Refinements to the boundary transformation vector representation of attractor shape deformation to enhance system parameter identification.

A new method of quantifying parameter changes in chaotic systems using estimates of how the boundaries of Poincare sections deform was recently developed. Refinements that improve the number and quality of the boundary transformation vectors produced by this method are proposed and analyzed here. Collectively, these refinements offer the ability to better match closely spaced linear segments of Poincare sections typical of fractal geometry, better handle boundary gaps, and more uniformly sample the boundary, resulting in additional data. The refinements are tested using Poincare sections constructed in three ways for five different dynamical systems and are shown to enhance results in all cases.

Management of uveal melanoma: a consensus-based provincial clinical practice guideline.

INTRODUCTION: Survival in uveal melanoma has remained unchanged since the early 1970s. Because outcomes are highly related to the size of the tumour, timely and accurate diagnosis can increase the chance for cure. METHODS: A consensus-based guideline was developed to inform practitioners. PubMed was searched for publications related to this topic. Reference lists of key publications were hand-searched. The National Guidelines Clearinghouse and individual guideline organizations were searched for relevant guidelines. Consensus discussions by a group of content experts from medical, radiation, and surgical oncology were used to formulate the recommendations. RESULTS: Eighty-four publications, including five existing guidelines, formed the evidence base. SUMMARY: Key recommendations highlight that, for uveal melanoma and its indeterminate melanocytic lesions in the uveal tract, management is complex and requires experienced specialists with training in ophthalmologic oncology. Staging examinations include serum and radiologic investigations. Large lesions are still most often treated with enucleation, and yet radiotherapy is the most common treatment for tumours that qualify. Adjuvant therapy has yet to demonstrate efficacy in reducing the risk of metastasis, and no systemic therapy clearly improves outcomes in metastatic disease. Where available, enrolment in clinical trials is encouraged for patients with metastatic disease. Highly selected patients might benefit from surgical resection of liver metastases.

Dosimetry study of [I-131] and [I-125]- meta-iodobenz guanidine in a simulating model for neuroblastoma metastasis.

The physical properties of I-131 may be suboptimal for the delivery of therapeutic radiation to bone marrow metastases, which are common in the natural history of neuroblastoma. In vitro and preliminary clinical studies have implied improved efficacy of I-125 relative to I-131 in certain clinical situations, although areas of uncertainty remain regarding intratumoral dosimetry. This prompted our study using human neuroblastoma multicellular spheroids as a model of metastasis. 3D dose calculations were made using voxel-based Medical Internal Radiation Dosimetry (MIRD) and dose-point-kernel (DPK) techniques. Dose distributions for I-131 and I-125 labeled mIBG were calculated for spheroids (metastases) of various sizes from 0.01 cm to 3 cm diameter, and the relative dose delivered to the tumors was compared for the same limiting dose to the bone marrow. Based on the same data, arguments were advanced based upon the principles of tumor control probability (TCP) to emphasize the potential theoretical utility of I-125 over I-131 in specific clinical situations. I-125-mIBG can deliver a higher and more uniform dose to tumors compared to I-131 mIBG without increasing the dose to the bone marrow. Depending on the tumor size and biological half-life, the relative dose to tumors of less than 1 mm diameter can increase several-fold. TCP calculations indicate that tumor control increases with increasing administered activity, and that I-125 is more effective than I-131 for tumor diameters of 0.01 cm or less. This study suggests that I-125-mIBG is dosimetrically superior to I-131-mIBG therapy for small bone marrow metastases from neuroblastoma. It is logical to consider adding I-125-mIBG to I-131-mIBG in multi-modality therapy as these two isotopes could be complementary in terms of their cumulative dosimetry.

Sci-Sat AM: Brachy - 08: MRI-guided planning and maximum achievable HR-CTV doses in cervix brachytherapy.

PURPOSE: To present an institutional experience with MRI-based intracavitary brachytherapy planning for cervix cancer treatments using the EMBRACE protocol and to evaluate maximum HR-CTV doses that can be achieved when OAR (bladder, rectum, and sigmoid) doses are allowed to equal GECESTRO recommended thresholds. METHOD: Dose metrics from treatment plans for 20 patients created using MR images (for contouring HR-CTV and OARs) fused with CT images (for applicator reconstruction) are presented. Starting with a standard Manchester loading, plans were manually optimized (MO) by adjusting dwell positions and times to obtain the desired HR-CTV D90 target coverage of 35 Gy while limiting OAR doses to below recommended tolerances. In addition, retrospective planning was done using: (i) volume optimization (VO) to compare differences with MO in obtaining the desired target coverage; and (ii) MO and VO techniques to get the highest possible HR-CTV coverage by allowing OAR doses to equal tolerance values. The latter plans are referred to as MAX plans. RESULTS AND CONCLUSIONS: 3D MRI-guided treatment planning for cervix brachytherapy was shown to improve dose-volume coverage of the target and OARs. MO could conform HR-CTV D90 to the prescribed dose similar to the VO technique. Sigmoid was often the dose limiting structure. With respect to the prescribed HR-CTV D90 dose of 35 Gy, MAX plans could increase the prescribed dose by about 22% and 30% for MO and VO plans, respectively, without exceeding OAR thresholds. Consequently, dose escalation for MRI-guided cervix brachytherapy appears feasible should clinical circumstances warrant.

Consequences of the spectral response of an a-Si EPID and implications for dosimetric calibration.

One of the attractive features of amorphous silicon electronic portal imaging devices (a-Si EPIDs) as dosimetric tools is that for open fields they are known to exhibit a generally linear relation between pixel value and incident energy fluence as measured by an ion chamber. It has also been established that a-Si EPIDs incorporating high atomic number phosphors such as Gd2O2S:Tb exhibit a disproportionately large response to low-energy (<1 MeV) photons. The present work examines the consequences of this hypersensitivity in a commercially available EPID, the Varian aS500, with respect to energy fluence calibration in a 6 MV radiotherapy beam. EPIDs may be deployed in situations where the spectrum of the incident beam is modified by passing through a compensator or through a patient or phantom. By examining the specific case of a beam hardened by passage through compensator material, we show that the discrepancy between open and attenuated beam calibration curves can be as high as 8%. A Monte Carlo study using a comprehensive model of the aS500 shows that this difference can be explained by spectral changes, and further suggests that it can be reduced by the addition of an external copper plate. We consider configurations with the plate placed directly on top of the EPID cassette and 15 cm above the cassette, supported by Styrofoam. In order to reduce the maximum discrepancy to <4%, it was found that a copper thickness of approximately 0.7 cm was required in the elevated configuration. Improvement was minimal with the copper in the contact configuration. Adding 0.7 cm of copper in the elevated configuration reduced the contrast-to-noise ratio by 19% and the modulation transfer for a given spatial frequency by 30%.

Comprehensive Monte Carlo calculation of the point spread function for a commercial a-Si EPID.

Images produced by commercial amorphous silicon electronic portal imaging devices (a-Si EPIDs) are subject to multiple blurring processes. Implementation of these devices for fluence measurement requires that the blur be removed from the images. A standard deconvolution operation can be performed to accomplish this assuming the blur kernel is spatially invariant and accurately known. This study determines a comprehensive blur kernel for the Varian aS500 EPID. Monte Carlo techniques are used to derive a dose kernel and an optical kernel, which are then combined to yield an overall blur kernel for both 6 and 15 MV photon beams. Experimental measurement of the line spread function (LSF) is used to verify kernel shape. Kernel performance is gauged by comparing EPID image profiles with in-air dose profiles measured using a diamond detector (approximating fluence) both before and after the EPID images have been deconvolved. Quantitative comparisons are performed using the chi metric, an extension of the well-known y metric, using acceptance criteria of 0.0784 cm (1 pixel width) distance-to-agreement (deltad) and 2% of the relative central axis fluence (deltaD). Without incorporating any free parameters, acceptance was increased from 49.0% of pixels in a cross-plane profile for a 6 MV 10 x 10 cm2 open field to 92.0%. For a 10 x 10 cm2 physically wedged field, acceptance increased from 40.3% to 73.9%. The effect of the optical kernel was found to be negligible for these chi acceptance parameters, however for (deltaD= 1%, deltad = 0.0784 cm) we observed an improvement from 66.1% (without) to 78.6% (with) of chi scores <1 (from 20.6% before deconvolution). It is demonstrated that an empirical kernel having a triple exponential form or a semiempirical kernel based on a simplified model of the detector stack can match the performance of the comprehensive kernel.

Metastatic adenocarcinoma of the cervix in a delivery-induced traumatic lower vaginal tear.

BACKGROUND: Noncontiguous vaginal metastasis is rare in cervical cancer and is usually reported in the context of traumatic implantation. Traumatic vaginal implantation of cervical carcinoma has been documented in episiotomy, port site, or incision scars. CASE: We report the only case in the literature with vaginal metastasis associated with traumatic vaginal tear presenting with concomitant metastasis and the second case in the literature with a concomitant vaginal metastasis. Treatment consisted of organ-sparing chemoradiotherapy. Although the previous literature suggests that nonsurgical management of traumatic implantation metastases is associated with survivals of less than 1 year, there is no confirmed recurrent disease after 1 year of follow-up in our reported case. CONCLUSION: The feasibility and initial favorable outcome with chemoradiation is demonstrated in this rare presentation.

A medical needle drive for the study of interstitial implant mechanics.

We describe the construction and test performance of a computer-controlled medical needle drive. The drive represents one facet of a larger project whose aim is to investigate experimentally the mechanics of needle introduction in radioactive 'seed' prostate implants, with a view to identifying ways of making incremental improvements in needle placement accuracy. It is capable of mimicking a range of motions imparted to a needle by a clinical practitioner, and of monitoring the compressive force at the needle tip in real time via an in-line load cell. Tests involving driving needles into porcine gelatin samples using a variety of velocity profiles confirm intended operation. The drive will permit us to introduce needles in a controlled and reproducible manner into a realistic prostate phantom currently being designed.

Autofluorescence characteristics of immortalized and carcinogen-transformed human bronchial epithelial cells.

Tissue autofluorescence has been explored as a potential method of noninvasive pre-neoplasia (pre-malignancy) detection in the lung. Here, we report the first studies of intrinsic cellular autofluorescence from SV40 immortalized and distinct tobacco-carcinogen-transformed (malignant) human bronchial epithelial cells. These cell lines are useful models for studies seeking to distinguish between normal and pre-neoplastic human bronchial epithelial cells. The cells were characterized via spectrofluorimetry and confocal fluorescence microscopy. Spectrofluorimetry revealed that tryptophan was the dominant fluorophore. No change in tryptophan emission intensity was observed between immortalized and carcinogen-transformed cells. Confocal autofluorescence microscopy was performed using a highly sensitive, spectrometer-coupled instrument capable of limiting emission detection to specific wavelength ranges. These studies revealed two additional endogenous fluorophores, whose excitation and emission characteristics were consistent with nicotinamide adenine dinucleotide (NADH) and flavins. In immortalized human bronchial epithelial cells, the fluorescence of these species was localized to cytoplasmic granules. In contrast, the carcinogen-transformed cells showed an appreciable decrease in the fluorescence intensity of both NADH and flavins and the punctate, spatial localization of the autofluorescence was lost. The observed autofluorescence decrease was potentially the result of changes in the redox state of the fluorophores. The random cytoplasmic fluorescence pattern found in carcinogen-transformed cells may be attributed to changes in the mitochondrial morphology. The implications of these results to pre-neoplasia detection in the lung are discussed.

In vivo NADH fluorescence monitoring as an assay for cellular damage in photodynamic therapy.

In this study the endogenous fluorescence signal attributed to reduced nicotinamide adenine dinucleotide (NADH) has been measured in response to photodynamic therapy (PDT)-induced damage. Measurements on cells in vitro have shown that NADH fluorescence decreased relative to that of controls after treatment with a toxic dose of PDT, as measured within 30 min after treatment. Similarly, assays of cell viability indicated that mitochondrial function was reduced immediately after treatment in proportion to the dose delivered, and the proportion of this dose response did not degrade further over 24 h. Measurements in vivo were used to monitor the fluorescence emission spectrum and the excited state lifetime of NADH in PDT-treated tissue. The NADH signal was defined as the ratio of the integrated fluorescence intensity of the 450 +/- 25 nm emission band relative to the fluorescence intensity integrated over the entire 400-600 nm range of collection. Measurements in murine muscle tissue indicated a 22% reduction in the fluorescence signal immediately after treatment with verteporfin-based PDT, using a dose of 2 mg/kg injected 15 min before a 48 J/cm2 light dose at 690 nm. Control animals without photosensitizer injection had no significant change in the fluorescence signal from laser irradiation at the same doses. This signal was monotonically correlated to the deposited dose used here and could provide a direct dosimetric measure of PDT-induced cellular death in the tissue being treated.

Measurement of relative output for 90Sr ophthalmic applicators using radiochromic film.

The treatment of various superficial lesions of the eye has, for many years, been conducted using strontium 90 (90Sr) ophthalmic applicators that have a steep dose gradient near their surface. A new applicator acquired by a treatment facility must have its output compared with that of any older applicators already in use to ensure consistent treatments. These measurements may be done using available dosimeters such as film and thermoluminescent detectors. Our work made use of radiochromic film and a document scanner to perform relative output measurements for 4 different 90Sr ophthalmic applicators acquired from the same manufacturer (Amersham Healthcare, Arlington Heights, IL) over a span of 28 years. Relative outputs were found to vary by < 10% with respect to the manufacturer's values, which is well within the uncertainty limit for absolute output of 20% specified by the manufacturer. The film measurements were verified using thermoluminescent dosimeters. Radiochromic film was also used to obtain a percentage depth dose curve and a 2 dimensional isodose distribution in a plane perpendicular to the active surface for the newest applicator (SIA 20).

Experimental determination of the anisotropy function and anisotropy factor for model 6711 I-125 seeds.

Model 6711 125I seeds are commonly used in permanent brachytherapy implants. While recommended dose distribution parameters for these sources have been published by AAPM TG-43, several investigators have recently questioned the presence of seemingly unphysical fluctuations in the anisotropy function data. Seeking to understand these, we measured the dimensions of eight model 6711 seeds radiographically, and made a new experimental determination of the anisotropy function and factor using thermoluminescent dosimeters (TL-100 chips and minicubes) in a solid water phantom. It was found that variations in seed capsule end weld thickness, and movement within the capsule of the Ag rod onto which the 125I is adsorbed, were present for all sources and thus contributed to experimental uncertainty. Averaging results from two different sources, from data acquired at the same time from diametrically opposed quadrants of the phantom, and from repeated measurements yielded anisotropy function values similar to those of TG-43 but characterized by greater precision (< or = 3% for radial distance r < or = 3 cm and < or = 1% for r > or = 4 cm), an absence of sharp fluctuations, and reduced magnitudes at r = 1 cm. The measured values can be well represented by an analytic function similar to that proposed by Furhang and Anderson to fit the TG-43 data. Values of the anisotropy factor derived from this function by integration exhibit little variation with r, in agreement with earlier diode data but in contrast to TG-43 data, and can also be represented by an analytic function. Finally, a difference in TLD chip and minicube reproducibility, observed here and by earlier investigators, is explained by reference to recent work (done concurrently with ours) as stemming from variations in dosimeter orientation and automated reader positioning/heating for minicubes.

C-terminal domain of the mitotic apparatus protein p62 targets the protein to the nucleolus during interphase.

Mitotic apparatuses from sea urchin embryos contain a protein (p62), previously shown to be required for mitotic progression. This protein localizes to the mitotic apparatus during cell division in urchin embryos and mammalian tissue culture cells. We show here by immunofluorescence that p62 is localized to the nucleus of mammalian cells during interphase and is highly concentrated in nucleoli. In addition, a fusion protein composed of full-length p62 and green fluorescent protein also localizes to nucleoli when expressed in COS-7 cells in culture. Analysis of the primary sequence of p62 reveals three distinct domains of the protein based on amino acid charge distribution: the acidic N-terminal domain, the basic C-terminal domain, and the central, M-domain, which contains alternating subdomains of clusters of acidic and basic residues. To identify the domain important for nucleolar localization during interphase, specific domains of p62 alone, or in combination with each other or with beta-galactosidase were fused to green fluorescent protein. Following confirmation of the fusion constructs by sequence analysis, the constructs were expressed in mammalian cells, expression was confirmed by immunoblotting, and the fusion proteins were localized via fluorescence microscopy. The data demonstrate that the C-terminal domain of p62 is both necessary and sufficient for the nuclear localization and nucleolar binding of p62 that is observed during interphase.

Combined experimental and Monte Carlo verification of 137Cs brachytherapy plans for vaginal applicators.

Dose rates in a phantom around a shielded and an unshielded vaginal applicator containing Selectron low-dose-rate 137Cs sources were determined by experiment and Monte Carlo simulation. Measurements were performed with thermoluminescent dosimeters in a white polystyrene phantom using an experimental protocol geared for precision. Calculations for the same set-up were done using a version of the EGS4 Monte Carlo code system modified for brachytherapy applications into which a new combinatorial geometry package developed by Bielajew was recently incorporated. Measured dose rates agree with Monte Carlo estimates to within 5% (1 SD) for the unshielded applicator, while highlighting some experimental uncertainties for the shielded applicator. Monte Carlo calculations were also done to determine a value for the effective transmission of the shield required for clinical treatment planning, and to estimate the dose rate in water at points in axial and sagittal planes transecting the shielded applicator. Comparison with dose rates generated by the planning system indicates that agreement is better than 5% (1 SD) at most positions. The precision thermoluminescent dosimetry protocol and modified Monte Carlo code are effective complementary tools for brachytherapy applicator dosimetry.

Purification of tubulin and microtubule-associated proteins by membrane ion-exchange chromatography.

Microtubules, composed of tubulin and microtubule-associated proteins (MAPs), can be isolated using routine procedures from homogenates of vertebrate brain. Often, it is necessary then to purify the tubulin from the MAPs, and normally this purification is effected by standard techniques of ion-exchange chromatography. However, such procedures can be expensive, both in the consumption of buffers and other expensive components (e. g. GTP) and in investigator time. Here, we demonstrate that membrane ion exchangers mounted in syringe filter cartridges can be used to separate tubulin from MAPs in a matter of minutes, compared to the several hours that are normally required for typical chromatographic procedures using phosphocellulose orDEAE. The resulting tubulin is competent to assemble into microtubules upon either addition of the purified MAPs or addition of the microtubule-stabilizing drug Taxol. Thus, the procedure should be useful to investigators requiring a rapid and effective purification of tubulin for use in assembly studies or in vitro motility assays.

Monte Carlo dosimetry of the VariSource high dose rate 192Ir source.

The purpose of the work is to calculate basic dosimetry data for a VariSource high dose rate 192Ir source in water. These basic dosimetry data, expressed in the dose calculation formalism endorsed by the Interstitial Collaborative Working Group and AAPM Task group 43, include the dose rate constant, the radial dose function, and the anisotropy function. A modified version of the EGS4 Monte Carlo code was used to calculate (1) the transverse-axis dose distribution at radial distances from 0.1 to 14 cm, (2) the two-dimensional dose distribution for axial and radial distances from 0.1 cm to 10 cm, and (3) the air-kerma strength, for the VariSource high dose rate 192Ir source. From these Monte Carlo results the basic dosimetry data were derived. The calculated dose rate constant for the high dose rate source is 1.044 +/- 0.2% cGy h-1 per unit air-kerma strength. The anisotropy function exhibits 40%-60% deviations from isotropy at positions on the long axis. The radial dose function for the source is nearly identical to that for a microSelectron high dose rate 192Ir source, except at radial distances smaller than 0.5 cm where values for VariSource are 1.7%-2.8% smaller. These basic dosimetry data were compared with corresponding results from other authors for high and low dose rate 192Ir sources, as well as with Meisberger's fitting formula.

Influence of source geometry and materials on the transverse axis dosimetry of 192Ir brachytherapy sources.

Monte Carlo dose rates on the transverse axis in water and air kerma strengths normalized to unit source activity were calculated for a low dose rate steel-clad 192Ir source. MicroSelectron high dose rate and pulsed dose rate 192Ir sources, and a VariSource high dose rate 192Ir source, as well as five other hypothetical cylindrical 192Ir source designs. Based on these results, the dependence of dose rate and air kerma strength on source geometry and materials was analysed. Source geometry and attenuation in the core material are the important factors determining basic dosimetric characteristics. Core length, h, only affects the dose rate on the transverse axis at radial distances r < 4 h, over which the dose rate decreases nonlinearly with increasing core length. By comparison, core diameter, d, influences the air kerma strength and dose rate at all radial distances; these decrease linearly with increasing core diameter. Based on their dosimetric characteristics, pertinent dosimetry modelling for four actual 192Ir sources is suggested, and similarities and differences in the dose rate constant and radial dose function between these sources are explained.

Influence of catheter materials and tissue composition on low dose rate iridium-192 seed implant dosimetry.

PURPOSE: To quantify the perturbing influence of catheter materials and tissue composition on the dose distribution in water around a low dose rate, steel encapsulated Ir-192 seed. METHODS AND MATERIALS: The EGS4 Monte Carlo code was used to estimate point doses in a bounded phantom within a cylinder with a radius of 3 cm surrounding the source. Simulations were performed in water and soft tissue media for an unadorned seed, and then in soft tissue for a nylon-ribbon-encased seed inside steel and nylon catheters. The latter simulations were repeated including inactive seeds on either side of the source at spacings of 1.0 and 0.5 cm. Sufficient numbers of photon histories were run to reduce the relative statistical uncertainty of most dose estimates to <0.1%. Contributions from primary and scattered photons were scored separately. RESULTS: For the unadorned source, doses in soft tissue were uniformly approximately 1% lower than in water. Introduction of either catheter perturbed the dose in soft tissue by <0.4% along the transverse source axis, r. In the long axis direction, d, dose in soft tissue for the steel catheter relative to the unadorned source fell with increasing distance and decreasing radius, r, and trended oppositely for the nylon catheter. Neighboring seeds did not affect the dose distribution except at r = 0.2 cm for seeds spaced at 0.5 cm, where dose fell approximately 8% in the interval d = 4-7 cm. For several Paris system implant geometries, the presence of catheters altered basal doses in a systematic manner. CONCLUSION: Perturbations of the dose distribution for LDR Ir-192 seeds in water introduced by treatment catheters and tissue composition are small but systematic. If desired, they can be accounted for in clinical volumes of interest by simple adjustment of dose calculation parameters.

Molecular characterization of p62, a mitotic apparatus protein required for mitotic progression.

A 62-kDa (p62) mitotic apparatus-associated protein is important for the proper progression of mitosis in sea urchin embryos (Dinsmore, J. H., and Sloboda, R. D. (1989) Cell 53, 769-780). We have isolated and characterized a full-length p62 cDNA of 3374 base pairs which encodes an extremely acidic polypeptide of 411 amino acids having a calculated Mr of 46,388 and a pI of 4.01; p62 is a unique protein with no significant identity to any known proteins. Southern and Northern blot analyses demonstrate that the gene for p62 is present once in the sea urchin genome and the corresponding mRNA is present in unfertilized eggs and in early embryos through and up to the gastrula stage. Sequence analysis suggests certain regions may participate in chromatin association and microtubule binding, an observation that is consistent with previous immunological data (Ye, X., and Sloboda, R. D. (1995) Cell Motil. Cytoskeleton 30, 310-323) as well as data reported herein. Confocal microscopy reveals that during interphase the protein binds to chromatin in the nuclei of sea urchin eggs. In the germinal vesicles of clam oocytes at prophase of meiosis I, p62 binds to the condensed chromosomes. Currently, truncated clones of p62 are being used to identify the tubulin and chromatin binding domains.