Effect of Observer Experience in the Differentiation Between Benign and Malignant Liver Tumors After Ultrasound Contrast Agent Injection

Objective. The purpose of this study was to assess the impact of the observer level of experience on the diagnostic performance of contrast‐enhanced ultrasound imaging (CEUS) for differentiation between benign and malignant liver tumors. Methods. From a computerized search, we retrospectively identified 286 biopsy‐proven liver tumors (105 hepatocellular carcinomas, 48 metastases, 7 intra‐hepatic cholangiocarcinomas, 33 liver hemangiomas, and 93 nonhemangiomatous benign lesions) in 235 patients (140 male and 95 female; mean age ± SD, 56 ± 11 years) who underwent CEUS after sulfur hexafluoride‐filled microbubble injection. The digital cine clips recorded during the arterial (10–35 seconds from injection), portal (50–120 seconds), and late (130–300 seconds) phases were analyzed by 6 independent observers without experience (group 1, observers 1–3) or with 2 to 10 years of experience in CEUS (group 2, observers 4–6). Specific training in the diagnostic and interpretative criteria was provided to the inexperienced observers. Each observer used a 5‐point scale to grade diagnostic confidence: 1, definitely benign; 2, probably benign; 3, indeterminate; 4, probably malignant; or 5, definitely malignant on the basis of the enhancement pattern during the arterial phase and enhancement degree during the portal and late phases compared with the liver (hypoenhancement indicating malignant and isoenhancement to hyperenhancement indicating benign). Results. The analysis of observer diagnostic confidence revealed higher intragroup (κ = 0.63–0.83) than intergroup (κ = 0.47–0.63) observer agreement. The experienced observers showed higher diagnostic performance in malignancy diagnosis than did inexperienced observers (overall accuracy: group 1, 63.3%–72.8%; group 2, 75.9%–93.1%; P < .05, χ² test). Conclusions. The diagnostic performance of CEUS in liver tumor characterization was dependant on the observer's level of experience.     

Contrast‐Enhanced Ultrasonography With SonoVue

Objective. We investigated the ability of contrast‐enhanced ultrasonography with SonoVue (Bracco SpA, Milan, Italy), a sulfur hexafluoride microbubble contrast agent, to reveal differences between benign and malignant focal splenic lesions. Methods. In a prospective study we investigated 35 lesions in 35 patients (24 male and 11 female; mean age ± SD, 54 ± 15 years) with focal splenic lesions detected by B‐mode ultrasonography. After intravenous injection of 1.2 to 2.4 mL of SonoVue, the spleen was examined continuously for 3 minutes using low–mechanical index ultrasonography with contrast‐specific software. The final diagnosis was established by histologic examination, computed tomography, or magnetic resonance imaging. Results. In 14 patients, the splenic lesions were malignant (metastasis, n = 6; non‐Hodgkin lymphoma, n = 6; and Hodgkin lymphoma, n = 2). In 21 patients, the focal splenic lesions were benign (ischemic lesion, n = 6; echogenic cyst, n = 5; abscess, n = 4; hemangioma, n = 3; hematoma, n = 1; hemophagocytosis syndrome, n = 1; and splenoma, n = 1. Typical findings for benign lesions were 2 arrival patterns: no contrast enhancement (neither in the early nor in the parenchymal phase; P < .05) and the beginning of contrast enhancement in the early phase followed by contrast enhancement in the parenchymal phase 60 seconds after injection. In contrast, the combination of contrast enhancement in the early phase followed by rapid wash‐out and demarcation of the lesion without contrast enhancement in the parenchymal phase (60 seconds after injection) was typical for malignant lesions (P < .001). Conclusions. Contrast‐enhanced ultrasonography is helpful in the differentiation between benign and malignant lesions of the spleen.     

PET imaging of prostate tumors with 18F‐Al‐NOTA‐MATBBN

Overexpression of the gastrin‐releasing peptide receptor (GRPR) in prostate cancer provides a promising target for detection the disease. MATBBN is a new bombesin analog originating from the GRPR antagonists with a hydrophilic linker. In this study NOTA‐conjugated MATBBN was labeled by the Al¹⁸F method and the potential of ¹⁸F‐Al‐NOTA‐MATBBN for prostate tumor PET imaging was also evaluated. NOTA‐MATBBN was radiolabeled with ¹⁸F using Al¹⁸F complexes. Partition coefficient, in vitro stability and GRPR binding affinity were also determined. PET studies were performed with ¹⁸F‐Al‐NOTA‐MATBBN in PC‐3 tumor‐bearing mice. ¹⁸F‐Al‐NOTA‐MATBBN can be produced within 30 min with a decay‐corrected yield of 62.5 ± 2.1% and a radiochemical purity of >98%. The logP octanol–water value for the Al¹⁸F‐labeled BBN analog was ?2.40 ± 0.07 and the radiotracer was stable in phosphate‐buffered saline and human serum for 2 h. The IC₅₀ values of displacement for the ¹⁸F‐Al‐NOTA‐MATBBN with MATBBN was 126.9 ± 2.75 nm . The PC‐3 tumors were clearly visible with high contrast after injection of the labeled peptide. At 60 min post‐injection, the tumor uptakes for ¹⁸F‐Al‐NOTA‐MATBBN and ¹⁸F‐FDG were 4.59 ± 0.43 and 1.98 ± 0.35% injected dose/g, and tumor to muscle uptake radios for two tracers were 6.77 ± 1.10 and 1.78 ± 0.32, respectively. Dynamic PET revealed that ¹⁸F‐Al‐NOTA‐MATBBN was excreted mainly through the kidneys. GRPR‐binding specificity was also demonstrated by reduced tumor uptake of ¹⁸F‐Al‐NOTA‐MATBBN after coinjection with excess unlabeled MATBBN peptide at 1 h post‐injection. NOTA‐ MATBBN could be labeled rapidly with ¹⁸F using one step method. ¹⁸F‐Al‐NOTA‐MATBBN may be a promising PET imaging agent for prostate cancer. Copyright © 2014 John Wiley & Sons, Ltd.     

Syntheses and preliminary evaluation of [18F]AlF‐NOTA‐G‐TMTP1 for PET imaging of high aggressive hepatocellular carcinoma

The goal of this study is to evaluate a new ¹⁸F‐labeled imaging agent for diagnosing high metastatic (aggressive) hepatocellular carcinoma using positron emission tomography (PET). The new ¹⁸F‐labeled imaging agent [¹⁸F]AlF‐NOTA‐G‐TMTP1 was synthesized and radiolabeled with ¹⁸F using NOTA‐AlF chelation method. The tumor‐targeting characteristics of [¹⁸F]AlF‐NOTA‐G‐TMTP1 was assessed in HepG2, SMCC‐7721, HCC97L and HCCLM3 xenografts. The total synthesis time was about 20 min with radiochemical yield of 25 ± 6%. The specific activity was about 11.1–14.8 GBq/µmol at the end of synthesis based on the amount of peptide used and the amount of radioactivity trapped on the C₁₈ column. The log P value of [¹⁸F]AlF‐NOTA‐G‐TMTP1 was ‐3.166 ± 0.022. [¹⁸F]AlF‐NOTA‐G‐TMTP1 accumulated in SMCC‐7721 and HCCLM3 tumors (high metastatic potential) in vivo and result in tumor/muscle (T/M) ratios of 4.5 ± 0.3 and 4.7 ± 0.2 (n = 4) as measured by PET at 40 min post‐injection (p.i.). Meanwhile, the tumor/muscle (T/M) ratios of HepG2 and HCC97L tumors (low metastatic potential) were1.6 ± 0.3 and 1.8 ± 0.4. The tumor uptake of [¹⁸F]AlF‐NOTA‐G‐TMTP1 could be inhibited 61.9% and 57.6% by unlabeled G‐TMTP1 in SMCC‐7721 and HCCLM3 xenografts at 40 min p.i., respectively. Furthermore, [¹⁸F]AlF‐NOTA‐G‐TMTP1 showed pretty low activity in the liver and intestines in all tumor bearing mice, such in vivo distribution pattern would be advantageous for the detection of hepatic carcinoma. Overall, [¹⁸F]AlF‐NOTA‐G‐TMTP1 may specifically target high metastatic or/and aggressive hepatocellular carcinoma with low background activity and, therefore, holds the potential to be used as an imaging agent for detecting tumor lesions within the liver area. Copyright © 2016 John Wiley & Sons, Ltd.     

In‐vivo high‐resolution X‐ray microtomography for liver and spleen tumor assessment in mice

The present study sought to validate the use of glycery1‐2‐oley‐1,3‐bis‐[7‐(3‐amino‐2,4,6‐triiodophenyl)‐ heptanoate] (DHOG) contrast agent for mouse spleen tumor and liver metastasis imaging by high‐resolution X‐ray microtomography. Three groups of female nude mice were compared: controls (n = 5), and mice injected with 2.5 × 10⁶ STC1 tumor cells in the spleen, imaged at 15 days (group G15, n = 5) and at 30 days (group G30, n = 5, of which one died before imaging). Micro‐CT scans (X‐ray voltage, 50 kVp; anode current, 200 µA; exposure time, 632 ms; 180 rotational steps resulting in 35 µm isotropic spatial resolution) were acquired at 0, 0.75, 2 and 4 h after i.v. injection of DHOG. CT number (Hounsfield units: HU) and contrast‐to‐noise ratios (CNR) were determined in three organs. Statistical analysis was performed by Mann–Whitney U‐test. Contrast enhancement in normal spleen and liver increased, respectively to 1020 ± 159 and 351 ± 27 HU over baseline at 4 h, and 482 ± 3 and 203 ± 14 HU on day 6 after a single contrast injection. Automated three‐dimensional reconstruction and modeling of the spleen provided accurate and quantifiable images. Spleen tumor and liver metastases did not take up DHOG, making them detectable in contrast to the increased signal in normal tissue. The smallest liver metastasis detected measured 0.3 mm in diameter. High‐resolution X‐ray micro‐CT in living mice using DHOG contrast agent allowed visualization and volume quantification of normal spleen and of spleen tumor and its liver metastases. Copyright © 2007 John Wiley & Sons, Ltd.     

Diagnostic Parameters to Differentiate Benign From Malignant Ovarian Masses With Contrast‐Enhanced Transvaginal Sonography

Objective. The aim of this study was to evaluate diagnostic parameters to differentiate between benign versus malignant ovarian masses using contrast‐enhanced transvaginal sonography (TVS). Methods. Thirty‐three consecutive patients with 36 morphologically abnormal ovarian masses (solid or cystic with papillary excrescences, focally thickened walls, or irregular solid areas) smaller than 10 cm received a microbubble contrast agent intravenously while undergoing pulse inversion harmonic TVS. The following parameters were assessed: presence of contrast enhancement, time to peak enhancement, peak contrast enhancement, half wash‐out time, and area under the enhancement curve (AUC). Tumor histologic analysis was used to distinguish benign from malignant ovarian tumors. Results. Twenty‐six benign masses and 10 malignancies were studied. Of all examined criteria, an AUC of greater than 787 seconds^?1 was the most accurate diagnostic criterion for ovarian cancer, with 100.0% sensitivity and 96.2% specificity. Additionally, peak contrast enhancement of greater than 17.2 dB (90.0% sensitivity and 98.3% specificity) and half wash‐out time of greater than 41.0 seconds (100.0% sensitivity and 92.3% specificity) proved to be useful. Conclusions. Our data suggest that the AUC, peak enhancement, and half wash‐out time had the greatest diagnostic accuracy for contrast‐enhanced TVS in differentiation between benign and malignant ovarian masses.     

PET of EGFR with 64Cu‐cetuximab‐F(ab′)2 in mice with head and neck squamous cell carcinoma xenografts

Overexpression of the epidermal growth factor receptor (EGFR) is linked to an adverse outcome in various solid tumors. Cetuximab is an EGFR inhibitor, which in combination with radiotherapy improves locoregional control and survival in a subgroup of patients with head and neck squamous cell carcinomas (HNSCCs). The aim of this study was to develop and characterize an EGFR‐directed PET tracer, ⁶⁴Cu‐cetuximab‐F(ab′)₂, to determine the systemic accessibility of EGFR. Mice with HNSCC xenografts, UT‐SCC‐8 (n = 6) or UT‐SCC‐45 (n = 6), were imaged 24 h post injection with ⁶⁴Cu‐NODAGA‐cetuximab‐F(ab′)₂ using PET/CT. One mouse for each tumor model was co‐injected with excess unlabeled cetuximab 3 days before radiotracer injection to determine non‐EGFR‐mediated uptake. Ex vivo biodistribution of the tracer was determined and tumors were analyzed by autoradiography and immunohistochemistry. The SUV_max of UT‐SCC‐8 tumors was higher than that of UT‐SCC‐45: 1.5 ± 1.0 and 0.8 ± 0.2 (p < 0.05), respectively. SUV_max after in vivo blocking of EGFR with cetuximab was 0.4. Immunohistochemistry showed that UT‐SCC‐8 had a significantly higher EGFR expression than UT‐SCC‐45: 0.50 ± 0.19 versus 0.12 ± 0.08 (p < 0.005), respectively. Autoradiography indicated that ⁶⁴Cu‐cetuximab‐F(ab′)₂ uptake correlated with EGFR expression in both tumors: r = 0.86 ± 0.06 (UT‐SCC‐8) and 0.90 ± 0.06 (UT‐SCC‐45). ⁶⁴Cu‐cetuxmab‐F(ab′)₂ is a promising PET tracer to determine expression of EGFR in vivo. Clinically, this tracer has the potential to be used to determine cetuximab targeting of tumors and possibly to non‐invasively monitor the response to EGFR‐inhibitor treatment. Copyright © 2015 John Wiley & Sons, Ltd.     

Imaging integrin alpha‐v‐beta‐3 expression in tumors with an 18F‐labeled dimeric RGD peptide

Integrin α_vβ₃ receptors are expressed on activated endothelial cells during neovascularization to maintain tumor growth. Many radiolabeled probes utilize the tight and specific association between the arginine–glycine–aspartatic acid (RGD) peptide and integrin α_vβ₃, but one main obstacle for any clinical application of these probes is the laborious multistep radiosynthesis of ¹⁸F. In this study, the dimeric RGD peptide, E‐[c(RGDfK)]₂, was conjugated with NODAGA and radiolabeled with ¹⁸F in a simple one‐pot process with a radiolabeling yield of 20%, the whole process lasting only 45 min. NODAGA‐E‐[c(RGDfK)]₂ labeled with ¹⁸F at a specific activity of 1.8 MBq nmol^?1 and a radiochemical purity of 100% could be achieved. The logP value of ¹⁸F‐labeled NODAGA‐E‐[c(RGDfK)]₂ was ?4.26 ± 0.02. In biodistribution studies, ¹⁸F‐NODAGA‐E‐[c(RGDfK)]₂ cleared rapidly from the blood with 0.03 ± 0.01 percentage injected dose per gram (%ID g^?1) in the blood at 2 h p.i., mainly via the kidneys, and showed good in vivo stability. Tumor uptake of ¹⁸F‐NODAGA‐E‐[c(RGDfK)]₂ (3.44 ± 0.20 %ID g^?1, 2 h p.i.) was significantly lower than that of reference compounds ⁶⁸Ga‐labeled NODAGA‐E‐[c(RGDfK)]₂ (6.26 ± 0.76 %ID g^?1; p <0.001) and ¹¹¹In‐labeled NODAGA‐E‐[c(RGDfK)]₂ (4.99 ± 0.64 %ID g^?1; p < 0.01). Co‐injection of an excess of unlabeled NODAGA‐E‐[c(RGDfK)]₂ along with ¹⁸F‐NODAGA‐E‐[c(RGDfK)]₂ resulted in significantly reduced radioactivity concentrations in the tumor (0.85 ± 0.13 %ID g^?1). The α_vβ₃ integrin‐expressing SK‐RC‐52 tumor could be successfully visualized by microPET with ¹⁸F‐labeled NODAGA‐E‐[c(RGDfK)]₂. In conclusion, NODAGA‐E‐[c(RGDfK)]₂ could be labeled rapidly with ¹⁸F using a direct aqueous, one‐pot method and it accumulated specifically in α_vβ₃ integrin‐expressing SK‐RC‐52 tumors, allowing for visualization by microPET. Copyright © 2013 John Wiley & Sons, Ltd.     

[68Ga]‐HP‐DO3A‐nitroimidazole: a promising agent for PET detection of tumor hypoxia

The goal of this study is to evaluate a new ⁶⁸Ga‐based imaging agent for detecting tumor hypoxia using positron emission tomography (PET). The new hypoxia targeting agent reported here, [⁶⁸Ga]‐HP‐DO3A‐nitroimidazole ([⁶⁸Ga]‐HP‐DO3A‐NI), was constructed by linking a nitroimidazole moiety with the macrocyclic ligand component of ProHance®, HP‐DO3A. The hypoxia targeting capability of this agent was evaluated in A549 lung cancer cells in vitro and in SCID mice bearing subcutaneous A549 tumor xenografts. The cellular uptake assays showed that significantly more [⁶⁸Ga]‐HP‐DO3A‐NI accumulates in hypoxic tumor cells at 30, 60 and 120 min than in the same cells exposed to 21% O₂. The agent also accumulated in hypoxic tumors in vivo to give a tumor/muscle ratio (T/M) of 5.0 ± 1.2 (n = 3) as measured by PET at 2 h post‐injection (p.i.). This was further confirmed by ex vivo biodistribution data. In addition, [⁶⁸Ga]‐HP‐DO3A‐NI displayed very favorable pharmacokinetic properties, as it was cleared largely through the kidneys with little to no accumulation in liver, heart or lung (%ID/g < 0.5%) at 2 h p.i. The specificity of the agent for hypoxic tissues was further validated in a comparative study with a control compound, [⁶⁸Ga]‐HP‐DO3A, which lacks the nitroimidazole moiety, and by PET imaging of tumor‐bearing mice breathing air versus 100% O₂. Given the commercial availability of cGMP ⁶⁸Ge/⁶⁸Ga generators and the ease of ⁶⁸Ga labeling, the new agent could potentially be widely applied for imaging tumor hypoxia prior to radiation therapy. Copyright © 2015 John Wiley & Sons, Ltd.     

Magnetic resonance imaging of atherosclerosis by targeting extracellular matrix deposition with Gadofluorine M

As previously reported, Gadofluorine M‐enhanced magnetic resonance imaging clearly demarcates atherosclerotic plaques from the normal vessel wall. To date, the underlying mechanism has remained unknown. Gadofluorine M is a gadolinium‐containing macrocyclic contrast agent containing hydrophilic and hydrophobic moieties. To elucidate the mechanism of accumulation, fluorescently labeled and radioactively labeled derivates of Gadofluorine M were used to determine affinity and specificity of Gadofluorine M binding to blood serum and plaque components in vitro and for the distribution within the plaque of WHHL rabbits in vivo. Gadofluorine M binds to serum albumin, leading to a breakdown of micelles after intravenous injection. The affinity of Gadofluorine M to serum albumin is k_D = 2 µmol/l. Gadofluorine then penetrates the atherosclerotic plaque while bound to albumin and then accumulates within the extracellular, fibrous parts of the plaque by binding to collagens, proteoglycans and tenascin, having the same affinity to these plaque constituents as to albumin. In contrast, weak binding was determined to LDL (k_D = 2 mmol/l) and even no binding to hyaluronic acid. The driving force of binding and accumulation is the hydrophobic moiety of the molecules interacting with hydrophobic plaque materials. Thus, Gadofluorine M accumulates within the fibrous plaque or in the fibrous cap of a plaque containing high amounts of extracellular matrix components, but not in the lipid‐rich areas. In combination with high‐resolution MRI, Gadofluorine M might enable the detection of thin‐cap fibroatheromas, also named the vulnerable plaque. Copyright © 2007 John Wiley & Sons, Ltd.     

Multi‐modal magnetic resonance imaging and histology of vascular function in xenografts using macromolecular contrast agent hyperbranched polyglycerol (HPG‐GdF)

Macromolecular gadolinium (Gd)‐based contrast agents are in development as blood pool markers for MRI. HPG‐GdF is a 583 kDa hyperbranched polyglycerol doubly tagged with Gd and Alexa 647 nm dye, making it both MR and histologically visible. In this study we examined the location of HPG‐GdF in whole‐tumor xenograft sections matched to in vivo DCE‐MR images of both HPG‐GdF and Gadovist. Despite its large size, we have shown that HPG‐GdF extravasates from some tumor vessels and accumulates over time, but does not distribute beyond a few cell diameters from vessels. Fractional plasma volume (fPV) and apparent permeability–surface area product (aPS) parameters were derived from the MR concentration–time curves of HPG‐GdF. Non‐viable necrotic tumor tissue was excluded from the analysis by applying a novel bolus arrival time (BAT) algorithm to all voxels. aPS derived from HPG‐GdF was the only MR parameter to identify a difference in vascular function between HCT116 and HT29 colorectal tumors. This study is the first to relate low and high molecular weight contrast agents with matched whole‐tumor histological sections. These detailed comparisons identified tumor regions that appear distinct from each other using the HPG‐GdF biomarkers related to perfusion and vessel leakiness, while Gadovist‐imaged parameter measures in the same regions were unable to detect variation in vascular function. We have established HPG‐GdF as a biocompatible multi‐modal high molecular weight contrast agent with application for examining vascular function in both MR and histological modalities. Copyright © 2015 John Wiley & Sons, Ltd.     

Assessment of tumor angiogenesis: dynamic contrast‐enhanced MRI with paramagnetic nanoparticles compared with Gd‐DTPA in a rabbit Vx‐2 tumor model

The purpose of this study was to evaluate the suitability of a macromolecular MRI contrast agent (paramagnetic nanoparticles, PNs) for the characterization of tumor angiogenesis. Our aim was to estimate the permeability of PNs in developing tumor vasculature and compare it with that of a low molecular weight contrast agent (Gd‐DTPA) using dynamic contrast‐enhanced MRI (DCE). Male New Zealand white rabbits (n = 5) underwent DCE MRI 12–14 days after Vx‐2 tumor fragments were implanted into the left hind limb. Each contrast agent (PNs followed by Gd‐DTPA) was evaluated using a DCE protocol and transendothelial transfer coefficient (K_i) maps were calculated using a two‐compartment model. Two regions of interest (ROIs) were located within the tumor core and hindlimb muscle and five ROIs were placed within the tumor rim. Comparisons were performed using repeated measures analysis of variance (ANOVA). The K_i values estimated using PNs were significantly lower than those obtained for Gd‐DTPA (p = 0.018). When PNs and Gd‐DTPA data were analyzed separately, significant differences were identified among tumor rim ROIs for PNs (p < 0.0001), but not for Gd‐DTPA data (p = 0.34). The mean K_i for the tumor rim was significantly greater than that of either the core or the hindlimb muscle for both contrast agents (p < 0.05 for each comparison). In summary, the extravasation of Gd‐DTPA was far greater than that of PNs, suggesting that PNs can reveal regional differences in tumor vascular permeability that are not otherwise apparent with clinical contrast agents such as Gd‐DTPA. These results suggest that PNs show potential for the noninvasive delineation of tumor angiogenesis. Copyright © 2010 John Wiley & Sons, Ltd.     

Dynamic fluorescent imaging with indocyanine green for monitoring the therapeutic effects of photoimmunotherapy

A new type of monoclonal antibody (mAb)‐based, highly specific phototherapy (photoimmunotherapy; PIT) that uses a near‐infrared (NIR) phthalocyanine dye, IRDye700DX (IR700) conjugated with an mAb, has recently been described. NIR light exposure leads to immediate, target‐selective necrotic cell death. However, tumor shrinkage takes several days to occur, making it difficult to detect earlier changes in the tumor. In this study, Panitumumab targeting the epidermal growth factor receptor (EGFR1) conjugated to IR700 was used to treat EGFR‐expressing A431 tumor cells and in vivo xenografts. PIT was performed at varying doses of NIR light (10, 30, 50 and 100 J cm^?2) in xenograft tumors in mice. Indocyanine green (ICG) dynamic imaging was evaluated for monitoring cytotoxic effects for the first hour after PIT. Our results demonstrated a statistical difference (p < 0.05) in ICG intensity between control and PIT treated tumors in the higher light exposure groups (50 J cm^?2: 2.94 ± 0.35 vs 5.22 ± 0.92, p = 0.02; and 100 J cm^?2: 3.56 ± 0.96 vs 5.71 ± 1.43, p = 0.008) as early as 20 min post ICG injection. However, no significant difference (p > 0.05) in ICG intensity between control and PIT treated tumors was evident in the lower light exposure group at any time points up to 60 min (10 J cm^?2: 1.92 ± 0.49 vs 1.71 ± 0.3, p = 0.44; and 30 J cm^?2: 1.57 ± 0.35 vs 2.75 ± 0.59, p = 0.07). Similarly, the retention index (background to corrected uptake ratio of ICG) varied with light exposure. In conclusion, ICG may serve as a potential indicator of acute cytotoxic effects of mAb‐IR700‐induced PIT even before morphological changes can be seen in targeted tumors. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.     

DCE‐MRI in experimental chronic pancreatitis

To assess pancreatic perfusion in experimental chronic pancreatitis (CP) by dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI). DCE MRI on a 1.5 T MR scanner was performed on 21 piglets with the ligation of pancreatic duct. They were divided into four groups based on pathology, including seven normal pigs and seven, three and four piglets with grade I, II and III CP, respectively. The signal intensity measured in the pancreatic body on DCE MRI was plotted against time to create a signal intensity–time (SI–T) curve for each piglet. The steepest slope (SS), time‐to‐peak (TTP) and peak enhancement ratio (PER) of the SI–T curve were noted. In the four groups, on the SI–T curve derived from DCE MRI, the SS was, respectively, 10.88 ± 1.20, 10.59 ± 1.02, 6.67 ± 1.31 and 5.48 ± 1.97%/s (F = 20.509, p = 0.000) from normal piglets to piglets with grade III CP. The TTP was 13.82 ± 3.09, 12.31 ± 5.52, 20.55 ± 3.79 and 37.26 ± 14.56 s (F = 10.681, p = 0.000) and the PER was 62.95 ± 20.20, 60.44 ± 20.00, 46.33 ± 22.70 and 67.65 ± 32.66% (F = 0.529, p = 0.668), respectively. The SS (r = –0.719, p = 0.000) and TTP (r = 0.538, p = 0.012) of the SI–T curve was correlated to the severity of CP, respectively. DCE MRI has a potential to diagnose moderate to advanced CP. The SS and TTP of the SI–T curve were correlated to the severity of CP. Copyright © 2009 John Wiley & Sons, Ltd.     

DWI鉴别诊断实质性肝脏肿瘤的价值

目的 探讨DWI鉴别诊断实质性肝脏良性与恶性肿瘤的价值。 方法 回顾性分析经病理证实的7例肝腺瘤、14例肝局灶性增生(FNH)及32例肝脏恶性肿瘤患者(25例肝癌和7例转移瘤)的DWI定量分析结果,比较肝脏FNH和腺瘤与肝脏恶性肿瘤ADC值的差异。 结果 7例肝腺瘤9个病灶的平均ADC值为(1.05±0.28)×10^-3 mm²/s,14例FNH 18个病灶的平均ADC值为(1.13±0.46)×10^-3 mm²/s,32例肝脏恶性肿瘤49个病灶的平均ADC值为(0.96±0.29)×10^-3 mm²/s(b＝800 s/mm²)。FNH、肝腺瘤与肝脏恶性肿瘤的平均ADC值之间差异无统计学意义(P均>0.05)。 结论 ADC值对实质性肝脏良性肿瘤(FNH和肝腺瘤)与肝脏恶性肿瘤的鉴别无帮助。     

Dynamic manganese‐enhanced magnetic resonance imaging can detect chronic cryoinjury‐induced infarction in pig hearts in vivo

The purpose was to investigate whether MnCl₂ can serve as an MRI contrast agent to detect chronic cryoinjury infarction in pigs in vivo and whether MnCl₂ causes significant hemodynamic disturbances. Hearts were subjected to a topical 2 min cryothermia to establish myocardial infarction (MI). Thereafter GdDTPA‐enhanced MRI was performed at 0, 1, 2 and 3 weeks using a 3 T scanner. Four weeks post‐cryoinjury the pigs underwent in vivo Mn‐enhanced magnetic resonance imaging (MEMRI). MnCl₂ (70 μmol/kg, 14 min) was infused i.v. intermittently (n = 4) or continuously (n = 5) and T₁‐weighted images were acquired every 2 min simultaneously recording heart rate and arterial blood pressure. Either infusion scheme led to an immediate increment in MR signal intensity (SI) within the left ventricular (LV) blood pool and LV normal and cryoinjured myocardium, which reached a maximum at the end of infusion. No significant difference was observed between the normal and cryoinjured myocardium. After infusion termination, SI decreased faster within the LV blood pool and the MI, as compared with the normal myocardium in either group, resulting in significant contrast between the MI and normal tissue (intermittent: 18 ± 7 vs 49 ± 13%, p = 0.002; continuous: 19 ± 8 vs 36 ± 9%, p = 0.004). Infarction sizes were similar in Mn²⁺‐ and GdDTPA‐enhanced images at 4 and 3 weeks post injury, respectively. Thus, in vivo MEMRI differentiated infarcted from normal myocardium in pig hearts subjected to 4‐week cryoinjury. Compared with intermittent infusion, continuous infusion minimized hemodynamic fluctuations. Copyright © 2011 National Research Council Canada.     

Evaluation of tumor affinity of mono‐[123I]iodohypericin and mono‐[123I]iodoprotohypericin in a mouse model with a RIF‐1 tumor

In this study we have compared the tumour‐seeking properties of mono‐[¹²³I]iodoprotohypericin and mono‐[¹²³I]iodohypericin in C3H mice with a subcutaneous radiation‐induced fibrosarcoma‐1 tumor. After intravenous injection, both tracers were rapidly cleared from all organs and were retained by the tumors. There was no significant difference in tumor uptake of the two tracers at all studied time points (p > 0.05). To study the plausible mechanism of hypericin and mono‐iodohypericin uptake in tumor, their plasma binding profile was investigated. Both agents show high affinity for low‐density lipoproteins and to a lesser extent high‐density lipoproteins and other heavy proteins. Mono‐[¹²³I]iodohypericin appears to be more promising as a tumor diagnostic agent, given its faster clearance from all organs. Copyright © 2007 John Wiley & Sons, Ltd.     

Regional heterogeneity changes in DCE‐MRI as response to isolated limb perfusion in experimental soft‐tissue sarcomas

Experimental evidence supports an association between heterogeneity in tumor perfusion and response to chemotherapy/radiotherapy, disease progression and malignancy. Therefore, changes in tumor perfusion may be used to assess early effects of tumor treatment. However, evaluating changes in tumor perfusion during treatment is complicated by extensive changes in tumor type, size, shape and appearance. Therefore, this study assesses the regional heterogeneity of tumors by dynamic contrast‐enhanced MRI (DCE‐MRI) and evaluates changes in response to isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan. Data were acquired in an experimental cancer model, using a macromolecular contrast medium, albumin–(Gd–DTPA)45. Small fragments of BN 175 (a soft‐tissue sarcoma) were implanted in eight brown Norway rats. MRI of five drug‐treated and three sham‐treated rats was performed at baseline and 1 h after ILP intervention. Properly co‐registered baseline and follow‐up DCE‐MRI were used to estimate the volume transfer constant (K^trans) pharmacokinetic maps. The regional heterogeneity was estimated in 16 tumor sectors and presented in cumulative map‐volume histograms. On average, ILP‐treated tumors showed a decrease in regional heterogeneity on the histograms. This study shows that heterogenic changes in regional tumor perfusion, estimated using DCE‐MRI pharmacokinetic maps, can be measured and used to assess the short‐term effects of a potentially curative treatment on the tumor microvasculature in an experimental soft‐tissue sarcoma model. Copyright © 2013 John Wiley & Sons, Ltd.     

Concentration‐independent MRI of pH with a dendrimer‐based pH‐responsive nanoprobe

The measurement of extracellular pH (pH_e) has significant clinical value for pathological diagnoses and for monitoring the effects of pH‐altering therapies. One of the major problems of measuring pH_e with a relaxation‐based MRI contrast agent is that the longitudinal relaxivity depends on both pH and the concentration of the agent, requiring the use of a second pH‐unresponsive agent to measure the concentration. Here we tested the feasibility of measuring pH with a relaxation‐based dendritic MRI contrast agent in a concentration‐independent manner at clinically relevant field strengths. The transverse and longitudinal relaxation times in solutions of the contrast agent (GdDOTA‐4AmP)₄₄‐G5, a G5–PAMAM dendrimer‐based MRI contrast agent in water, were measured at 3 T and 7 T magnetic field strengths as a function of pH. At 3 T, longitudinal relaxivity (r₁) increased from 7.91 to 9.65 mM^?1 s^?1 (on a per Gd³⁺ basis) on changing pH from 8.84 to 6.35. At 7 T, r₁ relaxivity showed pH response, albeit at lower mean values; transverse relaxivity (r₂) remained independent of pH and magnetic field strengths. The longitudinal relaxivity of (GdDOTA‐4AmP)₄₄‐G5 exhibited a strong and reversible pH dependence. The ratio of relaxation rates R₂/R₁ also showed a linear relationship in a pH‐responsive manner, and this pH response was independent of the absolute concentration of (GdDOTA‐4AmP)₄₄‐G5 agent. Importantly, the nanoprobe (GdDOTA‐4AmP)₄₄‐G5 shows pH response in the range commonly found in the microenvironment of solid tumors. Copyright © 2015 John Wiley & Sons, Ltd.