in Alzheimer's disease.

Alzheimer's disease (AD) is a complex age-related pathology, the etiology of which has not been firmly delineated. Among various histological stigmata, AD-affected brains display several cellular dysfunctions reflecting enhanced oxidative stress, inflammation process and calcium homeostasis disturbance. Most of these alterations are directly or indirectly linked to amyloid ß-peptides (Aß), the production, molecular nature and biophysical properties of which likely conditions the degenerative process. It is particularly noticeable that, in a reverse control process, the above-described cellular dysfunctions alter Aß peptides levels. ß-secretase ßAPP-cleaving enzyme 1 (BACE1) is a key molecular contributor of this cross-talk. This enzyme is responsible for the primary cleavage generating the N-terminus of "full length" Aß peptides and is also transcriptionally induced by several cellular stresses. This review summarizes data linking brain insults to AD-like pathology and documents the key role of BACE1 at the cross-road of a vicious cycle contributing to Aß production.

Nuclear factor-κB regulates ßAPP and ß- and γ-secretases differently at physiological and supraphysiological Aß concentrations.

Anatomical lesions in Alzheimer disease-affected brains mainly consist of senile plaques, inflammation stigmata, and oxidative stress. The nuclear factor-κB (NF-κB) is a stress-activated transcription factor that is activated around senile plaques. We have assessed whether NF-κB could be differentially regulated at physiological or supraphysiological levels of amyloid ß (Aß) peptides. Under these experimental conditions, we delineated the putative NF-κB-dependent modulation of all cellular participants in Aß production, namely its precursor ßAPP (ß-amyloid precursor protein) and the ß- and γ-secretases, the two enzymatic machines involved in Aß genesis. Under physiological conditions, NF-κB lowers the transcriptional activity of the promoters of ßAPP, ß-secretase (ß-site APP-cleaving enzyme 1, BACE1), and of the four protein components (Aph-1, Pen-2, nicastrin, presenilin-1, or presenilin-2) of the γ-secretase in HEK293 cells. This was accompanied by a reduction of both protein levels and enzymatic activities, thereby ultimately yielding lower amounts of Aß and AICD (APP intracellular domain). In stably transfected Swedish ßAPP-expressing HEK293 cells triggering supraphysiological concentrations of Aß peptides, NF-κB activates the transcription of ßAPP, BACE1, and some of the γ-secretase members and increases protein expression and enzymatic activities, resulting in enhanced Aß production. Our pharmacological approach using distinct NF-κB kinase modulators indicates that both NF-κB canonical and alternative pathways are involved in the control of Aß production. Overall, our data demonstrate that under physiological conditions, NF-κB triggers a repressive effect on Aß production that contributes to maintaining its homeostasis, while NF-κB participates in a degenerative cycle where Aß would feed its own production under pathological conditions.

Optimization of staging of the neck with prophylactic central and lateral neck dissection for papillary thyroid carcinoma.

OBJECTIVE: To analyze the yield and rate of node metastases (pN1) for prophylactic central (CND) and lateral neck dissection (LND) for papillary thyroid carcinoma, the risk factors for pN1, and outcomes. BACKGROUND: Prophylactic CND and LND are not routinely employed. Adjuvant radioiodine treatment may be modulated, however, by surgical staging of the neck. METHODS: Retrospective study, consecutive patients ultrasonographically classified cN0 treated with prophylactic CND, and lateral LND (levels III and IV). The number of nodes was resected and the incidence of pN1 was recorded. RESULTS: For 317 patients (254 women, mean age 44 years, mean tumor size 17 mm), the number of lymph nodes was 5 for unilateral CND, 9 for bilateral CND, and 12 for LND. pN1 stage was 42% overall: 23% for unilateral CND, 39% for bilateral CND, and 23% for LND (median number of metastatic nodes = 2 for each). Fifty-five percent of the patients staged pN1 had metastatic nodes in the lateral neck. Ten percent had more than 10 metastatic nodes and/or more than 3 nodes with extra capsular spread. pN1 was correlated with tumor size (P = 0.0025), extrathyroidal tumor extension (P < 0.0001), male sex (P = 0.0006), and age younger than 45 years (P = 0.0003). Permanent hypoparathyroidism and unintentional recurrent nerve paralysis occurred in 2 cases each. Patients staged pN0 received less radioiodine than patients staged pN1 (median 30 vs 100 mCi, P < 0.0001). CONCLUSIONS: For staging, bilateral prophylactic CND is preferable to unilateral CND. Prophylactic CND with LND optimizes staging providing a basis for a personalized approach for adjuvant radioiodine.

Is (18)F-fluorodeoxyglucose-PET/CT useful for the presurgical characterization of thyroid nodules with indeterminate fine needle aspiration cytology?

BACKGROUND: Thyroid nodules found incidentally on (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) have been shown to be malignant in 30%-50% of cases. The American Thyroid Association recommends performing fine needle aspiration cytology (FNAC) for thyroid nodules showing FDG uptake. On the other hand, the role of FDG-PET in characterizing thyroid nodules with indeterminate cytology before surgery is not clear. The goal of this study was to evaluate the role of FDG-PET/computed tomography (CT) in predicting malignancy of thyroid nodules with indeterminate FNAC and to correlate FDG uptake with pathological and ultrasonographic (US) features. METHODS: Between November 2006 and October 2009, 55 patients (42 women, mean age: 50 years) planned for surgery for 56 thyroid nodules with indeterminate FNAC were prospectively included and considered for analysis. All patients underwent presurgical FDG-PET/CT (Siemens Biograph, mean FDG injected activity: 165 MBq) and neck US. Pathology of the corresponding surgical specimen was the gold standard for statistical analysis. RESULTS: At pathology 34 nodules were benign, 10 were malignant (7 papillary and 3 follicular carcinomas), and 12 were tumors of uncertain malignant potential (TUMP). The median size of the thyroid nodules was 21 mm (range: 10-57). Sensitivity, specificity, positive (PPV), and negative predictive (NPV) values of FDG-PET in detecting cancer/TUMP were 77%, 62%, 57%, and 81%, respectively. In multivariate analysis, cellular atypia was the only factor predictive of FDG uptake (p<0.001). Hurthle cells and poorly differentiated components were independent predictive factors of high (≥5) SUV Max (p=0.02 and p=0.02). Sensitivity, specificity, PPV, and NPV of US in detecting cancer/TUMP were 82%, 47%, 50%, and 80%, respectively. In multivariate analysis, hypervascularization was correlated with malignancy/TUMP (p=0.007) and cystic features were correlated with benignity (p=0.03). CONCLUSION: Adding FDG-PET findings to neck US provided no diagnostic benefit. The sensitivity and specificity of FDG-PET in the presurgical evaluation of indeterminate thyroid nodules are too low to recommend FDG-PET routinely.

Quantitative functional imaging by dynamic contrast enhanced ultrasonography (DCE-US) in GIST patients treated with masatinib.

OBJECTIVES: To determine the quantitative parameters of DCE-US for predicting early functional response of patients with metastatic gastrointestinal stromal tumors (GIST). MATERIALS AND METHODS: Phase II multicentre clinical trial in patients with metastatic GIST treated with masatinib mesylate (7.5 mg/kg daily by oral route) Patients followed using three different imaging techniques: 1) DCE-US before treatment and on days 1, 7, 15 and after 1, 2, 4, 6 months and every 3 months. 2) CT assessments, using RECIST criteria, before treatment, after 2, 4, 6 months and then every 3 months. 3) FDG PET before treatment and after 1 month. RESULTS: Twenty patients included and followed-up for up to 36 months, with 269 DCE-US examinations performed. No significant changes in the 7 selected DCE-US variables on day 1 and 7 vs baseline. On day 15, significant reductions in all the variables related to blood volume recorded: area under the curve (AUC) (p = 0. 004), area under the wash-in (AUWI) (p = 0.002), area under the wash-out (AUWO) (p = 0.002) and Peak Intensity (p = 0.005). Also slope of wash-in changed significantly (p = 0.003). An important reduction in Standard Uptake Values (SUV) recorded in 7/11 patients (PFS >18 months). Decrease in DCE-US AUC, AUWI and AUWO values on day 7 were predictive of PET-CT results. CONCLUSIONS: AUC AUWI, AUWO are the DCE-US parameters related to blood volume that at D 15 can predict the response of GISTs to treatment with masatinib. Additional studies are ongoing.

Immunohistochemical characterization of calcitonin gene-related peptide in the trigeminal system of the familial hemiplegic migraine 1 knock-in mouse.

INTRODUCTION: Familial hemiplegic migraine type 1 (FHM-1) is caused by mutations in the CACNA1A gene, with the R192Q mutation being the most common. Elevated calcitonin gene-related peptide (CGRP) levels in acute migraine and clinical trials using CGRP receptor antagonists suggest CGRP-related mechanisms are important in migraine. METHODS: Wild-type and R192Q knock-in mice were anaesthetized and perfused. Using immunohistochemical staining, the expression of CGRP in the trigeminocervical complex (TCC) and in the trigeminal and dorsal root ganglia was characterized. RESULTS: There was a 38% reduction in the percentage of CGRP-immunoreactive cells in the trigeminal ganglia (p < 0.001) of R192Q knock-in mice compared to wild-type animals. The size distribution profile of CGRP-immunoreactive cells within the trigeminal ganglia demonstrated no significant difference in cell diameter between the two groups (p ≥ 0.56). CGRP expression was also reduced in thoracic ganglia of R192Q knock-in mice (21% vs. 27% in wild-type group; p < 0.05), but not in other ganglia. In addition, decreased CGRP immunoreactivity was observed in the superficial laminae of the TCC in R192Q knock-in mice, when compared to the control group (p < 0.005). CONCLUSION: The data demonstrates that the FHM-1 CACNA1A mutation alters CGRP expression in the trigeminal ganglion and TCC. This suggests further study of these animals is warranted to characterize better the role of these mutations in the neurobiology of migraine.

Imaging of melanoma: usefulness of ultrasonography before and after contrast injection for diagnosis and early evaluation of treatment.

High-frequency ultrasound (8-14 MHz) is routinely used to display cutaneous melanomas. Maximum thickness measurement (Breslow index) has been shown to be well correlated to histologic findings for lesions of more than 0.75 mm. Some morphological criteria (strong delineation, hypoechoic texture, homogeneity) have been reported to help differentiate between malignant and benign pigmented blue lesions, but remain insufficient. Vascular ultrasound analysis using Doppler mode provides additional information and showed good specificity for malignancy (90%-100%), but variable sensitivity (34%-100%). Recent advances in ultrasound imaging allow functional evaluation. Likewise, dynamic contrast-enhanced ultrasound using contrast medium injection and specific perfusion and quantification software showed promising results in clinical and preclinical trials for early prediction of tumor response to target treatments.

Dynamic contrast-enhanced ultrasonography (DCE-US) and anti-angiogenic treatments.

Dynamic contrast-enhanced ultrasonography (DCE-US) is a current functional imaging technique enabling a quantitative assessment of tumor perfusion using raw linear data. DCE-US allows calculating several parameters as slope of wash-in or area under the curve representing, respectively, blood flow or blood volume. Decrease of vascularization can easily be detected in responders after 1 or 2 weeks of anti-angiogenic treatment for gastrointestinal stromal tumors (GIST), renal cell carcinoma (RCC), and hepatocellular carcinoma (HCC) and is correlated with progression-free survival and overall survival in RCC or HCC. DCE-US is supported by the French National Cancer Institute (INCa), which is currently studying the technique in metastatic breast cancer, melanoma, colon cancer, gastrointestinal stromal tumors and renal cell carcinoma, as well as in primary hepatocellular carcinoma, to establish the optimal perfusion parameters and timing for quantitative anticancer efficacy assessments. Currently 479 patients are included in 19 centers and the preliminary results on 400 patients with 1096 DCE-US demonstrated that the area under the curve (AUC) quantified at 1 month could be a robust parameter to predict response at 6 months.

Advanced hepatocellular carcinoma: early evaluation of response to bevacizumab therapy at dynamic contrast-enhanced US with quantification--preliminary results.

PURPOSE: To investigate whether there is any correlation between standard efficacy endpoints-specifically, tumor response, progression-free survival, and overall survival-and tumor perfusion parameters measured by using dynamic contrast material-enhanced ultrasonography (US) in patients with advanced hepatocellular carcinoma (HCC) treated with bevacizumab. MATERIALS AND METHODS: The institutional review board approved the study, and all patients provided written informed consent before their enrollment. Between June 3, 2005, and September 28, 2007, 42 patients (33 men, nine women; median age, 62 years; age range, 23-84 years) participated in this phase II study of single-agent bevacizumab treatment. Tumor response (based on RECIST [response evaluation criteria in solid tumors]) at 2 months was assessed in 37 patients, and progression-free survival and overall survival were assessed in all 42 patients. Dynamic contrast-enhanced US (ie, dynamic US) was performed before treatment (day 0); on days 3, 7, 14, and 60 after treatment; and every 2 months thereafter. Tumor perfusion parameters were estimated quantitatively from contrast material uptake curves constructed from raw linear data. The changes in dynamic US functional parameters between day 0 and the later time points were compared between treatment responders and nonresponders by using nonparametric tests. Given multiple comparisons, P < .001 indicated significance. RESULTS: The percentage decrease in several dynamic US parameters between day 0 and day 3 showed trends toward correlation with (a) tumor response in terms of total area under the time-intensity curve (AUC) (P = .02), AUC during wash in (P = .04), AUC during washout (P = .02), and time to peak intensity (P = .03); (b) progression-free survival in terms of time to peak intensity (P = .028); and (c) overall survival in terms of AUC (P = .002) and AUC during washout (P = .003). CONCLUSION: Dynamic US can be used to quantify dynamic changes in tumor vascularity as early as 3 days after bevacizumab administration in patients with HCC. These early changes in tumor perfusion may be predictive of tumor response at 2 months, progression-free survival, and overall survival, and they may be potential surrogate measures of the effectiveness of antiangiogenic therapy in patients with HCC.

Dynamic contrast-enhanced ultrasonography (DCE-US): a new tool for the early evaluation of antiangiogenic treatment.

Dynamic contrast-enhanced ultrasonography (DCE-US) is a new functional technique enabling a quantitative assessment of solid tumor perfusion using raw linear data. DCE-US allows the calculation of parameters as slope of wash-in or area under the curve (AUC) representing, respectively, blood flow or blood volume. Reduction in tumor vascularization can easily be detected in responders after 1 or 2 weeks and is correlated with progression-free survival and overall survival in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). DCE-US is supported by the French National Cancer Institute (INCa), which is currently studying the technique in metastatic breast cancer, melanoma, colon cancer, gastrointestinal stromal tumors and renal cell carcinoma, as well as in primary hepatocellular carcinoma, to establish the optimal perfusion parameters and timing for quantitative anticancer efficacy assessments. Currently 490 patients are included in 20 centers and the preliminary results on 400 patients with 1,096 DCE-US demonstrated that AUC could be a robust parameter to predict response.