Cancer cell proliferation is inhibited by specific modulation frequencies.

BACKGROUND: There is clinical evidence that very low and safe levels of amplitude-modulated electromagnetic fields administered via an intrabuccal spoon-shaped probe may elicit therapeutic responses in patients with cancer. However, there is no known mechanism explaining the anti-proliferative effect of very low intensity electromagnetic fields. METHODS: To understand the mechanism of this novel approach, hepatocellular carcinoma (HCC) cells were exposed to 27.12 MHz radiofrequency electromagnetic fields using in vitro exposure systems designed to replicate in vivo conditions. Cancer cells were exposed to tumour-specific modulation frequencies, previously identified by biofeedback methods in patients with a diagnosis of cancer. Control modulation frequencies consisted of randomly chosen modulation frequencies within the same 100 Hz-21 kHz range as cancer-specific frequencies. RESULTS: The growth of HCC and breast cancer cells was significantly decreased by HCC-specific and breast cancer-specific modulation frequencies, respectively. However, the same frequencies did not affect proliferation of nonmalignant hepatocytes or breast epithelial cells. Inhibition of HCC cell proliferation was associated with downregulation of XCL2 and PLP2. Furthermore, HCC-specific modulation frequencies disrupted the mitotic spindle. CONCLUSION: These findings uncover a novel mechanism controlling the growth of cancer cells at specific modulation frequencies without affecting normal tissues, which may have broad implications in oncology.

Treatment of advanced hepatocellular carcinoma with very low levels of amplitude-modulated electromagnetic fields.

BACKGROUND: Therapeutic options for patients with advanced hepatocellular carcinoma (HCC) are limited. There is emerging evidence that the growth of cancer cells may be altered by very low levels of electromagnetic fields modulated at specific frequencies. METHODS: A single-group, open-label, phase I/II study was performed to assess the safety and effectiveness of the intrabuccal administration of very low levels of electromagnetic fields amplitude modulated at HCC-specific frequencies in 41 patients with advanced HCC and limited therapeutic options. Three-daily 60-min outpatient treatments were administered until disease progression or death. Imaging studies were performed every 8 weeks. The primary efficacy end point was progression-free survival 6 months. Secondary efficacy end points were progression-free survival and overall survival. RESULTS: Treatment was well tolerated and there were no NCI grade 2, 3 or 4 toxicities. In all, 14 patients (34.1%) had stable disease for more than 6 months. Median progression-free survival was 4.4 months (95% CI 2.1-5.3) and median overall survival was 6.7 months (95% CI 3.0-10.2). There were three partial and one near complete responses. CONCLUSION: Treatment with intrabuccally administered amplitude-modulated electromagnetic fields is safe, well tolerated, and shows evidence of antitumour effects in patients with advanced HCC.

Implementation of talairach atlas based automated brain segmentation for radiation therapy dosimetry.

Radiotherapy for brain cancer inevitably results in irradiation of uninvolved brain. While it has been demonstrated that irradiation of the brain can result in cognitive deficits, dose-volume relationships are not well established. There is little work correlating a particular cognitive deficit with dose received by the region of the brain responsible for the specific cognitive function. One obstacle to such studies is that identification of brain anatomy is both labor intensive and dependent on the individual performing the segmentation. Automatic segmentation has the potential to be both efficient and consistent. Brains2 is a software package developed by the University of Iowa for MRI volumetric studies. It utilizes MR images, the Talairach atlas, and an artificial neural network (ANN) to segment brain images into substructures in a standardized manner. We have developed a software package, Brains2DICOM, that converts the regions of interest identified by Brains2 into a DICOM radiotherapy structure set. The structure set can be imported into a treatment planning system for dosimetry. We demonstrated the utility of Brains2DICOM using a test case, a 34-year-old man with diffuse astrocytoma treated with three-dimensional conformal radiotherapy. Brains2 successfully applied the Talairach atlas to identify the right and left frontal, parietal, temporal, occipital, subcortical, and cerebellum regions. Brains2 was not successful in applying the ANN to identify small structures, such as the hippocampus and caudate. Further work is necessary to revise the ANN or to develop new methods for identification of small structures in the presence of disease and radiation induced changes. The segmented regions-of-interest were transferred to our commercial treatment planning system using DICOM and dose-volume histograms were constructed. This method will facilitate the acquisition of data necessary for the development of normal tissue complication probability (NTCP) models that assess the probability of cognitive complications secondary to radiotherapy for intracranial and head and neck neoplasms.

Local hyperthermia with interstitial techniques.

The heating of deep visceral tumors with implanted electrodes and with self-regulating ferromagnetic thermoseeds was investigated. Clinical trials on six patients heated with implanted electrodes indicate that good local tumor control can be obtained by application of hyperthermia during a normal course of radiotherapy. The heating method was found practical, and neither toxicity nor severe patient discomfort was encountered. However, temperature inhomogeneity within the tumor volume remains a problem. Theoretical studies and an animal experiment indicate that temperature homogeneity can be largely improved by heating the tumor with thermoseeds made of an alloy of 70.4% nickel and 29.6% copper. The highly temperature-dependent rate of heat production in the vicinity of the Curie point, about 50 degrees for this material, provides automatic temperature regulation.

Effect of Foley catheters on seed positions and urethral dose in (125)I and (103)Pd prostate implants.

PURPOSE: To estimate the perturbation of seed position and urethral dose, subsequent to withdrawal of urethral catheters. METHODS AND MATERIALS: A mathematical model based on the volume incompressibility of tissues was used to compute seed positions and doses following removal of the Foley. The model assumed that the central axis of the urethra remains stationary, and that prostate tissue and seeds move radially toward the center of the urethra to fill the void left by the catheter. Seed motion has also been measured using transrectal ultrasound. RESULTS: Based on the computations, seeds located originally close to the urethra travel relatively large distances toward the urethra upon Foley removal, whereas seeds located further away move substantially less. This seed motion leads to higher urethral doses than shown in a standard treatment plan. Dose enhancements increase with catheter size, decrease with increasing prostate volume, are more pronounced for (103)Pd than for (125)I, and range between 3.5% and 32.4%. Postimplant dosimetry is equally affected if images are taken with urethral catheters in place, showing lower urethral doses than actually delivered. Preliminary ultrasound based measurements of seed motion agree with the theory. CONCLUSION: During the implantation procedure, 12 fr or smaller urethral catheters are preferable to larger diameter catheters if urine drainage is sufficient. Treatment planners should avoid planning seeds at 5 mm or closer from the urethra. Special caution is indicated in prostates having about 20 cm(3) or smaller volumes, and when (103)Pd is used. Postimplant dosimetry is susceptible to the same errors.

Expedient set-up of tangential breast fields with a simple gantry attachment.

A novel technique for setting up tangential fields is described. The technique uses a simple device (Breast Aligner) which attaches to the collimator of the treatment unit. The function of the Breast Aligner is similar to conventional front and back pointers except that the beam edge rather than central ray is defined. By delineating beam entrance and exit points at the posterior field edge, the device greatly simplifies and expedites set-up, and enhances precision of port alignment. Additional advantageous features include: (a) the ability to compensate for small inadvertent variations from the initial set-up position or for patient movement between the set-up of opposing ports, (b) the ability to visually check port alignment in the treatment position immediately before irradiation, and (c) decreased chance of human and equipment error by eliminating the need for measurements and calculations at the time of treatment. Our method can be used for SSD or SAD techniques and, with minor adjustment, is applicable for establishment of coplanar cephalad field borders as required at the junction of a supraclavicular field.

Quality assurance system to correct for errors arising from couch rotation in linac-based stereotactic radiosurgery.

PURPOSE: The purpose of this project was the development of a quality assurance (QA) system that would provide geographically accurate targeting for linac-based stereotactic radiosurgery (LBSR). METHODS AND MATERIALS: The key component of our QA system is a novel device (Alignment Tool) for expedient measurement of gantry and treatment table excursions (wobble) during rotation. The Alignment Tool replaces the familiar pencil-shaped pointers with a ball pointer that is used with the field light of the accelerator to indicate alignment of beam and target. Wobble is measured prior to each patient treatment and analyzed together with the BRW coordinates of the target by a spreadsheet. The corrections required to compensate for any imprecisions are identified, and a printout generated indicating the floor stand coordinates for each couch angle used to place the target at isocenter. RESULTS: The Alignment Tool has an inherent accuracy of measurement better than 0.1 mm. The overall targeting error of our QA method, found by evaluating 177 target simulator films of 55 foci in 40 randomly selected patients, was 0.47 +/- 0.23 mm. The Alignment Tool was also valuable during installation of the floor stand and a supplemental collimator for the accelerator. CONCLUSIONS: The QA procedure described allows accurate targeting in LBSR, even when couch rotation is imprecise. The Alignment Tool can facilitate the installation of any stereotactic irradiation system, and can be useful for annual QA checks as well as in the installation and commissioning of new accelerators.

A clinically practical electron cone for the treatment of head and neck cancer.

PURPOSE: The purpose of the work was to develop a practical electron cone and to compare its dosimetry with that of the conventional applicator collimation system. METHODS AND MATERIALS: The electron cone consists of the upper part of a manufacturer-supplied electron applicator and an institution-built rectangular extension tube which produces a 12 cm x 6 cm field at 100 cm SSD while maintaining an air gap of 5 cm between the patient. RESULTS: The compact size of the cone allows electron irradiation without having to reposition the patient after photon treatment. The radiation field is very similar to that of a standard 15 cm x 15 cm applicator with a 12 cm x 6 cm field restricting insert. Radiation leakage at the surface of the special cone is typically less than 1% of the useful beam at dmax. During 12 years of clinical use the special cone proved itself very practical in the treatment of more than 300 patients. CONCLUSION: An electron cone practical for clinical use with dosimetry comparable to the conventional applicator was developed.

Ferromagnetic thermoseeds: suitable for an afterloading interstitial implant.

Previous studies have shown implantable ferromagnetic thermoseeds to be a promising hyperthermia method. However, migration from the implant site and chemical toxicity caused by corrosion of the thermoseed alloy have proven to be potential hazards. These problems could be overcome by placing the thermoseeds into removable catheters similar to those used for afterloading interstitial brachytherapy. As an additional merit, the method would allow convenient combination of heat and radiation therapy. To test the clinical performance of this method, we compared temperature distributions and biologic effects in canine muscle and transmissible venereal tumors for bare thermoseeds and thermoseeds contained within catheters. We found no significant difference in the heating patterns and similar tissue changes when all implants were removed immediately after heating. More severe tissue changes were present around bare thermoseeds that were retained. This suggests that catheters provide a safe and reliable method for thermoseed hyperthermia which would allow convenient combination with interstitial radiation.

Hyperthermia with implanted electrodes: in vitro and in vivo correlations.

Hyperthermia as a treatment for cancer has elicited much recent interest. However, major difficulties persist both in the technology for heating deep-seated tumors, and in thermal dosimetry. We have investigated a heating technique for deep-seated neoplasms that employs an internal implanted electrode and an external electrode to apply radiofrequency current to a tumor mass. The internal electrode consists of an array of stainless steel needles or wires which define a Faraday cage within the tumor, while the external electrode consists of a variety of electrical conductors at the skin surface. Phantom measurements have closely reproduced calculated temperature distributions. The temperature profiles within the volume enclosed by the internal electrode show relatively homogenous heating. Temperature measurements in a rat tumor model have demonstrated that significant heating within such an internal electrode array is easily obtained. The heating may extend some centimeters outside the electrode. Using a dog model we have shown that with such a treatment technique the temperature profiles obtained are reproducible both spatially and temporally. A case report of a clinical application is presented. A 5 cm bronchogenic carcinoma was easily heated without significant heating of the surrounding normal lung, and without apparent toxicity. Such a technique may be applicable to a variety of operable but unresectable neoplasms. The reproducibility and relative homogeneity of heating suggest possible usefulness in combined modality trials.

Pharmacokinetics, immune response, and biodistribution of iodine-131-labeled chimeric mouse/human IgG1,k 17-1A monoclonal antibody.

Pharmacokinetics, immunogenicity, and biodistribution of a 131I-labeled mouse/human chimeric monoclonal antibody (C-17-1A) was studied in six metastatic colon cancer patients. Pharmacokinetics obtained from serum radioactivity or chimera concentration were identical after 5 mCi of 131I-C-17-1A with mean alpha half-lives of 17.6 +/- 2.3 and 19.7 +/- 2.9 and mean beta half-lives of 100.9 +/- 16.1 and 106.4 +/- 14.1 hr, respectively. HPLC analysis documented the monomeric chimeric 17-1A without evidence of immune complexes or free 131I. None of the patients developed antibody after 131I-chimeric 17-1A exposure. Radiolocalization occurred in known areas of disease greater than 4 cm in all patients. The half-life of total-body radioactivity was 58 +/- 7 hr by whole-body counts and 64 +/- 13 hr by urine measurements. Whole-body and bone marrow dose estimates ranged from 0.75-1.03 and 0.76-1.05 rad/mCi, respectively. These studies confirm the prolonged circulation and reduced immunogenicity of chimeric 17-1A versus murine 17-1A. Marrow radiation exposure using antibodies with prolonged circulation is a critical factor in planning for radioimmunotherapeutic applications.

A new type of grid.

A new type of grid is discussed. It is anticipated that it will have the same primary transmission as and will eliminate scatter more efficiently than a conventional linear grid of equal thickness and lead content. The construction of the new type of grid is similar to a conventional one except that the lead strips are arranged in zigzag rather than linear pattern. Geometrically ideal "zigzag" and linear grids were constructed and their performance tested. The scatter transmitted by the ideal zigzag grid was one-half that of the comparable ideal linear grid. The implications regarding the improved scatter-eliminating capabilities of a practical zigzag grid are discussed.

The design and performance of a scanning multiple slit assembly.

A scanning multiple slit assembly (SMSA) has been constructed for the purpose of reducing scatter in medical radiography. The SMSA consists of a series of long, narrow beam-defining slits above the patient that are aligned and synchronously moved with scatter-eliminating slots beneath the patient during an exposure. Evidence, based on measurements of the ratio of scattered-to-primary radiation imaged and radiographs of patients, is presented indicating that such a device is a practical and efficient method of reducing scatter and improving contrast compared to conventional grids. The design considerations and trade-offs associated with the choice of slit width, slit separation distance, and aft slot depth are discussed along with the effect of these parameters on the SMSA's performance. The various problems encountered in obtaining a uniform scan and the manner in which they were handled are also discussed.

Hyperthermia with implanted electrodes.

A general solution is given for the steady state form of the heat conduction equation applied to a simple tumor model which is imagined as being heated by means of electrical currents flowing between metallic electrodes. The model assumes a homogeneous tumor with no bloodflow. The solution for the special case of constant temperature and potential at the surface of the heated volume is examined in detail. The solution shows that there exists, independent of the particular tumor and electrode geometry, a close relationship between the steady state temperature distribution and the electrical potential. Among the more important implications of this relationship are that equipotential surfaces within the heated volume are also isothermal surfaces and that no areas of excessive heat at or near any sharp edges or corners of the electrodes should develop, despite the high electric field intensity. Based on the theory, a procedure is outlined which might greatly facilitate the determination of temperature distributions in phantoms. Finally, the usefulness and the limitations of the theoretical models in clinical hyperthermia are discussed.

Temperature distributions in hyperthermia by electromagnetic induction: a theoretical model for the thorax.

Steady-state temperature solutions to the bioheat equation are presented for magnetic induction heating of a thoracic model consisting of a spherical tumor embedded in lung tissue which is layered by muscle and fatty tissue. Analytical solutions are presented for each of the tissue regions along with their numerical evaluations over a range of physical characteristics, including surface cooling effects. A strong dependence of tumor temperature on size and blood perfusion rate is shown to exist and can be used to optimize treatment parameters. Tendencies of the chest muscles and overlaying fatty tissue to overheat, particularly in the case of an obese patient, are discussed along with the alleviating influence of surface cooling. Healthy lung tissue, on the other hand, is shown to be safe from any significant damage in such a heating situation. Transient times required for tumors to achieve thermal equilibrium are computed and shown to depend strongly on tumor size and, to a lesser extent, on blood perfusion rate. Finally, the overall results obtained from the model are compared with available clinical data and are found to be in line with those observations.

Temperature distributions in tumor models heated by self-regulating nickel-copper alloy thermoseeds.

Needle-shaped thermoseeds have been manufactured from an alloy consisting of 70.4% nickel and 29.6% copper. The magnetic properties of the alloy were measured at various temperatures and from this the heating power produced by a thermoseed exposed to an electromagnetic induction field was computed as a function of the seed temperature. Calorimetric measurements were also performed. From these data, temperature distributions in simple tumor models assumed to be heated by an array of nickel-copper implants were computed. It was found that the nickel-copper implants produce substantially better temperature homogeneity than readily available constant power seeds, especially in tumors with unpredictable rates of blood perfusion or when the implant arrangement is not perfectly regular. Since such conditions are likely to be present in actual patients, the nickel-copper implants should be very useful in clinical hyperthermia.

Real-time monitoring and verification of in vivo high dose rate brachytherapy using a pinhole camera.

We investigated a pinhole imaging system for independent in vivo monitoring and verification of high dose rate (HDR) brachytherapy treatment. The system consists of a high-resolution pinhole collimator, an x-ray fluoroscope, and a standard radiographic screen-film combination. Autofluoroscopy provides real-time images of the in vivo Ir-192 HDR source for monitoring the source location and movement, whereas autoradiography generates a permanent record of source positions on film. Dual-pinhole autoradiographs render stereo-shifted source images that can be used to reconstruct the source dwell positions in three dimensions. The dynamic range and spatial resolution of the system were studied with a polystyrene phantom using a range of source strengths and dwell times. For the range of source activity used in HDR brachytherapy, a 0.5 mm diameter pinhole produced sharp fluoroscopic images of the source within the dynamic range of the fluoroscope. With a source-to-film distance of 35 cm and a 400 speed screen-film combination, the same pinhole yielded well recognizable images of a 281.2 GBq (7.60 Ci) Ir-192 source for dwell times in the typical clinical range of 2 to 400 s. This 0.5 mm diameter pinhole could clearly resolve source positions separated by lateral displacements as small as 1 mm. Using a simple reconstruction algorithm, dwell positions in a phantom were derived from stereo-shifted dual-pinhole images and compared to the known positions. The agreement was better than 1 mm. A preliminary study of a patient undergoing HDR treatment for cervical cancer suggests that the imaging method is clinically feasible. Based on these studies we believe that the pinhole imaging method is capable of providing independent and reliable real-time monitoring and verification for HDR brachytherapy.

In vivo urethral dose measurements: a method to verify high dose rate prostate treatments.

Radiation doses delivered in high dose rate (HDR) brachytherapy are susceptible to many inaccuracies and errors, including imaging, planning and delivery. Consequently, the dose delivered to the patient may deviate substantially from the treatment plan. We investigated the feasibility of using TLD measurements in the urethra to estimate the discrepancy in treatments for prostate cancer. The dose response of the 1 mm diam, 6 mm long LiF rods that we used for the in vivo measurements was calibrated with the 192Ir HDR source, as well as a 60Co teletherapy unit. A train of 20 rods contained in a sterile plastic tube was inserted into the urethral (Foley) catheter for the duration of a treatment fraction, and the measured doses were compared to the treatment plan. Initial results from a total of seven treatments in four patients show good agreement between theory and experiment. Analysis of any one treatment showed agreement within 11.7% +/- 6.2% for the highest dose encountered in the central prostatic urethra, and within 10.4% +/- 4.4% for the mean dose. Taking the average over all seven treatments shows agreement within 1.7% for the maximum urethral dose, and within 1.5% for the mean urethral dose. Based on these initial findings it seems that planned prostate doses can be accurately reproduced in the clinic.

Practical aspects of ferromagnetic thermoseed hyperthermia.

Thermoseeds are needle-shaped devices that are interstitially placed into tumors, similar to brachytherapy implants. Heating is accomplished by an externally applied electromagnetic induction field, requiring no connections to an external power source. Thermoseeds made of special alloys provide automatic temperature control. Therapeutic efficacy has been demonstrated in initial clinical applications.

An investigation and explanation of the fall-off of x-ray tube current during an exposure.

It was observed that the radiation output of x-ray tubes falls off exponentially during an exposure with a time constant of about 120 ms. The equilibrium value is approximately 15% lower than that at the beginning of the exposure. The clinically noticeable consequences are discrepancies in x-ray generator calibration, the loss of the strict mA s (tube current X exposure time) linearity, and, in scanning devices, the possibility of artefact generation. A systematic investigation of the phenomenon revealed that it is caused by the cooling of the cathode due to evaporation of electrons. Theoretical expressions for the magnitude and time constant of the fall-off derived from basic thermodynamics are in good agreement with the observations. A simple mA stabilisation circuit which prevents the fall-off is described.