Sviluppo di un metodo di radioterapia adattativa tramite immagini portali e Cone-Beam CT

Il presente lavoro, svolto presso il servizio di Fisica Sanitaria dell’Azienda Ospedaliera Universitaria di Parma, consiste nello sviluppo di un metodo innovativo di radioterapia adattativa. Il metodo è stato applicato a pazienti affetti da varie patologie, trattati con tecnica VMAT, (Volumetric Modulated Arc Therapy), altamente conformata al target. Il metodo sviluppato si compone di due fasi: nella prima fase vengono effettuate due analisi su immagini portali, di ricostruzione della dose all'isocentro e l'analisi gamma 2D. Se almeno una di queste fallisce, si interviene con la seconda fase, che vede l'acquisizione della CBCT del paziente e la taratura in densità elettronica della stessa. Si calcola dunque il piano su CBCT, previa operazione di contouring da parte del medico e, infine, si esegue l'analisi gamma 3D sulle matrici di dose calcolate sulla CT e sulla CBCT del paziente, quantificando gli indici gamma sulle strutture PTV, CTV e OAR di interesse clinico. In base ai risultati, se necessario, si può intervenire sul piano di trattamento. Le analisi gamma 2D e 3D sono state svolte avvalendosi di un software toolkit chiamato GADD-23 (Gamma Analysis on 2D and 3D Dose Distributions) implementato e sviluppato appositamente in ambiente Matlab per questo lavoro di tesi; in particolare, la realizzazione di GADD-23 è stata resa possibile grazie all'interazione con due software di tipo open-source, Elastix e CERR, specifici per l’elaborazione e la registrazione di immagini mediche. I risultati ottenuti mostrano come il metodo sviluppato sia in grado di mettere in luce cambiamenti anatomici che alcuni pazienti hanno subìto, di tipo sistematico, in cui è possibile prendere in considerazione una ripianificazione del trattamento per correggerli, o di tipo casuale, sui quali può essere utile condurre l'attenzione del medico radioterapista, sebbene non sia necessario un replanning.

Intensity-modulated radiotherapy for a rendu-osler-weber disease patient with recurrent severe epistaxis: a case report

We present a case of a Rendu-Osler-Weber disease patient with recurrent life threatening epistaxis demanding multiple blood transfusions despite of repetitive endoscopic laser and electrocoagulations, endovascular embolisation, septodermoplasty, and long-term intranasal dressings. As alternative treatment modalities repeatedly failed and the patient became almost permanently dependent on nasal dressing, we performed a highly conformal intensity-modulated radiotherapy of the nasal cavity; a total dose of 50 Gy in 2 Gy single fractions was applied. The therapy was very well tolerated, no acute toxicities occurred. Two weeks after the last radiation dose had been applied, the nasal dressing could be removed without problems. Endoscopical control revealed an almost avascular white mucosa without any trace of bleeding spots; previously existing hemangiomas and crusts had disappeared. After a 1-year-follow up, the patient had no significant recurrent epistaxis.

Laser-guided lumbar medial branch kryorhizotomy

The authors describe a modification of the medial branch kryorhizotomy technique for the treatment of lumbar facet joint syndrome using a fluoroscopy-based laser-guided method. A total of 32 patients suffering from lumbar facet joint syndrome confirmed by positive medial nerve block underwent conventional or laser-guided kryorhizotomy. The procedural time (20.6 +/- 1.0 vs 16.3 +/- 0.9 minutes, p < 0.01), fluoroscopy time (54.1 +/- 3.5 vs 28.2 +/- 2.4 seconds, p < 0.01), radiation dose (407.5 +/- 32.0 vs 224.1 +/- 20.3 cGy/cm(2), p < 0.01), and patient discomfort during the procedure (7.1 +/- 0.4 vs 5.2 +/- 0.4 on the visual analog scale, p < 0.01) were significantly reduced in the laser-guided group. There was a tendency for a better positioning accuracy when the laser guidance method was used (3.0 +/- 0.3 vs 2.2 +/- 0.3 mm of deviation from the target points, p > 0.05). No difference in the outcome was observed between the 2 groups of patients (visual analog scale score 3.5 +/- 0.2 vs 3.3 +/- 0.3, p > 0.05). This improved minimally invasive surgical technique offers advantages to conventional fluoroscopy-based kryorhizotomy.

Synchrotron X-ray interlaced microbeams suppress paroxysmal oscillations in neuronal networks initiating generalized epilepsy

Radiotherapy has shown some efficacy for epilepsies but the insufficient confinement of the radiation dose to the pathological target reduces its indications. Synchrotron-generated X-rays overcome this limitation and allow the delivery of focalized radiation doses to discrete brain volumes via interlaced arrays of microbeams (IntMRT). Here, we used IntMRT to target brain structures involved in seizure generation in a rat model of absence epilepsy (GAERS). We addressed the issue of whether and how synchrotron radiotherapeutic treatment suppresses epileptic activities in neuronal networks. IntMRT was used to target the somatosensory cortex (S1Cx), a region involved in seizure generation in the GAERS. The antiepileptic mechanisms were investigated by recording multisite local-field potentials and the intracellular activity of irradiated S1Cx pyramidal neurons in vivo. MRI and histopathological images displayed precise and sharp dose deposition and revealed no impairment of surrounding tissues. Local-field potentials from behaving animals demonstrated a quasi-total abolition of epileptiform activities within the target. The irradiated S1Cx was unable to initiate seizures, whereas neighboring non-irradiated cortical and thalamic regions could still produce pathological oscillations. In vivo intracellular recordings showed that irradiated pyramidal neurons were strongly hyperpolarized and displayed a decreased excitability and a reduction of spontaneous synaptic activities. These functional alterations explain the suppression of large-scale synchronization within irradiated cortical networks. Our work provides the first post-irradiation electrophysiological recordings of individual neurons. Altogether, our data are a critical step towards understanding how X-ray radiation impacts neuronal physiology and epileptogenic processes.

Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients

PURPOSE: To assess the outcomes and patterns of failure in solitary plasmacytoma (SP). METHODS AND MATERIALS: The data from 258 patients with bone (n = 206) or extramedullary (n = 52) SP without evidence of multiple myeloma (MM) were collected. A histopathologic diagnosis was obtained for all patients. Most (n = 214) of the patients received radiotherapy (RT) alone; 34 received chemotherapy and RT, and 8 surgery alone. The median radiation dose was 40 Gy. The median follow-up was 56 months (range 7-245). RESULTS: The median time to MM development was 21 months (range 2-135), with a 5-year probability of 45%. The 5-year overall survival, disease-free survival, and local control rate was 74%, 50%, and 86%, respectively. On multivariate analyses, the favorable factors were younger age and tumor size <4 cm for survival; younger age, extramedullary localization, and RT for disease-free survival; and small tumor and RT for local control. Bone localization was the only predictor of MM development. No dose-response relationship was found for doses >30 Gy, even for larger tumors. CONCLUSION: Progression to MM remains the main problem. Patients with extramedullary SP had the best outcomes, especially when treated with moderate-dose RT. Chemotherapy and/or novel therapies should be investigated for bone or bulky extramedullary SP.

Hypothetical mortality risk associated with spiral tomography of the maxilla and mandible prior to endosseous implant treatment

Radiation dose delivered from the SCANORA radiography unit during the cross-sectional mode for dentotangential projections was determined. With regard to oral implantology, patient situations of an edentulous maxilla and mandible as well as a single tooth gap in regions 16 and 46 were simulated. Radiation doses were measured between 0.2 and 22.5 mGy to organs and tissues in the head and neck region when the complete maxilla or mandible was examined. When examining a single tooth gap, only 8% to 40% of that radiation dose was generally observed. Based on these results, the mortality risk was estimated according to a calculation model recommended by the Committee on the Biological Effects of Ionizing Radiations. The mortality risk ranged from 31.4 x 10(-6) for 20-year-old men to 4.8 x 10(-6) for 65-year-old women when cross-sectional imaging of the complete maxilla was performed. The values decreased by 70% when a single tooth gap in the molar region of the maxilla was radiographed. The figures for the mortality risk for examinations of the complete mandible were similar to those for the complete maxilla, but the mortality risk decreased by 80% if only a single tooth gap in the molar region of the mandible was examined. Calculations according to the International Commission on Radiological Protection carried out for comparison did not reveal the decrease of the mortality risk with age and resulted in a higher risk value in comparison to the group of 35-year old individuals in calculations according to the Committee on the Biological Effects of Ionizing Radiations.

Hypothetical mortality risk associated with spiral computed tomography of the maxilla and mandible

In the present study, dose measurements have been conducted following examination of the maxilla and mandible with spiral computed tomography (CT). The measurements were carried out with 2 phantoms, a head and neck phantom and a full body phantom. The analysis of applied thermoluminescent dosimeters yielded radiation doses for organs and tissues in the head and neck region between 0.6 and 16.7 mGy when 40 axial slices and 120 kV/165 mAs were used as exposure parameters. The effective dose was calculated as 0.58 and 0.48 mSv in the maxilla and mandible, respectively. Tested methods for dose reduction showed a significant decrease of radiation dose from 40 to 65%. Based on these results, the mortality risk was estimated according to calculation models recommended by the Committee on the Biological Effects of Ionizing Radiations and by the International Commission on Radiological Protection. Both models resulted in similar values. The mortality risk ranges from 46.2 x 10.6 for 20-year-old men to 11.2 x 10(-6) for 65-year-old women. Using 2 methods of dose reduction, the mortality risk decreased by approximately 50 to 60% to 19.1 x 10(-6) for 20-year-old men and 5.5 x 10(-6) for 65-year-old women. It can be concluded that a CT scan of the maxillofacial complex causes a considerable radiation dose when compared with conventional radiographic examinations. Therefore, a careful indication for this imaging technique and dose reduction methods should be considered in daily practice.

Hypervascular liver tumors: low tube voltage, high tube current multi-detector row CT for enhanced detection--phantom study

PURPOSE: To prospectively evaluate, for the depiction of simulated hypervascular liver lesions in a phantom, the effect of a low tube voltage, high tube current computed tomographic (CT) technique on image noise, contrast-to-noise ratio (CNR), lesion conspicuity, and radiation dose. MATERIALS AND METHODS: A custom liver phantom containing 16 cylindric cavities (four cavities each of 3, 5, 8, and 15 mm in diameter) filled with various iodinated solutions to simulate hypervascular liver lesions was scanned with a 64-section multi-detector row CT scanner at 140, 120, 100, and 80 kVp, with corresponding tube current-time product settings at 225, 275, 420, and 675 mAs, respectively. The CNRs for six simulated lesions filled with different iodinated solutions were calculated. A figure of merit (FOM) for each lesion was computed as the ratio of CNR2 to effective dose (ED). Three radiologists independently graded the conspicuity of 16 simulated lesions. An anthropomorphic phantom was scanned to evaluate the ED. Statistical analysis included one-way analysis of variance. RESULTS: Image noise increased by 45% with the 80-kVp protocol compared with the 140-kVp protocol (P < .001). However, the lowest ED and the highest CNR were achieved with the 80-kVp protocol. The FOM results indicated that at a constant ED, a reduction of tube voltage from 140 to 120, 100, and 80 kVp increased the CNR by factors of at least 1.6, 2.4, and 3.6, respectively (P < .001). At a constant CNR, corresponding reductions in ED were by a factor of 2.5, 5.5, and 12.7, respectively (P < .001). The highest lesion conspicuity was achieved with the 80-kVp protocol. CONCLUSION: The CNR of simulated hypervascular liver lesions can be substantially increased and the radiation dose reduced by using an 80-kVp, high tube current CT technique.

Assessment of vertical facial and dentoalveolar changes using panoramic radiography

The purpose of the study was to analyse longitudinal vertical facial and dentoalveolar changes using panoramic radiographs (PRs) and to compare the results with measurements on lateral cephalometric radiographs (LCRs) in order to determine whether, under certain circumstances, the radiation dose for a patient may be reduced by taking only a PR instead of a PR and a LCR. Pre- and post-treatment PRs and LCRs of 30 (15 females and 15 males) orthodontically treated adolescents (mean age pre-treatment 10.9 years, post-treatment 13.4 years) were analysed using Pearson's correlation coefficients and gender differences using Fisher's z-transformation. The results revealed that most variables exhibited larger absolute values on PRs than on LCRs. Comparison of dentoskeletal morphology between the LCRs and the PRs revealed moderate to high, mostly statistically significant, interrelations both before and after orthodontic treatment. The lowest correlations were found for the maxillary jaw base angle (NL/H; r= 0.35***) and the highest for the gonial angle (ML/RL; r = 0.90***). However, when assessing the combined growth and treatment changes from before to after treatment, only weak to moderate, not statistically significant, interrelations were found between LCRs and PRs. Anterior face height (AFH; r = 0.43***), the mandibular plane angle (ML/H; r = 0.06*), and the distance of the incisal tip of the most extruded mandibular incisor to the ML-line (ii-ML; r = -0.21*) were the only statistically significant parameters. The average group differences for growth and treatment changes, however, were small for most parameters. Analysis of vertical facial and dentoalveolar parameters on PRs delivers a moderate approximation to the situation depicted on LCRs. However, PRs cannot be recommended for the analysis of individual longitudinal changes in vertical facial and dentoalveolar parameters.

The results of surgery, with or without radiotherapy, for primary spinal myxopapillary ependymoma: a retrospective study from the rare cancer network

PURPOSE: The aim of this study was to assess the outcome of patients with primary spinal myxopapillary ependymoma (MPE). MATERIALS AND METHODS: Data from a series of 85 (35 females, 50 males) patients with spinal MPE were collected in this retrospective multicenter study. Thirty-eight (45%) underwent surgery only and 47 (55%) received postoperative radiotherapy (RT). Median administered radiation dose was 50.4 Gy (range, 22.2-59.4). Median follow-up of the surviving patients was 60.0 months (range, 0.2-316.6). RESULTS: The 5-year progression-free survival (PFS) was 50.4% and 74.8% for surgery only and surgery with postoperative low- (<50.4 Gy) or high-dose (>or=50.4 Gy) RT, respectively. Treatment failure was observed in 24 (28%) patients. Fifteen patients presented treatment failure at the primary site only, whereas 2 and 1 patients presented with brain and distant spinal failure only. Three and 2 patients with local failure presented with concomitant spinal distant seeding and brain failure, respectively. One patient failed simultaneously in the brain and spine. Age greater than 36 years (p = 0.01), absence of neurologic symptoms at diagnosis (p = 0.01), tumor size >or=25 mm (p = 0.04), and postoperative high-dose RT (p = 0.05) were variables predictive of improved PFS on univariate analysis. In multivariate analysis, only postoperative high-dose RT was independent predictors of PFS (p = 0.04). CONCLUSIONS: The observed pattern of failure was mainly local, but one fifth of the patients presented with a concomitant spinal or brain component. Postoperative high-dose RT appears to significantly reduce the rate of tumor progression.

Thoracolumbar spine fractures in patients who have sustained severe trauma: depiction with multi-detector row CT

PURPOSE: To determine if multi–detector row computed tomography (CT) can replace conventional radiography and be performed alone in severe trauma patients for the depiction of thoracolumbar spine fractures. MATERIALS AND METHODS: One hundred consecutive severe trauma patients who underwent conventional radiography of the thoracolumbar spine as well as thoracoabdominal multi–detector row CT were prospectively identified. Conventional radiographs were reviewed independently by three radiologists and two orthopedic surgeons; CT images were reviewed by three radiologists. Reviewers were blinded both to one another’s reviews and to the results of initial evaluation. Presence, location, and stability of fractures, as well as quality of reviewed images, were assessed. Statistical analysis was performed to determine sensitivity and interobserver agreement for each procedure, with results of clinical and radiologic follow-up as the standard of reference. The time to perform each examination and the radiation dose involved were evaluated. A resource cost analysis was performed. RESULTS: Sixty-seven fractured vertebrae were diagnosed in 26 patients. Twelve patients had unstable spine fractures. Mean sensitivity and interobserver agreement, respectively, for detection of unstable fractures were 97.2% and 0.951 for multi–detector row CT and 33.3% and 0.368 for conventional radiography. The median times to perform a conventional radiographic and a multi–detector row CT examination, respectively, were 33 and 40 minutes. Effective radiation doses at conventional radiography of the spine and thoracoabdominal multi–detector row CT, respectively, were 6.36 mSv and 19.42 mSv. Multi–detector row CT enabled identification of 146 associated traumatic lesions. The costs of conventional radiography and multi–detector row CT, respectively, were $145 and $880 per patient. CONCLUSION: Multi–detector row CT is a better examination for depicting spine fractures than conventional radiography. It can replace conventional radiography and be performed alone in patients who have sustained severe trauma.

Dosimetric properties of an amorphous silicon EPID for verification of modulated electron radiotherapy

Purpose: To investigate the dosimetric properties of an electronic portal imaging device (EPID) for electron beam detection and to evaluate its potential for quality assurance (QA) of modulated electron radiotherapy (MERT). Methods: A commercially available EPID was used to detect electron beams shaped by a photon multileaf collimator (MLC) at a source-surface distance of 70 cm. The fundamental dosimetric properties such as reproducibility, dose linearity, field size response, energy response, and saturation were investigated for electron beams. A new method to acquire the flood-field for the EPID calibration was tested. For validation purpose, profiles of open fields and various MLC fields (square and irregular) were measured with a diode in water and compared to the EPID measurements. Finally, in order to use the EPID for QA of MERT delivery, a method was developed to reconstruct EPID two-dimensional (2D) dose distributions in a water-equivalent depth of 1.5 cm. Comparisons were performed with film measurement for static and dynamic monoenergy fields as well as for multienergy fields composed by several segments of different electron energies. Results: The advantageous EPID dosimetric properties already known for photons as reproducibility, linearity with dose, and dose rate were found to be identical for electron detection. The flood-field calibration method was proven to be effective and the EPID was capable to accurately reproduce the dose measured in water at 1.0 cm depth for 6 MeV, 1.3 cm for 9 MeV, and 1.5 cm for 12, 15, and 18 MeV. The deviations between the output factors measured with EPID and in water at these depths were within ±1.2% for all the energies with a mean deviation of 0.1%. The average gamma pass rate (criteria: 1.5%, 1.5 mm) for profile comparison between EPID and measurements in water was better than 99% for all the energies considered in this study. When comparing the reconstructed EPID 2D dose distributions at 1.5 cm depth to film measurements, the gamma pass rate (criteria: 2%, 2 mm) was better than 97% for all the tested cases. Conclusions: This study demonstrates the high potential of the EPID for electron dosimetry, and in particular, confirms the possibility to use it as an efficient verification tool for MERT delivery.

Synchrotron x ray induced axonal transections in the brain of rats assessed by high-field diffusion tensor imaging tractography

Since approximately two thirds of epileptic patients are non-eligible for surgery, local axonal fiber transections might be of particular interest for them. Micrometer to millimeter wide synchrotron-generated X-ray beamlets produced by spatial fractionation of the main beam could generate such fiber disruptions non-invasively. The aim of this work was to optimize irradiation parameters for the induction of fiber transections in the rat brain white matter by exposure to such beamlets. For this purpose, we irradiated cortex and external capsule of normal rats in the antero-posterior direction with a 4 mm×4 mm array of 25 to 1000 µm wide beamlets and entrance doses of 150 Gy to 500 Gy. Axonal fiber responses were assessed with diffusion tensor imaging and fiber tractography; myelin fibers were examined histopathologically. Our study suggests that high radiation doses (500 Gy) are required to interrupt axons and myelin sheaths. However, a radiation dose of 500 Gy delivered by wide minibeams (1000 µm) induced macroscopic brain damage, depicted by a massive loss of matter in fiber tractography maps. With the same radiation dose, the damage induced by thinner microbeams (50 to 100 µm) was limited to their paths. No macroscopic necrosis was observed in the irradiated target while overt transections of myelin were detected histopathologically. Diffusivity values were found to be significantly reduced. A radiation dose ≤ 500 Gy associated with a beamlet size of < 50 µm did not cause visible transections, neither on diffusion maps nor on sections stained for myelin. We conclude that a peak dose of 500 Gy combined with a microbeam width of 100 µm optimally induced axonal transections in the white matter of the brain.

Clinical Impact of Couch Top and Rails on IMRT and Arc Therapy

Purpose: To evaluate the clinical impact of the Varian Exact Couch on dose and volume coverage to targets and critical structures and tumor control probability (TCP) for 6-MV IMRT and Arc Therapy. Methods: Five clinical prostate patients were planned with both, 6-MV 8-field IMRT and 6-MV 2-field RapidArc using the Eclipse treatment planning system (TPS). These plans neglected treatment couch attenuation, as is standard clinical practice. Dose distributions were then recalculated in Eclipse with the inclusion of the Varian Exact Couch (imaging couch top) and the rails in varying configurations. The changes in dose and coverage were evaluated using the DVHs from each plan iteration. We used a tumor control probability (TCP) model to calculate losses in tumor control resulting from not accounting for the couch top and rails. We also verified dose measurements in a phantom. Results: Failure to account for the treatment couch and rails resulted in clinically unacceptable dose and volume coverage losses to the target for both IMRT and RapidArc. The couch caused average dose losses (relative to plans that ignored the couch) to the prostate of 4.2% and 2.0% for IMRT with the rails out and in, respectively, and 3.2% and 2.9% for RapidArc with the rails out and in, respectively. On average, the percentage of the target covered by the prescribed dose dropped to 35% and 84% for IMRT (rails out and in, respectively) and to 18% and 17% for RapidArc (rails out and in, respectively). The TCP was also reduced by as much as 10.5% (6.3% on average). Dose and volume coverage losses for IMRT plans were primarily due to the rails, while the imaging couch top contributed most to losses for RapidArc. Both the couch top and rails contribute to dose and coverage losses that can render plans clinically unacceptable. A follow-up study we performed found that the less attenuating unipanel mesh couch top available with the Varian Exact couch does not cause a clinically impactful loss of dose or coverage for IMRT but still causes an unacceptable loss for RapidArc. Conclusions: Both the imaging couch top and rails contribute to dose and coverage loss to a degree that, if included, would prevent the plan from meeting clinical planning criteria. Therefore, the imaging and mesh couch tops and rails should be accounted for in Arc Therapy and the imaging couch and rails only in IMRT treatment planning.

A dosimetric study of radionuclide therapy for bone marrow ablation

In a phase I clinical trial, six multiple myeloma patients, who were non-responsive to conventional therapy and were scheduled for bone marrow transplantation, received Holmium-166 ($\sp{166}$Ho) labeled to a bone seeking agent, DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid), for the purpose of bone marrow ablation. The specific aims of my research within this protocol were to evaluate the toxicity and efficacy of $\sp{166}$Ho DOTMP by quantifying the in vivo pharmacokinetics and radiation dosimetry, and by correlating these results to the biologic response observed. The reproducibility of pharmacokinetics from multiple injections of $\sp{166}$Ho DOTMP administered to these myeloma patients was demonstrated from both blood and whole body retention. The skeletal concentration of $\sp{166}$Ho DOTMP was heterogenous in all six patients: high in the ribs, pelvis, and lumbar vertebrae regions, and relatively low in the femurs, arms, and head.^ A novel technique was developed to calculate the radiation dose to the bone marrow in each skeletal ROI, and was applied to all six $\sp{166}$Ho DOTMP patients. Radiation dose estimates for the bone marrow calculated using the standard MIRD "S" factors were compared with the average values derived from the heterogenous distribution of activity in the skeleton (i.e., the regional technique). The results from the two techniques were significantly different; the average of the dose estimates from the regional technique were typically 30% greater. Furthermore, the regional technique provided a range of radiation doses for the entire marrow volume, while the MIRD "S" factors only provided a single value. Dose volume histogram analysis of data from the regional technique indicated a range of dose estimates that varied by a factor of 10 between the high dose and low dose regions. Finally, the observed clinical response of cells and abnormal proteins measured in bone marrow aspirates and peripheral blood samples were compared with radiation dose estimates for the bone marrow calculated from the standard and regional technique. The results showed the regional technique values correlated more closely to several clinical response parameters. (Abstract shortened by UMI.) ^