Johannes P.A. Marijnissen

Residual Plaque Burden, Delivered Dose, and Tissue Composition Predict 6-Month Outcome After Balloon Angioplasty and β-Radiation Therapy

BACKGROUND Inhomogeneity of dose distribution and anatomic aspects of the atherosclerotic plaque may influence the outcome of irradiated lesions after balloon angioplasty (BA). We evaluated the influence of delivered dose and morphological characteristics of coronary stenoses treated with beta-radiation after BA. METHODS AND RESULTS Eighteen consecutive patients treated according to the Beta Energy Restenosis Trial 1.5 were included in the study. The site of angioplasty was irradiated with the use of a beta-emitting (90)Sr/(90)Y source. With the side branches used as anatomic landmarks, the irradiated area was identified and volumetric assessment was performed by 3D intracoronary ultrasound imaging after treatment and at 6 months. The type of tissue, the presence of dissection, and the vessel volumes were assessed every 2 mm within the irradiated area. The minimal dose absorbed by 90% of the adventitial volume (D(v90)Adv) was calculated in each 2-mm segment. Diffuse calcified subsegments and those containing side branches were excluded. Two hundred six coronary subsegments were studied. Of those, 55 were defined as soft, 129 as hard, and 22 as normal/intimal thickening. Plaque volume showed less increase in hard segments as compared with soft and normal/intimal thickening segments (P<0.0001). D(v90)Adv was associated with plaque volume at follow-up after a polynomial equation with linear and nonlinear components (r = 0.71; P = 0.0001). The multivariate regression analysis identified the independent predictors of the plaque volume at follow-up: plaque volume after treatment, D(v90)Adv, and type of plaque. CONCLUSIONS Residual plaque burden, delivered dose, and tiss composition play a fundamental role in the volumetric outcome at 6-month follow-up after beta-radiation therapy and BA.

Calibration of isotropic light dosimetry probes based on scattering bulbs in clear media

Miniature light detectors with isotropic response (isotropic light probes) permit quantitative measurement of light energy fluence rates in turbid media such as biological tissues. These isotropic probes are, for example, applied in photodynamic therapy to correlate light fluence in tissue with (tumour) tissue response, in vitro and in vivo. After description of its construction, two methods of calibration of an isotropic probe in air are discussed, in collimated and in diffuse light. The probe was first calibrated in air in collimated light, after which its response to diffuse light was checked in a flat and in a spherical geometry. Subsequently, the probes response to collimated light in clear media, for example, water or glycerine which have refractive indices larger than that of air, has been established experimentally. The diffusion approximation to the transport equation in a simple spherical geometry has been used to calculate the probes response as a function of the refractive index of clear media. The extent of agreement between theory and experiment indicates that the physical mechanisms are understood and indirectly validates the theoretical models.

Three-Dimensional Intravascular Ultrasound Assessment of Noninjured Edges of β-Irradiated Coronary Segments

BackgroundThe “edge effect,” late lumen loss at the margins of the treated segment, has become an important issue in the field of coronary brachytherapy. The aim of the present study was to assess the edge effect in noninjured margins adjacent to the irradiated segments after catheter-based intracoronary &bgr;-irradiation. Methods and ResultsFifty-three vessels were assessed by means of 3-dimensional intravascular ultrasound after the procedure and at 6- to 8-month follow-up. Fourteen vessels (placebo group) did not receive radiation (sham source), whereas 39 vessels were irradiated. In the irradiated group, 48 edges (5 mm in length) were identified as noninjured, whereas 18 noninjured edges were selected in the placebo group. We compared the volumetric intravascular ultrasound measurements of the noninjured edges of the irradiated vessels with the fully irradiated nonstented segments (IRS, n=27) (26-mm segments received the prescribed 100% isodose) and the noninjured edges of the vessels of the placebo patients. The lumen decreased (6 mm3) in the noninjured edges of the irradiated vessels at follow-up (P =0.001). We observed a similar increase in plaque volume in all segments: noninjured edges of the irradiated group (19.6%), noninjured edges of the placebo group (21.5%), and IRS (21.0%). The total vessel volume increased in the IRS in the 3 groups. No edge segment was subject to repeat revascularization. ConclusionsThe edge effect occurs in the noninjured margins of radiation source train in both irradiated and placebo patients. Thus, low-dose radiation may not play an important role in this phenomenon, whereas nonmeasurable device injury may be considered a plausible alternative explanation.

Ex vivo light dosimetry and Monte Carlo simulations for endobronchial photodynamic therapy

The light distribution during photodynamic therapy of the bronchial tree has been estimated by measuring the fluence rate in ex vivo experiments on dissected pig bronchi. The trachea was illuminated (630 nm) with a cylindrical diffuser and the fluence rate was measured with a fibre optic isotropic probe. The experiment with the diffuser on the central axis was also simulated with Monte Carlo techniques using the optical properties that were determined with a double-integrating-sphere set-up. The results from ex vivo experiments and the Monte Carlo simulations were found to agree within the error of measurement (15%), indicating that the Monte Carlo technique can be used to estimate the light distribution for varying geometries and optical properties. The results showed that the light fluence rate in the mucosa of the tracheal tract may increase by a factor of six compared to the fluence rate in air (in the absence of tissue). This is due to the scattering properties of the tissue and the multiple reflections within the cavity. Further ex vivo experiments showed that the positioning of the diffuser is critical for the fluence rate in the lesion to be treated. When the position of the diffuser was changed from the central axis to near the lesion, the fluence rate in the mucosa increased significantly by several orders of magnitude as compared to the initial (central) illumination. The inter- and intraspecimen variations in this increase were large (+/- 35%) because of variations in optical and geometrical properties and light source positioning, respectively. These variations might cause under- or overdosage resulting in either insufficient tumour necrosis or excessive normal tissue damage.

Performance of isotropic light dosimetry probes based on scattering bulbs in turbid media.

In a previous paper the calibration of an isotropic light detector in clear media was described and validated. However, in most applications the detector is used to measure light distribution in turbid (scattering) media, that is, in tissues or tissue equivalent optical phantoms. Despite its small diameter (typically 0.8 mm), inserting the detector in a turbid medium may perturb the light distribution and change the fluence rate at the point of measurement. In the present paper we estimate the error in the fluence rate measured by a detector in turbid media after calibration in a clear medium (air), using an optical phantom and detector bulbs of different optical properties. The experimental results are compared with calculations using the diffusion approximation to the transport equation in a spherical geometry. From measurements in optical phantoms and the results of the calculations it appears that introduction of the detector into a water-based turbid medium with refractive index, absorption- and scattering coefficients different from those of the detector bulb may require corrections to the detector response of up to 10-15%, in order to obtain the true fluence rate in that medium. The diffusion model is used to explore the detector response in a number of tissues of interest in photodynamic therapy, using tissue optical properties from the literature. Based on these model calculations it is estimated that in real tissues the fluence rate measured by the detector is up to 3% below the true value.

Endovascular brachytherapy in coronary arteries: the Rotterdam experience

Purpose: The use of endovascular coronary brachytherapy to prevent restenosis following percutaneous transluminal coronary angioplasty (PTCA) began in April 1997 at the Department of Interventional Cardiology of the Thoraxcenter at the University Hospital of Rotterdam. This article reviews the more than 250 patients that have been treated so far.Methods and Materials: The Beta-Cath System (Novoste), a manual, hydraulic afterloader with 12 90Sr seeds, was used in the Beta Energy Restenosis Trial (BERT-1.5, n=31), for compassionate use (n=25), in the Beta-Cath System trial (n=27) and in the Beta Radiation in Europe (BRIE, n=14). Since the Beta-Cath System has been commercialized in Europe, 57 patients have been treated and registered in RENO (Registry Novoste). In the Proliferation Reduction with Vascular Energy Trial (PREVENT), 37 patients were randomized using the Guidant-Nucletron remote control afterloader with a 32P source wire and a centering catheter. Radioactive 32P coated stents have been implanted in 102 patients. In the Isostent Restenosis Intervention Study 1 (IRIS 1), 26 patients received a stent with an activity of 0.75-1.5 µCi, and in the IRIS 2 (European 32P dose response trial), 40 patients were treated with an activity of 6-12 µCi. In two consecutive pilot trials, radioactive stents with non-radioactive ends (cold-end stents) and with ends containing higher levels of activity (hot-end stents) were implanted in 21 and 17 patients, respectively.Results: In the BERT-1.5 trial, the radiation dose, prescribed at 2 mm from the source train (non-centered), was 12 Gy (10 patients), 14 Gy (10 patients) and 16 Gy (11 patients). At 6-month follow-up, 8 out of 28 (29%) patients developed restenosis. The target lesion revascularization rate (TLR) was 7 out of 30 (23%) at 6 months and 8 out of 30 (27%) at 1 year. Two patients presented with late thrombosis in the first year. For compassionate use patients, a restenosis rate (RR) of 53% was observed. In the PREVENT trial, 34 of 37 patients underwent an angiographic 6-month follow-up. The doses prescribed at 0.5 mm depth into the vessel wall were 0 Gy (8), 28 Gy (9), 35 Gy (11) and 42 Gy (8). TLR was 14% in the irradiated patients and 25% in the placebo group. One patient developed late thrombosis. In the IRIS 1 trial, 23 patients showed an RR of 17% (in-stent). In the IRIS 2 trial, in-stent restenosis was not seen in 36 patients at 6-month follow-up. However, a high RR (44%) was observed at the stent edges.Conclusions: The integration of vascular brachytherapy in the catheterization laboratory is feasible and the different treatment techniques that are used are safe. Problems, such as edge restenosis and late thrombotic occlusion, have been identified as limiting factors of this technique. Solutions have been suggested and will be tested in future trials.

Light distribution by linear diffusing sources for photodynamic therapy

The distribution of the light emitted by linear light diffusers commonly employed in photodynamic therapy (PDT) has been investigated. A device is presented which measures the angular distribution of the exiting light at each point of the diffuser. With these data the fluence rate in air or in a cavity at some distance from the diffuser can be predicted. The results show that the light is scattered from the diffuser predominantly in the forward direction. Experiments and calculations show that the fluence rate in air and in a cavity of scattering tissue at some distance from the diffuser has a maximum near the tip of the diffuser, instead of near the middle. However, the fluence rate resulting from an interstitial diffuser in a purely scattering tissue phantom shows a maximum in the bisecting plane of the diffuser as would be predicted when the diffuser emitted light isotropically. The scattering nature of the tissue is expected to cancel the anisotropy of the diffuser.

Comparison of brachytherapy strategies based on dose-volume histograms derived from quantitative intravascular ultrasound.

PURPOSE We present in this paper the comparison, by simulation, of different treatment strategies based either on beta- or gamma-sources, both with and without a centering device. Ionizing radiation to prevent restenosis is an emerging modality in interventional cardiology. Numerous clinical studies are presently being performed or planned, but there is variability in dose prescription, and both gamma- and beta-emitters are used, leading to a wide range of possible dose distributions over the arterial vessel wall. This paper discusses the potential merits of dose-volume histograms (DVH) based on three-dimensional (3-D) reconstruction of electrocardiogram (ECG)-gated intravascular ultrasound (IVUS) to compare brachytherapy treatment strategies. MATERIALS AND METHODS DVH describe the cumulative distribution of dose over three specific volumes: (1) at the level of the luminal surface, a volume was defined with a thickness of 0.1 mm from the automatically detected contour of the highly echogenic blood-vessel interface; (2) at the level of the IVUS echogenic media-adventitia interface (external elastic lamina [EEL]), an adventitial volume was computed considering a 0.5-mm thickness from EEL; and (3) the volume encompassed between the luminal surface and the EEL (plaque + media). The IVUS data used were recorded in 23 of 31 patients during the Beta Energy Restenosis Trial (BERT) conducted in our institution. RESULTS On average, the minimal dose in 90% of the adventitial volume was 37 +/- 16% of the prescribed dose; the minimal dose in 90% of the plaque + media volume was 58 +/- 24% and of the luminal surface volume was 67 +/- 31%. The minimal dose in the 10% most exposed luminal surface volume was 296 +/- 42%. Simulations of the use of a gamma-emitter and/or a radioactive source train centered in the lumen are reported, with a comparison of the homogeneity of the dose distribution. CONCLUSIONS It is possible to derive DVH from IVUS, to evaluate the dose delivered to different parts of the coronary wall. This process should improve our understanding of the mechanisms of action of brachytherapy.

Fractionated stereotactic radiotherapy for uveal melanoma, late clinical results

PURPOSE To determine local control, late toxicity and metastatic free survival (MFS) of patients treated with fractionated stereotactic radiation therapy (fSRT) for uveal melanoma (UM). METHODS AND MATERIALS Between 1999 and 2007, 102 UM patients were included in a prospective study of a single institution (median follow-up (FU) 32 months; median tumor thickness 6 mm); five fractions of 10 Gy were given. Primary endpoints were local tumor control and late toxicity (including visual outcome and eye preservation). Secondary endpoint was MFS. RESULTS Local tumor control was achieved in 96% of the patients. Fifteen enucleations were performed, 2-85 months after radiation. Four eyes were enucleated because of local tumor progression. Nine patients developed grade 3 or 4 neovascular glaucoma (NVG), 19 developed severe retinopathy, 13 developed opticoneuropathy grade 3 or 4, 10 developed cataract grade 3, and 10 patients suffered from keratitis sicca. Best corrected visual acuity (BCVA) decreased from a mean of 0.26 at diagnosis to 0.16, 3 months after radiation and it gradually declined to 0.03, 4 years after therapy. The 5-year actuarial MFS was 75% (95% CIs: 62-84%). CONCLUSIONS fSRT is an effective treatment modality for uveal melanoma with a good local control. With that, fSRT is a serious eye sparing treatment modality. However, our FU is relatively short. Also, the number of secondary enucleations is substantial, mainly caused by NVG.

A comparison of intravascular source designs based on the beta particle emitter 114mIn/114In. Line source versus stepping source.

BACKGROUND Catheter-based intravascular brachytherapy (IVB) sources of the next generation will have to meet high demands in terms of miniaturization, flexibility, safety, reliability, costs and versatility. The radionuclide pair 114mIn/114In (half-life 49.51 days, maximum beta energy 2.0 MeV, average beta energy 0.78 MeV) is an attractive beta emitter for application in such a source. METHODS Since metallic indium is unfit for the manufacture of a brachytherapy source, the feasibility, safety and dosimetric properties of a design concept comprising a linear array of ceramic In2O3 spheres within a thin-walled, superelastic Ni/Ti capsule are investigated. RESULTS Neutron activation of enriched In2O3 spheres yields a specific activity sufficiently high for the manufacture of a stepping source, keeping treatment times limited to a few minutes. Although 114mIn/114In also emits some gamma radiation, the effective doses received by members of the medical staff are an order of magnitude lower than those received from fluoroscopy. The dose distributions about a 40-mm line source and a 5-mm stepping source (outer diameter 0.36 mm) are calculated using MCNP4C. Dose-volume histograms (DVHs) are calculated for the line source (centered and noncentered) and the stepping source (centered) using the geometry of a human coronary artery. CONCLUSION The results show that a centered stepping source with optimized dwell times delivers the most homogenous dose within the target volume.