Laser-induced thermal therapy for tumor ablation

Image-guided ablation of tumors is assuming an increasingly important role in many oncology services as a minimally invasive alternative to conventional surgical interventions for patients who are not good candidates for surgery. Laser-induced thermal therapy (LITT) is a percutaneous tumor-ablation technique that utilizes high-power lasers placed interstitially in the tumor to deliver therapy. Multiple laser fibers can be placed into the treatment volume and, unlike other interstitial heating techniques, can be fired simultaneously to rapidly treat large volumes of tissue. Modern systems utilize small, compact, high-power laser diode systems with actively cooled applicators to help keep tissue from charring during procedures. Additionally, because this approach to thermal therapy is easily made magnetic resonance (MR) compatible, the incorporation of magnetic resonance imaging (MRI) for treatment planning, targeting, monitoring, and verification has helped to expand the number of applications in which LITT can be applied safely and effectively. We provide an overview of the clinically used technology and algorithms that provide the foundations for current state-of-the-art MR-guided LITT (MRgLITT), including procedures in the brain, liver, bone, and prostate as examples. In addition to advances in imaging and delivery, such as the incorporation of nanotechnology, next-generation MRgLITT systems are anticipated to incorporate an increasing presence of in silico-based modeling of MRgLITT procedures to provide human-assisted computational tools for planning, MR model-assisted temperature monitoring, thermal-dose assessment, and optimal control.     

肝肿瘤热消融机器人定位导航系统的研究

目的 设计一种结合计算机辅助手术路径规划、电磁定位和机器人技术的肝肿瘤热消融机器人定位导航系统,利用机械臂将消融针精准定位在规划的进针路径上.方法 将介入热消融治疗的临床需求量化为多项约束条件,使用加权求和方法求解多目标优化问题,实现计算机辅助手术路径规划.导航定位系统中存在多个坐标系,使用基于成对点集配准的奇异值分解算法完成空间坐标转换,将规划的手术路径映射到机器人坐标系下.构建机械臂目标位置和姿态矩阵,利用运动学方法求解各关节角度,从而将机械臂定位在规划的进针路径上.最后以本文设计的导航系统作为穿刺实验组,常规穿刺方法作为对照组,利用腹部体模进行系统精度验证.结果 使用本系统进行穿刺的平均进针误差(1.11 mm)、平均进针次数(1次)、平均进针时间(11.4 s)都明显优于常规的穿刺方法(5.38 mm、4.6次、62.2 s).结论 基于图像处理、电磁定位和机器人技术构建的热消融机器人定位导航系统能够降低手术穿刺难度,提高消融治疗效率.     

Potential of gene therapy for brain tumors

Brain tumors comprise a broad spectrum of biological and clinical entities making it unlikely for any single therapeutic approach to be universally applicable. In particular, malignant glioblastoma multiforme have defied all current therapeutic modalities. Gene therapy offers the potential to augment current neurosurgical, radiation and drug treatments with little increase in morbidity. Many therapeutic transgenes have shown efficacy in experimental models, including generation of toxic compounds, enzymatic activation of pro-drugs, expression of tumor suppressor or apoptotic proteins, inhibition of angiogenesis and enhancement of immune responses to tumor antigens. Vectors have been used as gene delivery vehicles and as cytotoxic agents in their own right by selective replication and lysis of tumor cells, thereby also generating vectors on-site. Brain tumors appear to offer some "Achilles' heels" in that they are usually contained within the brain and represent a unique dividing cell population there. However, the heterogeneous and invasive characteristics of these tumor cells, as well as sequestration of tumor antigens within a relatively immune privileged location present serious problems for effective therapy. This review will focus on current transgene/vector strategies, including novel therapeutic genes, combinational therapies and new delivery modalities, the latter of which appears to be the rate limiting factor for gene therapy of brain tumors in humans.     

Gene therapy for neurological disorders and brain tumors

Gene Therapy For Neurological Disorders and Brain Tumors by E.A. Chiocca and X.O. Breakefield. Humana Press, Totowa, New Jersey, 1998, 464 p.     

Radiofrequency thermal ablation of liver tumors in an interventional MR-Unit

Percutaneous imaging-guided ablative therapies using thermal energy sources have received much recent attention as minimally invasive strategies for the treatment of malignant liver tumors. Especially tumor ablation using radiofrequency has been shown to be a reliable method using percutaneous image-guided techniques and promising results have been reported in early clinical investigations for the ablation of primary and secondary malignant liver tumors. In this article we outline technical considerations, laboratory and clinical experiences with radiofrequency ablation. Furthermore, we present our experience with MR-guided radiofrequency ablation in an 0.2 T interventional MR-unit. We performed a total of 23 MR-guided ablation in 12 patients with 17 hepatic tumors (1.3–3.0 cm in diameter). Technical success was observed in 88% and the follow-up examinations confirmed a complete necrosis of the entire tumor in 76% of cases.     

Design of a PC-based multimedia telemedicine system for brain function teleconsultation

During time-critical brain surgery, the detection of developing cerebral ischemia is particularly important because early therapeutic intervention may reduce the mortality of the patient. The purpose of this system is to provide an efficient means of remote teleconsultation for the early detection of ischemia, particularly when subspecialists are unavailable. The hardware and software design architecture for the multimedia brain function teleconsultation system including the dedicated brain function monitoring system is described. In order to comprehensively support remote teleconsultation, multi-media resources needed for ischemia interpretation were included: EEG signals, CSA, CD-CSA, radiological images, surgical microscope video images and video conferencing. PC-based system integration with standard interfaces and the operability over the Ethernet meet the cost-effectiveness while the modular software was customized with a diverse range of data manipulations and control functions necessary for shared workspace and standard interfaces.     

Radiofrequency ablation followed by radiation therapy for large primary lung tumors

We report the clinical experience of radiofrequency ablation followed by radiation therapy for large primary lung tumors. Two patients with large primary lung tumors were treated with combined radiofrequency ablation and radiation therapy, and good local control was observed. Combined radiofrequency ablation and radiation therapy that involves minimally invasive techniques appears to be promising for the treatment of large lung tumors.     

Potentials and limitations of adenovirus-p53 gene therapy for brain tumors

We investigated the antineoplastic potentials of recombinant adenovirus containing wild-type p53 cDNA (Ad5CMV-p53) for malignant gliomas. In four human glioma cell lines (U-251 and LG expressing endogenous mutant p53, and U-87 and EFC-2 expressing wild-type p53) and two rat glioma cell lines (9L and C6, each expressing mutant and wild-type p53), gene transfer efficiency determined by X-gal staining and Western blotting was varied (10-99% at 10-500 multiplicity of infection, MOI). Growth inhibitory effect was drastic (>90% at 100 MOI) in U-251 cells and only moderate or minimal in other cell lines harboring wild-type p53 or low gene transfer efficiency. Ex vivo transduction of U-251 cells with Ad5CMV-p53 suppressed the in vivo tumorigenicity of the cells. Histopathologic examination for Ad5CMV-p53 toxicity to rat brains showed inflammatory reactions in half of the tested brains at 10(8) MOI. U-251 cells were inoculated intracerebrally in nude mice and injected Ad5CMV-p53 into the tumor, in which neither the tumor suppression nor the survival benefit was observed. In conclusion, heterogeneity of the cellular subpopulations of malignant glioma in p53 status, variable and insufficient gene delivery to tumor, and adenoviral toxicity to brain at higher doses may be limiting factors to be solved in developing adenovirus-p53 gene therapy for malignant gliomas.     

Repetitive photodynamic therapy of malignant brain tumors.

The probability of achieving local control with current single-shot, intraoperative photodynamic therapy (PDT) treatments of intracerebral gliomas seems improbable due to the length of time required to deliver adequate light fluences to depths of 1-2 cm in the resection margin. Additionally, due to the short doubling time of many malignant gliomas, the kill rate per cell doubling indicates that it seems unlikely that a single treatment would be sufficient to prevent tumor recurrence. Multiple repetitive treatments would therefore seem required. In this publication we primarily review our work examining the effects of repetitive PDT on malignant brain tumor cells both in vitro and in vivo. The in vitro therapy response of human and rat glioma spheroids to 5-aminolevulinic acid (ALA)-mediated PDT in repetitive form was investigated. The results indicated that PDT repeated at relatively long intervals (weeks) was more effective at inhibiting spheroid growth than either daily fractionated PDT or single-treatment regimes. The in vivo response to repetitive treatment was evaluated in a rodent glioma model where BT4C cell line tumors were established in the brains of inbred BD-IX rats. Microfluorometry of frozen tissue sections showed that PpIX is produced with a 10-20:1 tumor to normal tissue selectivity ratio 4 hr after ALA injection. Preliminary evidence of increased efficacy of repetitive PDT and low fluence rate treatment is presented.     

Gene therapy for brain tumors: Basic developments and clinical implementation

Glioblastoma multiforme (GBM) is the most common and deadliest of adult primary brain tumors. Due to its invasive nature and sensitive location, complete resection remains virtually impossible. The resistance of GBM against chemotherapy and radiotherapy necessitate the development of novel therapies. Gene therapy is proposed for the treatment of brain tumors and has demonstrated pre-clinical efficacy in animal models. Here we review the various experimental therapies that have been developed for GBM including both cytotoxic and immune stimulatory approaches. We also review the combined conditional cytotoxic immune stimulatory therapy that our lab has developed which is dependent on the adenovirus mediated expression of the conditional cytotoxic gene, Herpes Simplex Type 1 Thymidine Kinase (TK) and the powerful DC growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Combined delivery of these vectors elicits tumor cell death and an anti-tumor adaptive immune response that requires TLR2 activation. The implications of our studies indicate that the combined cytotoxic and immunotherapeutic strategies are effective strategies to combat deadly brain tumors and warrant their implementation in human Phase I clinical trials for GBM.     

Vector delivery methods and targeting strategies for gene therapy of brain tumors

Efficient virus and non-virus vector systems for gene transfer to tumor cells have been developed and tested in cell culture and in animal experiments. With some of the earliest and most comprehensively evaluated vectors, such as retroviruses, advanced clinical trials were performed in tumor patients. Malignant primary brain tumors (gliomas) have been chosen for the first clinical studies on novel gene therapy approaches because these tumors are non-metastatic and develop on the largely postmitotic background of normal glial and neuronal tissue. However, the human cancer gene therapy studies performed so far were not as successful as preclinical animal experiments. Furthermore, the clinical studies did not address major limiting factors for in vivo gene therapy, such as insufficient gene transfer rates to the tumor with the used local delivery modalities, and the resulting inability of a particular transgene-prodrug system to confer permanently eradicating cytotoxicity to the whole neoplasm. Critical evaluation of gene transfer and therapy studies has led to the conclusion that, even using identical vectors, the anatomical route of vector administration can dramatically affect both the efficiency of tumor transduction and its spatial distribution, as well as the extent of intratumoral and intracerebral transgene expression. This review concentrates on different physical methods for vector delivery to malignant primary brain tumors in experimental or clinical settings: stereotactic or direct intratumoral injection or convection-enhanced bulk-flow interstitial delivery; intrathecal and intraventricular injection; and intravascular infusion with or without modification of the blood-tumor-barrier. The advantages and drawbacks of the different modes and delivery routes of in vivo vector application, and the possibilities for tumor targeting by modifications of the native tropism of virus vectors or by using tissue-specific or inducible transgene expression are summarized.     

Gadolinium neutron capture therapy for brain tumors: a computer study.

A Monte Carlo computer study of the total dose distribution from neutrons and prompt gamma emissions (but excluding the contribution from conversion and Auger electrons) for gadolinium neutron capture therapy of brain tumors has been carried out in order to test the theoretic feasibility of this modality using commercially available magnetic resonance contrast media. The three-dimensional dose distribution calculations were performed in a spherical head phantom with a spherical tumor at the center. Potentially achievable gadolinium concentrations of 150 micrograms/g of tissue in tumor and 3 micrograms/g in normal tissue were assumed with enrichment to 79.9% gadolinium-157, as supplied by Oak Ridge National Laboratory. Irradiation was assumed to be with a 2-keV monoenergetic cylindrical epithermal neutron beam having a radius of 4 cm. The three-dimensional thermal neutron fluence resulting from the 2-keV beam propagation through the tissue was modeled. For a single neutron beam, the maximum dose is delivered within the tumor but the dose is very inhomogeneous across the tumor volume due to rapid decrease of thermal neutron fluence with depth. Two parallel opposed neutron beams deliver to the interface of normal and malignant tissue 70%-80% of the maximum dose received at the center of the tumor. To deliver an average tumor dose of 500 cGy in 10 min would require a 2-keV source neutrons number of 8.0 x 10(11) per s within the geometry of the beam.     

In-vitro and in-vivo histochemical and thermal studies using a thermal balloon endometrial ablation system for varying treatment times

BACKGROUND: To assess the immediate zone of thermal necrosis (ZTN) using an enzyme histochemical staining technique and serosal temperatures for the Cavaterm endometrial balloon ablation system for different treatment times. METHODS: A thermal balloon ablation was performed initially post- (n = 6) and subsequently pre-hysterectomy (n = 15). Eight to 12 tissue blocks from each uterus were sectioned and stained using diaphorase respiratory enzyme techniques. Patients in the in-vivo group had temperature measurements taken from four serosal points, a myometrial gradient profile, the balloon surface and the endocervical canal. RESULTS: The serosal temperature sensors did not demonstrate any rise in temperature above 44.1 degrees C. The mean temperature at the anterior wall, posterior wall, fundus and cornual areas was 37.1 (SD 1.3), 36.8 (SD 1.0), 37.4 (SD 1.8) and 36.7 degrees C (SD 1.0), respectively. The immediate mean maximum ZTN was greatest for the 15-min treatment time (3.1 mm, SD 1.5) compared to the 10- and 7-min treatment times (3.0 mm, SD 1.4 and 2.2 mm, SD 0.7, respectively). The maximum ZTN recorded was 5.6 mm. No full thickness injuries were demonstrated either histochemically or suggested by the temperature studies. CONCLUSIONS: This study confirms that Cavaterm thermal balloon ablation produces a reproducible thermal injury without evidence of serosal heating. Results suggest that the treatment time could be reduced to 10-min with no detrimental effect on the clinical outcomes. This hypothesis is currently being evaluated by clinical trials.