Roberto Miceli

Myc Down-Regulation Sensitizes Melanoma Cells to Radiotherapy by Inhibiting MLH1 and MSH2 Mismatch Repair Proteins

Purpose: Melanoma patients have a very poor prognosis with a response rate of <1% due to advanced diagnosis. This type of tumor is particularly resistant to conventional chemotherapy and radiotherapy, and the surgery remains the principal treatment for patients with localized melanoma. For this reason, there is particular interest in the melanoma biological therapy. Experimental Design: Using two p53 mutant melanoma models stably expressing an inducible c-myc antisense RNA, we have investigated whether Myc protein down-regulation could render melanoma cells more susceptible to radiotherapy, reestablishing apoptotic p53-independent pathway. In addition to address the role of p53 in the activation of apoptosis, we studied the effect of Myc down-regulation on radiotherapy sensitivity also in a p53 wild-type melanoma cell line. Results: Myc down-regulation is able per se to induce apoptosis in a fraction of the cell population (∼40% at 72 hours) and in combination with γ radiation efficiently enhances the death process. In fact, ∼80% of apoptotic cells are evident in Myc down-regulated cells exposed to γ radiation for 72 hours compared with ∼13% observed after only γ radiation treatment. Consistent with the enhanced apoptosis is the inhibition of the MLH1 and MSH2 mismatch repair proteins, which, preventing the correction of ionizing radiation mismatches occurring during DNA replication, renders the cells more prone to radiation-induced apoptosis. Conclusions: Data herein reported show that Myc down-regulation lowers the apoptotic threshold in melanoma cells by inhibiting MLH1 and MSH2 proteins, thus increasing cell sensitivity to γ radiation in a p53-independent fashion. Our results indicate the basis for developing new antitumoral therapeutic strategy, improving the management of melanoma patients.

Cone-beam computed tomography in hypofractionated stereotactic radiotherapy for brain metastases

BackgroundTo assess interfraction translational and rotational setup errors, in patients treated with image-guded hypofractionated stereotactic radiotherapy, immobilized by a thermoplastic mask and a bite-block and positioned using stereotactic coordinates.Methods37 patients with 47 brain metastases were treated with hypofractionated stererotactic radiotherapy. All patients were immobilized with a combination of a thermoplastic mask and a bite-block fixed to a stereotactic frame support. Daily cone-beam CT scans were acquired for every patient before the treatment session and were matched online with planning CT images, for 3D image registration. The mean value and standard deviation of all translational (X, Y, Z) and rotational errors (θx, θy, θz) were calculated for the matching results of bone matching algorithm.ResultsA total of 194 CBCT scans were analyzed. Mean +/- standard deviation of translational errors (X, Y, Z) were respectively 0.5 +/- 1.6 mm (range -5.7 and 5.9 mm) in X; 0.4 +/- 2.7 mm (range -8.2 and 12.1 mm) in Y; 0.4 +/- 1.9 mm (range -7.0 and 14 mm) in Z; median and 90th percentile were respectively within 0.5 mm and 2.4 mm in X, 0.3 mm and 3.2 mm in Y, 0.3 mm and 2.2 mm in Z. Mean +/- standard deviation of rotational errors (θx, θy, θz) were respectively 0.0 degrees+/- 1.3 degrees (θx) (range -6.0 degrees and 3.1 degrees); -0.1 degrees +/- 1.1 degrees (θy) (range -3.0 degrees and 2.4 degrees); -0.6 degrees +/- 1.4 degrees (θz) (range -5.0 degrees and 3.3 degrees). Median and 90th percentile of rotational errors were respectively within 0.1 degrees and 1.4 degrees (θx), 0.0 degrees and 1.2 degrees (θy), 0.0 degrees and 0.9 degrees (θz). Mean +/- SD of 3D vector was 3.1 +/- 2.1 mm (range 0.3 and 14.9 mm); median and 90th percentile of 3D vector was within 2.7 mm and 5.1 mm.ConclusionsHypofractionated stereotactic radiotherapy have the significant limitation of uncertainty in interfraction repeatability of the patient setup; image-guided radiotherapy using cone-beam computed tomography improves the accuracy of the treatment delivery reducing set-up uncertainty, giving the possibility of 3-dimensional anatomic informations in the treatment position.

Preliminary Studies for a CBCT Imaging Protocol for Offline Organ Motion Analysis: Registration Software Validation and CTDI Measurements

Cone-beam X-ray volumetric imaging in the treatment room, allows online correction of set-up errors and offline assessment of residual set-up errors and organ motion. In this study the registration algorithm of the X-ray volume imaging software (XVI, Elekta, Crawley, United Kingdom), which manages a commercial cone-beam computed tomography (CBCT)-based positioning system, has been tested using a homemade and an anthropomorphic phantom to: (1) assess its performance in detecting known translational and rotational set-up errors and (2) transfer the transformation matrix of its registrations into a commercial treatment planning system (TPS) for offline organ motion analysis. Furthermore, CBCT dose index has been measured for a particular site (prostate: 120 kV, 1028.8 mAs, approximately 640 frames) using a standard Perspex cylindrical body phantom (diameter 32 cm, length 15 cm) and a 10-cm-long pencil ionization chamber. We have found that known displacements were correctly calculated by the registration software to within 1.3 mm and 0.4°. For the anthropomorphic phantom, only translational displacements have been considered. Both studies have shown errors within the intrinsic uncertainty of our system for translational displacements (estimated as 0.87 mm) and rotational displacements (estimated as 0.22°). The resulting table translations proposed by the system to correct the displacements were also checked with portal images and found to place the isocenter of the plan on the linac isocenter within an error of 1 mm, which is the dimension of the spherical lead marker inserted at the center of the homemade phantom. The registration matrix translated into the TPS image fusion module correctly reproduced the alignment between planning CT scans and CBCT scans. Finally, measurements on the CBCT dose index indicate that CBCT acquisition delivers less dose than conventional CT scans and electronic portal imaging device portals. The registration software was found to be accurate, and its registration matrix can be easily translated into the TPS and a low dose is delivered to the patient during image acquisition. These results can help in designing imaging protocols for offline evaluations.

Transient effects of tumor location on the functional architecture at rest in glioblastoma patients: three longitudinal case studies

BackgroundThe cognitive function of brain tumor patients is affected during the treatment. There is evidence that gliomas and surgery alter the functional brain connectivity but studies on the longitudinal effects are lacking.MethodsWe acquired longitudinal (pre- and post-radiotherapy) resting-state functional magnetic resonance imaging on three selected glioblastoma patients. These cases were selected to study three models: a lesion involving a functional hub within a central system, a lesion involving a peripheral node within a central system and a lesion involving a peripheral node of a non-central system.ResultsWe found that, as expected, the tumor lesion affects connections in close vicinity, but when the lesion relates to a functional hub, these changes involve long-range connections leading to diverse connectivity profiles pre- and post-radiotherapy. In particular, a global but temporary improvement in the post-radiotherapy connectivity was obtained when treating a lesion close to a network hub, such as the posterior Cingulate Cortex.ConclusionsThis suggests that this node re-establishes communication to nodes further away in the network. Eventually, these observed effects seem to be transient and on the long-term the tumor burden leads to an overall decline of connectivity following the course of the pathology. Furthermore, we obtained that the link between hubs, such as the Supplementary Motor Area and posterior Cingulate Cortex represents an important backbone by means of which within and across network communication is handled: the disruption of this connection seems to imply a strong decrease in the overall connectivity.

Intra-parotid facial nerve schwannoma with intra-temporal extension; a case report. Is there a role for stereotactic radiotherapy?☆

Facial nerve schwannoma (FNS) is an extremely rare benign tumour that may arise anywhere along the course of the facial nerve; the standard treatment is total removal via microsurgery. Stereotactic radiotherapy has been shown to be effective in the treatment of skull base tumours, in particular for acoustic neuromas; it is interesting to notice that also the few data existing in literature about the use of radiotherapy for non acoustic schwannomas show an excellent local control rate and few adverse effects. Here we report a case of facial nerve neuroma, involving the nerve sheath from the geniculate ganglion to the parotid gland, treated with fractionated stereotactic radiotherapy after debulking surgery.

Image-guided-radiotherapy retreatment of spine metastasis: a case report and radiobiological evaluation.

Aims and background The present case report describes vertebral metastasis retreatment using kilovoltage cone-beam computed tomography (CBCT) for setup error correction, in order to improve target irradiation and prevent spinal cord toxicity. We evaluated the feasibility of the second radiation therapy course on the overlapping treatment volume. Methods and study design A patient with metastatic kidney cancer, previously treated to the tenth dorsal vertebra with conventional radiation planning (21 Gy; 3 × 7 Gy), underwent retreatment. In order to deliver 30 Gy (15 × 2 Gy) to the target volume with the second irradiation, we evaluated the residual dose that could be received by the spinal cord. We calculated the biologically effective dose according to the linear-quadratic model, using an α/β ratio of 2 Gy. A 3-dimensional conformal plan was generated; CBCT imaging was used to ensure accurate repositioning. Results A total of 15 CBCT scans were performed; the mean setup corrections in the lateral, longitudinal and vertical directions were 3.38 mm (SD 2.09; range, −0.2 mm ÷ 7.6 mm), 2.13 mm (SD 3.38; range, −5.9 mm ÷ 6 mm), and −1.28 mm (SD 2.02; range, −7.1 mm ÷ 0.3 mm), respectively. Conclusion Image-guided radiotherapy is an alternative approach for the retreatment of spine tumors; it ensures accurate patient setup correction and high-precision treatment delivery, which are required for target volumes very close to critical structures. Free full text available at www.tumorionline.it

EP-1882: Brain connectivity changes in the presence of a glioblastoma

Conclusion: Digital reflex camera can be used for quantitatively evaluate skin reactions. Moreover, it should be used to predict acute skin toxicity since the first 2 weeks of treatment. Early detection of acute skin reactions should improve patients’ quality of life. The proposed method seems to be sensitive to the radiotherapic technique (3D CRT vs Tomotherapy). The present results may be expanded by the study of the correlation with fractionation and other treatment parameters.

Evaluation of serrated intraprostatic gold coils positional stability using on-board cone beam computed tomography scans acquired throughout the radiation treatment course

PURPOSE To investigate intraprostatic gold coils positional stability analyzing intermarker distance in on-board cone beam computed tomography (CBCT) scans acquired throughout the entire treatment course. METHODS AND MATERIALS A total of 29 fiducial markers (FMs) were implanted in 10 patients through the transperineal approach, under ultrasound guidance. After 2 weeks from the FM implantation, all the patients underwent CT and magnetic resonance imaging under radiation therapy-planning conditions. The planning CT was the reference CT (CTref) used to calculate the initial intermarker distances. For every patient, 8 CBCTi (i varying from 1 to 8) acquired once a week during the treatment course were selected to calculate intermarker distances and compared with CTref. Reconstructed images of CBCTi were exported to the treatment planning system, and every FM was contoured. A point of interest at the center of mass of each contoured FM was created. The mean coordinates obtained for point of interest at the center of mass of FMs were used to calculate relative marker distances on CTref and CBCTi. RESULTS No patient developed postimplantation complications. A total of 224 marker distance variations (MDVs) were calculated for all 29 markers. The average directional variation of all MDVs (± standard deviation [SD]) was -0.14 ± 0.86 mm. The average absolute variations of all MDVs (± SD) were 0.71 ± 0.51 mm. The largest observed variation was 1.9 mm. All patients had not significant temporal trends in their marker distances. The SD of the MDVs was computed for each set of markers in all 10 patients. The SDs ranged between 0.4 and 1.1 mm in individual patients. The average of the mean SDs was 0.6 mm. CONCLUSIONS The three-dimensional definition of each fiducial marker volume, using on-board CBCT, demonstrated the stability of FMs position throughout the entire radiation therapy treatment course.