Main applications of hybrid PET‐MRI contrast agents: a review

In medical imaging, the continuous quest to improve diagnostic performance and optimize treatment strategies has led to the use of combined imaging modalities. Positron emission tomography (PET) and computed tomography (CT) is a hybrid imaging existing already for many years. The high spatial and contrast resolution of magnetic resonance imaging (MRI) and the high sensitivity and molecular information from PET imaging are leading to the development of this new hybrid imaging along with hybrid contrast agents. To create a hybrid contrast agent for PET‐MRI device, a PET radiotracer needs to be combined with an MRI contrast agent. The most common approach is to add a radioactive isotope to the surface of a small superparamagnetic iron oxide (SPIO) particle. The resulting agents offer a wide range of applications, such as pH variation monitoring, non‐invasive angiography and early imaging diagnosis of atherosclerosis. Oncology is the most promising field with the detection of sentinel lymph nodes and the targeting of tumor neoangiogenesis. Oncology and cardiovascular imaging are thus major areas of development for hybrid PET‐MRI imaging systems and hybrid contrast agents. The aim is to combine high spatial resolution, high sensitivity, morphological and functional information. Future prospects include the use of specific antibodies and hybrid multimodal PET‐MRI‐ultrasound‐fluorescence imaging with the potential to provide overall pre‐, intra‐ and postoperative patient care. Copyright © 2015 John Wiley & Sons, Ltd.     

Evaluation of superparamagnetic iron oxide nanoparticles (Endorem®) as a photoacoustic contrast agent for intra‐operative nodal staging

Detection of tumor metastases in the lymphatic system is essential for accurate staging of malignancies. Commercially available superparagmagnetic nanoparticles (SPIOs) accumulate in normal lymph tissue after injection at a tumor site, whereas less or no accumulation takes place in metastatic nodes, thus enabling lymphatic staging using MRI. We verify for the first time the potential of SPIOs, such as Endorem® as a novel photoacoustic (PA) contrast agent in biological tissue. We injected five Wistar rats subcutaneously with variable amounts of Endorem® and scanned the resected lymph nodes using a tomographic PA setup. Findings were compared using histology, vibrating sample magnetometry (VSM) and 14 T MR‐imaging. Our PA setup was able to detect the iron oxide accumulations in all the nodes containing the nanoparticles. The distribution inside the nodes corresponded with both MRI and histological findings. VSM revealed that iron quantities inside the nodes varied between 51 ± 4 and 11 ± 1 µg. Nodes without SPIO enhancement did not show up in any of the PA scans. Iron oxide nanoparticles (Endorem®) can be used as a PA contrast agent for lymph node analysis and a distinction can be made between nodes with and nodes without the agent. This opens up possibilities for intra‐operative nodal staging for patients undergoing nodal resections for metastatic malignancies. Copyright © 2012 John Wiley & Sons, Ltd.     

Utility of diffusion-weighted imaging in the diagnosis of inguinal lymph node metastasis with malignant melanoma

Malignant melanoma is a malignancy of pigment-producing cells (melanocytes) located predominantly in the skin. Nodal metastases are an adverse prognostic factor compromising long term patient survival. Therefore, accurate detection of regional nodal metastases is required for optimization of treatment. Computed tomography (CT) and magnetic resonance imaging (MRI) remain the primary imaging modalities for regional staging of malignant melanoma. However, both modalities rely on size-related and morphological criteria to differentiate between benign and malignant lymph nodes, decreasing the sensitivity for detection of small metastases. Surgery is the primary mode of therapy for localized cutaneous melanoma. Patients should be followed up for metastases after surgical removal. We report here a case of inguinal lymph node enlargement with a genital vesicular lesion with a history of surgery for malignant melanoma on her thigh two years ago. CT and diffusion weighted-MRI (DW-MRI) were applied for the lymph node identification. DW-MRI revealed malignant lymph nodes due to malignant melanoma metastases correlation with pathological findings.     

乳腺癌淋巴结可切除性的影像学评估研究进展

乳腺癌腋窝淋巴结清扫术根据病情不同有不同程度的清扫方式,这要求术前提供乳腺癌淋巴结的详细影像学结果,以评估其可切除性。评估乳腺癌淋巴结可切除性的影像学手段多种多样,包括超声、X线、CT、MRI、核医学等,其中MRI的诊断性能最佳,能够提供丰富的影像学信息。在乳腺癌淋巴结可切除性方面,使用mDIXON技术应用于腋窝血管成像,提供腋窝淋巴结与血管关系的详细信息,指导乳腺癌淋巴结清扫术的术前评估和制定手术方案,降低手术出血量。     

Patterns of lymphatic drainage and lymph node involvement in esophageal cancer

The esophagus has a complex pattern of lymphatic drainage. Lymph node involvement and number of lymph node metastases are very important prognostic factors, and the newly revised TNM staging system for esophageal cancer reflects this. Knowledge of the location and nomenclature of the common nodal stations in the thorax and upper abdomen is essential for the accurate staging of these patients. PET–CT and EUS are essential in the routine staging of esophageal cancer patients. The aim of this pictorial review is to present the nodal stations, nomenclature and location of regional lymph nodes in esophageal cancer using PET–CT and EUS images from selected patient cases. We will review the EUS and PET–CT imaging for a number of patients with esophageal cancer, using cases which highlight the advantages and diagnostic pitfalls for these imaging modalities.     

Metastasis of primary breast angiosarcoma to axillary and supraclavicular lymph nodes: a rare case diagnosed using imaging data

Primary breast angiosarcoma (PBA) is a rare malignant tumor. PBA usually undergoes hematogenous metastasis; lymph node metastasis is very rare in such patients, and metastasis of PBA to the supraclavicular lymph nodes has not previously been reported. Here, we describe a rare case of PBA manifested by a diffuse enlargement of the left breast, with metastasis to the left axillary and bilateral supraclavicular lymph nodes. Contrast-enhanced ultrasound and positron emission tomography findings indicated a malignant lesion, whereas magnetic resonance imaging suggested a benign lesion. Core needle biopsy identified the lesion as a lymphangioma, and the histological characteristics suggested a high-grade angiosarcoma. Multimodal imaging and perfusion patterns obtained using various contrast agents can thus help to diagnose PBA.     

254例鼻咽癌颈淋巴结转移的MRI诊断

目的进行大样本鼻咽癌颈淋巴结转移的MRI研究,旨在探索鼻咽癌颈淋巴结转移的规律及MRI信号特点。方法收集经病理组织学确诊的初治鼻咽癌315例,全部病例进行鼻咽部MRI检查,行自旋回波轴位、冠状、矢状位T1WI、轴位T2WI扫描及常规增强MRI扫描。结果315例患者中,254例(80.6%)有淋巴结转移,咽后淋巴结最常受累。鼻咽病灶位于双侧者,其颈淋巴结转移率明显较单侧者高。与鼻咽病灶均匀信号不同,颈部转移淋巴结的中央坏死、包膜外侵犯及融合发生率较高。结论鼻咽癌颈淋巴结转移发生率高,以咽后淋巴结最多见。鼻咽病灶位于双侧者淋巴结转移率明显较单侧者高。鼻咽癌颈部转移淋巴结的坏死、包膜外侵犯及融合发生率较高。     

In vivo real‐time lymphatic draining using quantum‐dot optical imaging in mice

The lymphatic system is essential for fluid regulation and for the maintenance of host immunity. However, in vivo lymph flow is difficult to track in real time, because of the lack of an appropriate imaging method. In this study, we combined macro‐zoom fluorescence microscopy with quantum‐dot (Qdot) optical lymphatic imaging to develop an in vivo real‐time optical lymphatic imaging method that allows the tracking of lymph through lymphatic channels and into lymph nodes. After interstitial injection of Qdots in a mouse, rapid visualization of the cervical lymphatics and cervical lymph nodes was achieved. Real‐time monitoring of the injected Qdots revealed that the cortex of the node enhanced first followed by a net‐like pattern in the central portion of the node. Histology revealed that the rim and net‐like enhancing regions corresponded to the subcapsular sinuses and medullary sinuses respectively. Additionally, multiplexed two‐color real‐time lymphatic tracking was performed with two different Qdots. With this real‐time imaging system, we successfully tracked microscopic lymphatic flow in vivo. This method could have a potential impact for lymphatic research in visualizing normal or abnormal functional lymphatic flows. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.     

CT指数及MR成像对盆腔淋巴结转移诊断价值的研究

目的探讨CT指数及MR成像对盆腔淋巴结转移诊断价值。材料与方法 2011年9月到2015年2月选择在湖北省十堰市房县人民医院肿瘤科就诊的56例宫颈癌初诊患者,都进行CT指数及MRI成像检测与对比,并且进行了病理分析。结果在56例患者中,手术病理判断为淋巴结转移38例,转移阳性率为67.9%。CT检测显示淋巴结转移阳性患者的淋巴结多为原型、中心有坏死、多合并存在包膜外侵,并且大小明显高于淋巴结转移阴性患者(P0.05)。MRI DWI图像显示淋巴结转移阳性患者的ADC值明显低于淋巴结转移阴性患者(P0.05),而eADC值明显高于淋巴结转移阴性患者(P0.05)。与手术病理结果对比,CT与MR诊断淋巴结转移的敏感性为97.4%和100.0%,特异性都为100.0%,对比差异都无统计学意义(P0.05)。结论宫颈癌盆腔淋巴结转移在临床上比较常见,可导致CT影像图特征的变化与MR成像参数的改变,CT指数及MRI成像对盆腔淋巴结转移都是非常敏感与特异的检测手段,值得在临床上推广应用。     

超声对良、恶性浅表淋巴结病变的鉴别诊断及其进展

许多疾病表现为浅表淋巴结肿大,临床需要有效的方法鉴别淋巴结的良、恶性。应用高频超声能够观察淋巴结的结构和血流分布,并进行血流动力学分析,近年来出现的超声造影能够进一步观察淋巴结的血流灌注情况,恶性淋巴结呈现特征性的血流灌注特征,以此鉴别淋巴结性质准确性高。超声应作为鉴别浅表淋巴结病变的首选影像学检查方法,对疾病的早期发现与诊断有重要意义。本文综述了超声对良、恶性浅表淋巴结病变的鉴别要点。     

MR and optical imaging of early micrometastases in lymph nodes: triple labeling with nano‐sized agents yielding distinct signals

Few imaging methods are available for depicting in vivo cancer cell migration within the lymphatic system. Detection of such early micrometastases requires extremely high target to background. In this study, we dual‐labeled human breast cancer cells (MDA‐MB468) with a small particle of iron oxide (SPIO) and a quantum dot (QD), and tracked these cells in the lymphatic system in mice using in vivo MRI and optical imaging. A generation‐6 gadolinium‐dendrimer‐based MRI contrast agent (Gd‐G6) was employed for visualizing regional lymphatic channels and nodes. Since Gd‐G6 shortened T₁ leading to high signal, whereas SPIO‐labeled cancer cells greatly lowered signal, a small number of cells were simultaneously visualized within the draining lymphatic basins. One million dual‐labeled cancer cells were subcutaneously injected into the paws of mice 24 h prior to imaging. Then whole body images were acquired pre‐ and post‐intracutaneous injection of Gd‐G6 with 3D‐T₁w‐FFE and balanced‐FFE sequences for cancer cell tracking and MR lymphangiography. In vivo MRI clearly visualized labeled cancer cells migrating from the paw to the axillary lymph nodes using draining lymphatics. In vivo optical imaging using a fluorescence surgical microscope demonstrated tiny cancer cell clusters in the axillary lymph node with high spatial resolution. Thus, using a combination of MRI and optical imaging, it is possible to depict macro‐ and early micrometastases within the lymphatic system. This platform offers a versatile research tool for investigating and treating lymphatic metastases in animal models. Copyright © 2011 John Wiley & Sons, Ltd.     

Solid silica nanoparticles: applications in molecular imaging

Silica and silica‐based nanoparticles have been widely used for therapeutic and diagnostic applications in cancer mainly through delivery of drugs, genes and contrast agents. Development of synthesis methods has provided the possibility of fabricating silica nanoparticles with different sizes in nanometer ranges as well as silica‐based multimodal nanoparticles with many innovative properties and intriguing applications in biomedicine. The surface of silica particles facilitates different methods of surface modifications and allows conjugation of various biomolecules such as proteins and nucleic acids. In this review, different methods of fabrication of silica and silica‐based nanoparticles, their surface modification and the application of these nanoparticles in molecular imaging are discussed. Overall, the aim of this review is to address the development of silica and silica‐based multifunctional nanoparticles that are introduced mainly for molecular imaging applications using optical, magnetic (MRI), X‐ray (computed tomography) and multimodal imaging techniques. Copyright © 2014 John Wiley & Sons, Ltd.     

CT and MR imaging in Hodgkin's disease--present and future

Initial staging of Hodgkin's disease is crucial to determine the location and extent of disease, and is the hallmark for the choice of treatment. At present, the established radiological technique for staging Hodgkin's disease is computed tomography (CT). Modern multidetector row CT scanners allow fast imaging from the scull base to the groins during a single breath hold with a spatial resolution of approximately 1 mm. Both, nodal and extranodal involvement of Hodgkin's disease can be diagnosed with CT. Magnetic resonance (MR) imaging is another useful cross-sectional imaging modality for staging Hodgkin's disease. The development of fast MR imaging techniques has considerably reduced imaging time without compromising the quality of MR images. As a consequence, MR imaging is now considered to be as diagnostic as CT for staging Hodgkin's disease. The excellent soft-tissue contrast and the lack of exposure to ionizing radiation are the main advantages of MR imaging. For the detection of extranodal Hodgkin's disease, MR imaging is superior to assess involvement of the brain, the spinal cord and bone marrow; while CT allows excellent evaluation of lung disease. Common major problems in staging Hodgkin's disease are still the detection of nodal involvement in normal sized lymph nodes and residual tumor masses after therapy. In the future, newly developed lymphotropic contrast agents for MR imaging might be helpful to answer these questions.     

Nodes or no nodes: CT of adenopathy

Computed tomography (CT) is the diagnostic modality of choice in the staging of abdominal malignancies. Metastatic disease in the lymph nodes is defined on CT as nodal enlargement. The presence of enlarged nodes does not preclude inflammatory involvement. There are clues that will indicate whether enlarged nodes are malignant or not (i.e., associated bony destruction). This paper will delineate normal nodal anatomy of the abdomen and pelvis. Clinical examples will be used to demonstrate normal structures simulating adenopathy and malignant adenopathy will be illustrated in lymphoma, seminoma, carcinoma of the cervix, prostate, and other pelvic malignancies.     

MR imaging of lymph nodes in the head and neck

This article reviews imaging-based nodal classification, recent advancements in MR techniques for lymph node imaging, and characteristics of MR imaging for neck lymphadenopathy. Further technical development of MR imaging is necessary to improve accuracy of lymph node metastases in patients with N0 neck. Development of new tissue-specific MR contrast agents and functional imaging studies to address biologic activity of lymph nodes are essential in the future.     

Does quantification of USPIO uptake‐related signal loss allow differentiation of benign and malignant normal‐sized pelvic lymph nodes?

Ultrasmall superparamagnetic iron oxide (USPIO) particles are promising contrast media, especially for molecular and cellular imaging besides lymph node staging owing to their superior NMR efficacy, macrophage uptake and lymphotropic properties. The goal of the present prospective clinical work was to validate quantification of signal decrease on high‐resolution T₂‐weighted MR sequences before and 24–36 h after USPIO administration for accurate differentiation between benign and malignant normal‐sized pelvic lymph nodes. Fifty‐eight patients with bladder or prostate cancer were examined on a 3 T MR unit and their respective lymph node signal intensities (SI), signal‐to‐noise (SNR) and contrast‐to‐noise (CNR) were determined on pre‐ and post‐contrast 3D T₂‐weighted turbo spin echo (TSE) images. Based on histology and/or localization, USPIO‐uptake‐related SI/SNR decrease of benign vs malignant and pelvic vs inguinal lymph nodes was compared. Out of 2182 resected lymph nodes 366 were selected for MRI post‐processing. Benign pelvic lymph nodes showed a significantly higher SI/SNR decrease compared with malignant nodes (p < 0.0001). Inguinal lymph nodes in comparison to pelvic lymph nodes presented a reduced SI/SNR decrease (p < 0.0001). CNR did not differ significantly between benign and malignant lymph nodes. The receiver operating curve analysis yielded an area under the curve of 0.96, and the point with optimal accuracy was found at a threshold value of 13.5% SNR decrease. Overlap of SI and SNR changes between benign and malignant lymph nodes were attributed to partial voluming, lipomatosis, histiocytosis or focal lymphoreticular hyperplasia. USPIO‐enhanced MRI improves the diagnostic ability of lymph node staging in normal‐sized lymph nodes, although some overlap of SI/SNR‐changes remained. Quantification of USPIO‐dependent SNR decrease will enable the validation of this promising technique with the final goal of improving and individualizing patient care. Copyright © 2012 John Wiley & Sons, Ltd.     

Lymph node staging

Cancers of the head and neck (HNC) include cancers of the larynx, nasal passages/nose, oral cavity, pharynx, salivary glands, buccal regions, and thyroid. In these cancers, lymph node staging and localization of pathological lymph nodes are necessary to decide on either (neo) adjuvant or surgical therapy and are a major factor for the prognosis in HNC patients. Cervical node metastases have different incidence, and their presence is associated with a decrease in global survival to roughly half and with higher recurrence rates. The node metastases can be categorized in the following 2 groups: overt (clinical) or nonovert (occult). The latter can be subcategorized as metastases detectable by traditional methods (eg, staining) or "submicroscopic" metastases, only evident with immunohistochemical or molecular analysis. Compared with clinical invasive and laboratory examinations, which may have complications and are expensive, radiology plays an important role in lymph node staging. Mainly, the overt node metastases are the field of radiological imaging, and second, the detection of nonovert metastases is important and holds promise for the future because many patients of those initially classified as cN0 have, in fact, occult metastatic disease (pN1). Vice versa, radiological imaging has to avoid false-positive results that can lead to an elective or radical neck dissection, which are associated with increased morbidity and mortality and thus overshadow the improvement in survival. Radiological imaging plays a role not only as an initial staging of N+ but also in the case of N0 due to the continuing controversy for the treatment of N0 patients. A close observation of the patient may reveal a positive node in the follow-up. The imaging modalities used for the node staging in HNC patients include ultrasound, contrast-enhanced computed tomography, contrast-enhanced magnetic resonance imaging (MRI), and positron emission tomography scans. None of the above-mentioned methods reaches a 100% sensitivity or specificity, and the accuracy of the exact number of metastases or levels involved has not been studied; thus, neck dissection with subsequent pathological examination remains the gold standard for node staging. Among the described cross-sectional imaging modalities, MRI presents a lot of advantages mainly due to the increased soft tissue contrast and the ability to obtain tissue characteristics in different sequences, including diffusion- and perfusion-weighted sequences and proton spectroscopy imaging. The lack of the radiation burden makes MRI suitable for a close follow-up of the patient, and the imaging with the use of new intravenous contrast material (such as ultrasmall iron oxide particles) seems superior to the conventional. In this article, we will focus on the lymph node MRI staging in HNC patients and the MR anatomy of the nodes, the necessary diagnostic workup, and the advantages of the method over computed tomography. The possibilities of the new imaging sequences and the treatment implications will be addressed as well.     

USPIO enhanced lymph node MRI using 3D multi‐echo GRE in a rabbit model

Ultrasmallsuperparamagnetic iron oxide (USPIO) has been suggested to be a negative MR contrast agent to detect metastatic lymph nodes. Previously reported studies have evaluated the diagnostic performance of USPIO‐enhanced MR lymph node imaging based on signal intensity. In this study, we investigate the specific performance of three different parametric approaches (normalized signal intensity, R₂* and susceptibility) using 3D multi‐echo gradient echo to quantify the USPIO particles in lymph nodes. Nine rabbits with VX2 tumor implants were scanned before and after USPIO injection. From 3D multi‐echo GRE magnitude and phase data, we generated multi‐echo combined T₂*‐weighted images, an R₂* map, and a quantitative susceptibility map. Eighteen lymph nodes (nine reactive and nine metastatic) were evaluated and showed remarkable signal drops in the area of USPIO accumulation. On parametric analysis, the R₂* difference before and after USPIO injection was significantly different (p < 0.05) between reactive and metastatic lymph nodes; in contrast, the normalized signal intensity and susceptibility were not significantly different between the nodes. Our study showed the potential utility of USPIO‐enhanced MRI using R2* mapping from 3D multi‐echo GRE for the detection of lymph node metastasis and parametric analysis of lymph node status in a rabbit model. Copyright © 2016 John Wiley & Sons, Ltd.     

Delivery of gadolinium-labeled nanoparticles to the sentinel lymph node: comparison of the sentinel node visualization and estimations of intra-nodal gadolinium concentration by the magnetic resonance imaging.

Sentinel node imaging is commonly performed prior to surgery for breast cancer and melanoma. While current methods are based on radio-lymphoscintigraphy, MR lymphangiography (MRL) offers the benefits of better spatial resolution without ionizing radiation. However, the optimal nanoparticle for imaging the sentinel nodes remains unclear. Gadolinium-labeled (Gd) contrast agents ranging in diameter from <1 to 12 nm were evaluated to determine which size provides the most rapid and most concentrated delivery of contrast agent to the lymph nodes in a mouse model of lymphatic metastases. Specifically, PAMAM-G2, -G4, -G6 and -G8, and DAB-G5 Gd-dendrimer agents, as well as Gadomer-17 and Gd-DTPA, were compared. Among these agents, the G6 Gd dendrimer depicted the lymphatics and lymph nodes with the highest peak concentrations and this occurred 24-36 min post-injection (p<0.01; all except G8). Based on ex vivo concentration phantoms, high accumulations of Gd(III) ions occurred within lymph nodes (1.7-4.4 mM Gd/270-680 ppm Gd) with high target to background ratios (>100). These concentrations are sufficient to contemplate the use of Gd-neutron capture therapy of regional lymph nodes. Thus, when injected interstitially, the PAMAM-G6 Gd dendrimer not only provides excellent opacification of sentinel lymph nodes, but also provides the potential for targeted therapy of sentinel lymph nodes.     

Hypopharyngeal cancer

Hypopharyngeal cancers are usually squamous cell carcinomas (SCCs) that has the worst prognosis among the head and neck cancers. Overall, 5-year survival rate remains poor despite recent improvements in diagnostic imaging, radiation and chemotherapy, and improved surgical techniques. Hypopharyngeal cancers tend to present with advanced primary disease, and nodal metastasis is highly likely. The most important features determining prognosis are the size and extent of local spread of the primary carcinoma and the extent of involvement of regional lymph nodes. Distant metastasis at presentation is more common in hypopharyngeal cancers than in other head and neck cancers. Poor survival rate is partly due to emergence of second primary cancers but also to development of distant metastasis. Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) remain the mainstay of initial radiological evaluation of hypopharyngeal cancer. Imaging usually results in upstaging of the tumor at presentation. Meticulous evaluation of the extent of the primary tumor with attention to spread to the subsites of the hypopharynx, larynx, and cartilage invasion are necessary for accurate staging. After surgery and radiation therapy, it is difficult with CT and MR to differentiate residual and recurrent tumor from edema and scarring. Fluorine 18-fluoro-deoxy-glucose -positron emission tomography (FDG-PET) has high sensitivity in detection of occult, residual, and recurrent tumors but has low specificity. Combined PET and CT increase specificity and are increasingly being used to image posttreatment cases. Other newer imaging modalities such as diffusion-weighted imaging (DWI), MR spectroscopy, and MRI with superparamagnetic iron oxide (SPIO) contrast agent are reported to be useful and should be used more widely in difficult cases.