Simultaneous hyperthermia-chemotherapy effect by arterial injection of Fe(Salen) for femur tumor.

We previously identified a novel nanomagnetic particle, N,N'-bis(salicylidene)ethylenediamine iron [Fe(Salen)]. Fe(Salen) not only shows antitumor effects but also magnetic properties. We found that Fe(Salen) can be used for magnet-guided drug delivery and visualization of accumulated drug by magnetic resonance imaging (MRI) because of its magnetism. In addition, Fe(Salen) can generate heat by itself when exposed to an alternating current magnetic field (AMF), resulting in a hyperthermia effect. Herein, we partly elucidated the antitumor mechanism of Fe(Salen) and carried out an i.v. repeated dose toxicity study to decide the therapeutic amount. Furthermore, we evaluated the antitumor effect of selective intra-arterial injection or i.v. injection of Fe(Salen) by catheter and the hyperthermia effect of Fe(Salen) when exposed to AMF in vivo. We used a rabbit model grafted with VX2 cells (rabbit squamous cell carcinoma) on the right leg. Intra-arterial injection of Fe(Salen) showed a greater antitumor effect than did i.v. injection. The combination of Fe(Salen) intra-arterial injection and AMF exposure showed a greater antitumor effect than did either Fe(Salen) or methotrexate (MTX) without AMF exposure, suggesting that AMF exposure greatly enhanced the antitumor effect of Fe(Salen) by arterial injection by catheter. This is the first report that the effectiveness of Fe(Salen) was evaluated in the point of administration route; that is, selective intra-arterial injection by catheter. Taken together, these results indicate a new administration route; that is, selective arterial injection of Fe(Salen) by catheter, and the development of a new strategy of simultaneous hyperthermia-chemotherapy in the future.

[MRI-assisted thermometry for regional hyperthermia and interstitial laser thermotherapy]. / MRT-gestützte Thermometrie in der regionalen Tiefenhyperthermie und interstitiellen Laserthermotherapie.

PURPOSE: To demonstrate the potential of quantitative MRI-assisted thermometry for the treatment of tumor patients with regional hyperthermia (RHT) and interstitial laser thermotherapy (ILTT). METHODS: Two patients and seven tissue samples were investigated using the T1-relaxation time and the chemical shift of the proton resonance frequency (PRF) as temperature sensitive MRI-parameters at 0.2 and 1.5 T. Thermotherapy was applied using either a dedicated MRI-hyperthermia hybrid system or a temperature controlled laser with 830 nm. RESULTS: Both patients were treated successfully showing clinical benefit. T1 and PRF are depending on the applied thermotherapy method and on the MR-system suitable for MRI-assisted thermometry. The clinical application based on phantom results is not necessarily adequate. CONCLUSION: Clinical application and phantom experiments of RHT and ILTT show the potential of MRI-assisted thermometry for further improvement of both minimal invasive thermotherapy methods. Further investigations concerning optimization of the MRI-techniques, the influence of perfusion or the determination of threshold values are necessary.

[Toxicosis of high-dose methotrexate (HD-MTX) for osteosarcoma, cured with treatment by leucovorin (LV) rescue and hemoperfusion--a case report].

A 17-year-old boy suffered from osteosarcoma in his left distal femur. He was treated with 4 courses of HD-MTX preoperatively, then a wide resection and replacement with endprosthesis was performed. After surgery, 4 more courses of HD-MTX were administered. In the last course of HD-MTX, the serum level of MTX had not decreased to a safe level after 48 hours following MTX administration. Liver and renal dysfunction then occurred, so massive leucovorin rescue and hemoperfusion were done. Fortunately, all complications disappeared. The patient is alive and well, and has been disease free for six years since surgery.

[Treatment of malignant or aggressive bone tumors with microwave induced hyperthermia].

Limb-sparing procedures have been well established for dealing with malignant bone tumors. Unfortunately, these procedures have different problems. We used an alternative operation combined with microwave-induced hyperthemia to modify the surgical methods. Thermotherapy with microwave intracorporeal irradiation was used to treat 112 patients with bone tumors. In this series, 79 had malignant tumors and 33 aggressive benigh tumors. Postoperatively, immune therapy was carried out regularly. The patients immunologic functions were monitored by assay of the subpopulation of T cells, IL-2 and sIL-2R (soluble IL-2 receptor). Follow-up varied from 3 to 50 months (mean 23 month) s. Excluding 5 patients with malignancy in the vertebrae treated for palliation, 107 were evaluated by oncological and orthopedic criteria. 10 patients had local recurrence and required amputation. The remaining 97 had excellent local control. In 12 of the 74 patients with malignancy of the extremities, lung metastasis occurred 4 months to 2 years after surgery. Pathological fracture occurred at devitalized bone in 8 patients. In 29 out of 40 tumor-free cases followed for more than 2 years, the knee joints functioned properly with almost full range of motion. Single photon emission computered tomography (SPECT) study revealed revascularization of the devitalized tumor bearing bone segment could accomplish in one year or more. The immune state was improved after thermotherapy plus immunotherapy in the majority of patients. These results indicated that the use of microwave hyperthermia and adjuvant immunotherapy in the surgical treatment of bone tumors can be considered a definitive procedure, which is safe and well-tolerated.

Thermal effects of acrylic cementation at bone tumour sites.

The use of acrylic bone cement as an adjunct to surgical excision of giant cell tumour of bone appears to reduce the incidence of tumour recurrence. Possible mechanisms for this apparent tumour inhibition include cytotoxic effects from the methylmethacrylate monomer and tissue hyperthermia from the heat of polymerization of the cement. This work presents a method for the prediction of temperature fields and resulting tissue necrosis arising from the implantation of polymethylmethacrylate (PMMA) at the site of a curretted giant cell tumour of bone. This is accomplished using a two-dimensional model based on geometry obtained from digitized MRI images of the distal femur. A general-coordinate, non-orthogonal grid generation technique is used and solutions are obtained with an alternating-direction implicit (ADI) finite-difference scheme. The nodal temperature histories are then used to evaluate the effect of variable defect size on the zone of thermally induced cell necrosis. The results suggest the depth of the necrotic region is quite sensitive to the size of the implant. In at least some cases, the heating effect is sufficient to cause significant necrosis of tumorigenic cells. Implanting a large mass of acrylic may risk overkill, damaging substantial amounts of healthy tissue.

[Microwave heating and neoadjuvant chemotherapy for malignant bone tumor].

Limb salvage is widely used but has different disadvantages. Attempting to establish a new limb conservative procedure, we treate patients with malignant bone tumor by intraoperative microwave heating on tumor bearing bone in place and neoadjvant chemotherapy. The tumors were localized at distal femur in 16, proximal tibia in 5, femur shaft in 2, and illia in 2. Pathological diagnosis showed osteosarcoma in 16 patents, parosteoal osteosarcoma in 4, chondrosarcoma in 3, and leiomyosarcoma in 2. The stage of tumor was II b in 18 patients, II a in 6, and III b in 3. Operative technique was wide resection for tumor in soft tissue, protecting the surrounding tissue from heat injury by copper net, and cheating tumor bone at 50 C for 15 minutes. Follow-up varied from 4 to 180 months (mean 57 months). The 5-, 10-years surviral rates were 70.19% and 54.83% respectively. Functional results of 21 patients were > 15 points by Enneking system. The advantages of the method and keeping the shape and continuity of the tumor bearing bone without osteotomy and internal fixation, controlling the time and temperature of heating treatment easily, benefiting for bone remodeling of heated bone. The indications, complications, and surgical procedure of this method were discussed in detail.

[On the method of hyperthermic chemotherapy by regional isolated perfusion for tumors of lower extremities].

From August 1990 to June 1993, 30 patients with osteosarcoma of lower extremities were treated with chemotherapy by hyperthermic regional isolated perfusion. There were 19 male and 11 female with a mean age of 21 (15-28) years. All of the tumors were located in the lower limbs: 20 on the femora, 9 on the tibiae and 1 on the fibula. Chemotherapy was going on for 60 minutes during hyperthermic regional isolated perfusion. Temperature was kept at 42 degrees C in deep soft tissue around the tumor during perfusion. The results showed that local edema of the limbs were reduced observably, tumors were shrunken and hardened after perfusion. Perimeter of the limbs were decreased and mobility of the limbs increased. Pathological examination indicated that all of the tumors responded well to the chemotherapy by perfusion and 90%-95% of the osteosarcoma cells were destroyed. Two cases were complicated with compression syndrome, and 1 with renal failure. The authors would suggest that hyperthermic regional isolated perfusion is an effective chemotherapeutic method in management of malignant tumors of limbs.

[Results of treating giant cell tumor with emphasis on local recurrence]. / Wyniki leczenia guza olbrzymiokomórkowego ze szczególnym uwzglednieniem wznowy miejscowej.

The paper presents results of treatment of 16 patients operated on because of giant cell tumor. Frequent local recurrence after curettage makes the authors to suggest more common use of the thermal or chemical destruction of the neoplastic cells to achieve oncologic sterility.

Antiblastic hyperthermic regional perfusion in the treatment of malignant neoplasms of the limbs.

The authors describe the theoretical principles and the experimental and clinical investigations that form the basis for the technique of selective hyperthermic perfusion of the limbs, with or without the addition of antiblastic agents. Neoplastic cells are much more sensitive to heat than normal cells, undergoing necrosis at a temperature of 42.5 to 43 degrees C. The authors discuss the histological appearances and the clinical results obtained in the treatment of 29 cases of malignant neoplasms of the limbs in which antiblastic hyperthermic perfusion was carried out one month before surgical removal of the neoplasm. The long term results show that antiblastic hyperthermic perfusion significantly reduces the risk of local recurrences in cases of resection and in some cases enables amputations rather than disarticulations to be performed. This type of treatment is particularly indicated in the highly undifferentiated and aggressive forms such as osteosarcoma, malignant fibrous histiocytoma, adamantinoma, fibrosarcoma, giant-cell sarcoma, Ewing's tumour, and synovioma.