Silver Nanoparticles (AgNPs) as Enhancers of Everolimus and Radiotherapy Sensitivity on Clear Cell Renal Cell Carcinoma.

Nanomedicine's advent has promised to revolutionize different biomedical fields, including oncology. Silver Nanoparticles (AgNPs) showed promising results in different tumor models. Clear cell Renal Cell Carcinoma (ccRCC) is especially challenging due to its late diagnosis, poor prognosis and treatment resistance. Therefore, defining new therapeutic targets and regimens could improve patient management. This study intends to evaluate AgNPs' effect in ccRCC cells and explore their potential combinatory effect with Everolimus and Radiotherapy. AgNPs were synthesized, and their effect was evaluated regarding their entering pathway, cellular proliferation capacity, ROS production, mitochondrial membrane depolarization, cell cycle analysis and apoptosis assessment. AgNPs were combined with Everolimus or used to sensitize cells to radiotherapy. AgNPs are cytotoxic to 786-O cells, a ccRCC cell line, entering through endocytosis, increasing ROS, depolarizing mitochondrial membrane, and blocking the cell cycle, leading to a reduction of proliferation capacity and apoptosis. Combined with Everolimus, AgNPs reduce cell viability and inhibit proliferation capacity. Moreover, 786-O is intrinsically resistant to radiation, but after AgNPs' administration, radiation induces cytotoxicity through mitochondrial membrane depolarization and S phase blockage. These results demonstrate AgNPs' cytotoxic potential against ccRCC and seem promising regarding the combination with Everolimus and sensitization to radiotherapy, which can, in the future, benefit ccRCC patients' management.

Epigenetic regulation of TP53 is involved in prostate cancer radioresistance and DNA damage response signaling.

External beam radiotherapy (RT) is a leading first-line therapy for prostate cancer (PCa), and, in recent years, significant advances have been accomplished. However, RT resistance can arise and result in long-term recurrence or disease progression in the worst-case scenario. Thus, making crucial the discovery of new targets for PCa radiosensitization. Herein, we generated a radioresistant PCa cell line, and found p53 to be highly expressed in radioresistant PCa cells, as well as in PCa patients with recurrent/disease progression submitted to RT. Mechanism dissection revealed that RT could promote p53 expression via epigenetic modulation. Specifically, a decrease of H3K27me3 occupancy at TP53 gene promoter, due to increased KDM6B activity, was observed in radioresistant PCa cells. Furthermore, p53 is essential for efficient DNA damage signaling response and cell recovery upon stress induction by prolonged fractionated irradiation. Remarkably, KDM6B inhibition by GSK-J4 significantly decreased p53 expression, consequently attenuating the radioresistant phenotype of PCa cells and hampering in vivo 3D tumor formation. Overall, this work contributes to improve the understanding of p53 as a mediator of signaling transduction in DNA damage repair, as well as the impact of epigenetic targeting for PCa radiosensitization.

IROCA-TES: Improving Quality in Radiation Oncology through Clinical Audits - Training and Education for Standardization.

Background: Clinical audits are an important tool to objectively assess clinical protocols, procedures, and processes and to detect deviations from good clinical practice. The main aim of this project is to determine adherence to a core set of consensus- based quality indicators and then to compare the institutions in order to identify best practices. Materials and methods: We conduct a multicentre, international clinical audit of six comprehensive cancer centres in Poland, Spain, Italy, Portugal, France, and Romania as a part of the project, known as IROCATES (Improving Quality in Radiation Oncology through Clinical Audits - Training and Education for Standardization). Results: Radiotherapy practice varies from country to country, in part due to historical, economic, linguistic, and cultural differences. The institutions developed their own processes to suit their existing clinical practice. Conclusions: We believe that this study will contribute to establishing the value of routinely performing multi-institutional clinical audits and will lead to improvement of radiotherapy practice at the participating centres.

Development of an independent MU calculation software for radiotherapy treatments with stereotactic cones.

PURPOSE: Development of an independent MU calculator (StereoCalc) with and without heterogeneity corrections for stereotactic treatments, in a Varian TrueBeam STx LINAC using stereotactic cones, with flattening filter-free photon energies. METHODS: Multiple depth curves and output factors were measured, following the dosimetry formalism for small fields proposed by the TRS-483. The developed StereoCalc imports and processes the beam data files and calculates the patient plans with and without heterogeneity correction. Validation of the developed software was carried out using phantoms. The accuracy of the StereoCalc software was verified in stereotactic patient plans. RESULTS: A maximum difference of 2.47% and 2.07% was obtained in the phantom validation tests with and without heterogeneity correction, respectively. The mean percentual difference of StereoCalc from cone dose calculation (CDC) in the clinical testing was 2.86% ±1.27% and 0.78% ±0.48% with and without heterogeneity correction, respectively. The largest differences found were 7.34% and 1.98%, respectively. CONCLUSIONS: The results obtained in this work show that the MU calculated with StereoCalc software is in good agreement with the values calculated by the treatment planning systems, both in static fields and arcs. We have also improved the software to consider heterogeneity corrections calculations. As expected, and as a major achievement of this work, some differences were observed when heterogeneities were considered. StereoCalc proved to be a powerful tool that can be integrated into the specific quality assurance program in a medical physics department for independent verification in stereotactic treatment with cones.

Segmentation of male pelvic organs on computed tomography with a deep neural network fine-tuned by a level-set method.

Computed Tomography (CT) imaging is used in Radiation Therapy planning, where the treatment is carefully tailored to each patient in order to maximize radiation dose to the target while decreasing adverse effects to nearby healthy tissues. A crucial step in this process is manual organ contouring, which if performed automatically could considerably decrease the time to starting treatment and improve outcomes. Computerized segmentation of male pelvic organs has been studied for decades and deep learning models have brought considerable advances to the field, but improvements are still demanded. A two-step framework for automatic segmentation of the prostate, bladder and rectum is presented: a convolutional neural network enhanced with attention gates performs an initial segmentation, followed by a region-based active contour model to fine-tune the segmentations to each patient's specific anatomy. The framework was evaluated on a large collection of planning CTs of patients who had Radiation Therapy for prostate cancer. The Surface Dice Coefficient improved from 79.41 to 81.00% on segmentation of the prostate, 94.03-95.36% on the bladder and 82.17-83.68% on the rectum, comparing the proposed framework with the baseline convolutional neural network. This study shows that traditional image segmentation algorithms can help improve the immense gains that deep learning models have brought to the medical imaging segmentation field.

Results of the IROCA international clinical audit in prostate cancer radiotherapy at six comprehensive cancer centres.

To assess adherence to standard clinical practice for the diagnosis and treatment of patients undergoing prostate cancer (PCa) radiotherapy in four European countries using clinical audits as part of the international IROCA project. Multi-institutional, retrospective cohort study of 240 randomly-selected patients treated for PCa (n = 40/centre) in the year 2015 at six European hospitals. Clinical indicators applicable to general and PCa-specific radiotherapy processes were evaluated. All data were obtained directly from medical records. The audits were performed in the year 2017. Adherence to clinical protocols and practices was satisfactory, but with substantial inter-centre variability in numerous variables, as follows: staging MRI (range 27.5-87.5% of cases); presentation to multidisciplinary tumour board (2.5-100%); time elapsed between initial visit to the radiation oncology department and treatment initiation (42-102.5 days); number of treatment interruptions ≥ 1 day (7.5-97.5%). The most common deviation from standard clinical practice was inconsistent data registration, mainly failure to report data related to diagnosis, treatment, and/or adverse events. This clinical audit detected substantial inter-centre variability in adherence to standard clinical practice, most notably inconsistent record keeping. These findings confirm the value of performing clinical audits to detect deviations from standard clinical practices and procedures.

JmjC-KDMs KDM3A and KDM6B modulate radioresistance under hypoxic conditions in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC), the most frequent esophageal cancer (EC) subtype, entails dismal prognosis. Hypoxia, a common feature of advanced ESCC, is involved in resistance to radiotherapy (RT). RT response in hypoxia might be modulated through epigenetic mechanisms, constituting novel targets to improve patient outcome. Post-translational methylation in histone can be partially modulated by histone lysine demethylases (KDMs), which specifically removes methyl groups in certain lysine residues. KDMs deregulation was associated with tumor aggressiveness and therapy failure. Thus, we sought to unveil the role of Jumonji C domain histone lysine demethylases (JmjC-KDMs) in ESCC radioresistance acquisition. The effectiveness of RT upon ESCC cells under hypoxic conditions was assessed by colony formation assay. KDM3A/KDM6B expression, and respective H3K9me2 and H3K27me3 target marks, were evaluated by RT-qPCR, Western blot, and immunofluorescence. Effect of JmjC-KDM inhibitor IOX1, as well as KDM3A knockdown, in in vitro functional cell behavior and RT response was assessed in ESCC under hypoxic conditions. In vivo effect of combined IOX1 and ionizing radiation treatment was evaluated in ESCC cells using CAM assay. KDM3A, KDM6B, HIF-1α, and CAIX immunoexpression was assessed in primary ESCC and normal esophagus. Herein, we found that hypoxia promoted ESCC radioresistance through increased KDM3A/KDM6B expression, enhancing cell survival and migration and decreasing DNA damage and apoptosis, in vitro. Exposure to IOX1 reverted these features, increasing ESCC radiosensitivity and decreasing ESCC microtumors size, in vivo. KDM3A was upregulated in ESCC tissues compared to the normal esophagus, associating and colocalizing with hypoxic markers (HIF-1α and CAIX). Therefore, KDM3A upregulation in ESCC cell lines and primary tumors associated with hypoxia, playing a critical role in EC aggressiveness and radioresistance. KDM3A targeting, concomitant with conventional RT, constitutes a promising strategy to improve ESCC patients' survival.

Multicentre clinical radiotherapy audit in rectal cancer: results of the IROCA project.

PURPOSE: To perform a clinical audit to assess adherence to standard clinical practice for the diagnosis, treatment, and follow-up of patients undergoing radiotherapy for rectal cancer treatment in four European countries. MATERIALS AND METHODS: Multi-institutional, retrospective cohort study of 221 patients treated for rectal cancer in 2015 at six European cancer centres. Clinical indicators applicable to general radiotherapy processes were evaluated. All data were obtained from electronic medical records. RESULTS: The audits were performed in the year 2017. We found substantial inter-centre variability in adherence to standard clinical practices: 1) presentation of cases at departmental clinical sessions (range, 0-100%) or multidisciplinary tumour board (50-95%); 2) pretreatment MRI (61.5-100%) and thoracoabdominal CT (15.0-100%). Large inter-centre differences were observed in the mean interval between biopsy and first visit to the radiotherapy department (range, 21.6-58.6 days) and between the first visit and start of treatment (15.1-38.8 days). Treatment interruptions ≥ 1 day occurred in 43.9% (2.5-90%) of cases overall. Treatment compensation was performed in 2.1% of cases. Treatment was completed in the prescribed time in 55.7% of cases. CONCLUSIONS: This multi-institutional clinical audit revealed that most centres adhered to standard clinical practices for most of the radiotherapy processes-related variables assessed. However, the audit revealed marked inter-centre variability for certain quality indicators, particularly inconsistent record keeping. Multiple targets for improvement and/or harmonisation were identified, confirming the value of routine clinical audits to detect potential deviations from standard clinical practice.

Urethra-Sparing Stereotactic Body Radiation Therapy for Prostate Cancer: Quality Assurance of a Randomized Phase 2 Trial.

PURPOSE: To present the radiation therapy quality assurance results from a prospective multicenter phase 2 randomized trial of short versus protracted urethra-sparing stereotactic body radiation therapy (SBRT) for localized prostate cancer. METHODS AND MATERIALS: Between 2012 and 2015, 165 patients with prostate cancer from 9 centers were randomized and treated with SBRT delivered either every other day (arm A, n = 82) or once a week (arm B, n = 83); 36.25 Gy in 5 fractions were prescribed to the prostate with (n = 92) or without (n = 73) inclusion of the seminal vesicles (SV), and the urethra planning-risk volume received 32.5 Gy. Patients were treated either with volumetric modulated arc therapy (VMAT; n = 112) or with intensity modulated radiation therapy (IMRT; n = 53). Deviations from protocol dose constraints, planning target volume (PTV) homogeneity index, PTV Dice similarity coefficient, and number of monitor units for each treatment plan were retrospectively analyzed. Dosimetric results of VMAT versus IMRT and treatment plans with versus without inclusion of SV were compared. RESULTS: At least 1 major protocol deviation occurred in 51 patients (31%), whereas none was observed in 41. Protocol violations were more frequent in the IMRT group (P < .001). Furthermore, the use of VMAT yielded better dosimetric results than IMRT for urethra planning-risk volume D98% (31.1 vs 30.8 Gy, P < .0001), PTV D2% (37.9 vs 38.7 Gy, P < .0001), homogeneity index (0.09 vs 0.10, P < .0001), Dice similarity coefficient (0.83 vs 0.80, P < .0001), and bladder wall V50% (24.5% vs 33.5%, P = .0001). To achieve its goals volumetric modulated arc therapy required fewer monitor units than IMRT (2275 vs 3378, P <.0001). The inclusion of SV in the PTV negatively affected the rectal wall V90% (9.1% vs 10.4%, P = .0003) and V80% (13.2% vs 15.7%, P = .0003). CONCLUSIONS: Protocol deviations with potential impact on tumor control or toxicity occurred in 31% of patients in this prospective clinical trial. Protocol deviations were more frequent with IMRT. Prospective radiation therapy quality assurance protocols should be strongly recommended for SBRT trials to minimize potential protocol deviations.

IMRT national audit in Portugal.

PURPOSE: The IAEA newly developed "end-to-end" audit methodology for on-site verification of IMRT dose delivery has been carried out in Portugal in 2018. The main goal was to evaluate the physical aspects of the head and neck (H&N) cancer IMRT treatments. This paper presents the national results. METHODS: All institutions performing IMRT treatments in Portugal, 20 out of 24, have voluntarily participated in this audit. Following the adopted methodology, a Shoulder, Head and Neck End-to-End phantom (SHANE) - that mimics an H&N region, underwent all steps of an IMRT treatment, according to the local practices. The measurements using an ionization chamber placed inside the SHANE phantom at four reference locations (three in PTVs and one in the spinal cord) and an EBT3 film positioned in a coronal plane were compared with calculated doses. FilmQA Pro software was used for film analysis. RESULTS: For ionization chamber measurements, the percent difference was within the specified tolerances of ±5% for PTVs and ±7% for the spinal cord in all participating institutions. Considering film analysis, gamma passing rates were on average 96.9%±2.9% for a criterion of 3%/3 mm, 20% threshold, all above the acceptance limit of 90%. CONCLUSIONS: The national results of the H&N IMRT audit showed a compliance between the planned and the delivered doses within the specified tolerances, confirming no major reasons for concern. At the same time the audit identified factors that contributed to increased uncertainties in the IMRT dose delivery in some institutions resulting in recommendations for quality improvement.

Characterization of Extrafocal Dose Influence on the Out-of-Field Dose Distribution by Monte Carlo Simulations and Dose Measurements.

Out-of-field scattered and transmitted extrafocal radiation may induce secondary cancer in long-term survivors of external radiotherapy. Pediatric patients have higher life expectancy and tend to receive higher secondary radiation damage due to geometric and biological factors. The goal of this study is to characterize the location and the magnitude of extrafocal dose regions in the case of three-dimensional conformal radiotherapy and volumetric arc therapy, to apply this information to clinical treatment cases, and to provide mitigation strategies. Extrafocal dose has been investigated in a Varian TrueBeam linac equipped with a high-definition 120 multileaf collimator using different physical and virtual phantoms, dose calculation (including Monte Carlo techniques), and dose measurement methods. All Monte Carlo calculations showed excellent agreement with measurements. Treatment planning system calculations failed to provide reliable results out of the treatment field. Both Monte Carlo calculations and dose measurements showed regions with higher dose (extrafocal dose areas) when compared to the background. These areas start to be noticeable beyond 11 cm from the isocenter in the direction perpendicular to the multileaf collimator leaves' travel direction. Out-of-field extrafocal doses up to 160% of the mean dose transmitted through the closed multileaf collimator were registered. Two overlapping components were observed in the extrafocal distribution: the first is an almost elliptical blurred dose distribution, and the second is a well-defined rectangular dose distribution. Extra precautions should be taken into consideration when treating pediatric patients with a high-definition 120 multileaf collimator to avoid directing the extrafocal radiation into a radiosensitive organ during external beam therapy.

Optimization of skin dose using in-vivo MOSFET dose measurements in bolus/non-bolus fraction ratio: A VMAT and a 3DCRT study.

In-phantom and in-vivo three dimensional conformal radiation therapy (3DCRT) and volumetric modulated arc therapy (VMAT) skin doses, measured with and without bolus in a female anthropomorphic phantom RANDO and in patients, were compared against treatment planning system calculated values. A thorough characterization of the metal oxide semiconductor field effect transistor measurement system was performed prior to the measurements in phantoms and patients. Patients with clinical indication for postoperative external radiotherapy were selected. Skin dose showed higher values with 3DCRT technique compared with VMAT. The increase in skin dose due to the use of bolus was quantified. It was observed that, in the case of VMAT, the bolus effect on the skin dose was considerable when compared with 3DCRT. From the point of view of treatment time, bolus cost, and positioning reproducibility, the use of bolus in these situations can be optimized.

Urethra-sparing stereotactic body radiotherapy for prostate cancer: how much can the rectal wall dose be reduced with or without an endorectal balloon?

BACKGROUND: This is a dosimetric comparative study intended to establish appropriate low-to-intermediate dose-constraints for the rectal wall (Rwall) in the context of a randomized phase-II trial on urethra-sparing stereotactic body radiotherapy (SBRT) for prostate cancer. The effect of plan optimization on low-to-intermediate Rwall dose and the potential benefit of an endorectal balloon (ERB) are investigated. METHODS: Ten prostate cancer patients, simulated with and without an ERB, were planned to receive 36.25Gy (7.25Gyx5) to the planning treatment volume (PTV) and 32.5Gy to the urethral planning risk volume (uPRV). Reference plans with and without the ERB, optimized with respect to PTV and uPRV coverage objectives and the organs at risk dose constraints, were further optimized using a standardized stepwise approach to push down dose constraints to the Rwall in the low to intermediate range in five sequential steps to obtain paired plans with and without ERB (Vm1 to Vm5). Homogeneity index for the PTV and the uPRV, and the Dice similarity coefficient (DSC) for the PTV were analyzed. Dosimetric parameters for Rwall including the median dose and the dose received by 10 to 60% of the Rwall, bladder wall (Bwall) and femoral heads (FHeads) were compared. The monitor units (MU) per plan were recorded. RESULTS: Vm4 reduced by half D30%, D40%, D50%, and Dmed for Rwall and decreased by a third D60% while HIPTV, HIuPRV and DSC remained stable with and without ERB compared to Vmref. HIPTV worsened at Vm5 both with and without ERB. No statistical differences were observed between paired plans on Rwall, Bwall except a higher D2% for Fheads with and without an ERB. CONCLUSIONS: Further optimization to the Rwall in the context of urethra sparing prostate SBRT is feasible without compromising the dose homogeneity to the target. Independent of the use or not of an ERB, low-to-intermediate doses to the Rwall can be significantly reduced using a four-step sequential optimization approach.

Primo software as a tool for Monte Carlo simulations of intensity modulated radiotherapy: a feasibility study.

BACKGROUND: IMRT provides higher dose conformation to the target and dose sparing to surrounding tissues than 3DCRT. Monte Carlo method in Medical Physics is not a novelty to approach dosimetric problems. A new PENELOPE based code named PRIMO recently was published. The most intriguing features of PRIMO are the user-friendly approach, the stand-alone property and the built-in definition of different linear accelerators models. Nevertheless, IMRT simulations are not yet implemented. METHODS: A Varian Trilogy with a Millennium120 MLC and a Varian Novalis with 120HD MLC were studied. A RW3 multi-slab phantom was irradiated with Gafchromic films inserted between slabs. An Expression 10000XL scanner (Seiko Epson Corp., Nagano, Japan) was used to digitalize the films. PTW-Verisoft software using the global Gamma Function (2%, 2 mm) was used to compare simulated and experimental results. The primary beam parameters were adjusted to best match reference data previously obtained in a water phantom. Static MLC simulations were performed to validate the MLC models in use. Two Dynamic IMRT preliminary tests were performed with leaves moving with constant and variable speed. A further test of an in phantom delivery of a real IMRT field allowed simulating a clinical-like MLC modulation. RESULTS: Simulated PDD, X- and Y-profiles in reference conditions showed respectively 100.0%, 100.0% and 99.4% of Gamma points < 1 (2%, 2 mm). Static MLC simulations showed 100.0% of Gamma points < 1 with the 120HD MLC and 99.1% with the Millennium compared with the scanned images. The fixed speed test showed 99.5 and 98.9% of Gamma points < 1 respectively with two different MLC configuration-sampling algorithms when the 120HD MLC was used. The higher modulation MLC motion simulation showed 99.1% of Gamma points < 1 with respect to the experimental. This result depends on the number of the fields to reproduce the MLC motion, as well as calculation time. The clinical-like simulation showed 96.2% of Gamma points < 1 using the same analysis conditions. CONCLUSIONS: The numerical model of the Varian Trilogy and Novalis in the PRIMO software was validated. The algorithms to simulate MLC motion were considered reliable. A clinical-like procedure was successfully simulated.

Improving radiation oncology through clinical audits: Introducing the IROCA project.

As radiotherapy practice and processes become more complex, the need to assure quality control becomes ever greater. At present, no international consensus exists with regards to the optimal quality control indicators for radiotherapy; moreover, few clinical audits have been conducted in the field of radiotherapy. The present article describes the aims and current status of the international IROCA "Improving Radiation Oncology Through Clinical Audits" project. The project has several important aims, including the selection of key quality indicators, the design and implementation of an international audit, and the harmonization of key aspects of radiotherapy processes among participating institutions. The primary aim is to improve the processes that directly impact clinical outcomes for patients. The experience gained from this initiative may serve as the basis for an internationally accepted clinical audit model for radiotherapy.

Effects of shielding on pelvic and abdominal IORT dose distributions.

PURPOSE: To study the impact of shielding elements in the proximity of Intra-Operative Radiation Therapy (IORT) irradiation fields, and to generate graphical and quantitative information to assist radiation oncologists in the design of optimal shielding during pelvic and abdominal IORT. METHOD: An IORT system was modeled with BEAMnrc and EGS++ Monte Carlo codes. The model was validated in reference conditions by gamma index analysis against an experimental data set of different beam energies, applicator diameters, and bevel angles. The reliability of the IORT model was further tested considering shielding layers inserted in the radiation beam. Further simulations were performed introducing a bone-like layer embedded in the water phantom. The dose distributions were calculated as 3D dose maps. RESULTS: The analysis of the resulting 2D dose maps parallel to the clinical axis shows that the bevel angle of the applicator and its position relative to the shielding have a major influence on the dose distribution. When insufficient shielding is used, a hotspot nearby the shield appears near the surface. At greater depths, lateral scatter limits the dose reduction attainable with shielding, although the presence of bone-like structures in the phantom reduces the impact of this effect. CONCLUSIONS: Dose distributions in shielded IORT procedures are affected by distinct contributions when considering the regions near the shielding and deeper in tissue: insufficient shielding may lead to residual dose and hotspots, and the scattering effects may enlarge the beam in depth. These effects must be carefully considered when planning an IORT treatment with shielding.

Gafchromic XR-QA2 film as a complementary dosimeter for hand-monitoring in CTF-guided biopsies.

Computed tomography fluoroscopy (CTF) is a useful imaging technique to guide biopsies, particularly lung biopsies, but it also has the potential for very high hand exposures, despite use of quick-check method and needle holders whenever feasible. Therefore, reliable monitoring is crucial to ensure the safe use of CTF. This is a challenge, because ring dosimeters monitor exposure only at the base of one finger, while the fingertips may be exposed to the highly collimated CT beam. In this work we have explored the possibility of using Gafchromic XR-QA2 self-developing film as a complementary dosimeter to quantify hand exposure during CTF-guided biopsies. A glove used in a previous study and designed to contain 11 TLDs was adapted to include Gafchromic strips 7 mm wide, covering the fingers. A total of 22 biopsies were successfully performed wearing this GafTLD glove under sterile gloves, and the IR reported no difficulty or reduction of dexterity while wearing it. Comparison of dose distributions obtained from digitization of the Gafchromic film strips and absolute Hp(0.07) readings from TLDs showed good agreement, despite some positional uncertainty due to relative movement. Per procedure, doses at the base of the ring finger can be as low as 3%-8% of hand dose maximum. Accumulated dose at the base of the ring finger was four times lower than the dose maximum.

Erratum: Attenuation measurements show that the presence of a TachoSil surgical patch will not compromise target irradiation in intra-operative electron radiation therapy or high-dose-rate brachytherapy.

After publication of this study [1], the authors noticed that the funding was incorrectly acknowledged. The correct Acknowledgements section can be found below: "This work was partly funded by Fundação para a Ciência e Tecnologia (FCT), in the framework of the project PTDC/SAU-ENB/117631/2010, which is cofinanced by FEDER, through Programa Operacional Fatores de Competitividade - COMPETE of QREN (reference FCOMP-01-0124-FEDER-021141)."

Attenuation measurements show that the presence of a TachoSil surgical patch will not compromise target irradiation in intra-operative electron radiation therapy or high-dose-rate brachytherapy.

BACKGROUND: Surgery of locally advanced and/or recurrent rectal cancer can be complemented with intra-operative electron radiation therapy (IOERT) to deliver a single dose of radiation directly to the unresectable margins, while sparing nearby sensitive organs/structures. Haemorrhages may occur and can affect the dose distribution, leading to an incorrect target irradiation. The TachoSil (TS) surgical patch, when activated, creates a fibrin clot at the surgical site to achieve haemostasis. The aim of this work was to determine the effect of TS on the dose distribution, and ascertain whether it could be used in combination with IOERT. This characterization was extended to include high dose rate (HDR) intraoperative brachytherapy, which is sometimes used at other institutions instead of IOERT. METHODS: CT images of the TS patch were acquired for initial characterization. Dosimetric measurements were performed in a water tank phantom, using a conventional LINAC with a hard-docking system of cylindrical applicators. Percentage Depth Dose (PDD) curves were obtained, and measurements made at the depth of dose maximum for the three clinically used electron energies (6, 9 and 12MeV), first without any attenuator and then with the activated patch of TS completely covering the tip of the IOERT applicator. For HDR brachytherapy, a measurement setup was improvised using a solid water phantom and a Farmer ionization chamber. RESULTS: Our measurements show that the attenuation of a TachoSil patch is negligible, both for high energy electron beams (6 to 12MeV), and for a HDR (192)Ir brachytherapy source. Our results cannot be extrapolated to lower beam energies such as 50 kVp X-rays, which are sometimes used for breast IORT. CONCLUSION: The TachoSil surgical patch can be used in IORT procedures using 6MeV electron energies or higher, or HDR (192)Ir brachytherapy.