Hyperthermia of metastatic brain tumor with implant heating system: a preliminary clinical results

Metastatic brain tumors were treated by interstitial hyperthermia with an Implant Heating System, which consists of three major parts: ferromagnetic implant (thermoseed), generator of high frequency (240 KHz) and induction coil (30 cm in diameter). The implant is made of Fe-Pt alloy, 1.8 mm in diameter and 15 to 20 mm in length, whose Curie point is 68 - 69 degrees C. Seven cases of metastatic brain tumor, 5 from lung cancer, one from breast cancer and another from colon cancer, were involved in this study. One or several implants were placed inside the tumor by CT guided stereotaxis, or manually inserted at craniotomy. Interstitial hyperthermia at 44 - 46 degrees C was made by IHS for 30 to 60 minutes twice or three times a week. External irradiation was simultaneously combined with hyperthermia in 6 cases. Repeated, longterm hyperthermia (8 - 45 times) was possible in all cases except one, whose treatment was discontinued due to migration of the implant. No other serious side effect was found in any cases during and after the treatment. Repeated CT scans reveal complete response in 2, minor response in one and progression in 3 cases. Therefore this preliminary clinical study indicates that interstitial hyperthermia with IHS is very useful and promising method for treating intracranial metastases.     

Interstitial hyperthermia of malignant brain tumors by an implant heating system using stereotactic techniques.

Interstitial hyperthermia of malignant brain tumors has been produced by a heated ferromagnetic implant with a low Curie point. Induction heating of the implant, which is stereotactically implanted in a tumor, is obtained by eddy currents in a high-frequency magnetic field. Safe, repeated and long-term treatment of 35 cases of malignant brain tumors has been done using this system. The overall response rate was 31.4%, but the rate for metastatic brain tumors, deep-seated gliomas and others were 50.0, 36.8 and 33.3%, respectively. Deep-seated gliomas were more effectively treated than superficial gliomas by combination with radiation therapy. The common pathological finding was a clearly demarcated coagulative necrosis of ellipsoid shape around the implant.     

Effect of combined treatment with magnetic induction hyperthermia and chemotherapy in a rabbit brain tumor model

The effects of interstitial magnetic induction hyperthermia alone and in combination with chemotherapy were evaluated in a rabbit brain tumor model. VX2 carcinoma cells were implanted intracerebrally in 28 rabbits. The animals were divided into four groups of seven each, and the experimental protocols were started on the 7th day after inoculation. Group 1 underwent hyperthermia alone by means of implantation of a needle (Fe-Pt alloy) in the tumor, which was maintained at 45 degrees C for 30 minutes. Group 2 received 12.5 mg/kg ACNU intravenously via a lateral ear vein. In Group 3, 10 minutes after injection of ACNU, hyperthermia was induced in the same manner as in Group 1. Group 4 were controls and received no treatment. The four groups were evaluated and compared in terms of length of survival and pathological features of their brain tumors at the time of death. The mean survival times of Groups 1, 2, 3, and 4 were 14.7, 14.7, 17.3, and 12.3 days, respectively. Statistically significant differences were found between Groups 1 and 4 and between Groups 3 and 4, but not between Groups 1 and 2. Pathological findings in the hyperthermia group included necrosis around the implant. The tumor cells surrounding the necrotic area had degenerated and the vessels were dilated and static. Thus, in this rabbit brain tumor model, hyperthermia alone was significantly superior to no treatment, and combined treatment with hyperthermia and chemotherapy was more effective than either treatment alone.     

Interstitial hyperthermia of malignant gliomas with implant heating system

Twenty four cases of malignant gliomas, histologically 12 glioblastomas, 10 astrocytoma GIII and 2 astrocytoma GII, were treated by interstitial hyperthermia with Implant Heating System (IHS). IHS has three major parts, generator of high frequency (240KHz), magnetic coil and metal implant manufactured from FePt alloy. Theoretically the brain tumor can be heated by heat conduction through the heated implants. Several implants were placed inside the brain tumor directly by operation, or by CT stereotactic procedure. The patients were divided into two groups according to the tumor location as (A) in cortical or subcortical region (13 cases) and (B) in thalamus or basal ganglia (11 cases). Hyperthermia, 60 minutes each, 2 to 3 times per week, was safely repeated in all the cases. External irradiation was always combined with hyperthermia in most of the cases and with chemotherapy in some of them. Follow-up CTs demonstrate a remarkable response in many cases of B group. In fact ICR, 4PR and 3MR were achieved in this group, resulting in 45.5% of the response. In contrast gliomas in A group showed a less favorable response, resulting in 23.1% of the response (3 PRs in 13 cases). Although the overall response rate was not so high, it seems to be encouraging that gliomas in thalamus and basal ganglia, those which are usually unresectable, showed a good response. More favorable results can be expected by further improvement of the system and related techniques.     

Radiofrequency hyperthermia for malignant brain tumors: preliminary results of clinical trials

Local hyperthermia by 13.56-MHz radiofrequency (RF) capacitive heating was evaluated in 16 patients with malignant brain tumors. Intracranial heating during operation was performed in 4 patients. RF applicators with a cooling system were placed on the cerebral convexity and medial brain surface with the tumor between them. RF power was controlled to maintain the brain temperatures under 40 degrees C. Under this condition, the highest temperature of each tumor varied from 44 to 49 degrees C. After heating for about 60 minutes, 2 tumors showed regression on computed tomographic (CT) scans. Extracranial heating was performed in 12 patients with cerebral glioblastoma. RF applicators were placed on the lateral sides of the scalp and applied to diametrically opposite sides of the tumor. To avoid the influence of the skull on RF conduction, we performed a bilateral craniectomy slightly larger than the applicator at the initial operation. Heating was performed for approximately 60 minutes at each session and was repeated twice a week for a total of 4 to 10 times in combination with radiation and ACNU chemotherapy. No anesthetic agent was used during heating. Brain temperatures were maintained under 42 degrees C. The scalp under the applicators remained at 28-35 degrees C during heating, and no heat injury of the scalp was observed after repeated heating. The highest temperatures of the tumor or cavity after tumor removal were 45-46 degrees C in 3 cases, 43-44 degrees C in 3 cases, 42-43 degrees C in 4 cases, and 40-41 degrees C in 2 cases, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thermotherapy using magnetic nanoparticles combined with external radiation in an orthotopic rat model of prostate cancer

BACKGROUND: We evaluated the effects of thermotherapy using magnetic nanoparticles, also referred to as magnetic fluid hyperthermia (MFH), combined with external radiation, in the Dunning model of prostate cancer. METHODS: Orthotopic tumors were induced in 96 male Copenhagen rats. Animals were randomly allocated to eight groups, including controls and groups for dose-finding studies of external radiation. Treatment groups received two serial thermotherapy treatments following a single intratumoral injection of magnetic fluid or thermotherapy followed by external radiation (10 Gy). On day 20, after tumor induction, tumor weights in the treatment and control groups were compared and iron measurements in selected organs were carried out. RESULTS: Mean maximal and minimal intratumoral temperatures obtained were 58.7 degrees C (centrally) and 42.7 degrees C (peripherally) during the first thermotherapy and 55.4 degrees C and 42.3 degrees C, respectively, during the second of two treatment sessions. Combined thermotherapy and radiation with 20 Gy was significantly more effective than radiation with 20 Gy alone and reduced tumor growth by 87.5-89.2% versus controls. Mean iron content in the prostates on day 20 was 87.5% of the injected dose of ferrites, whereas only 2.5% was found in the liver. CONCLUSIONS: An additive effect was demonstrated for the combined treatment at a radiation dose of 20 Gy, which was equally effective in inhibiting tumor growth as radiation alone with 60 Gy. Serial heat treatments were possible without repeated injection of magnetic fluid. The optimal treatment schedules of this combination regarding temperatures, radiation dose, and fractionation need to be defined in further experimental studies.     

Combination studies of hyperthermia induced by the neodymium: yttrium-aluminum-garnet (Nd:YAG) laser as an adjuvant to photodynamic therapy

Photodynamic therapy (PDT) and hyperthermia have been investigated as treatments for several types of tumors. Studies have been done to determine the efficacy of each modality individually and recently in combination with each other. In this study, 630-nm light was delivered by an argon-dye laser and hyperthermia was induced using an Nd:YAG laser. Both lasers offer the ability of delivering the beams through a quartz fiberoptic alone or simultaneously. This study examines the efficacy of the simultaneous administration of PDT and selective hyperthermia at 44.5 degrees C in tumor control in the spontaneous mammary tumor (SMT-F) in DBA mice. Hyperthermia alone (44.5 degrees C, 30 min) resulted in complete destruction of tumors, with no subsequent regrowth in 6.6% of the mice treated. PDT alone (5 mg/kg dihematoporphyrin ether; 135 J/cm) resulted in a cure rate of approximately 10%, and the simultaneous treatment of the modalities resulted in a 32.8% cure rate after 90 days. These values are indicative of a synergistic interaction.     

Preoperative radiotherapy and chemotherapy in hypervascular, high-grade supratentorial astrocytomas.

From a group of ten patients with hypervascular, high-grade, supratentorial astrocytomas, five were treated with pre-operative radiotherapy alone, and five with radiotherapy in combination with cytostatic drugs. The aim was to investigate the timing of intracranial operations in the multimodality therapy of brain tumors. The tumor size was diminished only in one case, but tumor vascularization was reduced in half of the cases by the pre-operative treatment. Survival was not improved. Surgical treatment still should be the first of the therapeutic measures. Pre-operative radiotherapy may be of value to reduce tumor vascularization in hypervascular, centrally localized tumors.     

Two cases of von Recklinghausen's disease with multiple brain and spinal tumors]

The authors reported two cases of von Recklinghausen's disease with multiple brain tumors and multiple spinal tumors. The first case, a 21-year-old man who had a past history of optic gliomas was admitted because of gait disturbance. Computed tomography (CT) and magnetic resonance imaging (MRI) showed calcification of the basal ganglia, bilateral C-P angle tumors, cystic cerebellar tumor and arachnoid cyst in the quadrigeminal cistern. Myelography and MRI revealed multiple spinal tumors. Surgical management was performed and cerebellar tumor was histologically confirmed to be a pilocytic astrocytoma. Spinal tumors were also astrocytomas. The second patient, a 56-year-old woman suffered from right iliac pain, right hemiparesis and motor aphasia. CT revealed two round tumors in the left cerebral hemisphere and bilateral C-P angle tumors. Myelography and MRI demonstrated multiple intradural-extramedullary spinal tumors. Histologically, supratentorial tumors were transitional meningiomas and spinal tumors were neurinomas. It is well known that von Recklinghausen's disease is often associated with brain or spinal tumors. But, in the literature, only 22 cases of von Recklinghausen's disease combined with multiple brain tumors with different histological types and multiple spinal tumors have been reviewed. With our two cases, the average age of these 24 cases was 28.6 years old, nine cases were male and 15 cases were female. All patients had C-P angle tumors and 23 cases were combined with intracranial meningiomas. In this paper, the clinical features and diagnostic aspects were discussed.     

CT-guided stereotaxic implantation of the Ommaya reservoir for cystic brain tumors

We report the use of CT-guided stereotaxic system to implant Ommaya reservoir in 26 patients with cystic brain tumors consisting of 16 gliomas, 3 craniopharyngiomas, 3 metastatic brain tumors and 5 other and unknown pathologies, on the way of their biopsy. The entire procedure was carried out in the CT room using Leksell's CT stereotaxic system. In 24 cases with supratentorial tumors, it was at the option of the operator to take any approach such as frontal, posterior temporal and parietal approaches. Especially in 3 cases of craniopharyngioma, we inserted the tube into their cyst directly so that the ventricle should not be open to the cyst. Also in cases of a pontine glioma and a C-P angle metastatic tumor, we used retromastoid approach to the posterior fossa by making patient's heads turned about 30 to 40 degrees to contralateral side of the approach, with slight flexion of the neck. Minimal bleeding occurred during operation in one case, however, it showed no clinical symptoms. Advantages of this method are as follows: Operative invasion is minimal; The surgeon can check the course of the cannula and position of the tip of Ommaya tube even at operation, and can modify it, if necessary.     

Experimental studies on combined chemotherapy with hyperthermia and ethanol for advanced esophageal cancer. II. Effects of combined treatments on tumor growth in tumor-bearing mice

The combined effects of local hyperthermia, bleomycin and ethanol were investigated using Lewis lung carcinoma (3LL) in female C57BL/6 mice and FM3A tumors in female C3H/He mice. The combined treatments were performed on days 4 and 7 or on days 4, 7 and 10 after tumor implantation. Hyperthermia at 43 degrees C for 60 min or 15 mg/kg of bleomycin resulted in mild reductions of tumor growth, respectively, whereas hyperthermia at 41 degrees C for 60 min alone did not show antitumor effects. Synergistic effects were observed with 43 degrees C hyperthermia and bleomycin. Furthermore the effects were enhanced by the combined use of ethanol (10% ethanol, 0.05 ml, i.t.). The antitumor effects of combined treatments of 41 degrees C hyperthermia and bleomycin were not so remarkable as those of 43 degrees C hyperthermia and bleomycin. In the combination of 41 degrees C hyperthermia, bleomycin and ethanol, marked increase of antitumor effects was observed particularly in 3LL tumor. A possible application of these findings to clinical therapy for advanced esophageal cancer was discussed.     

The synergistic effect of hyperthermia and chemotherapy on murine transitional cell carcinoma

The in vivo effect of hyperthermia and chemotherapy was studied in a murine transitional cell carcinoma model. Localized hyperthermia (43.5C) of 60 and 90 minutes duration was combined with systemic doxorubicin hydrochloride, cis-platinum, cyclophosphamide or mitomycin to treat tumors implanted into the hind legs of C3H mice. The data were compared to the results obtained from the application of hyperthermia or chemotherapy alone as well as to the natural growth rate of untreated tumors. Untreated tumors grew with an exponential rate and had a doubling time of 4 +/- 1.5 days. Animals bearing such tumors survived for 25 +/- 7 days. When treated with hyperthermia alone, there was no significant reduction in the growth rate and no improvement was noted in the survival time. Treatment with doxorubicin hydrochloride, cyclophosphamide or mitomycin administered alone was likewise not effective. Cis-platinum alone was able to induce a minimal decrease in the growth rate. When the administration of chemotherapy was accompanied by hyperthermia, significant synergistic effect was noted for doxorubicin hydrochloride, cis-platinum and cyclophosphamide (p less than .01); only the mitomycin and hyperthermia combination failed to improve survival and decrease the growth rate. The duration of the hyperthermia exposure influenced the degree of tumor response. Hyperthermia of 90 minutes duration resulted in consistently greater decrease in tumor growth rate with doxorubicin hydrochloride, cis-platinum or cyclophosphamide than 60 minutes of hyperthermia combined with the same agents. These results indicate that local hyperthermia combined with doxorubicin hydrochloride, cis-platinum or cyclophosphamide can induce tumor regression, increase tumor doubling time and improve the survival of the tumor-bearing animal. Only the hyperthermia-mitomycin combination did not result in significant improvement from the baseline values. Thus, hyperthermia combined with selected chemotherapeutic agents can have an adjuvant effect in the treatment of established, implanted mouse bladder tumors.     

In vitro response of human glioblastoma and canine glioma cells to hyperthermia, radiation, and chemotherapy

Little is known about the sensitivity of human glioblastoma cells to hyperthermia alone and in combination with other therapies. We carried out in vitro cell survival studies on the human glioblastoma cell line U-87MG and our model canine glioma canine brain tumor (CBT) cells after multimodality treatment. Ionizing radiation was administered to flasks of cells in logarithmic growth at 500 rads (5 Gy) with consecutive treatment by hyperthermia, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), or cisplatin. Cells were treated with single doses of BCNU at 5 microM with sequentially added radiation or hyperthermia and at 1 to 2 micrograms/ml of cisplatin with hyperthermia. Hyperthermia was administered in a precision controlled water bath at 44 degrees C for 30 minutes in combination with chemotherapy or radiation. In general, the sensitivity of U-87MG and CBT cells was similar for all test regimens. For example, colony formation efficiency decreased by 64% in CBT cells and by 64.4% in U-87MG cells after hyperthermia alone at 44 degrees C for 60 minutes. All combinations of BCNU, hyperthermia, and radiation administered in vitro produced enhanced cell killing, but the effects of multiple modalities were generally additive in both cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)     

Brachytherapy of brain tumors.

Temporary implants of high-activity 125iodine sources have been used in the treatment of brain tumors since December 1979 at the University of California, San Francisco. For previously untreated patients who underwent external beam radiation therapy followed by implant boost, median survival from the date of diagnosis was 88 weeks for 34 patients with glioblastoma multiforme (GM) and 157 weeks for 29 patients with nonglioblastoma gliomas (NGM). For recurrent tumors treated with brachytherapy only, median survival from the date of the implant was 54 weeks for 45 patients with GM and 81 weeks for 50 patients with NGM. Finally, in 48 patients with recurrent tumors treated with combined hyperthermia and brachytherapy, median survival from the date of the implant was 46 weeks for 25 patients with GM and 44 weeks for 7 patients with metastases; 18-month survival was 65% for 16 patients with NGM. Brachytherapy appears to be a useful technique for the treatment of selected recurrent brain tumors and selected primary glioblastomas.     

Enhanced antitumor effects of bleomycin and moderate hyperthermia by additional use of ethanol

The combined effects of moderate local hyperthermia, bleomycin and ethanol were investigated with Lewis lung carcinoma tumors in female C57BL/6 mice. Different combinations of treatments were performed on days 4 and 7 after tumor implantation. Combined treatment of 41 degrees C hyperthermia and bleomycin resulted in mild reductions of tumor growth. Hyperthermia plus bleomycin led to marked reduction in tumor growth under the condition of a 43 degrees C temperature. The antitumor effects of 41 degrees C hyperthermia combined with bleomycin were enhanced by the additional use of ethanol, and these effects were more remarkable than those of 43 degrees C hyperthermia and bleomycin. A possible application of these findings to clinical therapy for advanced esophageal cancer was discussed.     

The effect of radiation therapy and hyperthermia on a human prostatic carcinoma cell line grown in athymic nude mice

The effect of radiation and/or hyperthermia on a human prostatic carcinoma xenograft in athymic nude mice was investigated. A human prostate carcinoma subline (1-LN-PC-3-1A) was inoculated subcutaneously in the thigh of male athymic nude mice. When tumors reached a size of approximately 200 mm.3, they were treated with either radiation (X) or hyperthermia (H) alone, or in combination (X + H). In the combined treatment, hyperthermia was delivered immediately after radiation exposure. Comparison of the time required to reach twice the tumor volume observed at the time of treatment was used to define therapeutic impact on tumor growth. The combined treatment resulted in median tumor volume doubling time of 35.5 days, compared to 18 days and 25.5 days, respectively, for hyperthermia or radiation alone. Analysis of tumor doubling time using a proportional hazards regression indicates that under the conditions of this experiment, the effect of radiation and hyperthermia for 1-LN-PC-3-1A tumors is additive. The impact of this treatment regimen in the management of prostatic cancer requires further investigation.     

Evaluation of magnetic fluid hyperthermia in a standard rat model of prostate cancer

PURPOSE: To examine the feasibility and potential of magnetic fluid hyperthermia (MFH) as a minimally invasive method for hyperthermia treatment of prostate cancer. MATERIALS AND METHODS: Orthotopic Dunning R3327 prostate tumors were induced in 20 male Copenhagen rats. The animals either received MFH treatment following intratumoral administration of magnetic fluids or were used as either tumor growth controls for determination of iron distribution in selected organs or as histologic controls without MFH treatment. The MFH treatments were carried out at 45 degrees C or 50 degrees C using an AC magnetic field applicator system designed for small animals. RESULTS: Sequential treatments with MFH were possible following a single intratumoral injection of magnetic fluid. Intratumoral temperatures of 50 degrees C and more were obtained and were monitored online using fluoro-optic thermometry. Four days after MFH treatments, 79% of the injected dose of ferrites was still present in the prostate. CONCLUSIONS: The successful intraprostatic nanoparticle infiltration and stable steady-state intratumoral treatment temperatures demonstrate the feasibility of MFH in a prostate cancer model. Efficacy and survival benefit must be confirmed in further experiments.     

无功能性胰岛细胞瘤的CT诊断

目的 探讨无功能性胰岛细胞瘤(NFICT)的CT表现.方法 回顾性分析经手术并经病理证实的17例NFICT的CT平扫和增强扫描所见.增强剂采用非离子型碘对比剂90 mL,注射流率3mL/s,测量胰腺和肿瘤动、静脉双期CT值.结果 CT扫描全组均发现肿瘤.平扫时肿瘤与胰腺实质比较,2例肿瘤为低密度,11例为混合性低密度,4例为等密度.5例于肿瘤内见限局性钙化.增强扫描17例肿瘤均有程度不同的强化.动脉期明显强化5例,中等强化6例,轻度强化6例.结论 NFICT的CT平扫表现为界限清楚的肿瘤,部分瘤体内有钙化.增强扫描肿瘤均有程度不同的强化,从动脉期到门静脉期呈持续性强化是NFICT的特征性表现.     

Enhanced tumor control following sequential treatments of photodynamic therapy (PDT) and localized microwave hyperthermia in vivo

Photodynamic therapy (PDT), or photoradiation therapy (PRT), utilizing hematoporphyrin derivative (HPD) as photosensitizer and an argon-dye laser system as the light source, was used alone and in combination with localized microwave hyperthermia (2450 MHz) to treat axillary tumors of the SMT-F mammary carcinoma in mice. Thirty-minute heat treatments were applied either immediately before or immediately after a standard PDT treatment of 630 nm light at 75 mW/cm2 for 30 min (135 J/cm2) given 24 hr post-7.5 mg/kg HPD, intraperitoneally (i.p.). Tumor control as judged by lack of tumor regrowth 35 days or longer after the combined treatments was compared to that following each treatment when given alone. Little or no enhancement of tumor control was seen when sublethal temperatures of 37.5, 38.5, and 39.5 degrees C were applied for 30 min immediately following the PDT treatment. However, increasing levels of enhancement were seen when heat treatments of 40.5 and 41.5 degrees C or 44.5 degrees C, given for 30 min, were applied immediately before or after the photodynamic treatment.     

Magnetic fluid hyperthermia (MFH)reduces prostate cancer growth in the orthotopic Dunning R3327 rat model

BACKGROUND: Magnetic fluid hyperthermia (MFH) is a new technique for interstitial hyperthermia or thermoablation based on AC magnetic field-induced excitation of biocompatible superparamagnetic nanoparticles. Preliminary studies in the Dunning tumor model of prostate cancer have demonstrated the feasibility of MFH in vivo. To confirm these results and evaluate the potential of MFH as a minimally invasive treatment of prostate cancer we carried out a systematic analysis of the effects of MFH in the orthotopic Dunning R3327 tumor model of the rat. METHODS: Orthotopic tumors were induced by implantation of MatLyLu-cells into the prostates of 48 male Copenhagen rats. Animals were randomly allocated to 4 groups of 12 rats each, including controls. Treatment animals received two MFH treatments following a single intratumoral injection of a magnetic fluid. Treatments were carried out on days 10 and 12 after tumor induction using an AC magnetic field applicator system operating at a frequency of 100 kHz and a variable field strength (0--18 kA/m). On day 20, animals were sacrificed and tumor weights in the treatment and control groups were compared. In addition, tumor growth curves were generated and histological examinations and iron measurements in selected organs were carried out. RESULTS: Maximum intratumoral temperatures of over 70 degrees C could be obtained with MFH at an AC magnetic field strength of 18 kA/m. At a constant field strength of 12.6 kA/m, mean maximal and minimal intratumoral temperatures recorded were 54.8 degrees C (centrally) and 41.2 degrees C (peripherally). MFH led to an inhibition of tumor growth of 44%-51% over controls. Mean iron content in the prostates of treated and untreated (injection of magnetic fluids but no AC magnetic field exposure) animals was 82.5%, whereas only 5.3% of the injected dose was found in the liver, 1.0% in the lung, and 0.5% in the spleen. CONCLUSIONS: MFH led to a significant growth inhibition in this orthotopic model of the aggressive MatLyLu tumor variant. Intratumoral deposition of magnetic fluids was found to be stable, allowing for serial MFH treatments without repeated injection. The optimal treatment schedules and temperatures for MFH need to be defined in further studies.