Canine spontaneous glioma: A translational model system for convection-enhanced delivery

Canine spontaneous intracranial tumors bear striking similarities to their human tumor counterparts and have the potential to provide a large animal model system for more realistic validation of novel therapies typically developed in small rodent models. We used spontaneously occurring canine gliomas to investigate the use of convection-enhanced delivery (CED) of liposomal nanoparticles, containing topoisomerase inhibitor CPT-11. To facilitate visualization of intratumoral infusions by real-time magnetic resonance imaging (MRI), we included identically formulated liposomes loaded with Gadoteridol. Real-time MRI defined distribution of infusate within both tumor and normal brain tissues. The most important limiting factor for volume of distribution within tumor tissue was the leakage of infusate into ventricular or subarachnoid spaces. Decreased tumor volume, tumor necrosis, and modulation of tumor phenotype correlated with volume of distribution of infusate (Vd), infusion location, and leakage as determined by real-time MRI and histopathology. This study demonstrates the potential for canine spontaneous gliomas as a model system for the validation and development of novel therapeutic strategies for human brain tumors. Data obtained from infusions monitored in real time in a large, spontaneous tumor may provide information, allowing more accurate prediction and optimization of infusion parameters. Variability in Vd between tumors strongly suggests that real-time imaging should be an essential component of CED therapeutic trials to allow minimization of inappropriate infusions and accurate assessment of clinical outcomes.     

Therapeutic efficacy of a polymeric micellar doxorubicin infused by convection-enhanced delivery against intracranial 9L brain tumor models

Convection-enhanced delivery (CED) with various drug carrier systems has recently emerged as a novel chemotherapeutic method to overcome the problems of current chemotherapies against brain tumors. Polymeric micelle systems have exhibited dramatically higher in vivo antitumor activity in systemic administration. This study investigated the effectiveness of CED with polymeric micellar doxorubicin (DOX) in a 9L syngeneic rat model. Distribution, toxicity, and efficacy of free, liposomal, and micellar DOX infused by CED were evaluated. Micellar DOX achieved much wider distribution in brain tumor tissue and surrounding normal brain tissue than free DOX. Tissue toxicity increased at higher doses, but rats treated with micellar DOX showed no abnormal neurological symptoms at any dose tested (0.1-1.0 mg/ml). Micellar DOX infused by CED resulted in prolonged median survival (36 days) compared with free DOX (19.6 days; p = 0.0173) and liposomal DOX (16.6 days; p = 0.0007) at the same dose (0.2 mg/ml). This study indicates the potential of CED with the polymeric micelle drug carrier system for the treatment of brain tumors.     

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.     

35例脑转移瘤MRI分析

目的回顾性分析经临床、手术及病理证实的35例脑转移瘤的MRI表现.方法35例病人,男27例,女8例,年龄29～77岁.均采用横轴位、矢状位、冠状位及增强扫描.结果35例病人125个病灶,瘤周水肿89个.增强前发现病灶86个.增强后发现病灶125例.脑转移实质性病灶84个,部分囊变坏死19个,完全囊变22个.原发恶性肿瘤肺癌22例,脑内胶质瘤5例,肾癌、结肠癌、鼻咽癌及淋巴肉瘤各2例.结论脑转移瘤中肺癌转移最多见;多发性脑转移瘤可有多种形态;小脑出现占位性病变应考虑到转移瘤的可能.     

Magnetic resonance imaging of intracranial tumors: intra-patient comparison of gadoteridol and ferumoxytol

This study aims to compare gadoteridol with ferumoxytol for contrast-enhanced and perfusion-weighted (PW) MRI of intracranial tumors. The final analysis included 26 patients, who underwent 3 consecutive days of 3T MRI. Day 1 consisted of anatomical pre- and postcontrast images, and PW MRI was acquired using gadoteridol (0.1 mmol/kg). On Day 2, the same MRI sequences were obtained with ferumoxytol (510 mg) and on Day 3, the anatomical images were repeated to detect delayed ferumoxytol-induced signal changes. The T₁-weighted images were evaluated qualitatively and quantitatively for enhancement volume and signal intensity (SI) changes; PW data were used to estimate the relative cerebral blood volume (rCBV). All 26 lesions showed 24-hour T₁-weighted ferumoxytol enhancement; 16 also had T₂-weighted hypointensities. In 6 patients, ferumoxytol-induced signal changes were noted in areas with no gadoteridol enhancement. Significantly greater (P< .0001) SI changes were seen with gadoteridol, and qualitative analyses (lesion border delineation, internal morphology, contrast enhancement) also showed significant preferences (P= .0121; P = .0015; P < .0001, respectively) for this agent. There was no significant difference in lesion enhancement volumes between contrast materials. The ferumoxytol-rCBV values were significantly higher (P = .0016) compared with the gadoteridol-rCBV values. In conclusion, ferumoxytol provides important information about tumor biology that complements gadoteridol imaging. The rCBV measurements indicate areas of tumor undergoing rapid growth, whereas the 24-hour scans mark the presence of inflammatory cells. Both of these functions provide useful information about tumor response to treatment. We suggest that dynamic and anatomical imaging with ferumoxytol warrant further assessment in brain tumor therapy.     

Convection-enhanced drug delivery: increased efficacy and magnetic resonance image monitoring

Convection-enhanced drug delivery (CED) is a novel approach to directly deliver drugs into brain tissue and brain tumors. It is based on delivering a continuous infusion of drugs via intracranial catheters, enabling convective distribution of high drug concentrations over large volumes of the target tissue while avoiding systemic toxicity. Efficient formation of convection depends on various physical and physiologic variables. Previous convection-based clinical trials showed significant diversity in the extent of convection among patients and drugs. Monitoring convection has proven to be an essential, yet difficult task. The current study describes the application of magnetic resonance imaging for immediate assessment of convection efficiency and early assessment of cytotoxic tissue response in a rat brain model. Immediate assessment of infusate distribution was obtained by mixing Gd-diethylenetriaminepentaacetic acid in the infusate prior to infusion. Early assessment of cytotoxic tissue response was obtained by subsequent diffusion-weighted magnetic resonance imaging. In addition, the latter imaging methodologies were used to establish the correlation between CED extent and infusate's viscosity. It was found that low-viscosity infusates tend to backflow along the catheter track, whereas high-viscosity infusates tend to form efficient convection. These results suggest that CED formation and extent may be significantly improved by increasing the infusate's viscosities, thus increasing treatment effects.     

单发脑转移瘤的MRI诊断

目的:探讨单发脑转移瘤(solitary brain metastasis,SBM)的MRI表现,提高对其诊断的准确性。方法:回顾性分析经临床综合确诊的38例SBM的MRI平扫及增强表现,分析病灶的部位、大小、瘤周水肿程度和瘤体的强化特点。结果:本组38例SBM中,发生于幕上31例,其中位于脑皮质和皮质下区28例;幕下7例。瘤体直径＜1.0cm有12例,1.0cm-3.0cm 19例,＞3.0cm 7例。增强扫描所有病灶均出现强化,其中结节型强化19例,环型强化11例,混合型强化8例。瘤周无水肿7例,轻度水肿11例,中度水肿13例,重度水肿7例。结论:SBM的MRI表现具有一定的特征性,MRI增强扫描对其诊断和鉴别诊断具有重要价值。     

Extensive Distribution of Liposomes in Rodent Brains and Brain Tumors Following Convection-Enhanced Delivery

Liposomes labeled with various markers were subjected to local-regional administration with either direct injection or convection-enhanced delivery (CED) into rodent brains and brain tumor models. Direct injection of liposomes containing attached or encapsulated fluorochromes and/or encapsulated gold particles indicated that tissue localization of liposomes could be sensitively and specifically detected in the central nervous system (CNS). When CED was applied, liposomes achieved extensive and efficient distribution within normal mouse brains. Co-infusion of mannitol further increased tissue penetration of liposomes. Liposomes were also loaded with gadodiamide to monitor their CNS distribution in rats by magnetic resonance imaging (MRI). CED-infused liposomes were readily seen on MRI scans as large regions of intense signal at 2 h, and more diffuse regions at 24 h. Finally, labeled liposomes were infused via CED into tumor tissue in glioma xenograft models in rodent hosts. In intracranial U-87 glioma xenografts, CED-infused liposomes had distributed throughout tumor tissue, including extension into surrounding normal tissue. Greater penetration was observed using 40 versus 90 nm liposomes, as well as with mannitol co-infusion. To our knowledge, this is the first report of CED infusion of liposomes into the CNS. We conclude that CED of liposomes in the CNS is a feasible approach, and offers a promising strategy for targeting therapeutic agents to brain tumors.     

Assessing extracranial tumors using diffusion-weighted whole-body MRI

Diffusion-weighted magnetic resonance imaging (DWI) provides qualitative and quantitative information about the random motion of water molecules in biological tissues and is able to give functional insight into tissue architecture and pathological changes on a cellular level. This technique has the major advantages of not requiring the administration of contrast agents and not exposing the patient to ionizing radiation. Recent technological advances have led to the development of diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) that allows screening of the whole body in 25 minutes. DWI and DWIBS have both revealed great potential in the field of oncology and proved to be useful for detecting and characterizing tumors and evaluating treatment response. This article reviews the basic principles and experimental setup of DWI and DWIBS and illustrates its potential application to the assessment of extracranial tumors. In addition, current limitations and challenges of this promising imaging procedure are discussed.     

Nanomedicine for drug delivery and imaging: a promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles

The diagnosis and treatment of cancer or tumor at the cellular level will be greatly improved with the development of techniques that enable the delivery of analyte probes and therapeutic agents into cells and cellular compartments. Organic and inorganic nanoparticles that interface with biological systems have recently attracted widespread interest in the fields of biology and medicine. The new term nanomedicine has been used recently. Nanoparticles are considered to have the potential as novel intravascular or cellular probes for both diagnostic (imaging) and therapeutic purposes (drug/gene delivery), which is expected to generate innovations and play a critical role in medicine. Target-specific drug/gene delivery and early diagnosis in cancer treatment is one of the priority research areas in which nanomedicine will play a vital role. Some recent breakthroughs in this field recently also proved this trend. Nanoparticles for drug delivery and imaging have gradually been developed as new modalities for cancer therapy and diagnosis. In this article, we review the significance and recent advances of gene/drug delivery to cancer cells, and the molecular imaging and diagnosis of cancer by targeted functional nanoparticles.     

Brain MRI findings in two cases with eclampsia

Neurological complications in patients with eclampsia are varied and include headache, visual disturbances, focal neurological deficits, altered mental status and coma. Occasionally, a focal neurological deficit includes a variety of visual disturbances. The pathophysiology of CNS abnormalities in patients with eclampsia is uncertain. Our cases, combined with a review of the literature, demonstrate that there is no correlation among severity of hypertension, parity, and location of lesions at initial magnetic resonance (MR) imaging findings or between the severity of hypertension and neurological symptoms. Two typical patterns are seen on MR images of patients with eclampsia. Lesions in the region of the posterior cerebral circulation are most common and are frequently associated with visual disturbances. Although there are lesions in the deep white matter or basal ganglia, a focal neurological deficit or alterations in mental status may not develop. This demonstrates the sensitivity of MR imaging in the detection of abnormalities in patients with eclampsia, even those without neurological deficits.     

Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump

Intracerebral convection-enhanced delivery (CED) of chemotherapeutic agents currently requires an externalized catheter and infusion system, which limits its duration because of the need for hospitalization and the risk of infection. To evaluate the feasibility of prolonged topotecan administration by CED in a large animal brain with the use of a subcutaneous implantable pump. Medtronic Synchromed-II pumps were implanted subcutaneously for intracerebral CED in pigs. Gadodiamide (28.7 mg/mL), with or without topotecan (136 μM), was infused at 0.7 mL/24 h for 3 or 10 days. Pigs underwent magnetic resonance imaging before and at 6 times points after surgery. Enhancement and FLAIR+ volumes were calculated in a semi-automated fashion. Magnetic resonance spectroscopy-based topotecan signature was also investigated. Brain histology was analyzed by hematoxylin and eosin staining and with immunoperoxidase for a microglial antigen. CED of topotecan/gadolinium was well tolerated in all cases (n = 6). Maximum enhancement volume was reached at day 3 and remained stable if CED was continued for 10 days, but it decreased if CED was stopped at day 3. Magnetic resonance spectroscopy revealed a decrease in parenchymal metabolites in the presence of topotecan. Similarly, the combination of topotecan and gadolinium infusion led to a FLAIR+ volume that tended to be larger than that seen after the infusion of gadolinium alone. Histological analysis of the brains showed an area of macrophage infiltrate in the ipsilateral white matter upon infusion with topotecan/gadolinium. Intracerebral topotecan CED is well tolerated in a large animal brain for up to 10 days. Intracerebral long-term CED can be achieved with a subcutaneously implanted pump and provides a stable volume of distribution. This work constitutes a proof of principle for the safety and feasibility for prolonged CED, providing a means of continuous local drug delivery that is accessible to the practicing neuro-oncologist.     

Magnetic nanoparticles as targeted delivery systems in oncology

BACKGROUND: Many different types of nanoparticles, magnetic nanoparticles being just a category among them, offer exciting opportunities for technologies at the interfaces between chemistry, physics and biology. Some magnetic nanoparticles have already been utilized in clinical practice as contrast enhancing agents for magnetic resonance imaging (MRI). However, their physicochemical properties are constantly being improved upon also for other biological applications, such as magnetically-guided delivery systems for different therapeutics. By exposure of magnetic nanoparticles with attached therapeutics to an external magnetic field with appropriate characteristics, they are concentrated and retained at the preferred site which enables the targeted delivery of therapeutics to the desired spot. CONCLUSIONS: The idea of binding chemotherapeutics to magnetic nanoparticles has been around for 30 years, however, no magnetic nanoparticles as delivery systems have yet been approved for clinical practice. Recently, binding of nucleic acids to magnetic nanoparticles has been demonstrated as a successful non-viral transfection method of different cell lines in vitro. With the optimization of this method called magnetofection, it will hopefully become another form of gene delivery for the treatment of cancer.     

63例小脑肿瘤的MRI分析

目的回顾性分析经临床、手术及病理证实的63例小脑肿瘤的MRI表现.方法63例病人,男39例,女24例,年龄6～78岁,平均年龄49.27岁.均采用横轴位、矢状位、冠状位及增强扫描.结果63例病人中,髓母细胞瘤10例,血管母细胞瘤7例,胶质瘤6例,动静脉畸形2例,囊虫病2例,转移瘤36例.结论发病年龄及发病部位对于小脑肿瘤的鉴别诊断具有重要价值,在诊断小脑肿瘤中,MRI优于CT.     

Diagnostic Accuracy of MRI Compared to CCT in Patients with Brain Metastases

Objectives. In patients with extracranial neoplasms, the occurrence and number of brain metastases (BM) are critical for further diagnostic approaches and therapeutic strategies and the patient's prognosis. Although widely accepted, there is surprisingly little evidence in the literature that MRI is superior to CCT. Therefore, in patients with solitary BM according to diagnostic contrast-enhanced computed tomography (CCT), we investigated, what additional information could be gained by contrast-enhanced magnetic resonance imaging (MRI). Methods/Results. Among 55 patients with solitary BM according to CCT, 17 had multiple BM on MRI (31%) and 38 had solitary BM in both. Based on a presumed binomial distribution of our data, we calculated a rate of at least 19% of patients with solitary BM on CCT, in which MRI would show multiple lesions (p=0.05). The two main characteristics for BM missed by CCT were the smaller diameter, which averages 2cm less than in BM identified with both modalities, and a preferential frontotemporal location. Conclusion. MRI is indeed superior to CCT in the diagnosis of BM the essential reasons besides detection of smaller lesions being a better soft tissue contrast, significantly stronger enhancement with paramagnetic contrast agents, the lack of bone artifacts, fewer partial volume effects, and direct imaging in three different planes. Therefore, MRI is indispensable in the diagnostic workup of patients with BM for choosing the optimum therapeutic approach, especially with regard to the decision whether to operate or to primarily irradiate the patient's metastases.     

MRI对乳腺含粘液良、恶性肿瘤的鉴别诊断价值

目的:探讨磁共振成像对乳腺含黏液良、恶性肿瘤鉴别诊断价值。方法:回顾性分析2018年12月至2021年02月经我院病理证实的乳腺含黏液肿瘤25例共26个病灶的术前MRI图像及临床病理资料,依据病理分为良性组及恶性组,比较良、恶性组的临床及MRI表现差异性。结果:25例患者共26个病灶纳入研究,良性肿瘤10例共10个病灶,恶性肿瘤15例共16个病灶。恶性组发病年龄高于良性组（P＜0.01）;病变的边缘多不规则,与良性组比较差异具有统计学意义（P＜0.01）;而两组间肿块大小、形态、动态增强曲线类型及ADC值无统计学差异（P＞0.05）。恶性组出现由周围向中央填充式渐进性强化,而良性组未出现,差异具有统计学意义（P＜0.01）。恶性组T2WI上的低信号分隔纤细并在增强后图像显示不清（31.25%,5/16）,良性组T2WI上的低信号分隔增强后显示清晰（30.00%,3/10）,差异具有统计学意义（P＜0.05）。结论:乳腺含黏液的恶性肿瘤患者发病年龄较良性肿瘤大,边缘多不规则,以不均匀强化为主,出现由周围向中央填充渐进性强化方式,T2WI序列的低信号分隔于增强后显示不清为较特征性表现。     

Pharmacological blood-brain barrier modification for selective drug delivery

Vasoactive agents have been identified through studies of peritumoral edema and effects on systemic capillaries. Abnormal blood-brain barrier or blood-tumor barrier can develop transient increases in permeability with the intraarterial delivery of vasoactive agents. Normal blood-brain barrier resists the effects of these compounds because of a biochemical barrier that may inactivate or become inert to vasoactive agents. Vaso-active compounds, including leukotrienes, bradykinin, and histamine appear to selectively increase permeability in abnormal brain capillaries. Intracarotid infusion of leukotrienes, bradykinin, and other vasoactive agents can increase drug delivery to diseased tissue.     

Practice MRI: Reducing the need for sedation and general anaesthesia in children undergoing MRI

The aim of this study was to evaluate the effectiveness of a practice magnetic resonance unit, in preparing children to undergo magnetic resonance procedures without general anaesthesia (GA) or sedation. The records of children who attended the practice MRI between February 2002 and April 2004 were retrospectively reviewed. Each record was assessed as to whether the child had passed or failed the practice MRI intervention. Those children who were considered to have passed and were proceeded to a clinical non‐GA MRI had the report of the clinical scan reviewed. If the scan had been reported as non‐diagnostic because of movement artefact it was classified as a failed scan, otherwise it was considered a pass. One hundred and thirty‐four children undertook a practice MRI (age range 4.1–16.1 years, median age 7.7 years, 47% boys) and 120/134 (90%) passed the practice session. In all, 117/120 (98%) subsequently had a clinical non‐GA MRI and 110/117 (94%) passed (median age 7.8 years, 47% boys). Preparation is a safe and effective method to reduce the need for sedation and GA in children undergoing a clinical MRI scan. It provides a positive medical experience for children, parents and staff, and results in cost savings for the hospital.     

pH-responsive mesoporous silica nanoparticles employed in controlled drug delivery systems for cancer treatment

In the fight against cancer, controlled drug delivery systems have emerged to enhance the therapeutic efficacy and safety of anti-cancer drugs. Among these systems, mesoporous silica nanoparticles （MSNs） with a functional surface possess obvious advantages and were thus rapidly developed for cancer treatment. Many stimuli-responsive materials, such as nanopartides, polymers, and inorganic materials, have been applied as caps and gatekeepers to control drug release from MSNs. This review presents an overview of the recent progress in the production of pH-responsive MSNs based on the pH gradient between normal tissues and the tumor microenvironment. Four main categories of gatekeepers can respond to acidic conditions. These categories will be described in detail.