MR thermometry-based feedback control of laser interstitial thermal therapy at 980 nm

BACKGROUND AND OBJECTIVES: The goal of this study was to explore the feasibility of magnetic resonance thermal imaging (MRTI)-based feedback control of intracerebral laser interstitial thermal therapy (LITT), using a computer workstation and 980-nm diode laser interfaced to an MR scanner. STUDY DESIGN/MATERIALS AND METHODS: A computer-controlled laser thermal therapy system was used to produce 12 ex vivo lesions in 3 canine and porcine brains and 16 in vivo lesions in 6 canines with diffusing tip fiberoptic applicators and energies from 54 to 900 J. MRTI predictions of thermal damage were correlated with histopathologic analysis. RESULTS: Under feedback control, no carbonization, vaporization, or applicator damage was observed. MRTI-based prediction of thermal dose was not significantly different from histological evaluation of achieved thermal necrosis. CONCLUSIONS: The computer-controlled thermal therapy system was effective at regulating heating, eliminating carbonization and vaporization, and protecting fiberoptic applicators. MRTI estimation of thermal dose accurately predicted achieved thermal necrosis.     

Image guided interstitial laser thermotherapy: a canine model evaluated by magnetic resonance imaging and quantitative autoradiography

Summary Objective. To determine the applicability and safety of a new canine model suitable for correlative magnetic resonance imaging (MRI) studies and morphological/pathophysiological examination over time after interstitial laser thermotherapy (ILTT) in brain tissue.Material and methods. A laser fibre (Diode Laser 830nm) with an integrated temperature feedback system was inserted into the right frontal white matter in 18 dogs using frameless navigation technique. MRI thermometry (phase mapping i.e. chemical shift of the proton resonance frequency) during interstitial heating was compared to simultaneously recorded interstitial fiberoptic temperature readings on the border of the lesion. To study brain capillary function in response to ILTT over time quantitative autoradiography was performed investigating the unidirectional blood-to-tissue transport of carbon-14-labelled alpha amino-isobutyric acid (transfer constant K of AIB) 12, 36 hours, 7, 14 days, 4 weeks and 3 months after ILTT.Results. All laser procedures were well tolerated, laser and temperature fibres could be adequately placed in the right frontal lobe in all animals. In 5 animals MRI-based temperature quantification correlated strongly to invasive temperature measurements. In the remaining animals the temperature fibre was located in the area of susceptibility artifacts, therefore, no temperature correlation was possible. The laser lesions consisted of a central area of calcified necrosis which was surrounded by an area of reactive brain tissue with increased permeability. Quantitative autoradiography indicated a thin and spherical blood brain barrier lesion. The magnitude of K of AIB increased from 12 hours to 14 days after ILTT and decreased thereafter. The mean value of K of AIB was 19 times (2 times) that of normal white matter (cortex), respectively.Conclusion. ILTT causes transient, highly localised areas of increased capillary permeability surrounding the laser lesion. Phase contrast imaging for MRI thermomonitoring can currently not be used for reliable temperature readings in vivo. The suggested new canine model proved to be safe, accurate, easy to use, and provides clinical, radiographic, pathological and physiological correlations.     

激光间质热治疗对大鼠脑胶质瘤细胞凋亡的影响

目的：探讨激光间质内热疗（ILTT）是否诱导大鼠C6脑胶质瘤细胞凋亡。方法：SD大鼠70只,尾状核接种C6鼠脑胶质瘤细胞20d,随机分为：空白对照组,实验对照组和ILTT后2,6,12,24,48h实验组,每组10只。ILTT后不同时段按不同的检测要求保存标本。电镜观察,流式细胞仪分析和脱氧核苷酸转移酶（TdT)原位末端标记（TUNEL)法分析ILTT诱导C6胶质瘤细胞凋亡的作用。结果：电镜观察其呈现典型的凋亡形态学变化,可见凋亡小体形成;TdT原位末端标记显示凋亡发生在ILTT效应灶周边部,流式细胞仪检查ILTT后6h为凋亡发生的高峰时间（19．4％）;24h明显下降（2．2％）;48h与对照组差异无显著性（P＞0．05）。结论：ILTT确能诱导C6细胞凋亡。     

Protection of fiber function by para-axial fluid flow in interstitial laser therapy of malignant tumors

In the past, interstitial laser therapy frequently has failed because of the damage to the bare fiber tip due to intense heat generated at the point of contact. Using a rat mammary tumor model, we describe a method of placing a 600 micron fiber inside a gauge 19 needle cannula after its insertion into the tumor. With this device continuous wave Nd:YAG laser is delivered to the target tumor while 0.9% saline flows para-axially into the tumor. Significant coagulation necrosis was induced with 500 joules at 5 watts, 100 seconds and 1 cc per minute of saline while the needle-fiber is pulled out of the tumor by 10 mm. The mean transmission loss after 500 joules was 2% in ten experiments. The tumor edema due to 1.5 ml of saline was transient. We conclude that successful hyperthermic coagulation necrosis by Nd:YAG laser can be achieved with minimal transmission loss by employing the above technique.     

Relation between polyporphyrin distribution and blood brain barrier changes in the rat glioma model.

Photofrin (a polyporphyrin mixture) distribution in a rat glioma model was studied in relation to changes in the blood brain barrier (BBB). At selected intervals after intraperitoneal injection of Photofrin, the concentration of polyporphyrins (PP) and Evans Blue Dye, an indicator of BBB permeability, were determined for tumor, brain adjacent to tumor (BAT), and normal brain tissue. Contrary to earlier reports of maximal accumulation at 4-24 hours, tumor levels of PP increased throughout the 96 hour measurement period. During the early stages of tumor development, PP uptake by tumor appeared to be less correlated to BBB disruption. We conclude that passive diffusion through an incompetent BBB does not completely explain PP accumulation in tumor tissue.     

Pc 4 photodynamic therapy of U87-derived human glioma in the nude rat

BACKGROUND AND OBJECTIVES: As a potential therapy for malignant glioma, we tested the phthalocyanine photosensitizer Pc 4 for: (1) rapid clearance from the vasculature, (2) specificity for glioma, and (3) tumoricidal photosensitizing capability. STUDY DESIGN/MATERIALS AND METHODS: Parenchymal injection of U87 cells into athymic rat brains (N = 100) was followed after 12 days by tail vein injection of 0.5 mg/kg Pc 4. After 1 day, the tumor was illuminated with either 5 (N = 11) or 30 (N = 16) J/cm(2) red light at 672 nm. Sacrifice was 1 day later. The brains from these 27 animals underwent H&E (necrosis) and TUNEL assay (apoptosis) histology. Pc 4 concentration of explanted brains and tumors (N = 16), and all blood samples (N = 52) were determined by HPLC-MS 1 day post Pc 4 administration. RESULTS: Tumor-specific apoptosis was almost uniformly seen; however, necrosis was found mostly in the high-light-dose group. Pc 4 concentration in bulk tumor averaged 3.8 times greater than in normal brain. CONCLUSIONS: These results warrant expanding this pre-clinical study to seek effective baseline Pc 4 drug- and light-doses and infusion-to-photoirradiation timing that would be necessary for a Pc 4-mediated PDT clinical trial for glioma patients.     

Photoradiation therapy causing selective tumor kill in a rat glioma model

We evaluated the effect of photoradiation therapy using the photosensitizer, hematoporphyrin derivative (HpD), and the argon-pumped rhodamine dye laser tuned to 630 nm in the rat C6 glioma model. Animal models of cerebral glioma were established by implanting 10(6) C6 glioma cells in adult Wistar rats, and craniotomies were performed on normal and tumor-bearing animals. HpD in doses of up to 80 mg/kg followed by craniotomy resulted in no damage to the normal brain, and laser light at doses of up to 1200 joules/cm2 without the prior administration of HpD produced no significant damage if the craniotomy site was irrigated with normal saline to prevent a temperature rise. Photoradiation caused no brain necrosis in non-tumor bearing animals if less than 20 mg of HpD per kg and 200 joules of red light per cm2 were used. At higher doses of HpD and light, cerebral necrosis did occur. The depth of necrosis depended on the dose of both HpD and light. Treatment with 40 mg of HpD per kg and 400 joules of light per cm2 resulted in cerebral necrosis in 50% of the treated animals. The mean depth of brain necrosis was 1.3 mm. Selective kill of a cerebral glioma with sparing of the normal brain was achieved with photoradiation therapy at doses of HpD of less than 20 mg/kg and light doses of less than 200 joules/cm2. At these doses, the mean depth of tumor kill was 4.5 mm. In 2 of 10 animals, the depth of tumor destruction was more than 6 mm.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fluorospectral study of the rat brain and glioma in vivo

An animal model of cerebral glioma was utilized by implanting C6 glioma cells into the brains of adult Wistar rats. Once tumors developed to 7–12 mm in diameter, we conducted continuous fluorimetry monitoring of glioma up to 24 hours using a fibre-optic system connected to an intensified multichannel photodetector after an intravenous injection of hematoporphyrin derivative (HPD) into the rats. The intensity of the fluorescence in normal brain reached a plateau 6 hours after intravenous injection of HPD while that in glioma reached a plateau 80 minutes after injection. These fluorescence intensities of glioma, brain adjacent to tumor (BAT), and surrounding normal brain were measured in vivo 24 hours after intravenous administration of 5 mg/kg of HPD. The ratio of fluorescence intensities between glioma and brain was 6.1 while the ratio between BAT and brain was 3.9. There were no obvious differences in shapes between the spectra of the natural fluorescence (autofluorescence) of rat glioma and brain but the intensity of autofluorescence was much weaker in glioma. There are many problems in spectroscopic studies of biological tissues in vivo. It cannot be overemphasized that very strict criteria must be applied in order to get accurate data. Fluorescence from HPD administration may be used to discriminate tumor tissue from surrounding normal brain tissue during operation if the measuring conditions could be kept constant. It is important to understand the photospectral properties of glioma and brain tissue in order to get the most benefits in clinical application of light-induced fluorescence or photoradiation therapy. © 1993 Wiley-Liss, Inc.     

Interstitial photodynamic therapy of nonresectable malignant glioma recurrences using 5-aminolevulinic acid induced protoporphyrin IX

BACKGROUND AND OBJECTIVE: Limited knowledge of the light and temperature distribution within the target volume in combination with non-selective accumulation of the applied photosensitizers (PS) has hampered the clinical relevance of interstitial photodynamic therapy (iPDT) for treatment of malignant glioma patients. The current pilot study focused on the development and the clinical implementation of an accurate and reproducible irradiation scheme for iPDT using 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) as a selectively working PS. STUDY DESIGN/MATERIALS AND METHODS: Monte Carlo simulations of fluence rate and heat transport simulations were performed using the optical properties of normal brain tissue infiltrated by tumor cells (absorption coefficient micro(a) = 0.2 cm(-1), reduced scattering coefficient: micro'(s) = 20 cm(-1)). A modified 3-D treatment-planning software was used to calculate both, the treatment-volume and the exact position of the light diffusers within the lesion. The feasibility and the risk of iPDT were tested in 10 patients with small and circumscribed recurrent malignant gliomas. RESULTS: The optimum distance between the implanted light diffusers was determined to be 9 mm with regard to both fluence rate and temperature distribution. For this distance a temperature increase above 42 degrees C was not expected to occur. Up to six cylindrical light diffusers were stereotactically implanted to achieve a complete irradiation of the tumor volume, which was possible in every single patient (mean tumor volume: 5.9 cm3). The total applied light fluence was between 4,320 J and 11,520 J. Side effects of iPDT were not observed. Median survival was 15 months. CONCLUSION: 5-ALA iPDT in combination with a 3-D treatment-planning (which was based on optical and thermal simulations) is a safe and feasible treatment modality. The clinical impact of these findings deserves further prospective evaluation.     

Intracerebral clysis in a rat glioma model

OBJECTIVE: Intracerebral clysis (ICC) is a new term we use to describe convection-enhanced microinfusion into the brain. This study establishes baseline parameters for preclinical, in vivo, drug investigations using ICC in a rat glioma model. METHODS: Intracranial pressure was measured, with an intraparenchymal fiber-optic catheter, in male Fischer rats 10, 15, 20, and 25 days after implantation of C6 glioma cells in the right frontal lobe (n = 80) and in control rats without tumor (n = 20), before and during ICC. A 25% albumin solution (100 microl) was infused through an intratumoral catheter at 0.5, 1.0, 2.0, 3.0, and 4.0 microl/min. Infusate distribution was assessed by infusion of fluorescein isothiocyanate-dextran (Mr 20,000), using the aforementioned parameters (n = 36). Brains were sectioned and photographed under ultraviolet light, and distribution was calculated by computer analysis (NIH Image for Macintosh). Safe effective drug distribution was demonstrated by measuring tumor sizes and apoptosis in animals treated with N,N'-bis(2-chloroethyl)-N-nitrosourea via ICC, compared with untreated controls. Magnetic resonance imaging noninvasively confirmed tumor growth before treatment. RESULTS: Intracranial pressure increased with tumor progression, from 5.5 mm Hg at baseline to 12.95 mm Hg on Day 25 after tumor cell implantation. Intracranial pressure during ICC ranged from 5 to 21 mm Hg and was correlated with increasing infusion volumes and increasing rates of infusion. No toxicity was observed, except at the higher ends of the tumor size and volume ranges. Fluorescein isothiocyanate-dextran distribution was greater with larger infusion volumes (30 microl versus 10 microl, n = 8, P < 0.05). No significant differences in distribution were observed when different infusion rates were compared while the volume was kept constant. At tolerated flow rates, the volumes of distribution were sufficient to promote adequate drug delivery to tumors. N,N'-Bis(2-chloroethyl)-N-nitrosourea treatment resulted in significant decreases in tumor size, compared with untreated controls. CONCLUSION: The C6 glioma model can be easily modified to study aspects of interstitial delivery via ICC and the application of ICC to the screening of potential antitumor agents for safety and efficacy.     

Effects of ALA-mediated photodynamic therapy on the invasiveness of human glioma cells

BACKGROUND AND OBJECTIVE: High-grade gliomas are characterized by rapid proliferation, angiogenesis, and invasive growth. Eradication or inhibition of infiltrating glioma cells poses a significant clinical challenge that is unlikely to be solved using conventional treatment regimens consisting of ionizing radiation and chemotherapeutic agents. In this study, we evaluated the effects of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) on the invasiveness of human glioma cells migrating from implanted multicell human tumor spheroids. STUDY DESIGN/MATERIALS AND METHODS: Tumor spheroids, derived from the human glioma cell line ACBT, were implanted into a gel matrix of collagen type I. Twenty-four hours following implantation there was a significant invasion into the surrounding gel by individual tumor cells to an average distance of 400 microm. The cultures were incubated in ALA for 4 hours and then exposed to 635 nm laser light in a titration of fluence level, fluence rate, and drug concentration. RESULTS: ALA-PDT at a light fluence of 6 J/cm(2) was sufficient to inhibit gloma cell migration distance by 80-90% compared to control cultures, but did not prevent spheroid growth nor was it cytotoxic to the migrating cells. The viability of the migrating cells both in control and PDT-treated cultures receiving 6 J/cm(2) was high, 85 and 65%, respectively. ALA-PDT at fluences of 25 J/cm(2) was clearly cytotoxic for both the infiltrating cells as well as the spheroids. Low fluence rates were more effective at inhibiting tumor cell infiltration than higher ones for a given total fluence. CONCLUSION: Measurement of cell survival, and results from cultures with blocked cell proliferation, indicated a direct migratory inhibition effect on the invading cells rather than cytotoxicity as the most likely mechanism for the inhibition of invasiveness observed following ALA-mediated PDT.     

Thermal changes in the canine prostate after transurethral balloon laser prostatectomy

The histological changes by transurethral balloon laserthermia were examined on 23 canine prostates. Immediately after treatment, three zones were observed; the coagulative zone treated over 60°C for 20 min formed an inner layer, the degenerative zone treated between 60 to 46.1°C surrounded the coagulative zone, and the intact zone treated below 46.1°C formed the outer layer. Coagulative necrosis of the gland, swelling of collagen fibers, and thrombus of the vessels occurred in the coagulative zone, shedding and vacuolation around the nuclei of the epithelial cells and stromal edema were observed in the degenerative zone, while thermal changes were minimal in the intact zone. Both coagulative and degenerative zones developed necrosis and started to slough off within 1 week, forming a cavity in the central portion of the prostate. Reepithelialization of the cavity was complete at 4 weeks and the ducts of the prostate gland opened to the surface of the cavity. This treatment preserved the excretory tract of the prostate gland. © 1994 Wiley-Liss, Inc.     

Fluorescent imaging in a glioma model in vivo

BACKGROUND AND OBJECTIVE: At the beginning of the 1980s, different laser types were used for stapes surgery to reduce potential harm to inner ear structures through manipulation with conventional instruments during stapedotomy. Most clinical studies were carried out with the CO2 or the argon laser. The Er:YAG laser has been used rarely in patients with otosclerosis. STUDY DESIGN/MATERIALS AND METHODS: In an experimental study on 54 human petrous bones, the optimal laser energy parameter for dissection of the posterior stapes crus and the footplate perforation were determined. With these parameters, stapedotomy was carried out with the Er:YAG laser in 29 patients with otosclerosis with a conventional dissection of the incudostapedial joint and the stapedius muscle tendon. The Er:YAG laser was used (60 or 100 mJ, 3-6 pulses) for dissection of the posterior stapes crus and footplate perforation. RESULTS: No intra- or postoperative complications were observed in all 29 patients. Vertigo and hearing loss were not observed intra- or postoperatively. The postoperative hearing results (improvement of the air-bone gap) was in all cases satisfactory (median remaining air bone gap, 8.1 dB). The median operation time was 29 minutes (15-42 minutes) and did not show a significant prolongation in comparison to the conventional technique. In 1 of the 29 patients, the footplate perforation needed to be carried out conventionally. CONCLUSION: For the first time, Er:YAG laser parameters have been optimized and refined in a human petrous bone model and were then used in a clinical setting. According to the presented results, the Er:YAG laser seemed to be a very suitable instrument for stapedotomy.     

The role of interstitial BCNU chemotherapy in the treatment of malignant glioma

BACKGROUND: Use of interstitial BCNU wafers in the treatment of malignant glioma is currently a controversial topic among neurosurgeons. Initial clinical studies indicated implantation of BCNU wafers into the postoperative tumor bed to be an acceptably safe, partially effective treatment for glioblastoma multiforme. Yet a more recent study has put the efficacy of this treatment in doubt, and there are potential complications associated with BCNU wafer use. OBJECTIVE: This article presents a review of the information presently available on BCNU wafers-both pro and con-to aid in the clinical decision-making process. The article focuses on studies of clinical efficacy (for initial use as well as in the setting of recurrent tumor), complications associated with BCNU wafers, and the experimental data, particularly related to BCNU penetration into the brain. RESULTS: Animal studies and computer simulations have shown that the depth of penetration of BCNU from wafers is limited. Yet in actual clinical use, the interstitial pressure within the wafer-laden tumor bed might be higher, convective flow greater, and delivery of BCNU to the brain more significant than predicted. CONCLUSION: Based on current information, use of interstitial BCNU wafers continues to be an option for treating malignant glioma. Additional clinical studies of BCNU wafers are currently underway.     

Boron neutron capture therapy of a rat glioma

The purpose of the present study was to utilize a well-established rat glioma to evaluate boron neutron capture therapy for the treatment of malignant brain tumors. Boron-10 (10B) is a stable isotope which, when irradiated with thermal neutrons, produces a capture reaction yielding high linear energy transfer particles (10B + 1nth----[11B]----4He(alpha) + 7Li + 2.79 MeV). The F98 tumor is an anaplastic glioma of CD Fischer rat origin with an aggressive biological behavior similar to that of human glioblastoma multiforme. F98 cells were implanted intracerebrally into the caudate nuclei of Fischer rats. Seven to 12 days later the boron-10-enriched polyhedral borane, Na2B12H11SH, was administered intravenously at a dose of 50 mg/kg body weight at varying time intervals ranging from 3 to 23.5 hours before neutron irradiation. Pharmacokinetic studies revealed blood 10B values ranging from 0.33 to 10.5 micrograms/ml depending upon the time after administration, a T1/2 of 6.2 hours, normal brain 10B concentrations of 0.5 microgram/g, and tumor values ranging from 1.1 to 12.8 micrograms/g. No therapeutic gain was seen if the capture agent was given at 3 or 6 hours before irradiation with 4 x 10(12) n/cm2 (10 MW-min; 429 cGy). A 13.5-hour preirradiation interval resulted in a mean survival of 37.8 days (P less than 0.01), compared to 30.5 days (P less than 0.03) for irradiated controls and 22.1 days for untreated animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

MRI/US成像融合引导的经会阴前列腺穿刺活检的单中心研究

目的:评估磁共振/超声(MRI/US)成像融合引导的经会阴前列腺穿刺活检对前列腺癌诊断的价值。方法:回顾性分析2014年9月~2016年3月我院行MRI/US成像融合引导的经会阴前列腺穿刺活检的121例患者资料,每例均行12针系统性穿刺活检(SB)+每个目标靶点(ROI)2针靶向穿刺活检(TB)。活检标本行病理学分析,获知Gleason评分和阳性单针癌组织长度。记录所有患者的临床、影像及病理资料,采用t检验、秩和检验、卡方检验等统计学方法对各项数据进行分析对比。结果:TB的前列腺癌单针阳性率(20.0%)以及高危前列腺癌单针阳性率(10.3%)均明显高于SB(12.7%和5.5%),差异均有统计学意义(P=0.001和P=0.002);TB的阳性单针癌组织长度高于SB,差异有统计学意义(P=0.046);TB的阳性针癌组织主要分化程度的Gleason评分、次要分化程度的Gleason评分、Gleason总评分均高于SB,但差异无统计学意义(P>0.05)。结论:MRI/US成像融合引导的前列腺穿刺活检中的TB较SB能够更有效地检出高危前列腺癌。在条件允许的情况下可推广应用MRI/US成像融合引导的前列腺穿刺活检技术。