Clinical application of MOSkin dosimeters to rectal wall in vivo dosimetry in gynecological HDR brachytherapy.

PURPOSE: Three MOSkins dosimeters were assembled over a rectal probe and used to perform in vivo dosimetry during HDR brachytherapy treatments of vaginal cancer. The purpose of this study was to verify the applicability of the developed tool to evaluate discrepancies between planned and measured doses to the rectal wall. MATERIALS AND METHODS: MOSkin dosimeters from the Centre for Medical Radiation Physics are particularly suitable for brachytherapy procedures for their ability to be easily incorporated into treatment instrumentation. In this study, 26 treatment sessions of HDR vaginal brachytherapy were monitored using three MOSkin mounted on a rectal probe. A total of 78 measurements were collected and compared to doses determined by the treatment planning system. RESULTS: Mean dose discrepancy was determined as 2.2±6.9%, with 44.6% of the measurements within ±5%, 89.2% within ±10% and 10.8% higher than ±10%. When dose discrepancies were grouped according to the time elapsed between imaging and treatment (i.e., group 1: ≤90min; group 2: >90min), mean discrepancies resulted in 4.7±3.6% and 7.1±5.0% for groups 1 and 2, respectively. Furthermore, the position of the dosimeter on the rectal catheter was found to affect uncertainty, where highest uncertainties were observed for the dosimeter furthest inside the rectum. CONCLUSIONS: This study has verified MOSkin applicability to in-patient dose monitoring in gynecological brachytherapy procedures, demonstrating the dosimetric rectal probe setup as an accurate and convenient IVD instrument for rectal wall dose verification. Furthermore, the study demonstrates that the delivered dose discrepancy may be affected by the duration of treatment planning.

BrachyView, a novel in-body imaging system for HDR prostate brachytherapy: Experimental evaluation.

PURPOSE: This paper presents initial experimental results from a prototype of high dose rate (HDR) BrachyView, a novel in-body source tracking system for HDR brachytherapy based on a multipinhole tungsten collimator and a high resolution pixellated silicon detector array. The probe and its associated position estimation algorithms are validated and a comprehensive evaluation of the accuracy of its position estimation capabilities is presented. METHODS: The HDR brachytherapy source is moved through a sequence of positions in a prostate phantom, for various displacements in x, y, and z. For each position, multiple image acquisitions are performed, and source positions are reconstructed. Error estimates in each dimension are calculated at each source position and combined to calculate overall positioning errors. Gafchromic film is used to validate the accuracy of source placement within the phantom. RESULTS: More than 90% of evaluated source positions were estimated with an error of less than one millimeter, with the worst-case error being 1.3 mm. Experimental results were in close agreement with previously published Monte Carlo simulation results. CONCLUSIONS: The prototype of HDR BrachyView demonstrates a satisfactory level of accuracy in its source position estimation, and additional improvements are achievable with further refinement of HDR BrachyView's image processing algorithms.

Radioembolization of hepatocarcinoma with (90)Y glass microspheres: development of an individualized treatment planning strategy based on dosimetry and radiobiology.

PURPOSE: The aim of this study was to optimize the dosimetric approach and to review the absorbed doses delivered, taking into account radiobiology, in order to identify the optimal methodology for an individualized treatment planning strategy based on (99m)Tc-macroaggregated albumin (MAA) single photon emission computed tomography (SPECT) images. METHODS: We performed retrospective dosimetry of the standard TheraSphere® treatment on 52 intermediate (n = 17) and advanced (i.e. portal vein thrombosis, n = 35) hepatocarcinoma patients with tumour burden < 50% and without obstruction of the main portal vein trunk. Response was monitored with the densitometric radiological criterion (European Association for the Study of the Liver) and treatment-related liver decompensation was defined ad hoc with a time cut-off of 6 months. Adverse events clearly attributable to disease progression or other causes were not attributed to treatment. Voxel dosimetry was performed with the local deposition method on (99m)Tc-MAA SPECT images. The reconstruction protocol was optimized. Concordance of (99m)Tc-MAA and (90)Y bremsstrahlung microsphere biodistributions was studied in 35 sequential patients. Two segmentation methods were used, based on SPECT alone (home-made code) or on coregistered SPECT/CT images (IMALYTICS™ by Philips). STRATOS™ absorbed dose calculation was validated for (90)Y with a single time point. Radiobiology was used introducing other dosimetric variables besides the mean absorbed dose D: equivalent uniform dose (EUD), biologically effective dose averaged over voxel values (BEDave) and equivalent uniform biologically effective dose (EUBED). Two sets of radiobiological parameters, the first derived from microsphere irradiation and the second from external beam radiotherapy (EBRT), were used. A total of 16 possible methodologies were compared. Tumour control probability (TCP) and normal tissue complication probability (NTCP) were derived. The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve was used as a figure of merit to identify the methodology which gave the best separation in terms of dosimetry between responding and non-responding lesions and liver decompensated vs non-decompensated liver treatment. RESULTS: MAA and (90)Y biodistributions were not different (71% of cases), different in 23% and uncertain in 6%. Response correlated with absorbed dose (Spearman's r from 0.48 to 0.69). Responding vs non-responding lesion absorbed doses were well separated, regardless of the methodology adopted (p = 0.0001, AUC from 0.75 to 0.87). EUBED gave significantly better separation with respect to mean dose (AUC = 0.87 vs 0.80, z = 2.07). Segmentation on SPECT gave better separation than on SPECT/CT. TCP(50%) was at 250 Gy for small lesion volumes (<10 cc) and higher than 1,000 Gy for large lesions (>10 cc). Apparent radiosensitivity values from TCP were around 0.003/Gy, a factor of 3-5 lower than in EBRT, as found by other authors. The dose-rate effect was negligible: a purely linear model can be applied. Toxicity incidence was significantly larger for Child B7 patients (89 vs 14%, p < 0.0001), who were therefore excluded from dose-toxicity analysis. Child A toxic vs non-toxic treatments were significantly separated in terms of dose averaged on whole non-tumoural parenchyma (including non-irradiated regions) with AUC from 0.73 to 0.94. TD50 was ≈ 100 Gy. No methodology was superior to parenchyma mean dose, which therefore can be used for planning, with a limit of TD15 ≈ 75 Gy. CONCLUSION: A dosimetric treatment planning criterion for Child A patients without complete obstruction of the portal vein was developed.

Radiation dose enhancement at tissue-tungsten interfaces in HDR brachytherapy.

HDR BrachyView is a novel in-body dosimetric imaging system for real-time monitoring and verification of the source position in high dose rate (HDR) prostate brachytherapy treatment. It is based on a high-resolution pixelated detector array with a semi-cylindrical multi-pinhole tungsten collimator and is designed to fit inside a compact rectal probe, and is able to resolve the 3D position of the source with a maximum error of 1.5 mm. This paper presents an evaluation of the additional dose that will be delivered to the patient as a result of backscatter radiation from the collimator. Monte Carlo simulations of planar and cylindrical collimators embedded in a tissue-equivalent phantom were performed using Geant4, with an (192)Ir source placed at two different source-collimator distances. The planar configuration was replicated experimentally to validate the simulations, with a MOSkin dosimetry probe used to measure dose at three distances from the collimator. For the cylindrical collimator simulation, backscatter dose enhancement was calculated as a function of axial and azimuthal displacement, and dose distribution maps were generated at three distances from the collimator surface. Although significant backscatter dose enhancement was observed for both geometries immediately adjacent to the collimator, simulations and experiments indicate that backscatter dose is negligible at distances beyond 1 mm from the collimator. Since HDR BrachyView is enclosed within a 1 mm thick tissue-equivalent plastic shell, all backscatter radiation resulting from its use will therefore be absorbed before reaching the rectal wall or other tissues. dosimetry, brachytherapy, HDR.

Measurements of gamma dose and thermal neutron fluence in phantoms exposed to a BNCT epithermal beam with TLD-700.

Gamma dose and thermal neutron fluence in a phantom exposed to an epithermal neutron beam for boron neutron capture therapy (BNCT) can be measured by means of a single thermoluminescence dosemeter (TLD-700). The method exploits the shape of the glow curve (GC) and requires the gamma-calibration GC (to obtain gamma dose) and the thermal-neutron-calibration GC (to obtain neutron fluence). The method is applicable for BNCT dosimetry in case of epithermal neutron beams from a reactor because, in most irradiation configurations, thermal neutrons give a not negligible contribution to the TLD-700 GC. The thermal neutron calibration is not simple, because of the impossibility of having thermal neutron fields without gamma contamination, but a calibration method is here proposed, strictly bound to the method itself of dose separation.

Online in vivo dosimetry in high dose rate prostate brchytherapy with MOSkin detectors: in phantom feasibility study.

MOSkin detectors were studied to perform real-time in vivo dose measurements in high dose rate prostate brachytherapy. Measurements were performed inside an urethral catheter in a gel phantom simulating a real prostate implant. Measured and expected doses were compared and the discrepancy was found to be within 8.9% and 3.8% for single MOSkin and dual-MOSkin configurations, respectively. Results show that dual-MOSkin detectors can be profitably adopted in prostate brachytherapy treatments to perform real-time in vivo dosimetry inside the urethra.

Prdm5 suppresses Apc(Min)-driven intestinal adenomas and regulates monoacylglycerol lipase expression.

PRDM proteins are tissue-specific transcription factors often deregulated in diseases, particularly in cancer where different members have been found to act as oncogenes or tumor suppressors. PRDM5 is a poorly characterized member of the PRDM family for which several studies have reported a high frequency of promoter hypermethylation in cancer types of gastrointestinal origin. We report here the characterization of Prdm5 knockout mice in the context of intestinal carcinogenesis. We demonstrate that loss of Prdm5 increases the number of adenomas throughout the murine small intestine on an Apc(Min) background. By using the genome-wide ChIP-seq (chromatin immunoprecipitation (ChIP) followed by DNA sequencing) and transcriptome analyses we identify loci encoding proteins involved in metabolic processes as prominent PRDM5 targets and characterize monoacylglycerol lipase (Mgll) as a direct PRDM5 target in human colon cancer cells and in Prdm5 mutant mouse intestines. Moreover, we report the downregulation of PRDM5 protein expression in human colon neoplastic lesions. In summary, our data provide the first causal link between Prdm5 loss and intestinal carcinogenesis, and uncover an extensive and novel PRDM5 target repertoire likely facilitating the tumor-suppressive functions of PRDM5.

HPV infection and intraepithelial lesions: comparison between HIV positive and negative women.

INTRODUCTION: Human Papillomavirus infections have been shown to be crucial for the development of cervical intraepithelial neoplasia and subsequent cervical cancer. The aim of this study is to describe the prevalence of different genotypes of HPV, in a population of HIV-positive women, compared to the negative ones, and their oncogenic risk. PATIENTS AND METHOD: A case-control study comparing HPV genotype distribution between 93 HIV-seropositive and 186 HIV-seronegative women, matched for age and severity of cervical lesions, who attending colposcopic service of our departments for periodical Pap smear and HPV DNA full genotyping by SPF-10 LiPA assay. RESULTS: No significant difference was found in genotype distribution between HIV positive and HIV negative women. Only the prevalence of HPV56 was higher in HIV positive women (p=0,046). The rates of HPV 6, 11, 16 and 18 were similar in both groups. The likelihood of the detection of three or more HPV genotypes was significantly associated with CIN (OR=2.0; 95% CI=1.1-3.8; p= 0.026) but only marginally to HIV-positive serostatus (OR=1.68; 95% CI=0.89-3.16; p= 0.1). High grade cervical lesions are associated with high risk viruses like HPV 16 and 18 and with multiple cervical HPV infections. CONCLUSIONS: The tendency to treat HIV disease with high active antiretroviral therapy may reduce the impact of immunosuppression and make the course of such HPV infections more similar to that among women who are not HIVinfected. As in immunocompetent women, high oncogenic risk viral type and multiple infections are associated with a histologically proven cervical intraepithelial lesions.

Solid state TL detectors for in vivo dosimetry in brachytherapy.

In vivo dosimetry provides information about the actual dose delivered to the patient treated with radiotherapy and can be adopted within a routinary treatment quality assurance protocol. Aim of this study was to evaluate the feasibility of performing in vivo rectal dosimetry by placing thermoluminescence detectors directly on the transrectal ultrasound probe adopted for on-line treatment planning of high dose rate brachytherapy boosts of prostate cancer patients. A suitable protocol for TLD calibration has been set up. In vivo measurements resulted to be in good agreement with the calculated doses, showing that the proposed method is feasible and returns accurate results.

A dosimetric treatment planning strategy in radioembolization of hepatocarcinoma with 90Y glass microspheres.

AIM: Our goal was to limit liver toxicity and to obtain good efficacy by developing a dosimetric treatment planning strategy. While several dosimetric evaluations are reported in literature, the main problem of the safety of the treatment is rarely addressed. Our work is the first proposal of a treatment planning method for glass spheres, including both liver toxicity and efficacy issues. METHODS: Fifty-two patients (series 1) had been treated for intermediated/advanced hepatocellular carcinoma (HCC) with glass spheres, according to the Therasphere® prescription of 120 Gy averaged on the injected lobe. They were retrospectively evaluated with voxel dosimetry, adopting the local deposition hypothesis. Regions of interest on tumor and non tumor parenchyma were drawn to determine the parenchyma absorbed dose, averaged also on non irradiated voxels, excluding tumor voxels. The relationship between the mean non tumoral parenchyma absorbed dose D and observed liver decompensation was analyzed. RESULTS: Basal Child-Pugh strongly affected the toxicity incidence, which was 22% for A5, 57% for A6, 89% for B7 patients. Restricting the analysis to our numerically richest class (basal Child-Pugh A5 patients), D median values were significantly different between toxic (median 90 Gy) and non toxic treatments (median 58 Gy) at a Mann-Withney test, (P=0.033). Using D as a marker for toxicity, the separation of the two populations in terms of area under ROC curve was 0.75, with 95% C.I. of [0.55-0.95]. The experimental Normal Tissue Complication Probability (NTCP) curve as a function of D resulted in the following values: 0%, 14%, 40%, 67% for D interval of [0-35] Gy, [35-70] Gy, [70-105] Gy, [105-140] Gy. DISCUSSION: A limit of about 70 Gy for the mean absorbed dose to parenchyma was assumed for A5 patients, corresponding to a 14% risk of liver decompensation. This result is applicable only to our administration conditions: glass spheres after a decay interval of 3.75 days. Different safety limit (40 Gy) are published for resin spheres, characterized by higher number of particle per GBq (more uniform irradiation, bigger biological effect for the same absorbed dose). CONCLUSION: As result of this study we suggest a constraint of about 70 Gy mean absorbed dose to liver non tumoral parenchyma, corresponding to about 15% probability of radioinduced liver decompensation while still aiming at achieving an absorbed of several hundreds of Gy to lesions.

Fricke gel-layer dosimetry in high dose-rate brachytherapy.

The aim of this study was to evaluate the reliability of Fricke gel-layer dosimeters for the measurement of in-phantom dose distributions produced by a ((192))Ir brachytherapy source. The doses obtained were compared to measurements performed with thermoluminescent dosimeters and treatment planning calculations. Fricke gel-layer dosimeters have proven to be a promising tool to measure three-dimensional dose distributions in high dose-rate brachytherapy.

Polymer gels for in-phantom dose imaging in radiotherapy.

Normoxic polymer gel dosimeters are studied, with the aim of achieving a valid and advantageous method for in-phantom 3D dose determinations. Developments were carried out in the application of such dosimetric material to the method based on dosimeter gel layers that has shown good reliability for absorbed dose imaging in radiotherapy. The technique has been improved, in particular taking care of minimizing the oxygen infiltration into the gel matrix in order to suitably avoid its effect of inhibiting the polymerization process after exposure. A suitable choice of the material of dosimeter walls has brought to achieve good steadiness in time of dosimeter sensitivity and satisfactory results in dose imaging and depth-dose profiling.

Dose imaging in a thorax phantom with lung-equivalent volume at the epithermal neutron beam of LVR-15 reactor.

A thorax phantom has been designed, consisting of PMMA and PE plates containing a cavity filled with a laboratory-made lung-substitute. Fricke-gel dosimeters have been placed in the lung-substitute volume, and the phantom has been irradiated at the epithermal column of LVR-15 reactor. Absorbed dose images have been obtained for both gamma radiation and charged particles emitted in the (10)B reactions with thermal neutrons. Measurements with thermoluminescence dosimeters (TLDs) and Monte Carlo (MC) calculations have been performed too, in order to attain inter-comparison of results.

In-phantom dose imaging with polymer gel layer dosimeters.

Gel dosimeters in form of layers have shown noticeable potentiality for in-phantom dose profiling and imaging in BNCT neutron fields. Such dosimeters give the possibility of achieving spatial dose distributions of each dose contribution in neutron fields. The various dose components are separated by means of pixel-to-pixel manipulations of pairs of images acquired with gel dosimeters having different isotopic compositions. The reliability of polymer-gel-layer dosimeters (PGLD) for BNCT has been studied and their utilisation limits have been inspected.

Dose distributions in phantoms irradiated in thermal columns of two different nuclear reactors.

In-phantom dosimetry studies have been carried out at the thermal columns of a thermal- and a fast-nuclear reactor for investigating: (a) the spatial distribution of the gamma dose and the thermal neutron fluence and (b) the accuracy at which the boron concentration should be estimated in an explanted organ of a boron neutron capture therapy patient. The phantom was a cylinder (11 cm in diameter and 12 cm in height) of tissue-equivalent gel. Dose images were acquired with gel dosemeters across the axial section of the phantom. The thermal neutron fluence rate was measured with activation foils in a few positions of this phantom. Dose and fluence rate profiles were also calculated with Monte Carlo simulations. The trend of these profiles do not show significant differences for the thermal columns considered in this work.

Gel dosimetry in the BNCT facility for extra-corporeal treatment of liver cancer at the HFR Petten.

A thorough evaluation of the dose inside a specially designed and built facility for extra-corporeal treatment of liver cancer by boron neutron capture therapy (BNCT) at the High Flux Reactor (HFR) Petten (The Netherlands) is the necessary step before animal studies can start. The absorbed doses are measured by means of gel dosemeters, which help to validate the Monte Carlo simulations of the spheroidal liver holder that will contain the human liver for irradiation with an epithermal neutron beam. These dosemeters allow imaging of the dose due to gammas and to the charged particles produced by the (10)B reaction. The thermal neutron flux is extrapolated from the boron dose images and compared to that obtained by the calculations. As an additional reference, Au, Cu and Mn foil measurements are performed. All results appear consistent with the calculations and confirm that the BNCT liver facility is able to provide an almost homogeneous thermal neutron distribution in the liver, which is a requirement for a successful treatment of liver metastases.

Skin and cutaneous melanocytic lesion simulation in biomedical optics with multilayered phantoms.

The complex inner layered structure of skin influences the photon diffusion inside the cutaneous tissues and determines the reflectance spectra formation. Phantoms are very useful tools to understand the biophysical meaning of parameters involved in light propagation through the skin. To simulate the skin reflectance spectrum, we realized a multilayered skin-like phantom and a multilayered skin phantom with a melanoma-like phantom embedded inside. Materials used were Al(2)O(3) particles, melanin of sepia officinalis and a calibrator for haematology systems dispersed in transparent silicon. Components were optically characterized with indirect techniques. Reflectance phantom spectra were compared with average values of in vivo spectra acquired on a sample of 573 voluntary subjects and 132 pigmented lesions. The phantoms' reflectance spectra agreed with those measured in vivo, mimicking the optical behaviour of the human skin. Further, the phantoms were optically stable and easily manageable, and represented a valid resource in spectra formation comprehension, in diagnostic laser applications and simulation model implementation, such as the Monte Carlo code for non-homogeneous media.

Multispectral imaging and artificial neural network: mimicking the management decision of the clinician facing pigmented skin lesions.

Various instruments based on acquisition and elaboration of images of pigmented skin lesions have been developed in an attempt to in vivo establish whether a lesion is a melanoma or not. Although encouraging, the response of these instruments, e.g. epiluminescence microscopy, reflectance spectrophotometry and fluorescence imaging, cannot currently replace the well-established diagnostic procedures. However, in place of the approach to instrumentally assess the diagnosis of the lesion, recent studies suggest that instruments should rather reproduce the assessment by an expert clinician of whether a lesion has to be excised or not. The aim of this study was to evaluate the performance of a spectrophotometric system to mimic such a decision. The study involved 1794 consecutively recruited patients with 1966 doubtful cutaneous pigmented lesions excised for histopathological diagnosis and 348 patients with 1940 non-excised lesions because clinically reassuring. Images of all these lesions were acquired in vivo with a multispectral imaging system. The data set was randomly divided into a train (802 reassuring and 1003 excision-needing lesions, including 139 melanomas), a verify (464 reassuring and 439 excision-needing lesions, including 72 melanomas) and a test set (674 reassuring and 524 excision-needing lesions, including 76 melanomas). An artificial neural network (ANN(1)) was set up to perform the classification of the lesions as excision-needing or reassuring, according to the expert clinicians' decision on how to manage each examined lesion. In the independent test set, the system was able to emulate the clinicians with a sensitivity of 88% and a specificity of 80%. Of the 462 correctly classified as excision-needing lesions, 72 (95%) were melanomas. No major variations in receiver operating characteristic curves were found between the test and the train/verify sets. On the same data set, a further artificial neural network (ANN(2)) was then architected to perform classification of the lesions as melanoma or non-melanoma, according to the histological diagnosis. Having set the sensitivity in recognizing melanoma to 95%, ANN(1) resulted to be significantly better in the classification of reassuring lesions than ANN(2). This study suggests that multispectral image analysis and artificial neural networks could be used to support primary care physicians or general practitioners in identifying pigmented skin lesions that require further investigations.

Optical devices used for image analysis of pigmented skin lesions: a proposal for quality assurance protocol using tissue-like phantoms.

Different technological tools have been developed to aid in the diagnosis of pigmented skin lesions, including cameras working with conventional RGB colour systems, epiluminescence microscopy and spectrophotometric methods using visible and near infrared wavelengths. All the different procedures should provide in an objective and reproducible fashion quantitative measurements of the colour and shape features of a given skin mole. At present, many devices have been introduced in experimental stages for clinical diagnosis, mainly used to provide to the clinicians an objective, computer-assisted second opinion. As for any diagnostic instruments, optical devices should also be subjected to a dedicated quality assurance protocol in order to evaluate the response repeatability of each device (intra-instrument agreement) and to check the accordance among the responses of different devices (inter-instrument agreement). The aim of this study was to design a quality assurance protocol for optical devices dedicated to image analysis of pigmented skin lesions and, in case, to detect cutaneous melanoma by using suitable tissue-like phantoms as standard references that enable testing of both hardware and software components. As an example, we report the results of intra-instrument and inter-instrument agreement when the protocol was applied on a series of 30 SpectroShade instruments, a novel optical device based on multi-spectral image analysis of colour and shape features of pigmented skin lesion.