Targeted therapy of glioblastoma stem-like cells and tumor non-stem cells using cetuximab-conjugated iron-oxide nanoparticles

Malignant gliomas remain aggressive and lethal primary brain tumors in adults. The epidermal growth factor receptor (EGFR) is frequently overexpressed in the most common malignant glioma, glioblastoma (GBM), and represents an important therapeutic target. GBM stem-like cells (GSCs) present in tumors are felt to be highly tumorigenic and responsible for tumor recurrence. Multifunctional magnetic iron-oxide nanoparticles (IONPs) can be directly imaged by magnetic resonance imaging (MRI) and designed to therapeutically target cancer cells. The targeting effects of IONPs conjugated to the EGFR inhibitor, cetuximab (cetuximab-IONPs), were determined with EGFR- and EGFRvIII-expressing human GBM neurospheres and GSCs. Transmission electron microscopy revealed cetuximab-IONP GBM cell binding and internalization. Fluorescence microscopy and Prussian blue staining showed increased uptake of cetuximab-IONPs by EGFR- as well as EGFRvIII-expressing GSCs and neurospheres in comparison to cetuximab or free IONPs. Treatment with cetuximab-IONPs resulted in a significant antitumor effect that was greater than with cetuximab alone due to more efficient, CD133-independent cellular targeting and uptake, EGFR signaling alterations, EGFR internalization, and apoptosis induction in EGFR-expressing GSCs and neurospheres. A significant increase in survival was found after cetuximab-IONP convection-enhanced delivery treatment of 3 intracranial rodent GBM models employing human EGFR-expressing GBM xenografts.     

Using anti-VEGF McAb and magnetic nanoparticles as double-targeting vector for the radioimmunotherapy of liver cancer

To study the biodistribution of a new radioimmunoconjugate-131I-anti-VEGF monoclonal antibody (Sc-7269)-Dextran Magnetic Nanoparticles (DMN) in nude mice bearing human liver cancer where an external magnetic field was focused on, and to evaluate its therapeutic effects and safety. Tumor Growth Delay (TGD) and tumor inhibition rate were observed as antitumor effect. Peripheral white blood cells counts and the loss of body weight were tested as an indicator of systemic toxicity. The results suggests that the radioimmunotherapy of intratumoral injection of 131I-Sc-7269-DMN may be safe and efficient for the treatment of liver cancer. Furthermore, the radioimmunotherapy using DMN as a 'carrier system' may be a highly potential approach in the treatment of other kind of tumors.     

血管母细胞瘤的 MRI 及 MRS 特点分析

目的：对血管母细胞瘤的 MRI 及 MRS 特点进行分析,提高对该病的认识并探讨 MRI 联合 MRS 检查对该病的诊断价值。方法：回顾性分析经病理证实的21例血管母细胞瘤的临床及影像学资料,分析病变部位、MRI 及 MRS 特点及其与患者的预后关系。结果：21例病例中,囊实性病变19例,呈典型“大囊小结节”样改变,实质性者2例。MRI 表现为病变囊性部分呈长 T1长 T2信号,增强扫描18例未见强化,1例囊壁轻微强化;附壁结节及病变实质部分 T1WI 呈等或稍低信号,T2WI 呈等或稍高信号,增强扫描明显强化,实质性病变内可见血管流空、脂肪及脑膜强化信号。MRS 示病变实性部分 Cho 及 Cr 峰明显增高,NAA 峰明显减低,可见高耸的“LL”峰。3例 VHL 中2例伴有其他肿瘤。结论：血管母细胞瘤的 MRI 表现具有特征性,在掌握典型血管母细胞瘤 MRI 特点的基础上,MRS 可以提供更多信息以提高对该病的早期诊断率。     

Application of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI)combined with magnetic resonance spectroscopy(MRS)in prostate cancer diagnosis

Objective The aim of the study was to investigate the application of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI)combined with magnetic resonance spectroscopy(MRS)in prostate cancer diagnosis.Methods In the outpatient department of our hospital(Sichuan Cancer Hospital,Chengdu,China),60 patients diagnosed with prostate disease were selected randomly and included in a prostate cancer group,60 patients with benign prostatic hyperplasia were included in a proliferation group,and 60 healthy subjects were included in a control group,from January 2013 to January 2017.Using Siemens Avanto 1.5 T high-field superconducting MRI for DCE-MRI and MRS scans,after the MRS scan was completed,we used the workstation spectroscopy tab spectral analysis,and eventually obtained the crest lines of the prostate metabolites choline(Cho),creatine(Cr),citrate(Cit),and the values of Cho/Cit,and(Cho+Cr)/Cit.Results Participants who had undergone 21-s,1-min,and 2-min dynamic contrast-enhanced MR revealed significant variations among the three groups.The spectral analysis of the three groups revealed a significant variation as well.DCE-MRI and MRS combined had a sensitivity of 89.67%,specificity of 95.78%,and accuracy of 94.34%.Conclusion DCE-MRI combined with MRS is of great value in the diagnosis of prostate cancer.     

Herceptin-directed nanoparticles activated by an alternating magnetic field selectively kill HER-2 positive human breast cells in vitro via hyperthermia

Purpose: HER-2 is in the EGF tyrosine kinase receptor family, overexpressed by many human cancers and minimally expressed by normal adult tissues. HER-2 expression in human cancers is correlated with reduced survival, increased metastasis, reduced apoptosis and increased proliferation. Herceptin is a humanised mouse antibody that targets and inactivates HER-2. In the present study, Herceptin was used to deliver ferric oxide-enriched nanoparticles to HER-2⁺ cancer cells. If exposed to alternating magnetic field (AMF), the nanoparticles heat. We tested the ability of AMF-activated Herceptin-directed nanoparticles to selectively kill HER-2⁺ human cancer cells.

Methods: Herceptin-conjugated nanoparticles were incubated with normal human mammary epithelial cells (HMEC)(HER-2^-) or malignant human mammary epithelial cells (SK-BR-3)(HER-2⁺). Cells were stained to detect Herceptin or iron and the kinetics of binding quantified. Once conditions were optimised for binding, cells were exposed to either antibody-directed or non-antibody-conjugated nanoparticles, washed and sham-treated or exposed to AMF and cell death quantified.

Results: SK-BR-3 cells bound Herceptin-directed nanoparticles in increasing amounts over 3?h but did not retain non-antibody conjugated nanoparticles. HMECs did not retain either nanoparticles. SK-BR-3 cells with bound Herceptin-directed-nanoparticles, exposed to AMF, died by apoptosis, quantifiable by Live/Dead and nuclear morphology assays and released LDH. Sham-treated SK-BR-3 cells with Herceptin-directed nanoparticles, HMECs with either nanoparticles, with or without AMF treatment, exhibited no increase in toxicity above baseline cell death using these three assays.

Conclusions: These studies demonstrate Herceptin-directed nanoparticles can selectively kill HER-2⁺ cancer cells via hyperthermia after AMF activation.     

术前MR影像特征对肝细胞癌手术切除术后早期复发的预测价值

目的:探究肝细胞癌(hepatocellular carcinoma,HCC)术前临床资料及MR影像特征对HCC手术切除术后早期复发(2年内复发)的预测价值。方法:回顾性分析2015年1月至2018年1月间在天津医科大学肿瘤医院行手术切除术的244例HCC患者资料。对可能影响HCC手术切除术后早期复发的术前临床资料及MR影像特征行单因素、多因素分析。所有患者出院后均规律随访,终点事件为术后2年内肝内复发。结果:单因素分析筛选出肿瘤最大径、肿瘤包膜、瘤周肝实质强化、环形强化、TTPVI、瘤内坏死、卫星灶、动态增强模式、DWI/T2WI不匹配等MR影像特征及甲胎蛋白(alpha-fetoprotein,AFP)、TNM分期、丙氨酸氨基转移酶(alanine aminotransferase,ALT)、谷氨酸氨基转移酶(glutamatergic aminotransferase,AST)、直接胆红素(direct bilirubin,DBIL)、γ-谷氨酰转肽酶(γ-glutamyl transferase,γ-GT)等临床资料为肝癌患者切除术后早期复发的影响因素。将上述变量纳入多因素Co...     

Patterns of injury in patients with radiographic occult fracture of neck of femur as determined by magnetic resonance imaging

The purpose of the present study was to review retrospectively our experience with MRI in patients over the age of 50 who present to the emergency department with inability to weight bear following a fall and whose initial radiographs were normal. The study was designed to establish the incidence and pattern of bone and soft tissue injuries in these patients and to determine whether MRI could provide predictive information regarding length of hospital stay. The present study demonstrated the practicality of a protocol using MRI to obtain rapid definitive diagnosis in patients with occult fractures of the pelvic ring and neck of femur. The present study also suggests that significant prognostic information with regard to length of hospital stay can be obtained from an early MRI scan.     

小剂量放射免疫治疗的可行性及安全性的实验研究

目的　研究多次小剂量放射免疫治疗 (RIT )对肿瘤小体积转移灶的预防和治疗作用及使用安全性。方法　采用高转移率的LA 795肺腺癌小鼠模型。比较在第 8天或第 15天施行肿瘤原发灶切除后分别给予分次小剂量RIT、化疗、单次大剂量RIT的抑瘤效果。观察正常小鼠放射免疫治疗后体重、外周血白细胞和血小板的改变及主要器官组织病理改变。结果　不同手术时间的综合治疗均显示 ,分次小剂量RIT组小鼠生存期延长 ,肺转移灶数减少 (分别有 3例和 2例无转移 ) ,疗效优于其它各组 (P<0 .0 5 )。提早手术并分次小剂量放射免疫治疗的疗效更佳 (P <0 .0 5 )。大、小 2种剂量131I C5 0对小鼠的白细胞、血小板的数量无显著影响 ;对骨髓及其它重要器官无明显的抑制和辐射损伤。结论　分次小剂量RIT优于化疗 ;提前手术加分次小剂量RIT疗效更优 ;131I C5 0小剂量放射免疫治疗是安全的。     

Magnetic Resonance Imaging (MRI) Appearances of Syringohydromyelia

Magnetic resonance imaging (MRI) examination of the spinal cord is now a first-line in vestigation for the evaluation of suspected syringohydromyelia. It is an accurate, non-invasive means of detecting cavities within the spinal cord and for assessing spinal cord size and the position of the cerebellar tonsils. It has considerable advantages over post-myelographic computerised tomography (CT). The current study discusses our initial experience of thirteen surgically proven cases of syringomyelia with special reference to appearances on T 1 and T2 weighted images and a discussion of the apparently confusing appearances of the cavities on the T2 weighted images.     

Nasopharyngeal adenoid cystic carcinoma: magnetic resonance imaging features in ten cases

Nasopharyngeal adenoid cystic carcinoma (NACC) is a rare malignancy with high local invasiveness. To date, there is no consensus on the imaging characteristics of NACC. To address this, we retrospectively reviewed 10 cases of NACC and summarized the magnetic resonance imaging (MRI) features. MR images of 10 patients with histologically validated NACC were reviewed by two experienced radiologists. The location, shape, margin, signal intensity, lesion texture, contrast enhancement patterns, local invasion, and cervical lymphadenopathy of all tumors were evaluated. Clinical and pathologic records were also reviewed. No patients were positive for antibodies against Epstein-Barr virus (EBV). The imaging patterns of primary tumors were classified into two types as determined by location, shape, and margin. Of all patients, 7 had tumors with a type 1 imaging pattern and 3 had tumors with a type 2 imaging pattern. The 4 tubular NACCs were all homogeneous tumors, whereas 3 (60%) of 5 cribriform NACCs and the sole solid NACC were heterogeneous tumors with separations or central necrosis on MR images. Five patients had perineural infiltration and intracranial involvement, and only 2 had cervical lymphadenopathy. Based on these results, we conclude that NACC is a local, aggressive neoplasm that is often negative for EBV infection and associated with a low incidence of cervical lymphadenopathy. Furthermore, MRI features of NACC vary in locations and histological subtypes.     

New magnetic resonance imaging techniques for the detection of breast cancer

Summary The importance of contrast agents in enhancing diagnoses from magnetic resonance images has been established in numerous cases. However, the development of a potent tissue-specific contrast agent, as a sensitive probe for early detection and investigation of the physiological characteristics of a tumor, has not yet been realized in MR imaging (MRI). In nuclear scintigraphy the technique has been demonstrated; however, the poor spacial resolution inherent to the modality and the substantial dose of radioactivity administered to the patient has hindered its widespread use. This article will review the different classes of contrast agents in MRI, with special focus on the strategies involved in the development of targeted tissue-specific MRI contrast agents for the early detection of breast cancer. The features of a new class of contrast agents for targeted MR imaging will be described. Gadolinium-containing melanin polymers (GMP's) have been synthesized as MR contrast agents in our laboratory. These GMP's demonstrate significantly higher relaxivities than any other paramagnetic contrast agents reported; consequently, they are extremely effective contrast enhancing, imaging agents by themselves. The successful coupling of these potent GMP's to a monoclonal antibody specific for breast carcinoma, the 323/A3 monoclonal antibody, suggests thatin vivo tissue-specific MR imaging, at the receptor level, will become feasible in the near future.     

乳腺MRI动态增强对良恶性病变的鉴别价值

Objective  

The aim of the study was to discuss the diagnostic value of dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) in distinguishing malignant tumors of breast from benign lesions.     

Multiparametric prostate magnetic resonance imaging in the evaluation of prostate cancer

Imaging has traditionally played a minor role in the diagnosis and staging of prostate cancer. However, recent controversies generated by the use of prostate‐specific antigen (PSA) screening followed by random biopsy have encouraged the development of new imaging methods for prostate cancer. Multiparametric magnetic resonance imaging (mpMRI) has emerged as the imaging method best able to detect clinically significant prostate cancers and to guide biopsies. Here, the authors explain what mpMRI is and how it is used clinically, especially with regard to high‐risk populations, and we discuss the impact of mpMRI on treatment decisions for men with prostate cancer. CA Cancer J Clin 2016;66:326‐336. © 2015 American Cancer Society     

Early detection of a deep-seated synovial sarcoma by magnetic resonance imaging

An 18-year-old man who complained of left thigh pain was referred to our institute. No abnormal findings were detected on physical examination and plain roentgenogram or gallium scintigram. On magnetic resonance imaging (MRI), a high-signal of 1-cm diameter was seen in the left vastus medialis muscle on T1- and T2-weighted images. The lesion was initially considered to be: (1) angiolipoma, which is usually associated with fatty tissue, based on the MR findings or (2) a sport-induced inflammation based on the patient's history of baseball playing. Because of the persistent thigh pain and similar findings on the second MRI, an excisional biopsy was performed; the lesion was diagnosed histologically as synovial sarcoma. Additional wide resection was carried out later, without adjuvant therapy. He has been disease-free for 3 years postoperatively. Many soft tissue sarcomas are discovered with extensive tumor formation and are accompanied by obvious abnormal findings on various imaging studies. It is extremely rare that deep-seated sarcomas are discovered without obvious abnormalities. To the best of our knowledge, this is one of the smallest detected deep-seated soft tissue sarcomas. MRI was the most sensitive and useful procedure for detecting the lesion. Physicians should recognize that painful lesions may possibly be synovial sarcoma, even if they are demonstrated as a subtle lesion of 1-cm diameter on MRI.     

The clinical value of combined use of MR imaging and multi-slice spiral CT in limb salvage surgery for orthopaedic oncology patients: initial experience in nine patients

Background

The purpose of this prospective study was to evaluate the value of the combined use of MR imaging and multi-slice spiral CT for limb salvage surgery in orthopaedic oncology patients.

Patients and methods

Nine consecutive patients with lower/upper limb malignant bone tumours (7 osteosarcomas and 2 chondrosarcomas) were treated with limb-salvaging procedures. Preoperative planning including determination of the osteotomy plane and diameters of the prosthesis was performed basing on the preoperative CT and MR images. The histopathology was performed as golden diagnostic criteria to evaluate the accuracy of CT and MR-based determination for tumour’s boundary.

Results

The tumour extension measured on MRI was consistent with the actual extension (P>0.05, paired Student’s t test), while the extension measured on CT imaging was less than the actual extension. The length, offset and alignment of the affected limb were reconstructed accurately after the operation. An excellent functional outcome was achieved in all patients.

Conclusions

In the present study, MRI was found to be superior to CT for determining the tumour extension, combined use of MRI and CT measurement provided high precision for the fit of the prosthesis and excellent functional results.     

磁共振成像在肺癌放射治疗中的应用价值

目的　探讨磁共振成像 (MRI)在肺癌放射治疗中的应用价值。方法　 37例经病理证实的肺癌行MRI检查 ,并与同期X线胸片或CT比较。结果　MRI对确定肺门纵隔淋巴结转移、肿瘤对肺门纵隔大血管侵犯优于CT和X线平片 ;MRI可辨别肺癌放疗后纤维化抑或肿瘤复发 ,区分肺门癌块与阻塞性肺不张 ;MRI和CT可检查出X线胸片难以显示隐匿部位的较小病灶。结论　MRI在肺癌的放射治疗中有一定的应用价值。     

Ultrasound is at least as good as magnetic resonance imaging in predicting tumour size post-neoadjuvant chemotherapy in breast cancer

BackgroundThe aim of this study was to evaluate the accuracy of clinical imaging of the primary breast tumour post-neoadjuvant chemotherapy (NAC) related to the post-neoadjuvant histological tumour size (gold standard) and whether this varies with breast cancer subtype. In this study, results of both magnetic resonance imaging (MRI) and ultrasound (US) were reported.MethodsPatients with invasive breast cancer were enrolled in the INTENS study between 2006 and 2009. We included 182 patients, of whom data were available for post-NAC MRI (n = 155), US (n = 123), and histopathological tumour size.ResultsMRI estimated residual tumour size with <10-mm discordance in 54% of patients, overestimated size in 28% and underestimated size in 18% of patients. With US, this was 63%, 20% and 17%, respectively. The negative predictive value in hormone receptor-positive tumours for both MRI and US was low, 26% and 33%, respectively. The median deviation in clinical tumour size as percentage of pathological tumour was 63% (P₂₅ = 26, P₇₅ = 100) and 49% (P₂₅ = 22, P₇₅ = 100) for MRI and US, respectively (P = 0.06).ConclusionsIn this study, US was at least as good as breast MRI in providing information on residual tumour size post-neoadjuvant chemotherapy. However, both modalities suffered from a substantial percentage of over- and underestimation of tumour size and in addition both showed a low negative predictive value of pathologic complete remission (Gov nr: NCT00314977).     

Effect on prognosis of bone marrow infiltration detected by magnetic resonance imaging in small cell lung cancer

The staging system of limited disease (LD) and extensive disease (ED) is widely used and has been shown to provide useful prognostic information in cases of small cell lung cancer (SCLC). However, accurate examinations are necessary for correct staging. In this report, we evaluated the clinical usefulness of magnetic resonance imaging (MRI) of bone marrow in SCLC. 37 patients with LD by standard staging and 41 with ED were examined with bone marrow MRI. Results of bone marrow MRI did not influence the choice of treatment in patients with LD. For subsequent analysis, patients with LD were divided into two groups: patients in whom bone marrow infiltration was detected with MRI (MRI-positive LD group) and those in whom it was not (MRI-negative LD group). Focal or diffuse metastases to bone marrow were detected with MRI in 46% (36/78) of all patients and 35% (13/37) of LD patients. The response rates to treatment in patients with MRI-positive LD were lower than those in patients with MRI-negative LD (P=0.006). The survival of patients with MRI-positive LD was worse than that of MRI-negative LD (generalised Wilcoxon test: P=0.0157), and closer to that of ED. Multivariate analyses using a Cox model that included the result of bone marrow MRI, performance status, chemotherapy regimen, radiotherapy and serum lactose dehydrogenase (LDH) level showed that the result of bone marrow MRI remained a prognostic factor in SCLC patients with limited disease. Bone marrow examination with MRI is useful for better staging of SCLC. According to our analysis of response rates and survival, MRI-positive LD should be considered a type of ED.