Genetically Engineered Probiotic Limosilactobacillus reuteri Releasing IL-22 (LR-IL-22) Modifies the Tumor Microenvironment, Enabling Irradiation in Ovarian Cancer.

Despite recent advances in cancer therapy, ovarian cancer remains the most lethal gynecological cancer worldwide, making it crucial and of the utmost importance to establish novel therapeutic strategies. Adjuvant radiotherapy has been assessed historically, but its use was limited by intestinal toxicity. We recently established the role of Limosilactobacillus reuteri in releasing IL-22 (LR-IL-22) as an effective radiation mitigator, and we have now assessed its effect in an ovarian cancer mouse model. We hypothesized that an LR-IL-22 gavage would enable intestinal radioprotection by modifying the tumor microenvironment and, subsequently, improving overall survival in female C57BL/6MUC-1 mice with widespread abdominal syngeneic 2F8cis ovarian cancer. Herein, we report that the LR-IL-22 gavage not only improved overall survival in mice when combined with a PD-L1 inhibitor by inducing differential gene expression in irradiated stem cells but also induced PD-L1 protein expression in ovarian cancer cells and mobilized CD8+ T cells in whole abdomen irradiated mice. The addition of LR-IL-22 to a combined treatment modality with fractionated whole abdomen radiation (WAI) and systemic chemotherapy and immunotherapy regimens can facilitate a safe and effective protocol to reduce tumor burden, increase survival, and improve the quality of life of a locally advanced ovarian cancer patient.

Inverse shielding and mutual exclusion for PET-MR hybrid imaging concerning induced positronium hyperfine splits radiations.

Prevalent PET imaging reconstructs 2γ-photon pairs emitted after an annihilation from para-positronium (p-Ps) and rejects 3γ events from ortho-positronium (o-Ps) as noises. The 3γ/2γ decay ratio is ~ 3/7 in human body theoretically but in fact significantly lower due to pick-off process, hence PET imaging quality is well controlled. In a PET-MR hybrid unit, the MR magnetic field alters positronium decay patterns through magnetic quenching: all o-Ps and excited p-Ps states are split into finer quantum states under strong magnetic field, thus transitions between some triplet and singlet finer states (mz = 0) were no longer forbidden, thus some o-Ps converts to p-Ps spontaneously by emitting hyperfine split (HFS) photons, which also drops 3γ/2γ ratio hence helps PET imaging quality. However, inverse magnetic quenching might also occur if any external source of HFS frequencies is nearby, thus many p-Ps convert to o-Ps by absorbing those HFS photons (induced HFS transitions). This will dramatically increase 3γ/2γ ratio and hence degrade PET imaging quality instantaneously. The HFS spectrum lies in a broad range of microwaves, from 0.02 to 200 GHz. To prevent inverse magnetic quenching, it is necessary to block external microwave sources outside the hybrid vault, by adding a thin metal layer at all directions of the vault. This could be achieved by adopting the metallic Faraday Cage, which was originally for MR shielding, with possible amendment if necessary. The frequencies of excitation pulses in MR imaging overlap with HFS spectrum, however, the chance for mutual interference during hybrid imaging is small, hence there seems no need to veto each other during hybrid scans.

Chemical Carcinogen (Dimethyl-benzanthracene) Induced Transplantable Cancer in Fanconi Anemia (Fanca-/-) Mice.

BACKGROUND/AIM: Patients with radiation sensitive Fanconi anemia (FA) are presenting with cancers of the oral cavity, oropharynx, and other anatomic locations. MATERIALS AND METHODS: Animal models for cancer in FA mice used orthotopic tumors from wild type mice. We derived a cancer cell line from Fanca-/- mice by topical application of the chemical carcinogen dimethyl benzanthracene (DMBA). RESULTS: A Fanca-/- mouse rhabdomyosarcoma was derived from a Fanca-/- (129/Sv) mouse. The in vitro clonogenic survival of the Fanca-/- clone 6 cancer cell line was consistent with the FA genotype. Transplanted tumors demonstrated hypoxic centers surrounded by senescent cells. CONCLUSION: This Fanca-/- mouse syngeneic cancer should provide a valuable resource for discovery and development of new normal tissue radioprotectors for patients with FA and cancer.

Release of Interferon-ß (IFN-ß) from Probiotic Limosilactobacillus reuteri-IFN-ß (LR-IFN-ß) Mitigates Gastrointestinal Acute Radiation Syndrome (GI-ARS) following Whole Abdominal Irradiation.

Irradiation can be an effective treatment for ovarian cancer, but its use is limited by intestinal toxicity. Thus, strategies to mitigate toxicity are important and can revitalize the current standard of care. We previously established that LR-IL-22 protects the intestine from WAI. We now hypothesize that LR-IFN-ß is an effective radiation protector and mitigator and is rapidly cleared from the digestive tract, making it an option for intestinal radioprotection. We report that the gavage of LR-IFN-ß during WAI provides improved intestinal barrier integrity and significantly preserves the numbers of Lgr5+GFP+ intestinal stem cells, improving survival. The rapid clearance of the genetically engineered probiotic from the digestive tract renders it a safe and feasible radiation mitigator. Therefore, the above genetically engineered probiotic is both a feasible and effective radiation mitigator that could potentially revolutionize the management of OC patients. Furthermore, the subsequent addition of platinum/taxane-based chemotherapy to the combination of WAI and LR-IFN-ß should reduce tumor volume while protecting the intestine and should improve the overall survival in OC patients.

A novel approach to infectious disease control and radiotherapy risk management.

BACKGROUND: Infectious disease outbreaks have always presented challenges to the operation of healthcare systems. In particular, the treatment of cancer patients within Radiation Oncology often cannot be delayed or compromised due to infection control measures. Therefore, there is a need for a strategic approach to simultaneously managing infection control and radiotherapy risks. PURPOSE: To develop a systematic risk management method that uses mathematical models to design mitigation efforts for control of an infectious disease outbreak, while ensuring safe delivery of radiotherapy. METHODS: A two-stage failure mode and effect analysis (FMEA) approach is proposed to modify radiotherapy workflow during an infectious disease outbreak. In stage 1, an Infection Control FMEA (IC-FMEA) is conducted, where risks are evaluated based on environmental parameters, clinical interactions, and modeling of infection risk. occupancy risk index (ORI) is defined as a metric for infection transmission risk level in each room, based on the degree of occupancy. ORI, in combination with ventilation rate per person (Rp ), is used to provide a broad infection risk assessment of workspaces. For detailed IC-FMEA of clinical processes, infection control failure mode (ICFM) is defined to be any instance of disease transmission within the clinic. Infection risk priority number (IRPN) has been formulated as a function of time, distance, and degree of protective measures. Infection control measures are then systematically integrated into the workflow. Since the workflow is perturbed by infection control measures, there is a possibility of introducing new radiotherapy failure modes or increased likelihood of existing failure modes. Therefore, in stage 2, a conventional radiotherapy FMEA (RT-FMEA) should be performed on the adjusted workflow. RESULTS: The COVID-19 pandemic was used to illustrate stage 1 IC-FMEA. ORI and Rp values were calculated for various workspaces within a clinic. A deep inspiration breath hold (DIBH) CT simulation was used as an example to demonstrate detailed IC-FMEA with ICFM identification and IRPN evaluation. A total of 90 ICFMs were identified in the DIBH simulation process. The calculated IRPN values were found to be progressively decreasing for workflows with minimal, moderate, and enhanced levels of protective measures. CONCLUSION: The framework developed in this work provides tools for radiotherapy clinics to systematically assess risk and adjust workflows during the evolving circumstances of any infectious disease outbreak.

Portal dosimetry correction method for validation of single isocenter VMAT plans for multiple brain metastases.

Portal dosimetry is one option for verification of volumetric-modulated arc therapy (VMAT) planning for multiple brain metastases. However, due to the changing response of the portal imager with photon beam energy, the dose transmitted through closed multileaf collimator (MLC) leaves or narrow MLC gaps may be underestimated by the imager. We present a simple method for correcting for these effects that may be implemented within the Eclipse treatment planning system. We recalculated the predicted portal dose with and without this correction for 20 multiple brain met VMAT plans. Before the correction, 3/20 composite plan fields passed our standard quality assurance (QA) criteria (54/80 individual fields); the average gamma passing rate for the composite plans was 76.9 ± 16.6%, and the average gamma value across the composite plans was 0.67 ± 0.23. After correction, 20/20 composite plan fields passed the QA criteria (80/80 individual fields); the average gamma passing rate for composite plans was 99.2 ± 1.4%, the average gamma value across the composite plans was 0.33 ± 0.90. A measure of plan complexity, the average leaf pair opening could be correlated to the gamma analysis results for the uncorrected plans but not for the corrected plans.

A multi-institutional evaluation of small field output factor determination following the recommendations of IAEA/AAPM TRS-483.

PURPOSE: The aim of this work was to test the implementation of small field dosimetry following TRS-483 and to develop quality assurance procedures for the experimental determination of small field output factors (SFOFs). MATERIALS AND METHODS: Twelve different centers provided SFOFs determined with various detectors. Various linac models using the beam qualities 6 MV and 10 MV with flattening filter and without flattening filter were utilized to generate square fields down to a nominal field size of 0.5 cm × 0.5 cm. The detectors were positioned at 10 cm depth in water. Depending on the local situation, the source-to-surface distance was either set to 90 cm or 100 cm. The SFOFs were normalized to the output of the 10 cm × 10 cm field. The spread of SFOFs measured with different detectors was investigated for each individual linac beam quality and field size. Additionally, linac-type specific SFOF curves were determined for each beam quality and the SFOFs determined using individual detectors were compared to these curves. Example uncertainty budgets were established for a solid state detector and a micro ionization chamber. RESULTS: The spread of SFOFs for each linac and field was below 5% for all field sizes. With the exception of one linac-type, the SFOFs of all investigated detectors agreed within 10% with the respective linac-type SFOF curve, indicating a potential inter-detector and inter-linac variability. CONCLUSION: Quality assurance on the SFOF measurements can be done by investigation of the spread of SFOFs measured with multiple detectors and by comparison to linac-type specific SFOFs. A follow-up of a measurement session should be conducted if the spread of SFOFs is larger than 5%, 3%, and 2% for field sizes of 0.5 cm × 0.5 cm, 1 cm × 1 cm, and field sizes larger than 2 cm × 2 cm, respectively. Additionally, deviations of measured SFOFs to the linac-type-curves of more than 7%, 3%, and 2% for field sizes 0.5 cm × 0.5 cm, 1 cm × 1 cm, and field sizes larger than 1 cm × 1 cm, respectively, should be followed up.

A detailed process map for clinical workflow of a new biology-guided radiotherapy (BgRT) machine.

PURPOSE: Biology-guided radiotherapy (BgRT) is a new external beam radiation therapy modality combining PET-CT with a linear accelerator that has the potential to track and treat one or more tumors in real-time. The use of PET and radiopharmaceutical tracers introduces new processes that are different from the existing treatment processes. In this study, we have developed a process map for the clinical implementation of a prototype BgRT machine. METHODS: A team of 13 members from various radiation therapy disciplines at our institution participated in developing a prospective process map for a prototype BgRT machine. The methodology provided by the AAPM TG 100 report was followed. In particular, the steps unique to the BgRT workflow, using hypofractionated stereotactic body radiation therapy with fluorodeoxyglucose radiolabeled with fluorine-18 (FDG) to guide beam delivery, were analyzed. RESULTS: The multi-disciplinary team in the department of radiation oncology at our institution developed a prospective process map for the clinical BgRT workflow. By focusing on the appropriate level of detail, 15 major subprocesses, 133 steps, and 248 substeps were identified and the process map was agreed upon as being useful, implementable, and manageable. Seventy-four steps from nine subprocesses, 55.6% of the whole process, were analyzed to be the BgRT unique steps. They originate mainly from: (1) acquiring multiple PET images at the BgRT machine with separate patient visits, (2) creating a unique biological treatment volume for BgRT plan (PTVBgRT ), and (3) BgRT plan optimization and treatment delivery using PET images. CONCLUSION: Using BgRT to irradiate multiple metastases in the same session will impact clinical workflow, thus a graphical process map depicting the new clinical workflow with an appropriate level of detail is critical for efficient, safe, and high-quality care. The prospective process map will guide the successful setup and use of the new BgRT system.

Intestinal Radiation Protection and Mitigation by Second-Generation Probiotic Lactobacillus-reuteri Engineered to Deliver Interleukin-22.

(1) Background: The systemic administration of therapeutic agents to the intestine including cytokines, such as Interleukin-22 (IL-22), is compromised by damage to the microvasculature 24 hrs after total body irradiation (TBI). At that time, there is significant death of intestinal microvascular endothelial cells and destruction of the lamina propria, which limits drug delivery through the circulation, thus reducing the capacity of therapeutics to stabilize the numbers of Lgr5+ intestinal crypt stem cells and their progeny, and improve survival. By its direct action on intestinal stem cells and their villus regeneration capacity, IL-22 is both an ionizing irradiation protector and mitigator. (2) Methods: To improve delivery of IL-22 to the irradiated intestine, we gavaged Lactobacillus-reuteri as a platform for the second-generation probiotic Lactobacillus-reuteri-Interleukin-22 (LR-IL-22). (3) Results: There was effective radiation mitigation by gavage of LR-IL-22 at 24 h after intestinal irradiation. Multiple biomarkers of radiation damage to the intestine, immune system and bone marrow were improved by LR-IL-22 compared to the gavage of control LR or intraperitoneal injection of IL-22 protein. (4) Conclusions: Oral administration of LR-IL-22 is an effective protector and mitigator of intestinal irradiation damage.

Dosimetric parameters related to occurrence of distant metastases and regional nodal relapse after SBRT for early-stage non-small cell lung cancer.

PURPOSE: Previous studies have suggested that the dose immediately outside the PTV may impact the incidence of distant metastases after stereotactic body radiation therapy (SBRT) for patients with early-stage non-small cell lung cancer (NSCLC). In particular, Diamant et al. [1,2] reported a correlation between the mean EQD2 of a 30 mm shell around the PTV and both local control and the rate of distant metastases. In this study, we assess this parameter and others in a series of patients with radiographically presumed or biopsy-proven early-stage NSCLC treated at our institution with stereotactic body radiotherapy (SBRT) between 2017 and 2019. MATERIALS/METHODS: We reviewed the dosimetry, local control, regional nodal relapse, and rate of distant metastases for 304 patients with 325 lesions treated with SBRT at our institution. Dosimetric parameters investigated include the prescribed dose, minimum and mean doses to the PTV, conformity index, and the mean EQD2 to a 30 mm shell around the PTV. Time to each event was defined from date of last fraction of SBRT to date of event, with event-free patients censored at last radiographic follow-up. Univariate (UVA) Cox regression analysis was performed on the collected parameters to assess for correlation with regional nodal relapse and rate of distant metastases. RESULTS: There was no significant correlation between the mean EQD2 dose to a 30 mm shell around the PTV and the rate of distant metastases. On UVA Cox proportional hazards analysis, positive predictors of reduced incidence of distant metastases were PTV <22 cc (vs. ≥22 cc, p = 0.01) and GTV <10 cc (vs. ≥10 cc, p < 0.01), with GTV <10 cc also being a positive predictor of reduced incidence of regional nodal relapse (p < 0.01). In the subset of patients treated with 4-5 fractions, mean EQD2 dose to the 30 mm shell around the PTV ≥21 Gy was associated with increased incidence of distant metastases (HR 2.42, 95% CI 1.06-5.53, p = 0.04), differing from prior data from Diamant et al. CONCLUSIONS: We did not observe a correlation between the rate of distant metastases and dose outside the PTV, as reported by other groups; rather, we noted an opposite trend in patients treated with 4-5 fractions. Our data show additional correlations between distant metastases and tumor size.

Prediction of conical collimator collision for stereotactic radiosurgery.

The purpose of this study is to predict the collision clearance distance of stereotactic cones with treatment setup devices in cone-based stereotactic radiosurgery (SRS). The BrainLAB radiosurgery system with a Frameless Radiosurgery Positioning Array and dedicated couch top was targeted in this study. The positioning array and couch top were scanned with CT simulators, and their outer contours of were detected. The minimum clearance distance was estimated by calculating the Euclidian distances between the surface of the SRS cones and the nearest surface of the outer contours. The coordinate transformation of the outer contour was performed by incorporating the Beam's Eye View at a planned arc range and couch angle. From the minimum clearance distance, the collision-free gantry ranges for each couch angle were sequentially determined. An in-house software was developed to calculate the clearance distance between the cone surface and the outer contours, and thus determine the occurrence of a collision. The software was extensively tested for various combinations of couch and arc angles at multiple isocenter locations for two combinations of cone-couch systems. A total of 50 arcs were used to validate the calculation accuracies of the software for each system. The calculated minimum distances and collision-free angles from the software were verified by physical measurements. The calculated minimum distances were found to agree with the measurements to within 0.3 ± 0.9 mm. The collision-free arc angles from the software also agreed with the measurements to within 1.1 ± 1.1° with a 5-mm safety margin for 20 arcs. In conclusion, the in-house software was able to calculate the minimum clearance distance with <1.0 mm accuracy and to determine the collision-free arc range for the cone-based BrainLab SRS system.

Anti-Ferroptosis Drug Enhances Total-Body Irradiation Mitigation by Drugs that Block Apoptosis and Necroptosis.

Mitigation of total-body irradiation (TBI) in C57BL/6 mice by two drugs, which target apoptosis and necroptosis respectively, increases survival compared to one drug alone. Here we investigated whether the biomarker (signature)directed addition of a third anti-ferroptosis drug further mitigated TBI effects. C57BL/6NTac female mice (30-33 g) received 9.25 Gy TBI, and 24 h or later received JP4-039 (20 mg/kg), necrostatin-1 (1.65 mg/kg) and/or lipoxygenase-15 inhibitor (baicalein) (50 mg/kg) in single-, dual- or three-drug regimens. Some animals were sacrificed at days 0, 1, 2, 3, 4 or 7 postirradiation, while the majority in each group were maintained beyond 30 days. For those mice sacrificed at the early time points, femur bone marrow, intestine (ileum), lung and blood plasma were collected and analyzed for radiation-induced and mitigator-modified levels of 33 pro-inflammatory and stress response proteins. Each single mitigator administered [JP4-039 (24 h), necrostatin-1 (48 h) or baicalein (24 h)] improved survival at day 30 after TBI to 25% (P = 0.0432, 0.2816 or 0.1120, respectively) compared to 5% survival of 9.25 Gy TBI controls. Mice were administered the drug individually based on weight (mg/kg). Drug vehicles comprised 30% cyclodextrin for JP4-039 and baicalein, and 10% Cremphor-EL/10% ethanol/80% water for necrostatin-1; thus, dual-vehicle controls were also tested. The dual-drug combinations further enhanced survival: necrostatin-1 (delayed to 72 h) with baicalein 40% (P = 0.0359); JP4-039 with necrostatin-1 50% (P = 0.0062); and JP4-039 with baicalein 60% (P = 0.0064). The three-drug regimen, timed to signature directed evidence of onset after TBI of each death pathway in marrow and intestine, further increased the 30-day survival to 75% (P = 0.0002), and there was optimal normalization to preirradiation levels of inflammatory cytokine and stress response protein levels in plasma, intestine and marrow. In contrast, lung protein levels were minimally altered by 9.25 Gy TBI or mitigators over 7 days. Significantly, elevated intestinal proteins at day 7 after TBI were reduced by necrostatin-1-containing regimens; however, normalization of plasma protein levels at day 7 required the addition of JP4-039 and baicalein. These findings indicate that mitigator targeting to three distinct cell death pathways increases survival after TBI.

Assessment of deep inspiration breath hold technique setup reproducibility using mega voltage imaging for left breast cancer radiation therapy-integrated network study.

We evaluated daily setup reproducibility of deep inspiration breath hold (DIBH) using mega voltage (MV) imaging for left breast cancer radiation therapy. Analysis of 109 left breast cancer patients across UPMC Hillman Cancer Center network treated using DIBH technique with daily MV imaging was done. Patient characteristics, MV imaging procedure used and inter-fraction directional shifts were collected. For the statistical analyses, we separated all patients into 2 groups in each of the following 3 categories; (1) obese (BMI ≥ 30) vs nonobese, (2) mastectomy vs lumpectomy, (3) internal mammary node (IMN) treatment vs no IMN treatment. The group mean inter-fraction directional shifts were as following: (1) 0.7 mm (superior), 0.8 mm (inferior); (2) 0.65 mm (left), 0.64 mm (right); (3) 0.89 mm (anterior), 0.83 mm (posterior). Also, any directional shift ≥ 2 mm, ≥ 3 mm, ≥ 4 mm, ≥ 5 mm, ≥ 10 mm was found to be 52.9%, 37.6%, 30.9%, 21.9%, 3.7% of total fractions, respectively. In the stratified analysis, obese patients had larger directional shifts (p < 0.05) and highly associated with number of fractions for ≥ 5 mm in any directional shift compared to nonobese patients (29% vs 17%; p = 0.04). DIBH setup for left breast cancer treatment at our large cancer center network was reproducible with any mean directional shifts less than 1.0 mm using MV imaging. Daily imaging would be more beneficial for obese patients compared to nonobese patients.

Which Dose Specification Should Be Used for NRG Radiation Therapy Trials: Dose-to-Medium or Dose-to-Water?

PURPOSE: To compare the doses calculated by the Analytical Anisotropic Algorithm (AAA), Acuros dose-to-medium, and Acuros dose-to-water for the patients with lung cancer treated at our institution and show that further investigation and clarification are needed about what dose specifications should be used for NRG clinical trials. METHODS AND MATERIALS: Twenty-one patients with lung cancer who previously received intensity modulated radiation therapy or volumetric modulated arc therapy-based treatments at our institution were analyzed by recalculating their plans for each one with the AAA algorithm (reviewed and approved by our radiation oncologists) and with both reporting modes of the Acuros algorithm. All plans used the same monitor units as the original approved plan and a 2.5-mm grid size. For each patient, D100 of clinical target volume (CTV) and CTV coverage ratios in each plan were compared, and dose distributions and dose-volume histograms calculated by AAA, Acuros dose-to-water (Dw,m), and Acuros dose-to-medium (Dm,m) were compared as well. RESULTS: Differences between CTV D100 calculated by AAA and Acuros Dm,m were larger than the differences between AAA and Acuros XB Dw,m for all patients. When D100 of CTV was evaluated, the largest difference between AAA and Acuros Dm,m was 14.12% and between AAA and Acuros XB Dw,m was 3.68%. The average differences between the CTV D100 calculated by AAA and Acuros Dm,m was 5.39%. Coverage ratio between Acuros Dm,m and AAA ranges from 51.08% to 100% with an average of 91.32%; coverage ratio between Acuros Dw,m and AAA ranges from 87.2% to 100.41% with average of 98.94%; coverage ratio between Acuros Dm,m and Acuros Dw,m ranges from 58.58% to 100% with an average of 92.03%. CONCLUSIONS: The present study shows large and systematic differences in doses calculated by AAA and Acuros Dm,m. Therefore, further investigation and clarification are needed about which dose reporting mode should be used.

Early clinical experience with varian halcyon V2 linear accelerator: Dual-isocenter IMRT planning and delivery with portal dosimetry for gynecological cancer treatments.

PURPOSE: Varian Halcyon linear accelerator version 2 (The Halcyon 2.0) was recently released with new upgraded features. The aim of this study was to report our clinical experience with Halcyon 2.0 for a dual-isocenter intensity-modulated radiation therapy (IMRT) planning and delivery for gynecological cancer patients and examine the feasibility of in vivo portal dosimetry. METHODS: Twelve gynecological cancer patients were treated with extended-field IMRT technique using two isocenters on Halcyon 2.0 to treat pelvis and pelvic/or para-aortic nodes region. The prescription dose was 45 Gy in 25 fractions (fxs) with simultaneous integrated boost (SIB) dose of 55 or 57.5 Gy in 25 fxs to involved nodes. All treatment plans, pretreatment patient-specific QA and treatment delivery records including daily in vivo portal dosimetry were retrospectively reviewed. For in vivo daily portal dosimetry analysis, each fraction was compared to the reference baseline (1st fraction) using gamma analysis criteria of 4 %/4 mm with 90% of total pixels in the portal image planar dose. RESULTS: All 12 extended-field IMRT plans met the planning criteria and delivered as planned (a total of 300 fractions). Conformity Index (CI) for the primary target was achieved with the range of 0.99-1.14. For organs at risks, most were well within the dose volume criteria. Treatment delivery time was from 5.0 to 6.5 min. Interfractional in vivo dose variation exceeded gamma analysis threshold for 8 fractions out of total 300 (2.7%). These eight fractions were found to have a relatively large difference in small bowel filling and SSD change at the isocenter compared to the baseline. CONCLUSION: Halcyon 2.0 is effective to create complex extended-field IMRT plans using two isocenters with efficient delivery. Also Halcyon in vivo dosimetry is feasible for daily treatment monitoring for organ motion, internal or external anatomy, and body weight which could further lead to adaptive radiation therapy.

Application of TG-100 risk analysis methods to the acceptance testing and commissioning process of a Halcyon linear accelerator.

PURPOSE: A new type of linear accelerator (linac) was recently introduced into the market by a major manufacturer. Our institution is one of the early users of this preassembled and preconfigured dual-layer multileaf collimator (MLC), ring-gantry linac - Halcyon™ (1st version). We performed a set of full acceptance testing and commissioning (ATC) measurements for three Halcyon machines and compared the measured data with the standard beam model provided by the manufacturer. The ATC measurements were performed following the guidelines given in different AAPM protocols as well as guidelines provided by the manufacturer. The purpose of the present work was to perform a risk assessment of the ATC process for this new type of linac and investigate whether the results obtained from this analysis could potentially be used as a guideline for improving the design features of this type of linac. METHODS: AAPM's TG100 risk assessment methodology was applied to the ATC process. The acceptance testing process relied heavily on the use of a manufacturer-supplied phantom and the automated analysis of electronic portal imaging device (EPID) images. For the commissioning process, a conventional measurement setup and process (e.g., use of water tank for scanning) was largely used. ATC was performed using guidelines recommended in various AAPM protocols (e.g., TG-106, TG-51) as well as guidelines provided by the manufacturer. Six medical physicists were involved in this study. Process maps, process steps, and failure modes (FMs) were generated for the ATC procedures. Failure modes and effects analysis (FMEA) were performed following the guidelines given in AAPM TG-100 protocol. The top 5 and top 10 highest-ranked FMs were identified for the acceptance and commissioning procedures, respectively. Quality control measures were suggested to mitigate these FMs. RESULTS: A total of 38 steps and 88 FMs were identified for the entire ATC process. Fourteen steps and 34 FMs arose from acceptance testing. The top 5 FMs that were identified could potentially be mitigated by the manufacturer. For commissioning, a total of 24 steps and 54 potential FMs were identified. The use of separate measurement tools that are not machine-integrated has been identified as a cause for the higher number of steps and FMs generated from the conventional ATC approach. More than half of the quality control measures recommended for both acceptance and commissioning could potentially be incorporated by the manufacturer in the design of the Halcyon machine. CONCLUSION: This paper presents the results of FMEA and quality control measures to mitigate the FMs for the ATC process for Halcyon machine. Unique FMs that result from the differences in the ATC guidelines provided by the vendor and current conventional protocols, and the challenges of performing the ATC due to the new linac features and ring-gantry design were highlighted for the first time. The FMs identified in the present work along with the suggested quality control measures, could potentially be used to improve the design features of future ring-gantry type of linacs that are likely to be preassembled, preconfigured, and heavily reliant on automation and image guidance.

Correlation between real-time intraoperative and postoperative dosimetry and its implications on intraoperative planning.

PURPOSE: The purpose of this study was to study the correlation between intraoperative and postimplant dosimetry. We investigated the correlation between prostate (V150) and urethra (D30, D5) dose limits, and whether it is possible to increase prostate D90 and V100 in intraoperative planning without violating postimplant urethra and rectum dose limits. METHODS AND MATERIALS: Seventy-nine patients who underwent real-time ultrasound-guided prostate implants using intraoperative planning from 2013 to 2017 were analyzed. Forty-one of the 79 implants were 125I as monotherapy and the remainder was 103Pd as boost to external beam radiation therapy or external beam radiation therapy plus androgen deprivation therapy. Prescriptions followed the guidelines of AAPM TG-137. The urethra was catheterized during intraoperative implantation and postimplant imaging to facilitate the urethra identification. T2-cubed MRI and CT were acquired on the same day and about 1 month after the low-dose-rate procedure, and MRI was later fused with the CT scan for accurate delineation of the prostate and postimplant dosimetry evaluation. An institutionally based peer-review process and document procedure were established based on national recommendations. Correlation of dose parameters: D90, V150, V100 of prostate, D30, D5 of urethra, and V100 of rectum between intraoperative and postimplant plans were evaluated. RESULTS: D90 and V100 declined for all implants between intraoperative and postimplant dosimetry. On average, D90 declined by 17.5% and 21.7% for 125I and 103Pb implants, respectively. V100 declined for all implants between intraoperative and postimplant dosimetry but less pronounced. Prostate V150 and urethra D30 and D5 also showed different tendency of decline. Of the 79 implants, 60 did not meet the postimplant dosimetry target for prostate (V150 ≤ 50%), and 46 of the 60 implants met the optimal dosimetry targets for both D30 (<125%) and D5 (<150%), and the other 14 of the 60 implants failed to meet either the D30 or the D5 limits. All the implants met the postimplant target dose for rectum: V100≤ 1.3 cc. CONCLUSION: Intraoperative implant dosimetry could not accurately predict postimplant dosimetry; however, to avoid underdosage of prostate, intraoperative D90 should be close to 120% of prescribed dose and V100 needs to be close to 100% of prescribed dose. Prostate V150> 50% does not necessarily indicate the violation of urethra D30 and D5 dose limits. For most of the implants, target intraoperative D90 and V100 could be raised without violating urethra D30 and D5 limits recommended by American Brachytherapy Society in postimplant evaluation.

A novel method for the determination of field output factors and output correction factors for small static fields for six diodes and a microdiamond detector in megavoltage photon beams.

PURPOSE: The goal of this work is to provide a large and consistent set of data for detector-specific output correction factors, k Q clin , Q ref f clin , f ref , for small static fields for seven solid-state detectors and to determine field output factors, Ω Q clin , Q ref f clin , f ref , using EBT3 radiochromic films and W1 plastic scintillator as reference detectors on two different linear accelerators and four megavoltage photon beams. Consistent measurement conditions and recommendations given in the International Code of Practice TRS-483 for small-field dosimetry were followed throughout the study. METHODS: Ω Q clin , Q ref f clin , f ref were determined on two linacs, Elekta Versa HD and Varian TrueBeam, for 6 and 10 MV beams with and without flattening filter and for nine fields ranging from 0.5 × 0.5 cm2 to 10 × 10 cm2 . Signal readings obtained with EBT3 radiochromic films and W1 plastic scintillator were fitted by an analytical function. Volume averaging correction factors, determined from two-dimensional (2D) dose matrices obtained with EBT3 films and fitted to bivariate Gaussian function, were used to correct measured signals. k Q clin , Q ref f clin , f ref were determined empirically for six diodes, IBA SFD, IBA Razor, PTW 60008 P, PTW 60012 E, PTW 60018 SRS, and SN EDGE, and a PTW 60019 microDiamond detector. RESULTS: Field output factors and detector-specific k Q clin , Q ref f clin , f ref are presented in the form of analytical functions as well as in the form of discrete values. It is found that in general, for a given linac, small-field output factors need to be determined for every combination of beam energy and filtration (WFF or FFF) and field size as the differences between them can be statistically significant (P < 0.05). For different beam energies, the present data for k Q clin , Q ref f clin , f ref are found to differ significantly (P < 0.05) from the corresponding data published in TRS-483 mostly for the smallest fields (<1.5 cm). For the PTW microDiamond detector, statistically significant differences (P < 0.05) between k Q clin , Q ref f clin , f ref values were found for all investigated beams on an Elekta Versa HD linac for field sizes 0.5 × 0.5 cm2 and 0.8 × 0.8 cm2 . Significant differences in k Q clin , Q ref f clin , f ref between beams of a given energy but with and without flattening filters are found for measurements made in small fields (<1.5 cm) at a given linac. Differences in k Q clin , Q ref f clin , f ref are also found when measurements are made at different linacs using the same beam energy filtration combination; for the PTW microDiamond detector, these differences were found to be around 6% and were considered as significant. CONCLUSIONS: Selection of two reference detectors, EBT3 films and W1 plastic scintillator, and use of an analytical function, is a novel approach for the determination of Ω Q clin , Q ref f clin , f ref for small static fields in megavoltage photon beams. Large set of k Q clin , Q ref f clin , f ref data for seven solid-state detectors and four beam energies determined on two linacs by a single group of researchers can be considered a valuable supplement to the literature and the TRS-483 dataset.

Hypofractionated Whole-Breast Irradiation in Large-Breasted Women-Is There a Dosimetric Predictor for Acute Skin Toxicities?

PURPOSE: Underutilization of hypofractionated whole-breast irradiation (HF-WBI) in large-breasted women may be partially explained by concerns about dose heterogeneity. Although modern planning may mitigate this issue, validated dosimetric guidelines are lacking. Our clinical pathway mandates hypofractionation, guided by institutional dosimetric criteria for plan evaluation. We examined acute radiation dermatitis rates with HF-WBI in large-breasted patients when our guidelines are followed and evaluated factors predictive for dermatitis. METHODS AND MATERIALS: Patients with whole-breast clinical target volumes (WB-CTV) of ≥1000 cm3 treated with HF-WBI were reviewed. WB-CTV V105, V107, and V110 were assessed. Our guidelines recommend limiting V105 to <10% to 15% and V110 to 0%. The highest grade of acute dermatitis was recorded. Potential clinical and dosimetric predictors of dermatitis were analyzed using logistic regression. RESULTS: From 2012 to 2017, 505 breasts in 502 patients were treated with HF-WBI. The median WB-CTV was 1261.3 cm3 (interquartile range [IQR], 1115.3-1510.0). Most plans (99%) delivered 42.56 Gy in 16 fractions. A cavity boost of 10 Gy in 4 fractions was delivered in 99% of plans. Electrons were used in 69% of boost plans. Three-dimensional field-in-field technique was used in 68% of plans and inverse-planned intensity modulated radiation therapy in 32%. The median WB-CTV V105 was 9.7% (IQR, 5.6%-13.3%); the median WB-CTV V107 was 0.8% (IQR, 0.0%-2.5%). The WB-CTV V110 was 0% in 97.4% of plans (median, 0.0%; IQR, 0.0%-0.0%). Grade 1, 2, and 3 dermatitis rates were 55.0%, 40.8%, and 3.4%, respectively. On multivariate analysis, age >64 years (P = .016; odds ratio [OR] 4.0; 95% confidence interval [CI], 1.3-12.3), WB-CTV >1500 cm3 (P = .006; OR, 4.3; 95% CI, 1.5-12.3), body mass index ≥34 (P = .044; OR, 3.9; 95% CI, 1.0-14.5), and WB-CTV V105 >10% (P = .011; OR, 5.3; 95% CI, 1.5-19.3) predicted for grade 3 dermatitis. CONCLUSIONS: With our institutional dosimetric guidelines, grade 3 dermatitis rates with HF-WBI in large-breasted women was <5%. WB-CTV V105 should be optimized to <10% to keep grade 3 dermatitis rates <2%.