Study of myocardial cell inhomogeneity of the human heart: Simulation and validation using polarized light imaging.

PURPOSE: The arrangement or architecture of myocardial cells plays a fundamental role in the heart's function and its change was shown to be directly linked to heart diseases. Inhomogeneity level is an important index of myocardial cell arrangements in the human heart. The authors propose to investigate the inhomogeneity level of myocardial cells using polarized light imaging simulations and experiments. METHODS: The idea is based on the fact that the myosin filaments in myocardial cells have the same properties as those of a uniaxial birefringent crystal. The method then consists in modeling the myosin filaments of myocardial cells as uniaxial birefringent crystal, simulating the behavior of the latter by means of the Mueller matrix, and measuring the final intensity of polarized light and consequently the inhomogeneity level of myocardial cells in each voxel through the use of crossed polarizers. The method was evaluated on both simulated and real tissues and under various myocardial cell configurations including parallel cells, crossed cells, and cells with random orientations. RESULTS: When myocardial cells run perfectly parallel to each other, all the polarized light was blocked by those parallel myocardial cells, and a high homogeneity level was observed. However, if myocardial cells were not parallel to each other, some leakage of the polarized light was observed, thus causing the decrease of the polarized light amplitude and homogeneity level. The greater the crossing angle between myocardial cells, the smaller the amplitude of the polarized light and the greater the inhomogeneity level. For two populations of myocardial cell crossing at an angle, the resulting azimuth angle of the voxel was the bisector of this angle. Moreover, the value of the inhomogeneity level began to decrease from a nonzero value when the voxel was not totally homogeneous, containing for example cell crossing. CONCLUSIONS: The proposed method enables the physical information of myocardial tissues to be estimated and the inhomogeneity level of a volume or voxel to be quantified, which opens new ways to study the microstructures of the human myocardium and helps understanding how heart diseases modify myocardial cells and change their mechanical properties.

Treatment delays using an automated afterloading low-dose-rate brachytherapy system.

PURPOSE: Low-dose-rate (LDR) brachytherapy is an integral treatment modality in radiation oncology. Clinical efficacy is based on experience with manual source loading and continuous dose delivery. With remote afterloading technology, sources may be loaded and unloaded during the treatment course to prevent radiation exposure to nursing staff members and visitors. The aim of this study was to investigate treatment interruptions in terms of frequency and duration as well as extension of the overall treatment time period. The potential clinical impact of treatment interruptions was also considered. MATERIALS AND METHODS: The treatment records of 20 patients who underwent brachytherapy in the Indiana University Department of Radiation Oncology administered with a Selectron LDR remote afterloader were reviewed. Results were tabulated and analysis performed with respect to 1) the number of interruptions, 2) delay time, 3) delay time (T(d)) as a function of total implant time (T), 4) the time of day that each interruption occurred, and 5) the time in minutes of each individual interruption. RESULTS: The mean number of interruptions was 44.9 per patient, (range, 24-76), with a mean prescription implantation duration of 45.7 hours and a mean actual treatment time of 51.2 hours resulting in a mean interruption time of 6.4 minutes per treatment hour. The number of interruptions was standardized and divided by the number of prescribed dose in grays, translating to 1.2 to 3.7 interruptions per gray delivered, with a mean of 1.6, resulting in an average T(d) of 11.21% (range, 7.35%-17.12%). CONCLUSION: Significant interruptions are frequent using remote afterloading LDR techniques, reducing the effective dose rate. Careful monitoring of such interruptions is warranted.

Update from the GHMonitorSM observational registry in children treated with recombinant human growth hormone (Saizen).

Since 2003, the GH MonitorSM, an observational registry, has collected data on pediatric subjects treated with Saizen (recombinant human growth hormone (r-hGH)) in the United States and Canada. This article provides an update on the demographic characteristics of subjects enrolled in the GHMonitorSM Registry. As of August 2007, 1733 subjects were enrolled (68.9% male). The most common primary diagnosis at screening was idiopathic growth hormone deficiency (56.5% of subjects).Of those subjects with available data, mean height standard deviation (SD) score was -2.1+/-1.0, mean weight SD score was -1.4+/-1.5, and mean body mass index SD score was -0.1+/-1.3. Among subjects in whom the presence or absence of other pituitary hormone deficiencies was recorded, 16.1% had multiple pituitary hormone deficiencies. Most patients reported high compliance with therapy (92.6% missed 0-3 doses per month); compliance was similar for all delivery devices (needle/syringe, cool.clickTM or one.clickTM) used. Two serious adverse events related to Saizen (hospitalization for placement of right frontal ventriculostomy and right frontal craniotomy for transcallosal resection of a large recurrent craniopharyngioma and left slipped capitofemoral epiphysis that required pinning of the right hip) were reported in the period from August 2006 to August 2007. This update of the GHMonitorSM Registry continues to provide insight into the characteristics of children treated with this agent and continued evidence of the efficacy and safety of Saizen in children.

Issues and trends in pediatric growth hormone therapy--an update from the GHMonitor observational registry.

The GHMonitor observational registry collates data on pediatric subjects receiving Saizen (recombinant human growth hormone (GH)) therapy. From January 2003 through August 2006, 1335 subjects were enrolled in the registry, approximately two-thirds of whom are male. The most common diagnosis in the registry is idiopathic growth hormone deficiency (58%). Most subjects in GHMonitor are receiving Saizen doses using a needle-free delivery device, the cool.click (73%). Mean height standard deviation scores show an improvement from -2.1 at screening to -1.1 following 3 years of Saizen therapy. To date, adverse events have been reported in 4% of subjects. Three serious adverse events were identified to be related to Saizen by the primary investigator: cellulitis at the injection site, behavioral problems/suicidal ideation, and enlargement of a craniopharyngioma. This article provides an update on data from the registry and briefly discusses topical and controversial issues in the treatment of pediatric patients requiring GH therapy.

Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years.

CONTEXT: The process of epiphyseal fusion during puberty is regulated by estrogen, even in males. OBJECTIVE: Our objective was to investigate whether anastrozole, a potent aromatase inhibitor, could delay bone age acceleration and increase predicted adult height in adolescent boys with GH deficiency. METHODS: Fifty-two adolescent males with GH deficiency treated with GH were randomized to cotreatment with anastrozole or placebo daily for up to 36 months. RESULTS: Fifty subjects completed 12 months, 41 completed 24 months, and 28 completed 36 months. Linear growth was comparable between groups; however, there was a significantly slower increase in bone age advancement from baseline in the anastrozole group vs. placebo group after 2 yr (+1.8+/-0.1 vs. +2.7+/-0.1 yr, P<0.0001) and after 3 yr (+2.5+/-0.2 vs. +4.1+/-0.1 yr, P<0.0001). This resulted in a net increase in predicted adult height of +4.5+/-1.2 cm in the anastrozole group at 24 months and +6.7+/-1.4 cm at 36 months as compared with a 1-cm gain at both time points in the placebo group. Estradiol and estrone concentrations increased less in the anastrozole group compared with placebo group. All boys on the aromatase inhibitor had normal tempo of virilization. Safety data, including glucose, and plasma lipid concentrations were comparable between groups. CONCLUSIONS: Anastrozole increases adult height potential of adolescent boys on GH therapy while maintaining normal pubertal progression after 2-3 yr. This treatment offers an alternative in promoting growth in GH-deficient boys in puberty. Long-term follow up is needed to elucidate fully the safety and efficacy of this approach.

The role of Gamma Knife Radiosurgery in the management of unresectable gross disease or gross residual disease after surgery in ependymoma.

PURPOSE/OBJECTIVE: To evaluate the efficacy and the toxicity of Gamma Knife (GK)-based stereotactic radiosurgery (SRS) in the management of gross disease in ependymoma. MATERIALS AND METHODS: Eight patients with 13 ependymomas were treated with GK-based SRS in our institution for gross disease. Five patients were treated for recurrent disease that developed after surgery and external beam radiotherapy (EBRT), two received SRS to the gross disease after surgery and EBRT, and one received SRS alone (in a 1.3 year old child). Median EBRT dose was 54.4 Gy (range 50-55.8 Gy). Median SRS dose was 14 Gy (range 12-20 Gy). Seven of eight (87.5%) patients had SRS to a single lesion and one of eight (12.5%) patients had treatment to six tumors in three different sessions. RESULTS: The median follow up was 30.2 months (range 8-65.4 months). Out of the eight patients treated with SRS, six (75%) were alive, four (50%) were alive with no recurrence, two (25%) were alive with recurrence, and two (25%) died of recurrent disease. Both patients treated with SRS as a boost were alive and without recurrence. Out of the five patients who received SRS as salvage treatment, three (60%) were alive, two (40%) were alive without recurrence, two (40%) developed distant failure, and three (60%) had in-field control. Two patients who received SRS to their brainstem lesions developed symptoms related to radionecrosis and were successfully treated with steroid with good control of symptoms. CONCLUSIONS: GK-based SRS appears to be a feasible and safe treatment modality for patients with ependymoma with unresectable gross disease or gross residual disease after surgery. SRS provides reasonable local control but out-of-field tumor progression remains an issue. For patients who receive SRS as a boost, the local control appears to be excellent.

Evaluation of underdosage in the external photon beam radiotherapy of glottic carcinoma: Monte Carlo study.

PURPOSE: Underdosage in the human larynx may be the true factor behind the decrease in local control rates. PATIENTS AND METHODS: To evaluate underdosage with Monte Carlo a CT-based geometrical model of the patient's neck (mathematical neck) was created. Dose was calculated for a pair of 6 Me V parallel-opposed photon beams modulated with 15 degree steel wedges. RESULTS: At least 5% of volume of 3.5 cm(3) hypothetical tumor near the air wall of the larynx receives less than 86% of the maximum tumor dose. The same volume received less than 91% of the maximum tumor dose when the mathematical neck had no air cavities. CONCLUSIONS: We conclude the significant underdosage at the air-tissue interface in the larynx occurs in traditional radiotherapy treatments, especially in the glottic part of the larynx.

Patient outcomes in the GHMonitor: the effect of delivery device on compliance and growth.

To determine the effect of method of growth hormone (GH) administration on patient outcomes, we studied data from the GHMonitor, an electronic database registry of North American children treated with Saizen GH (somatropin [rDNA origin] for injection). Data from 631 children, 305 treated with needle and syringe and 326 treated with cool.click needle-free device, were analyzed. The groups were balanced for factors known to affect GH treatment response. There was no difference in response to GH over 2 years of treatment whether assessed by growth rate, change in height SD score, or change in height age. Although the majority of patients were compliant with GH therapy (84.6% of needle-free delivery system [NFDS] and 76.3% of needle and syringe patients missed <3 doses per month), significantly more patients using needle and syringe missed over one-half of their prescribed GH dose (13.4% needle and syringe patients versus 6% of NFDS patients, P=.002). In this group of poorly compliant patients, growth rates were significantly lower than in patients who missed fewer doses. Thus in patients where compliance is an issue, use of the NFDS may result in better outcomes.

Monte carlo simulation of the Leksell Gamma Knife: II. Effects of heterogeneous versus homogeneous media for stereotactic radiosurgery.

The absence of electronic equilibrium in the vicinity of bone-tissue or air-tissue heterogeneity in the head can misrepresent deposited dose with treatment planning algorithms that assume all treatment volume as homogeneous media. In this paper, Monte Carlo simulation (PENELOPE) and measurements with a specially designed heterogeneous phantom were applied to investigate the effect of air-tissue and bone-tissue heterogeneity on dose perturbation with the Leksell Gamma Knife. The dose fall-off near the air-tissue interface caused by secondary electron disequilibrium leads to overestimation of dose by the vendor supplied treatment planning software (GammaPlan) at up to 4 mm from an interface. The dose delivered to the target area away from an air-tissue interface may be underestimated by up to 7% by GammaPlan due to overestimation of attenuation of photon beams passing through air cavities. While the underdosing near the air-tissue interface cannot be eliminated with any plug pattern, the overdosage due to under-attenuation of the photon beams in air cavities can be eliminated by plugging the sources whose beams intersect the air cavity. Little perturbation was observed next to bone-tissue interfaces. Monte Carlo results were confirmed by measurements. This study shows that the employed Monte Carlo treatment planning is more accurate for precise dosimetry of stereotactic radiosurgery with the Leksell Gamma Knife for targets in the vicinity of air-filled cavities.

Lung cancer radiation therapy: Monte Carlo investigation of "under dose" by high energy photons.

Loss of electronic equilibrium in lung tissue causes a build-up region in the tumor. Increasing the photon energy increases the depth at which electronic equilibrium is reestablished within the lung tumor. This study uses the Monte Carlo code PENELOPE for simulations of radiation treatment of tumor surrounded by lung. Six MV photons were compared to 15 MV photons using four beam arrangements in both homogeneous and heterogeneous media. The experimental results demonstrate that for every beam arrangement in heterogeneous media 15 MV photons delivered 5% to 10% lower dose to the tumor periphery than 6 MV photons. The simulations also show that in axial coplanar treatment plans, the loss of electronic equilibrium was greatest in the coronal plane. In conclusion there is a tumor sparing effect at the tumor-lung interface that is a function of beam energy. As an alternative to increasing beam energy, the addition of multiple beam angles with lower energy photons improved target coverage. If higher energy beams are required for patients with large separation, then adding multiple beam angles does offer some improved target coverage. The non-coplanar technique with the lower energy photons covered the tumor with a greatest isodose at the tumor periphery without tangential sparing in the coronal plane.

Monte Carlo simulation of the Leksell Gamma Knife: I. Source modelling and calculations in homogeneous media.

The Monte Carlo code PENELOPE has been used to simulate photon flux from the Leksell Gamma Knife, a precision method for treating intracranial lesions. Radiation from a single 6OCo assembly traversing the collimator system was simulated, and phase space distributions at the output surface of the helmet for photons and electrons were calculated. The characteristics describing the emitted final beam were used to build a two-stage Monte Carlo simulation of irradiation of a target. A dose field inside a standard spherical polystyrene phantom, usually used for Gamma Knife dosimetry, has been computed and compared with experimental results, with calculations performed by other authors with the use of the EGS4 Monte Carlo code, and data provided by the treatment planning system Gamma Plan. Good agreement was found between these data and results of simulations in homogeneous media. Owing to this established accuracy, PENELOPE is suitable for simulating problems relevant to stereotactic radiosurgery.