Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model.

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time imaging and acoustic energy modulation, this modality enables precise temperature control within a defined area. Many thermal applications are being explored with this noninvasive, nonionizing technology, such as hyperthermia generation, to release drugs from thermosensitive liposomal carriers. These drugs can include chemotherapies such as doxorubicin, for which targeted release is desired due to the dose-limiting systemic side effects, namely cardiotoxicity. Doxorubicin is a mainstay for treating a variety of malignant tumors and is commonly used in relapsed or recurrent rhabdomyosarcoma (RMS). RMS is the most common solid soft tissue extracranial tumor in children and young adults. Despite aggressive, multimodal therapy, RMS survival rates have remained the same for the past 30 years. To explore a solution for addressing this unmet need, an experimental protocol was developed to evaluate the release of thermosensitive liposomal doxorubicin (TLD) in an immunocompetent, syngeneic RMS mouse model using MRgHIFU as the source of hyperthermia for drug release.

Thermal combination therapies for local drug delivery by magnetic resonance-guided high-intensity focused ultrasound.

Several thermal-therapy strategies such as thermal ablation, hyperthermia-triggered drug delivery from temperature-sensitive liposomes (TSLs), and combinations of the above were investigated in a rhabdomyosarcoma rat tumor model (n = 113). Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) was used as a noninvasive heating device with precise temperature control for image-guided drug delivery. For the latter, TSLs were prepared, coencapsulating doxorubicin (dox) and [Gd(HPDO3A)(H2O)], and injected in tumor-bearing rats before MR-HIFU treatment. Four treatment groups were defined: hyperthermia, ablation, hyperthermia followed by ablation, or no HIFU. The intratumoral TSL and dox distribution were analyzed by single-photon emission computed tomography (SPECT)/computed tomography (CT), autoradiography, and fluorescence microscopy. Dox biodistribution was quantified and compared with that of nonliposomal dox. Finally, the treatment efficacy of all heating strategies plus additional control groups (saline, free dox, and Caelyx) was assessed by tumor growth measurements. All HIFU heating strategies combined with TSLs resulted in cellular uptake of dox deep into the interstitial space and a significant increase of tumor drug concentrations compared with a treatment with free dox. Ablation after TSL injection showed [Gd(HPDO3A)(H2O)] and dox release along the tumor rim, mirroring the TSL distribution pattern. Hyperthermia either as standalone treatment or before ablation ensured homogeneous TSL, [Gd(HPDO3A)(H2O)], and dox delivery across the tumor. The combination of hyperthermia-triggered drug delivery followed by ablation showed the best therapeutic outcome compared with all other treatment groups due to direct induction of thermal necrosis in the tumor core and efficient drug delivery to the tumor rim.

Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine.

PURPOSE: An inverse correlation has been established between tumor levels of the DNA repair protein alkylguanine-DNA alkyltransferase (AGT) and a positive outcome after alkylator chemotherapy. Quantitative imaging of AGT could provide important information for patient-specific cancer treatment. Several radiolabeled analogues of O6-benzylguanine (BG), a potent AGT inactivator, have been developed and shown to be capable of labeling pure AGT protein. Herein, two of these analogues--O6-3-[*I]iodobenzylguanine ([*I]IBG) and O6-3-[*I]iodobenzyl-2'-deoxyguanosine ([*I]IBdG)--were further evaluated in two murine xenograft models. (AcO)2-[131I]IBdG, a peracetylated derivative of IBdG, also was investigated as an alternative agent. METHODS: Several biodistribution studies of radioiodinated IBG and IBdG were performed in TE-671 human rhabdomyosarcoma and DAOY human medulloblastoma murine xenograft models. Mice were treated with BG or its nucleoside analogue dBG to deplete the tumor AGT content. The effect of unlabeled IBG and that of 7,8-benzoflavone (BF), an inhibitor of the cytochrome P-450 isozyme CYP1A2, on the tumor uptake of the tracers was determined. The uptake of (AcO)2-[131I]IBdG along with that of [125I]IBdG in DAOY cells in vitro was determined in the presence and absence of a nucleoside transporter inhibitor, dipyridamole. RESULTS: Pretreatment of mice either with BG or dBG failed to reduce tumor levels of [*I]IBG or [*I]IBdG even though such treatments completely depleted tumor AGT content. Treatment of mice with BF increased tumor uptake of [125I]IBG by 56%; however, differentiation of tumors with and without AGT still was not possible. (AcO)2-[131I]IBdG, a peracetylated derivative of IBdG, had a higher uptake in vitro in DAOY tumor cells. However, its uptake, like that of [125I]IBdG, was blocked by dipyridamole. CONCLUSIONS: Taken together, these results suggest that labeled agents that are more specific for cellular AGT and that are more metabolically stable are needed.

Use of computed tomography for the fabrication of a custom brachytherapy carrier: a clinical report.

Early methods of fabricating customized radiation carriers for inaccessible areas, such as the nasopharyngeal space, normally required the patient to be under conscious sedation or general anesthesia to allow impressions for indirect processing techniques. This article describes the use of computed tomography to design and fabricate a carrier for the intracavity application of iodine 125 seeds for a patient with rhabdomyosarcoma of the nasopharynx. With tomography printed copies, a wax pattern was formed, flasked, boiled out, and eventually replaced with silicone material. The patient had to be available only for a conventional thin-cut computed tomography scan without contrast; no fitting appointments or anesthesia were necessary. The indirect procedure eliminated discomfort from impression making and allowed for precise fabrication of the nasopharyngeal carrier. The described technique can be used for other intracavitary radiation applications.

Radiation-induced inhibition of tumor growth as monitored by PET using L-[1-11C]tyrosine and fluorine-18-fluorodeoxyglucose.

The potential use of PET to monitor radiotherapeutic effects on tumors has been evaluated with L-[1-11C]tyrosine and 18FDG. Single x-ray doses of 10, 30, or 50 Gy have been applied to rhabdomyosarcoma tumors growing in the flank of rats. Dose-dependent reductions of tracer uptake were registered by PET 4 and 12 days after treatment. These later effects on tracer uptake appeared to correlate with changes in tumor volume. Therefore, PET using L-[1-11C]tyrosine and 18FDG is suitable to monitor kinetics of tumor growth and tumor regression after radiotherapy. Direct effect on tracer uptake was not observed within 8 hr after irradiation. This indicates that, using PET, early predictions on the outcome of radiotherapy are not possible. When combining a radiation treatment with hyperthermia, radiation-induced inhibition of tumor growth was clearly enhanced. Tracer uptake remained at the pretreatment value, possibly due to invasion of host cells. From these experiments, it can be concluded that it is difficult to monitor a combined treatment of radiation and hyperthermia by PET.

PET measurements of hyperthermia-induced suppression of protein synthesis in tumors in relation to effects on tumor growth.

Hyperthermia-induced metabolic changes in tumor tissue have been monitored by PET. Uptake of L-[1-11C]tyrosine in rhabdomyosarcoma tissue of Wag/Rij rats was dose-dependently reduced after local hyperthermia treatment at 42, 45, or 47 degrees C. Tumor blood flow, as measured by PET with 13NH3, appeared to be unchanged. The L-[1-11C]tyrosine uptake data were compared to uptake data of L-[1-14C]tyrosine and with data on the incorporation of L-[1-14C]tyrosine into tumor proteins. After intravenous injection, the 14C data were obtained from dissected tumor tissue. Heat-induced inhibition of the incorporation of L-[1-14C]tyrosine into tumor proteins tallied with the L-[1-11C]tyrosine uptake data. Heat-induced inhibition of amino acid uptake in the tumor correlated well with regression of tumor growth. It is concluded that PET using L-[1-11C]tyrosine is eligible for monitoring the effect of hyperthermia on tumor growth.

CT and ultrasound imaging of pelvic rhabdomyosarcoma in children. A review of 56 patients.

We have retrospectively reviewed the radiographic and clinical features of 56 cases of pelvic rhabdomyosarcoma seen in three Pediatric Hospitals between 1960 and 1986. There were 35 boys and 21 girls. The study aimed at better defining the role played by the various imaging techniques in the investigation of these tumors. The role of diagnostic radiology is the detection and delineation of the primary tumor, its local spread and distant metastases at the time of diagnosis and on follow-ups. Intravenous urography (IVU) and to a lesser extent barium enema (BE) and cystography (VCUG) were used even after the availability of ultrasonography (US) and computed tomography (CT). These two modalities have only partly replaced the traditional radiographic techniques. All patients seen or followed after 1977 (28 patients) had both US and CT examinations. We have focused our discussion on these relatively new imaging modalities namely US and CT. Magnetic resonance was not utilized in any patient in this series. US was by far the best imaging technique available for lesions of the urinary bladder and those invading the bladder wall in children as it was possible to visualize, measure and follow these tumors. Scrotal US was used to confirm the clinical diagnosis of a paratesticular mass. CT showed to best advantage the tumour and its relationship to pelvic organs, musculature and bones.