Keeping those telomeres short! an innovative intratumoral long-term drug delivery system.

BACKGROUND: Telomerase activation and an alternative lengthening of telomeres (ALT) mechanism are two telomere-lengthening cancer cell survival mechanisms elicited by both chemo- and/or radiotherapy. Telomere lengthening interferes with cell lethality and results in the immortalization of cancer cells. To counteract these mechanisms, we developed a drug delivery system (DDS) consisting of a polymeric implant that is inserted directly into tumors. The DDS releases, continuously and gradually, a cationic porphyrin (PdTMPyP4) for >30 days after a single application, and inhibits telomerase activation. METHODS: The PdTMPyP4 porphyrin is incorporated into a poly(co-glycolic lactic)acid (PLGA) polymer, solidified and cut into small rods. PdTMPyP4 release from the rods was measured spectrophotometrically over time. Uptake of Pd in the DNA of in L428 Hodgkins lymphoma cells was measured by ICP-MS, and telomerase activation by the TRAP assay. The rods were placed into the growth medium of cells whose growth rate was measured for 11 and 19 days. The cylinders were also inserted directly into KHJJ murine mammary tumors borne on the thighs of BALB/c mice and the tumor growth rate measured. RESULTS: In vitro, >10(9)Pd atoms were measured in the DNA of each L428 cell and telomerase activity was reduced by ~15% within 24 h. A one-time application of the rod in the cell medium induced a factor of >5 greater lethality compared to a blank rod or untreated controls. In vivo, a one-time insertion of the rod into tumors resulted in the retardation of the growth rate by factors of 3-5 compared to untreated controls. Systemic uptake after intratumoral insertion of the rod was negligible. CONCLUSION: The results suggest that the direct intratumoral insertion of a PdTMPyP4-containing polymeric rod would be of benefit as an adjuvant treatment for patients undergoing chemo- or radiotherapy. By preventing the lengthening of telomeres and therefore the unrestricted growth of cancer cells, our DDS will provide a significant therapeutic advantage to these treatments without affecting normal tissues.

Samarium-153 EDTMP for metastatic bone pain palliation: the impact of europium impurities.

PURPOSE: To evaluate the impact on the radiation protection policies of the radiocontaminants in Samarium-153 ethylenediamine tetramethylene phosphonate ((153)Sm-EDTMP). METHODS: The internal contamination of patients treated with (153)Sm-EDMTP for palliation of painful disseminated multiple bone metastases due to long-lived impurities was assessed by direct measurements. These measurements were coupled with dose-rate measurements close to their bodies and spectroscopic analysis of the residual activity in post-treatment radiopharmaceutical vials. RESULTS: Whole-body counting carried out in six patients showed a 30-81-kBq europium -152 plus europium-154 contamination. The 0.85 mean (152)Eu- to -(154)Eu activity ratio obtained by direct counting was similar to that assessed by analysis of post-treatment residual activities in twelve radiopharmaceutical vials following radiopharmaceutical injection. CONCLUSIONS: The long-lived radiocontaminants in the patient's bodies and the treatment wastes require modifications of the applicable radiation protection policies.

Thermochromic phase-transitions of GafChromic films studied by z-scan and temperature-dependent absorbance measurements.

PURPOSE: Upon irradiation the active diacetylene layer of radiochromic films undergoes dose-dependent polymerization in the blue polydiacetylene form. Dose assessment is currently based on linear absorbance measurements. The scope of the present study was designed for the further understanding of the linear and, in particular, the nonlinear optical characteristics of such films and the utilization of these characteristics for devising alternative "reading" procedures. METHODS: The nonlinear optical interactions of laser light with previously irradiated GafChromic(®) HD-810 and MD55-2 films were studied by z-scan techniques. The focused laser beam strikes on the film, which is located at various distances from the focal spot. The beam induces linear and nonlinear absorption and refraction. The measurement of the transmitted power (open-aperture z-scan) allows the study of the nonlinear absorption. On the other hand, the measurement of the axial region of the transmitted beam (closed-aperture z-scan) is related to both nonlinear absorption and refraction effects. A 10 mW, 633 nm, linearly polarized He/Ne laser was employed as the light source. The transmittance measurements were coupled with absorbance measurements carried out over the whole visible spectrum and at various reading temperatures, in an attempt to clarify the underlying mechanisms dictating the observed effects. These effects were incorporated to an open-aperture z-scan model, developed for the purpose of comparison to the corresponding experimental curves. RESULTS: The transmittance data obtained by both open- and closed-aperture z-scan were found to be dose-dependent, thus allowing such transmittance techniques to be employed for dose assessment. Low power open-aperture z-scan measurements (sensitive to absorptive nonlinearities) revealed a stepwise two-photon excitation of the active layer, through an intermediate state. At higher laser intensities (and/or absorbed dose), the shapes of the z-scan curves were found to be more complicated. These shapes were attributed to a temperature-dependent (thermochromic) transition from the blue form to the conformer red form of the active material, a transition which appears to be irreversible at high intensities. This transition was incorporated into the open-aperture z-scan model which reproduced satisfactorily the corresponding experimental curves. Finally, the use of a chopped laser beam in the closed-aperture z-scan technique allowed artifact-free, high spatial resolution dose measurements using a laser beam of relatively high power. CONCLUSIONS: The model developed in the present study elucidates some of the effects related to film reading and the causes of some of the artifacts reported in the literature. Two-dimensional dose distributions can be assessed by z-scan; however, the merits of such a technique relative to those currently in use have to be further investigated.

Endovascular abdominal aortic aneurysm repair: methods of radiological risk reduction.

AIM: The management of abdominal aortic aneurysm with endovascular repair (EVAR) requires extended exposure to ionizing radiation, before, during and after the intervention. The aim of this study was to quantify the radiological risks to patients and operating team, and to develop strategies to assess and reduce them. METHODS: EVAR was carried out in 97 patients using either a low-power mobile or a high-power stationary fluoroscopic unit. Empirically determined relationships between the indicated dose area product (DAP) and peak skin dose, obtained by direct in vivo dosimetry in a subgroup of patients, were used to predict the peak skin dose. Individual worker monitoring was used to assess personnel radiological burden. RESULTS: The probability for radiation induced biological effects due to the repair itself and the preoperative and life-long surveillance, as carried out, was about 2.4 10-3. The peak skin dose of repairs was linearly correlated with the DAP and did not exceed 1.2 Gy. The collective effective dose of the staff that carried out repairs using the mobile unit was 5.5 and 8 µSv per repair using an angiographic and a surgical table, respectively. The use of the high-power fluoroscopic unit resulted in a many fold higher radiation burden to both patient and personnel. CONCLUSION: The optimum strategy, including equipment-related factors, procedure-conduct factors and follow-up procedures, has to be studied, justified and optimized in each medical facility.

A high-sensitivity multidetector whole-body counter.

A prototype multidetector shadow-shield whole-body counter is presented to be used as a monitor of internal contamination and as a tool in clinical research. The counter is equipped with 16 NaI(Tl) detectors located in the central region of a shielded tunnel surrounding the subject to be measured. The accuracy of the counting efficacy predictions was tested in a group of adults with various body shapes and sizes using X-ray absorptiometry. The precision of the total body potassium measurements allows the use of the counter in clinical follow-up studies.

Educational and training activities in personal dosimetry in Greece.

An individual monitoring programme is one of the main components of any radiation protection programme since it constitutes the mean for assessing and thus optimising the doses of occupationally exposed workers. The Greek Atomic Energy Commission (GAEC) is the competent authority for radiation protection and nuclear safety in Greece. GAEC's educational and training activities in the field of occupational radiation protection at the national and regional (Eastern Europe) level are presented, along with the relevant activities of the University of Ioannina in the region of North-West Greece, as an example of a local education and training programme. The curricula of two postgraduate courses addressed to qualified experts and medical physics experts and mainly the modules dedicated to individual monitoring are discussed as well.

Age at menarche, age at menopause and duration of fertility as risk factors for osteoporosis.

OBJECTIVE: To investigate the relationship of osteopenia and osteoporosis in apparently healthy postmenopausal patients with age at menarche, age at menopause and duration of fertility. PATIENTS AND METHODS: One hundred and twenty-four apparently healthy Greek postmenopausal women underwent spinal and hip X-ray absorptiometry scans. Among them, 47 were classified as normal (control group), 52 as osteopenic, and 25 as having osteoporosis. These groups were compared according to their age at menarche (three subgroups of 10-12, 13 and 14-16 years old), at menopause (three subgroups of 40-45, 46-50 and > or = 51 years old) and duration of fertility (four subgroups of < or = 30, 31-35, 36-40 and 41-45 years). RESULTS: The groups were not found to differ statistically according to age and age at menarche. However, decreased bone mineral density was found in patients with duration of fertility not exceeding 30 years (p = 0.034) and age at menopause less than 45 years (p = 0.034). No association was found between bone mineral density in Greek postmenopausal women and either number of live births or lactation. CONCLUSIONS: In postmenopausal females, the cumulative exposure to endogenous estrogens, measured as years of menstruation, seems to be a significant protective factor against the development of postmenopausal osteoporosis. Age at menopause between 40 and 45 years, but not age at menarche, correlated with low bone mineral density in postmenopausal females.

Radiochromic film dosimetry: reflection vs transmission scanning.

The objective of this study was to compare the transmission and the reflection scanning reading modes of radiochromic MD-55 films of a document scanner. The use of the red channel of the red-green-blue images results in measurement accuracy that did not differ between the two reading modes. On the other hand, the scanner uniformity and temporal stability, the long-term stability of the film readings and the dynamic range is superior using the reflection mode. The dynamic range of dose measurements can be extended up to least 500 Gy using the alternative color channels by both reading techniques. Similar backscattering dose factors close to high Z inhomogeneities were found using both scanning modes. In conclusion, the use of reflection scanning mode of MD55 films was superior to the traditionally used transmission mode.

Evolution of a focal brain lesion produced by interlaced microplanar X-rays.

Stereotactic radiosurgery has led to advances in the treatment of central nervous system disease. It relies upon the principle of delivering relatively high dose irradiation to a precise target, while exposing surrounding tissues to extremely low doses. We describe a novel radiosurgical approach using interlaced microplanar X-rays which we have termed "microradiosurgery." The use of microbeams allows for 1,000-times greater precision than current clinically employed techniques. As a demonstration of this new method, we produced a approximately 3.8 mm (3) lesion in the rat brain. The lesion was followed over a period of 216 days using 9.4 Tesla magnetic resonance imaging. Our results show a gradually developing lesion at the site of the interlaced beams. The lesion began as a high T2 signal only, but advanced to include a central area of low T1 and mixed T2 signal within 2 months. No lesion was observed in the other side of the brain which was exposed to non-interlaced microbeams only. Interlaced microbeams is an effective method to create focal brain microlesions. This technique may allow the future treatment of pathology not accessible by surgical or more traditional radiosurgical means.

Multi-detector row CT urography on a 16-row CT scanner in the evaluation of urothelial tumors.

The purpose of this study was to assess the role of multi-detector row CT urography (MDCTU), on a 16-row CT scanner in the evaluation of patients with painless hematuria, with emphasis placed in the detection of urothelial tumors. We retrospectively reviewed the MDCT urographies of 75 patients, referred for painless hematuria. The CT protocol included unenhanced images, obtained with a detector configuration of 16x1.5 mm and pitch of 1.2, nephrographic and excretory-phase images, obtained with a detector collimation of 16x0.75 mm and pitch of 1.2. Axial and coronal reformatted images were evaluated. Three-dimensional reformation of the excretory-phase images was performed using the volume-rendering technique. The standard of reference included clinical and imaging follow-up, cystoscopic, surgical and histologic findings. In 55 (73%) of 75 patients, the cause of hematuria was identified on MDCTU; the most common cause was urothelial cancer, including seven tumors with a diameter equal or smaller than 0.5 cm in diameter. Sixteen-row MDCTU provided satisfactory results in the investigation of patients with painless hematuria. The main advantage of the technique is its ability to detect uroepithelial malignancies.

Patient and personnel dosimetry in endovascular radiotherapy with 90Sr/90Y sources.

Endovascular brachytherapy (EVBT) is an established treatment to reduce the probability of restenosis after a percutaneous coronary intervention. The purpose of this study was to assess (1) the manufacturer's stated dosimetric data for (90)Sr/(90)Y source trains to be used in EVBT and (2) the procedure-related radiation burden. The radiation fields in water around six (90)Sr/(90)Y source trains were studied using phantoms made of 'solid water' and MD55-2 radiochromic films. The water equivalence of the phantom material was tested by applying quantitative computed tomography. Thermoluminescence dosemeters were used to assess personal radiation burden and crosscheck the dose distribution along the source trains. Technical failure was observed in one source train and this train was excluded from analysis. The measured dose rate in water at 2 mm radial distance was on average 8% higher than the manufacture's stated value (range of measured to stated values 1.05--1.15). The dose rate decreased exponentially with radial distance between 2 and 6 mm. The dose rate in contact with the source viewing window of the delivery devices ranged between 0.5 and 7.5 mGy h(-1). Low-energy photons were the main contributors to personal dose.

Computed tomographic virtual cystoscopy for the detection of urinary bladder neoplasms.

OBJECTIVE: To evaluate the role of computed tomographic virtual cystoscopy (CTVC) in the detection of bladder neoplasms and to compare CTVC at conventional and reduced milliAmperes-second (mAs) settings. METHODS: Twenty-four patients with known bladder neoplasms from previous conventional cystoscopy were examined with CTVC. The urinary bladder was insufflated with room air and helical CT data were obtained. Virtual images were created using volume rendering algorithms. In eight patients we used both regular (240) and reduced (70) mAs values. The lesions were recorded on transverse tomographic slices and virtual images and compared with conventional cystoscopy, operative and pathology results. RESULTS: All bladder lesions (30) seen on conventional cystoscopy were demonstrated with CTVC. Two lesions detected on imaging studies and subsequently found at operation were not seen on conventional cystoscopy. In a third case of a neobladder, conventional cystoscopy was impossible due to neoplastic involvement of the penis. In all cases the lesions were equally conspicuous with conventional and low mAs values. CONCLUSIONS: Computed tomographic virtual cystoscopy is a minimally invasive technique that can provide comprehensive information about urinary bladder tumors. Furthermore, low mAs studies are equally effective for the examination of such patients.

Prompt-gamma neutron activation analysis facility for in vivo body composition studies in small animals.

The design, calibration, dosimetry and performance evaluation of a prompt-gamma neutron activation analysis facility for in vivo body composition studies in small animals (i.e. rats or rabbits) is discussed. The system design was guided by Monte Carlo transport calculations using MCNP-4C code. A system was built and performance evaluation was made using a 185-GBq Pu-Be neutron source. Prompt-gamma rays produced by neutron capture reactions were detected by a combination of a NaI(Tl) scintillation and a HPGe semiconductor detectors. Nitrogen and chlorine were quantified by analysis of the 10.83-MeV and 6.11-MeV peaks, respectively. Appropriate corrections for the animal body size were determined. The facility described allows the in vivo determination of protein and extracellular space in sets of experimental animals.

Effects of delayed (24 h postintervention) beta-irradiation therapy after coronary angioplasty and stenting in de novo native coronary artery lesions; Results of a randomized clinical and intravascular ultrasound study.

BACKGROUND: The effects of brachytherapy performed 24 h postintervention in de novo native coronary artery lesions. METHODS AND RESULTS: Thirty-nine patients with 39 de novo coronary artery lesions were randomised to prompt (immediately after intervention, n=21) or delayed (24 h later, n=18) beta brachytherapy ((90)Sr/(90)Y) after been successfully revascularized with stenting. Clinical follow-up data up to 21 months (median time) were compared. After irradiation and at 6-month follow-up, paired volumetric analysis of the stented segment and the 5-mm proximal and distal reference segments was performed; this included measurements of the external elastic membrane, lumen, plaque, and media (external elastic membrane minus lumen), stent and intima hyperplasia (stent minus lumen). Baseline clinical and angiographic characteristics were similar in the two groups. Postintervention measurements of stent, lumen, and intima hyperplasia volumes as well as postintervention minimum lumen cross-sectional areas were not different. In the stented segments and in the segments 5 mm proximal and distal to the stent, similar changes of all IVUS measurements were measured in the two patient groups, but in the lumen volume at the proximal stent edge of patients irradiated 24 h postinjury. At 21 months median follow-up time, target lesion revascularization (TLR) was performed in 8 patients (38%) in the prompt irradiation group compared with 3 (17%) in the delayed (P=.17). CONCLUSION: Beta irradiation is similarly effective whether performed immediately after percutaneous coronary intervention or 24 h later.

Could X-ray microbeams inhibit angioplasty-induced restenosis in the rat carotid artery?

BACKGROUND: Parallel, thin (<100 microm) planes of synchrotron-generated X rays, have been shown to spare normal tissues and preferentially damage tumors in animal models. The aim of the present study was to assess the effect of such microbeams directed unidirectionally on angioplasted rat carotid arteries. METHODS AND MATERIALS: Three groups of Sprague-Dawley rats were studied: (a) rats with normal, untreated arteries, (b) rats treated by balloon angioplasty, but not irradiated, and (c) rats treated with balloon angioplasty and exposed to single fraction, unidirectional, parallel, microbeams an hour after angioplasty. The microbeam array, 15 mm widex7.6 mm high, consisting of 27-microm-wide beam slices, spaced 200 microm center-to-center laterally traversed the damaged artery. The in-depth in-beam dose was 150 Gy, the "valley" dose (dose midway between microbeams resulting mainly from X-ray scattering) was 4.5 Gy on average, and the "integrated" (averaged) dose was 26 Gy. RESULTS: Microbeam irradiation, as given in the present study, was tolerated, but was insufficient to significantly suppress the neointimal hyperplasia. DISCUSSION: The microbeam dose used is considered low. Dose escalation would be necessary to reach conclusive results regarding the X-ray microbeam efficacy to control restenosis.

External beam irradiation in angioplasted arteries of hypercholesterolemic rabbits. The dose and time effect.

PURPOSE: To study the dose and time effect of external beam irradiation on the morphometry of both angioplasted and nonangioplasted arteries in a hypercholesterolemic rabbit model. METHODS AND MATERIALS: Eight groups of rabbit femoral arteries were studied: arteries (a) with no intervention, (b) irradiated with a 12-Gy 6 MV X-ray dose, (c) with a 18-Gy, (d) treated with balloon angioplasty, (e) dosed with 12-Gy half an hour post-angioplasty, (f) dosed with 18-Gy half an hour post-angioplasty, (g) dosed with 12-Gy 48 h post angioplasty, (g) dosed with 18-Gy 48 h post angioplasty. RESULTS: External irradiation at either 12 or 18 Gy was not found to change vessel morphometry in noninjured arteries. The 12-Gy dose given soon after angioplasty further increased percentage stenosis (63% on the average), despite the preservation of the lumen cross-sectional area. Positive remodeling was not observed in arteries given 18-Gy half an hour post angioplasty to counterbalance the increased neointimal formation. Therefore, this treatment resulted in a drastic reduction in lumen area and in enhancement of percentage stenosis (84% on the average). On the contrary, the delayed irradiation of the angioplasted arteries at either 12 or 18 Gy was not found to influence any of the studied morphometric parameters 5 weeks after angioplasty. CONCLUSIONS: Uniform external beam irradiation up to 18 Gy was well tolerated by intact femoral arteries. Prompt 12- or 18-Gy irradiations accentuated percentage stenosis. However the lumen cross-sectional area was preserved only at the lower dose point. Delayed irradiation at any dose did not influence the restenosis process.

Thermoluminescence dosimetry for quality assurance in radiation therapy.

A methodology based on thermoluminescence dosimetry was developed to check the output of teletherapy units and the given doses. It was applied in a hospital as a part of an extemal quality audit programme. Over a 7 year period the mean ratios of the output doses measured by TLDs calibrated free-in-air to the doses measured at the hospital in a 6 MV X ray and in a 60Co unit were 1.000 +/- 0.024 (n = 86) and 0.997 +/- 0.027 (n=61), respectively. TLDs in capsules were attached to the patient's body or to a phantom to assess entrance, exit and midline doses and transmission. Factors were determined experimentally to relate the doses measured with TLDs in capsules and inside the body. The accuracy in given doses with pelvic and tangential breast fields and assessed via 752 in vivo measurements, was considered to be adequately good, taking into account the limitations of the equipment available in the hospital.

Dosimetry with radiochromic films: a document scanner technique, neutron response, applications.

The possibility of reading radiochromic films by the employment of a document scanner and associated software was explored. Dosimetric characteristics, such as the sensitivity of the technique, reproducibility in dose assessment, minimum detectable dose, film uniformity, OD variation with time, variation of OD due to multiple scans, polarity of the analyzing light, fast neutron response and thermal neutron yield were investigated. The technique was used to measure dose distributions in stereotactic radiotherapy, orthovoltage treatment and neutron capture therapy.

Response of avian embryonic brain to spatially segmented x-ray microbeams.

Duck embryo was studied as a model for assessing the effects of microbeam radiation therapy (MRT) on the human infant brain. Because of the high risk of radiation-induced disruption of the developmental process in the immature brain, conventional wide-beam radiotherapy of brain tumors is seldom carried out in infants under the age of three. Other types of treatment for pediatric brain tumors are frequently ineffective. Recent findings from studies in Grenoble on the brain of suckling rats indicate that MRT could be of benefit for the treatment of early childhood tumors. In our studies, duck embryos were irradiated at 3-4 days prior to hatching. Irradiation was carried out using a single exposure of synchrotron-generated X-rays, either in the form of parallel microplanar beams (microbeams), or as non-segmented broad beam. The individual microplanar beams had a width of 27 microm and height of 11 mm, and a center-to-center spacing of 100 microm. Doses to the exposed areas of embryo brain were 40, 80, 160 and 450 Gy (in-slice dose) for the microbeam, and 6, 12 and 18 Gy for the broad beam. The biological end point employed in the study was ataxia. This neurological symptom of radiation damage to the brain developed within 75 days of hatching. Histopathological analysis of brain tissue did not reveal any radiation induced lesions for microbeam doses of 40-160 Gy (in-slice), although some incidences of ataxia were observed in that dose group. However, severe brain lesions did occur in animals in the 450 Gy microbeam dose groups, and mild lesions in the 18 Gy broad beam dose group. These results indicate that embryonic duck brain has an appreciably higher tolerance to the microbeam modality, as compared to the broad beam modality. When the microbeam dose was normalized to the full volume of the irradiated tissue. i.e., the dose averaged over microbeams and the space between the microbeams, brain tolerance was estimated to be about three times higher to microbeam irradiation as compared with broad beam irradiation.

Boron neutron capture therapy of a murine mammary carcinoma using a lipophilic carboranyltetraphenylporphyrin.

The first control of a malignant tumor in vivo by porphyrin- mediated boron neutron capture therapy (BNCT) is described. In mice bearing implanted EMT-6 mammary carcinomas, boron uptake using a single injection of either p-boronophenylalanine (BPA) or mercaptoundecahydrododecaborane (BSH) was compared with either a single injection or multiple injections of the carboranylporphyrin CuTCPH. The BSH and BPA doses used were comparable to the highest doses of these compounds previously administered in a single injection to rodents. For BNCT, boron concentrations averaged 85 microg (10)B/g in the tumor and 4 microg (10)B/g in blood 2 days after the last of six injections (over 32 h) that delivered a total of 190 microg CuTCPH/g body weight. During a single 15, 20, 25 or 30 MW-min exposure to the thermalized neutron beam of the Brookhaven Medical Research Reactor, a tumor received average absorbed doses of approximately 39, 52, 66 or 79 Gy, respectively. A long-term (>200 days) tumor control rate of 71% was achieved at a dose of 66 Gy with minimal damage to the leg. Equivalent long-term tumor control by a single exposure to 42 Gy X rays was achieved, but with greater damage to the irradiated leg.