Universal evaluation of MLC models in treatment planning systems based on a common set of dynamic tests.

PURPOSE: To demonstrate the feasibility of characterising MLCs and MLC models implemented in TPSs using a common set of dynamic beams. MATERIALS AND METHODS: A set of tests containing synchronous (SG) and asynchronous sweeping gaps (aSG) was distributed among twenty-five participating centres. Doses were measured with a Farmer-type ion chamber and computed in TPSs, which provided a dosimetric characterisation of the leaf tip, tongue-and-groove, and MLC transmission of each MLC, as well as an assessment of the MLC model in each TPS. Five MLC types and four TPSs were evaluated, covering the most frequent combinations used in radiotherapy departments. RESULTS: Measured differences within each MLC type were minimal, while large differences were found between MLC models implemented in clinical TPSs. This resulted in some concerning discrepancies, especially for the HD120 and Agility MLCs, for which differences between measured and calculated doses for some MLC-TPS combinations exceeded 10%. These large differences were particularly evident for small gap sizes (5 and 10 mm), as well as for larger gaps in the presence of tongue-and-groove effects. A much better agreement was found for the Millennium120 and Halcyon MLCs, differences being within ± 5% and ± 2.5%, respectively. CONCLUSIONS: The feasibility of using a common set of tests to assess MLC models in TPSs was demonstrated. Measurements within MLC types were very similar, but TPS dose calculations showed large variations. Standardisation of the MLC configuration in TPSs is necessary. The proposed procedure can be readily applied in radiotherapy departments and can be a valuable tool in IMRT and credentialing audits.

Microparticles from tumors exposed to radiation promote immune evasion in part by PD-L1.

Radiotherapy induces immune-related responses in cancer patients by various mechanisms. Here, we investigate the immunomodulatory role of tumor-derived microparticles (TMPs)-extracellular vesicles shed from tumor cells-following radiotherapy. We demonstrate that breast carcinoma cells exposed to radiation shed TMPs containing elevated levels of immune-modulating proteins, one of which is programmed death-ligand 1 (PD-L1). These TMPs inhibit cytotoxic T lymphocyte (CTL) activity both in vitro and in vivo, and thus promote tumor growth. Evidently, adoptive transfer of CTLs pre-cultured with TMPs from irradiated breast carcinoma cells increases tumor growth rates in mice recipients in comparison with control mice receiving CTLs pre-cultured with TMPs from untreated tumor cells. In addition, blocking the PD-1-PD-L1 axis, either genetically or pharmacologically, partially alleviates TMP-mediated inhibition of CTL activity, suggesting that the immunomodulatory effects of TMPs in response to radiotherapy is mediated, in part, by PD-L1. Overall, our findings provide mechanistic insights into the tumor immune surveillance state in response to radiotherapy and suggest a therapeutic synergy between radiotherapy and immune checkpoint inhibitors.

Reconstruction of the electron source intensity distribution of a clinical linear accelerator using in-air measurements and a genetic algorithm.

BACKGROUND AND PURPOSE: The electron source intensity distribution of a clinical linear accelerator has a great influence on the calculation of output factors for small radiation fields where source occlusion by the collimating devices takes place. The purpose of this study was to present a new method for the electron source reconstruction problem. MATERIALS AND METHODS: The measurements were performed in-air using diode and 6 MV 1 × 1 cm2 photon field in flattening filter-free mode. In Monte Carlo simulation, an electron target area was divided into a number of square subsources. Then, the in-air doses in 2D silicon chip array were calculated individually from each subsource. A genetic algorithm search was applied in order to determine the optimal weight factors for all subsources that provide the best agreement between simulated and measured doses. RESULTS: It was found that the reconstructed electron source intensity from a clinical linear accelerator has the two-dimensional elliptical double Gaussian distribution. The source intensity distribution consisted of two intensity components along the in-plane (x) and cross-plane (y) directions characterized by full width half-maximum (FWHM): FWHMx1 = 0.27 cm, FWHMx2 = 0.08 cm, FWHMy1 = 0.24 cm, FWHMy2 = 0.06 cm, where broader components are 81% and 53% of the total intensity along × and y axis respectively. CONCLUSIONS: The obtained results demonstrated an elliptical double Gaussian intensity distribution of the incident electron source. We anticipate that the proposed method has universal applications independent of the type of linear accelerator, modality or energy.

ARTS mediates apoptosis and regeneration of the intestinal stem cell niche.

Stem cells (SCs) play a pivotal role in fueling homeostasis and regeneration. While much focus has been given to self-renewal and differentiation pathways regulating SC fate, little is known regarding the specific mechanisms utilized for their elimination. Here, we report that the pro-apoptotic protein ARTS (a Septin4 isoform) is highly expressed in cells comprising the intestinal SC niche and that its deletion protects Lgr5+ and Paneth cells from undergoing apoptotic cell death. As a result, the Sept4/ARTS-/- crypt displays augmented proliferation and, in culture, generates massive cystic-like organoids due to enhanced Wnt/ß-catenin signaling. Importantly, Sept4/ARTS-/- mice exhibit resistance against intestinal damage in a manner dependent upon Lgr5+ SCs. Finally, we show that ARTS interacts with XIAP in intestinal crypt cells and that deletion of XIAP can abrogate Sept4/ARTS-/--dependent phenotypes. Our results indicate that intestinal SCs utilize specific apoptotic proteins for their elimination, representing a unique target for regenerative medicine.

Dosimetric characterization of Elekta stereotactic cones.

PURPOSE: Dosimetry of small fields defined by stereotactic cones remains a challenging task. In this work, we report the results of commissioning measurements for the new Elekta stereotactic conical collimator system attached to the Elekta VersaHD linac and present the comparison between the measured and Monte Carlo (MC) calculated data for the 6 MV FFF beam. In addition, relative output factor (ROF) dependence on the stereotactic cone aperture variation was studied and penumbra comparison for small MLC-based and cone-based fields was performed. METHODS: Cones with nominal diameters of 15 mm, 12.5 mm, 10 mm, 7.5 mm, and 5 mm were employed in our study. Percentage depth dose (PDD), off-axis ratios (OAR), and ROF were measured using a stereotactic field diode (SFD). BEAMnrc code was used for MC simulations. RESULTS: MC calculated and measured PDDs for all cones agreed within 1%/0.5 mm, and OAR profiles agreed within 1%/0.5 mm. ROF obtained from the measurements and MC calculations agreed within 2% for all cone sizes. Small-field correction factors for the SFD detector Kfield,3 × 3 (SFD) were derived using MC calculations as a baseline and were found to be 0.982, 0.992, 0.997, 1.015, and 1.017 for the 5, 7.5, 10, 12.5, and 15-mm cones respectively. The difference in ROF was about 10%, 6%, 3.5%, 3%, 2.5%, and 2% for ±0.3 mm variations in 5, 7.5, 10, 12.5, and 15-mm cone aperture respectively. In case of single static field, cone-based collimation produced a sharper penumbra compared to the MLC-based. CONCLUSIONS: Accurate MC simulation can be an effective tool for verification of dosimetric measurements of small fields. Due to the very high sensitivity of output factors on the cone diameter, manufacture-related variations in cone size may lead to considerable variations in dosimetric characteristics of stereotactic cones.

Room scatter effects in Total Skin Electron Irradiation: Monte Carlo simulation study.

PURPOSE: Total Skin Electron Irradiation (TSEI) is a complex technique which usually involves the use of large electron fields and the dual-field approach. In this situation, many electrons scattered from the treatment room floor are produced. However, no investigations of the effect of scattered electrons in TSEI treatments have been reported. The purpose of this work was to study the contribution of floor scattered electrons to skin dose during TSEI treatment using Monte Carlo (MC) simulations. METHODS: All MC simulations were performed with the EGSnrc code. Influence of beam energy, dual-field angle, and floor material on the contribution of floor scatter was investigated. Spectrum of the scattered electrons was calculated. Measurements of dose profile were performed in order to verify MC calculations. RESULTS: Floor scatter dependency on the floor material was observed (at 20 cm from the floor, scatter contribution was about 21%, 18%, 15%, and 12% for iron, concrete, PVC, and water, respectively). Although total dose profiles exhibited slight variation as functions of beam energy and dual-field angle, no dependence of the floor scatter contribution on the beam energy or dual-field angle was found. The spectrum of the scattered electrons was almost uniform between a few hundred KeV to 4 MeV, and then decreased linearly to 6 MeV. CONCLUSIONS: For the TSEI technique, dose contribution due to the electrons scattered from the room floor may be clinically significant and should be taken into account during design and commissioning phases. MC calculations can be used for this task.

Perturbation effects of the carbon fiber-PEEK screws on radiotherapy dose distribution.

Radiation therapy, in conjunction with surgical implant fixation, is a common combined treatment in cases of bone metastases. However, metal implants generally used in orthopedic implants perturb radiation dose distributions. Carbon-Fiber Reinforced Polyetheretherketone (CFR-PEEK) material has been recently introduced for production of intramedullary nails and plates. The purpose of this work was to investigate the perturbation effects of the new CFR-PEEK screws on radiotherapy dose distributions and to evaluate these effects in comparison with traditional titanium screws. The investigation was performed by means of Monte Carlo (MC) simulations for a 6 MV photon beam. The project consisted of two main stages. First, a comparison of measured and MC calculated doses was performed to verify the validity of the MC simulation results for different materials. For this purpose, stainless steel, titanium, and CFR-PEEK plates of various thicknesses were used for attenuation and backscatter measurements in a solid water phantom. For the same setup, MC dose calculations were performed. Next, MC dose calculations for titanium, CFR-PEEK screws, and CFR-PEEK screws with ultrathin titanium coating were performed. For the plates, the results of our MC calculations for all materials were found to be in good agreement with the measurements. This indicates that the MC model can be used for calculation of dose perturbation effects caused by the screws. For the CFR-PEEK screws, the maximum dose perturbation was less than 5%, compared to more than 30% perturbation for the titanium screws. Ultrathin titanium coating had a negligible effect on the dose distribution. CFR-PEEK implants have good prospects for use in radiotherapy because of minimal dose alteration and the potential for more accurate treatment planning. This could favorably influence treatment efficiency and decrease possible over- and underdose of adjacent tissues. The use of such implants has potential clinical advantages in the treatment of bone metastases.

Validation of total skin electron irradiation (TSEI) technique dosimetry data by Monte Carlo simulation.

Total skin electron irradiation (TSEI) is a complex technique which requires many nonstandard measurements and dosimetric procedures. The purpose of this work was to validate measured dosimetry data by Monte Carlo (MC) simulations using EGSnrc-based codes (BEAMnrc and DOSXYZnrc). Our MC simulations consisted of two major steps. In the first step, the incident electron beam parameters (energy spectrum, FWHM, mean angular spread) were adjusted to match the measured data (PDD and profile) at SSD = 100 cm for an open field. In the second step, these parameters were used to calculate dose distributions at the treatment distance of 400 cm. MC simulations of dose distributions from single and dual fields at the treatment distance were performed in a water phantom. Dose distribution from the full treatment with six dual fields was simulated in a CT-based anthropomorphic phantom. MC calculations were compared to the available set of measurements used in clinical practice. For one direct field, MC calculated PDDs agreed within 3%/1 mm with the measurements, and lateral profiles agreed within 3% with the measured data. For the OF, the measured and calculated results were within 2% agreement. The optimal angle of 17° was confirmed for the dual field setup. Dose distribution from the full treatment with six dual fields was simulated in a CT-based anthropomorphic phantom. The MC-calculated multiplication factor (B12-factor), which relates the skin dose for the whole treatment to the dose from one calibration field, for setups with and without degrader was 2.9 and 2.8, respectively. The measured B12-factor was 2.8 for both setups. The difference between calculated and measured values was within 3.5%. It was found that a degrader provides more homogeneous dose distribution. The measured X-ray contamination for the full treatment was 0.4%; this is compared to the 0.5% X-ray contamination obtained with the MC calculation. Feasibility of MC simulation in an anthropomorphic phantom for a full TSEI treatment was proved and is reported for the first time in the literature. The results of our MC calculations were found to be in general agreement with the measurements, providing a promising tool for further studies of dose distribution calculations in TSEI.

Dequalinium blocks macrophage-induced metastasis following local radiation.

A major therapeutic obstacle in clinical oncology is intrinsic or acquired resistance to therapy, leading to subsequent relapse. We have previously shown that systemic administration of different cytotoxic drugs can induce a host response that contributes to tumor angiogenesis, regrowth and metastasis. Here we characterize the host response to a single dose of local radiation, and its contribution to tumor progression and metastasis. We show that plasma from locally irradiated mice increases the migratory and invasive properties of colon carcinoma cells. Furthermore, locally irradiated mice intravenously injected with CT26 colon carcinoma cells succumb to pulmonary metastasis earlier than their respective controls. Consequently, orthotopically implanted SW480 human colon carcinoma cells in mice that underwent radiation, exhibited increased metastasis to the lungs and liver compared to their control tumors. The irradiated tumors exhibited an increase in the colonization of macrophages compared to their respective controls; and macrophage depletion in irradiated tumor-bearing mice reduces the number of metastatic lesions. Finally, the anti-tumor agent, dequalinium-14, in addition to its anti-tumor effect, reduces macrophage motility, inhibits macrophage infiltration of irradiated tumors and reduces the extent of metastasis in locally irradiated mice. Overall, this study demonstrates the adverse effects of local radiation on the host that result in macrophage-induced metastasis.

Tolerance of the vaginal vault to high-dose rate brachytherapy and concomitant chemo-pelvic irradiation: Long-term perspective.

AIM/BACKGROUND: We sought to determine the tolerance level and complication rates of the vaginal vault to combined high-dose-rate intra-cavitary brachytherapy with concomitant chemo-radiotherapy. PATIENTS AND METHODS: A retrospective review of medical records of all the patients who received definitive chemo-radiotherapy for cervical cancer between 1998 and 2002 was undertaken. The records were reviewed for doses and for radiation-associated early and late sequelae of the vagina, rectum and bladder. Cumulative biological effective dose was calculated for two reference vaginal surface points. RESULTS: Fifty patients were included. Average age at diagnosis was 54 years. Median follow-up was 59 months. There were no recorded instances of acute grade IV toxicity. Maximal high-dose-rate vaginal surface dose (upper central point) was 103 Gy, and maximal brachytherapy lateral surface dose was 70 Gy. Maximal cumulative biological effective dose for the lateral surface reference point was 465.5 Gy3, and the maximal cumulative biological effective dose for the superior reference point was 878.6 Gy3. There were no cases of vaginal necrosis or fistulas, and no cases of grade IV late vaginal, rectal or bladder toxicity. No correlation was found between the maximal vaginal surface dose and vaginal, rectal or bladder toxicity. CONCLUSIONS: The maximal surface HDR brachytherapy dose of 103 Gy and the maximal cBED of 878.6 Gy3 were not associated with fistula or necrosis or other grade 3-4 vaginal complications. Concomitant chemo-radiotherapy, including pelvic radiotherapy and high-dose-rate intracavitary brachytherapy, is relatively safe for cervical cancer patients.

Hippocampal-sparing whole-brain radiotherapy using Elekta equipment.

The purpose of this study was to evaluate the feasibility of hippocampal-sparing whole-brain radiotherapy (HS WBRT) using the Elekta Infinity linear accelerator and Monaco treatment planning system (TPS). Ten treatment plans were created for HS-WBRT to a dose of 30 Gy (10 fractions). RTOG 0933 recommendations were applied for treatment planning. Intensity-modulated radiotherapy (IMRT) plans for the Elekta Infinity linear accelerator were created using Monaco 3.1 TPS-based on a nine-field arrangement and step-and-shoot delivery method. Plan evaluation was performed using D2% and D98% for the whole-brain PTV (defined as whole brain excluding hippocampus avoidance region), D100% and maximum dose to the hippocampus, and maximum dose to optic nerves and chiasm. Homogeneity index (HI) defined as (D2%-D98%)/Dmedian was used to quantify dose homogeneity in the PTV. The whole-brain PTV D2% mean value was 37.28 Gy (range 36.95-37.49Gy), and D98% mean value was 25.37 Gy (range 25.40-25.89 Gy). The hippocampus D100% mean value was 8.37 Gy (range 7.48-8.97 Gy) and the hippocampus maximum dose mean value was 14.35 Gy (range 13.48-15.40 Gy). The maximum dose to optic nerves and optic chiasm for all patients did not exceed 37.50 Gy. HI mean value was 0.36 (range 0.34-0.37). Mean number of segments was 105 (range 88-122) and mean number of monitor units was 1724 (range 1622-1914). Gamma evaluation showed that all plans passed 3%, 3 mm criteria with more than 99% of the measured points. These results indicate that Elekta equipment (Elekta Infinity linac and Monaco TPS) can be used for HS WBRT planning according to compliance criteria defined by the RTOG 0933 protocol.

Targeted therapy with low doses of 131I-MIBG is effective for disease palliation in highly refractory neuroblastoma.

BACKGROUND: Palliative treatment ore remains a significant clinical problem. OBJECTIVES: To retrospectively determine the clinical response to 131I-MIBG therapy at low doses in patients with refractory neuroblastoma. METHODS: We performed a retrospective chart review of 10 patients with neuroblastoma treated with 1311-MIBG at Rambam Health Care Campus from 1994 to 2012. Clinical data, number of 131I-MIBG courses delivered, toxicities, and clinical responses were reviewed. MIBG scan was performed after each course. RESULTS: Twenty-one courses of 131I-MIBG were delivered to 10 patients (3 girls, 7 boys). Their mean age was 3.8 years (range 1.5-6 years). All patients received several protocols of chemotherapy including the high dose form. Three patients received three courses of 131I-MIBG with a minimum of 6 weeks between each course, five patients received two courses, and two patients received only one course. An objective response to the first course was obtained in nine patients and to the second course in six of eight, and in three children who underwent the third course the pain decreased. One patient has no evidence of disease, four are alive with disease, and five died of the disease. No unanticipated toxicities were observed. CONCLUSIONS: Low dose 131I-MIBG is an effective and relatively non-toxic treatment in neuroblastoma disease palliation. Rapid and reproducible pain relief with 131I-MIBG was obtained in most of the children. Treatment with systemic radiotherapy in the form of low dose 131I-MIBG was easy to perform and effective in cases of disseminated neuroblastoma, demonstrating that this primary therapy can be used for palliative purposes.

Breast-conserving surgery and intraoperative electron radiotherapy in early breast cancer: experience at the Rambam Health Care Campus.

BACKGROUND: Local recurrences after breast-conserving surgery occur mostly at the site of the primary carcinoma. The main objective of postoperative radiotherapy is sterilization of residual cancer cells. Whole-breast radiotherapy is the standard of care, but its utility has recently been challenged in favor of radiotherapy limited to the area at highest risk of recurrence. Intraoperative electron radiotherapy (IOeRT) is an innovative technique for accelerated partial breast irradiation (APBI) that is applied to selected patients affected by early breast cancer. OBJECTIVES: To describe our experience with IOeRT at the Rambam Health Care Campus in Haifa since we began utilizing this modality in 2006. METHODS: From April 2006 to September 2010, 31 patients affected by unifocal invasive duct breast carcinoma < or = 2 cm diameter received wide local resection followed by intraoperative radiotherapy with electrons. Patients were evaluated for early and late complications, and other events, 1 month after surgery and every 3 months thereafter for the duration of the first 2 years. RESULTS: After a mean follow-up of 36 months, seven patients developed mild breast fibrosis and three suffered from mild postoperative infection. Rib fractures were observed in four patients before routine lead shielding was initiated. Additional whole-breast irradiation was given to four patients. None of the patients developed local recurrences or other ipsilateral cancers. Similarly, no contralateral cancers or distant metastases were observed. CONCLUSIONS: Intraoperative electron radiotherapy may be an alternative to external beam radiation therapy in an appropriate selected group of early-stage breast cancer patients. However, long-term results of clinical trials are required to better evaluate the indications and utility of this technique in the management of breast cancer.

Design and dosimetry characteristics of a commercial applicator system for intra-operative electron beam therapy utilizing ELEKTA Precise accelerator.

The design concept and dosimetric characteristics of a new applicator system for intraoperative radiation therapy (IORT) are presented in this work. A new hard-docking commercial system includes polymethylmethacrylate (PMMA) applicators with different diameters and applicator end angles and a set of secondary lead collimators. A telescopic device allows changing of source-to-surface distance (SSD). All measurements were performed for 6, 9, 12 and 18 MeV electron energies. Output factors and percentage depth doses (PDD) were measured in a water phantom using a plane-parallel ion chamber. Isodose contours and radiation leakage were measured using a solid water phantom and radiographic films. The dependence of PDD on SSD was checked for the applicators with the smallest and the biggest diameters. SSD dependence of the output factors was measured. Hardcopies of PDD and isodose contours were prepared to help the team during the procedure on deciding applicator size and energy to be chosen. Applicator output factors are a function of energy, applicator size and applicator type. Dependence of SSD correction factors on applicator size and applicator type was found to be weak. The same SSD correction will be applied for all applicators in use for each energy. The radiation leakage through the applicators is clinically acceptable. The applicator system enables effective collimation of electron beams for IORT. The data presented are sufficient for applicator, energy and monitor unit selection for IORT treatment of a patient.

Radiobiological effects of total body irradiation on the spinal cord.

Total body Irradiation (TBI) is often used for conditioning, prior to bone marrow transplantation. Doses of 8-14 Gy in 1-8 fractions over 1-4 days are administered using low dose rate external beam radiotherapy (EBRT). When necessary, consolidation EBRT using conventional doses, fractionation and dose rate is given. The irradiated volume usually contains critical organs such as spinal cord. The purpose of this study was to assess the biologic effect of TBI on the spinal cord in terms of EQD(2) (equivalent dose given in fractions of 2 Gy). EQD(2) values were calculated using the linear-quadratic generalized incomplete repair (IR) model that incorporates IR between fractions and low dose rate irradiation corrections and accounts for mono and bi-exponential repair. Three fractionation schemes were studied as function of dose rate: 8 Gy in 1 and 2 fractions and 12 Gy in 8 fractions. For the 12 Gy in 8 fractions scheme, the influence of dose rate on EQD(2) was limited because the effect of IR between fractions dominates. For the 8 Gy in 1 fraction scheme, significant sparing of the spinal cord may be achieved for low dose rate (5-20 cGy/min). The extent of effects depends on the parameters used. The IR model provides a useful mathematical framework for examination of the effects of fractionated treatments of varying dose rate. Reliable experimental data are needed for accurate assessment of radiation damage to the spinal cord following fractionated low dose rate TBI.

Definition of vaginal doses in intrauterine high-dose-rate brachytherapy.

PURPOSE: The aim of this study was to evaluate dosimetric aspects of high-dose-rate (HDR) intrauterine brachytherapy applications and to discuss a possible definition of vaginal points for dose reporting. METHODS AND MATERIALS: HDR brachytherapy was performed using a "Fletcher-like" applicator. Doses to the vaginal mucosa were assessed using 2 sets of points for each ovoid. Fifty treated patients were chosen for the analysis. Repeatability and reproducibility were analyzed. Total doses for the whole treatment at the vaginal points were calculated for each patient. The average dose for both ovoids was determined and the ratio of this dose to the dose at point "A" was calculated. The correlation between delivered doses and vaginal complications was tested statistically. RESULTS: Repeatability and reproducibility were found to be less than 1% compared with patient-to-patient variations (> 99%) for all points. The number of fractions and the number of patients in which the middle ovoid point was "representative" were calculated for the lateral and upper surfaces, respectively. The calculated vaginal-average to point "A" dose ratio was found to be 175% and 130% for the 20 and 25 mm ovoids, respectively. A correlation between delivered doses and the rate of complications was not found. CONCLUSIONS: The proposed method has been validated and allows calculations of vaginal doses. The vaginal-to-point "A" dose ratios allow a fast estimation of the vaginal dose for 20 and 25 mm ovoids. The doses delivered to our patients were below vaginal tolerance.