RND3 Potentiates Proinflammatory Activation through NOTCH Signaling in Activated Macrophages.

Macrophage activation is a complex process with multiple control elements that ensures an adequate response to the aggressor pathogens and, on the other hand, avoids an excess of inflammatory activity that could cause tissue damage. In this study, we have identified RND3, a small GTP-binding protein, as a new element in the complex signaling process that leads to macrophage activation. We show that RND3 expression is transiently induced in macrophages activated through Toll receptors and potentiated by IFN-γ. We also demonstrate that RND3 increases NOTCH signaling in macrophages by favoring NOTCH1 expression and its nuclear activity; however, Rnd3 expression seems to be inhibited by NOTCH signaling, setting up a negative regulatory feedback loop. Moreover, increased RND3 protein levels seem to potentiate NFκB and STAT1 transcriptional activity resulting in increased expression of proinflammatory genes, such as Tnf-α, Irf-1, or Cxcl-10. Altogether, our results indicate that RND3 seems to be a new regulatory element which could control the activation of macrophages, able to fine tune the inflammatory response through NOTCH.

Handling Patient Emergencies During Radiopharmaceutical Therapy.

PURPOSE: Radiopharmaceutical therapy (RPT) is a rapidly growing treatment modality. Though uncommon, patients may experience complications during their RPT treatment, which may trigger a rapid response from the hospital team. However, members of this team are typically not familiar with precautions for radiation safety. During these events, it is important to prioritize the patient's health over all else. There are some practices that can help minimize the risk of radiation contamination spread and exposure to staff while tending to the patient. METHODS AND MATERIALS: We formed a team to develop a standard protocol for handling patient emergencies during RPT treatment. This team consisted of an authorized user, radiation safety officer, medical physicist, nurse, RPT administration staff, and a quality/safety coordinator. The focus for developing this standardized protocol for RPT patient emergencies was 3-fold: (1) stabilize the patient; (2) reduce radiation exposure to staff; and (3) limit the spread of radiation contamination. RESULTS: We modified our hospital's existing rapid response protocol to account for the additional staff and tasks needed to accomplish all 3 of these goals. Each team member was assigned specific responsibilities, which include serving as a gatekeeper to restrict traffic, managing the crash cart, performing chest compressions, timing chest compressions, documenting the situation, and monitoring/managing radiation safety in the area. We developed a small, easy-to-read card for rapid response staff to read while they are en route to the area so they can be aware of and prepare for the unique circumstances that RPT treatments present. CONCLUSIONS: Though rapid response events with RPT patients are uncommon, it is important to have a standardized protocol for how to handle these situations beforehand rather than improvise in the moment. We have provided an example of how our team adapted our hospital's current rapid response protocol to accommodate RPT patients.

NOTCH4 potentiates the IL-13 induced genetic program in M2 alternative macrophages through the AP1 and IRF4-JMJD3 axis.

IL-13 signaling polarizes macrophages to an M2 alternatively activated phenotype, which regulates tissue repair and anti-inflammatory responses. However, an excessive activation of this pathway leads to severe pathologies, such as allergic airway inflammation and asthma. In this work, we identified NOTCH4 receptor as an important modulator of M2 macrophage activation. We show that the expression of NOTCH4 is induced by IL-13, mediated by Janus kinases and AP1 activity, probably mediated by the IL-13Rα1 and IL-13Rα2 signaling pathway. Furthermore, we demonstrate an important role for NOTCH4 signaling in the IL-13 induced gene expression program in macrophages, including various genes that contribute to pathogenesis of the airways in asthma, such as ARG1, YM1, CCL24, IL-10, or CD-163. We also demonstrate that NOTCH4 signaling modulates IL-13-induced gene expression by increasing IRF4 activity, mediated, at least in part, by the expression of the histone H3K27me3 demethylase JMJD3, and by increasing AP1-dependent transcription. In summary, our results provide evidence for an important role of NOTCH4 signaling in alternative activation of macrophages by IL-13 and suggest that NOTCH4 may contribute to the increased severity of lesions in M2 inflammatory responses, such as allergic asthma, which points to NOTCH4 as a potential new target for the treatment of these pathologies.

Logistical, technical, and radiation safety aspects of establishing a radiopharmaceutical therapy program: A case in Lutetium-177 prostate-specific membrane antigen (PSMA) therapy.

Prostate-specific membrane antigen (PSMA) is a cell surface protein highly expressed in nearly all prostate cancers, with restricted expression in some normal tissues. The differential expression of PSMA from tumor to non-tumor tissue has resulted in the investigation of numerous targeting strategies for therapy of patients with metastatic prostate cancer. In March of 2022, the FDA granted approval for the use of lutetium-177 PSMA-617 (Lu-177-PSMA-617) for patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. Therefore, the use of Lu-177-PSMA-617 is expected to increase and become more widespread. Herein, we describe logistical, technical, and radiation safety considerations for implementing a radiopharmaceutical therapy program, with particular focus on the development of operating procedures for therapeutic administrations. Major steps for a center in the U.S. to implement a new radiopharmaceutical therapy (RPT) program are listed below, and then demonstrated in greater detail via examples for Lu-177-PSMA-617 therapy.

Failure modes and effects analysis of pediatric I-131 MIBG therapy: Program design and potential pitfalls.

BACKGROUND: There is growing interest among pediatric institutions for implementing iodine-131 (I-131) meta-iodobenzylguanidine (MIBG) therapy for treating children with high-risk neuroblastoma. Due to regulations on the medical use of radioactive material (RAM), and the complexity and safety risks associated with the procedure, a multidisciplinary team involving radiation therapy/safety experts is required. Here, we describe methods for implementing pediatric I-131 MIBG therapy and evaluate our program's robustness via failure modes and effects analysis (FMEA). METHODS: We formed a multidisciplinary team, involving pediatric oncology, radiation oncology, and radiation safety staff. To evaluate the robustness of the therapy workflow and quantitatively assess potential safety risks, an FMEA was performed. Failure modes were scored (1-10) for their risk of occurrence (O), severity (S), and being undetected (D). Risk priority number (RPN) was calculated from a product of these scores and used to identify high-risk failure modes. RESULTS: A total of 176 failure modes were identified and scored. The majority (94%) of failure modes scored low (RPN <100). The highest risk failure modes were related to training and to drug-infusion procedures, with the highest S scores being (a) caregivers did not understand radiation safety training (O = 5.5, S = 7, D = 5.5, RPN = 212); (b) infusion training of staff was inadequate (O = 5, S = 8, D = 5, RPN = 200); and (c) air in intravenous lines/not monitoring for air in lines (O = 4.5, S = 8, D = 5, RPN = 180). CONCLUSION: Through use of FMEA methodology, we successfully identified multiple potential points of failure that have allowed us to proactively mitigate risks when implementing a pediatric MIBG program.

Clinical Outcomes of Patients With Unresectable Primary Liver Cancer Treated With Yttrium-90 Radioembolization With an Escalated Dose.

Purpose: Yttrium-90 (90Y) radioembolization with an escalated dose has been shown to improve clinical outcomes compared with standard dose radioembolization, but there are few data on the local control of primary liver tumors. We reported the clinical outcomes of patients with unresectable primary liver tumors treated with 90Y radioembolization with an escalated dose. Methods and Materials: Clinical data of patients with unresectable hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and biphenotypic tumors (cHCC-CC) treated with radioembolization with an escalated dose (≥150 Gy) between 2013 and 2020 with >3 months follow-up were retrospectively reviewed. The primary endpoint was freedom from local progression. Clinical response was defined by Modified Response Evaluation Criteria in Solid Tumours and toxic effects were assessed using Common Terminology Criteria for Adverse Events version 5.0. Results: Fifty-three patients with HCC and 15 patients with CC/cHCC-CC were analyzed. The median dose delivered was 205 Gy (interquartile range, 183-253 Gy) and 198 Gy (interquartile range, 154-234 Gy) for patients with HCC and CC/cHCC-CC, respectively. The 1-year freedom from local progression rate was 54% (95% confidence interval [CI], 38%-78%) for patients with HCC and 66% (95% CI, 42%-100%) for patients with CC/cHCC-CC. For patients with HCC, United Network for Organ Sharing nodal stage 1 (P = .01), nonsolitary tumors (P = .02), pretreatment α-fetoprotein of >7.7 ng/mL (P = .006), and ≤268 Gy dose delivered (P = .003) were predictors for local progression on multivariate Cox analysis. No patients with HCC who received a dose >268 Gy had a local tumor progression. The 1-year overall survival for patients with HCC was 74% (95% CI, 61%-89%). After radioembolization, 5 (7%) patients had grade 3 ascites, and 4 (6%) patients had grade 3/4 hyperbilirubinemia. Conclusions: Treatment of unresectable primary liver tumors with 90Y radioembolization with an escalated dose was safe and well tolerated. Delivery of >268 Gy may improve local tumor control of HCC. Determination of the maximum tolerated dose needs to be performed in the context of future prospective dose-escalation trials to further evaluate the safety and efficacy of such an approach.

NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling.

NOTCH4 is a member of the NOTCH family of receptors whose expression is intensively induced in macrophages after their activation by Toll-like receptors (TLR) and/or interferon-γ (IFN-γ). In this work, we show that this receptor acts as a negative regulator of macrophage activation by diminishing the expression of proinflammatory cytokines, such as IL-6 and IL-12, and costimulatory proteins, such as CD80 and CD86. We have observed that NOTCH4 inhibits IFN-γ signaling by interfering with STAT1-dependent transcription. Our results show that NOTCH4 reprograms the macrophage response to IFN-γ by favoring STAT3 versus STAT1 phosphorylation without affecting their expression levels. This lower activation of STAT1 results in diminished transcriptional activity and expression of STAT1-dependent genes, including IRF1, SOCS1 and CXCL10. In macrophages, NOTCH4 inhibits the canonical NOTCH signaling pathway induced by LPS; however, it can reverse the inhibition exerted by IFN-γ on NOTCH signaling, favoring the expression of NOTCH-target genes, such as Hes1. Indeed, HES1 seems to mediate, at least in part, the enhancement of STAT3 activation by NOTCH4. NOTCH4 also affects TLR signaling by interfering with NF-κB transcriptional activity. This effect could be mediated by the diminished activation of STAT1. These results provide new insights into the mechanisms by which NOTCH, TLR and IFN-γ signal pathways are integrated to modulate macrophage-specific effector functions and reveal NOTCH4 acting as a new regulatory element in the control of macrophage activation that could be used as a target for the treatment of pathologies caused by an excess of inflammation.

Does the sequence of high-dose rate brachytherapy boost and IMRT for prostate cancer impact early toxicity outcomes? Results from a single institution analysis.

BACKGROUND: We present the first report comparing early toxicity outcomes with high-dose rate brachytherapy (HDR-BT) boost upfront versus intensity modulated RT (IMRT) upfront combined with androgen deprivation therapy (ADT) as definitive management for intermediate risk or higher prostate cancer. METHODS AND MATERIALS: We reviewed all non-metastatic prostate cancer patients who received HDR-BT boost from 2014 to 2019. HDR-BT boost was offered to patients with intermediate-risk disease or higher. ADT use and IMRT target volume was based on NCCN risk group. IMRT dose was typically 45 Gy in 25 fractions to the prostate and seminal vesicles ± pelvic lymph nodes. HDR-BT dose was 15 Gy in 1 fraction, delivered approximately 3 weeks before or after IMRT. The sequence was based on physician preference. Biochemical recurrence was defined per ASTRO definition. Gastrointestinal (GI) and Genitourinary (GU) toxicity was graded per CTCAE v5.0. Pearson Chi-squared test and Wilcoxon tests were used to compare toxicity rates. P-value < 0.05 was significant. RESULTS: Fifty-eight received HDR-BT upfront (majority 2014-2016) and 57 IMRT upfront (majority 2017-2018). Median follow-up was 26.0 months. The two cohorts were well-balanced for baseline patient/disease characteristics and treatment factors. There were differences in treatment sequence based on the year in which patients received treatment. Overall, rates of grade 3 or higher GI or GU toxicity were <1%. There was no significant difference in acute or late GI or GU toxicity between the two groups. CONCLUSION: We found no significant difference in GI/GU toxicity in intermediate-risk or higher prostate cancer patients receiving HDR-BT boost upfront versus IMRT upfront combined with ADT. These findings suggest that either approach may be reasonable. Longer follow-up is needed to evaluate late toxicity and long-term disease control.

Radiation-Induced Brachial Plexopathy in Patients With Breast Cancer Treated With Comprehensive Adjuvant Radiation Therapy.

PURPOSE: Our purpose was to describe the risk of radiation-induced brachial plexopathy (RIBP) in patients with breast cancer who received comprehensive adjuvant radiation therapy (RT). METHODS AND MATERIALS: Records for 498 patients who received comprehensive adjuvant RT (treatment of any residual breast tissue, the underlying chest wall, and regional nodes) between 2004 and 2012 were retrospectively reviewed. All patients were treated with conventional 3 to 5 field technique (CRT) until 2008, after which intensity modulated RT (IMRT) was introduced. RIBP events were determined by reviewing follow-up documentation from oncologic care providers. Patients with RIBP were matched (1:2) with a control group of patients who received CRT and a group of patients who received IMRT. Dosimetric analyses were performed in these patients to determine whether there were differences in ipsilateral brachial plexus dose distribution between RIBP and control groups. RESULTS: Median study follow-up was 88 months for the overall cohort and 92 months for the IMRT cohort. RIBP occurred in 4 CRT patients (1.6%) and 1 IMRT patient (0.4%) (P = .20). All patients with RIBP in the CRT cohort received a posterior axillary boost. Maximum dose to the brachial plexus in RIBP, CRT control, and IMRT control patients had median values of 56.0 Gy (range, 49.7-65.1), 54.8 Gy (47.4-60.5), and 54.8 Gy (54.2-57.3), respectively. CONCLUSIONS: RIBP remains a rare complication of comprehensive adjuvant breast radiation and no clear dosimetric predictors for RIBP were identified in this study. The IMRT technique does not appear to adversely affect the development of this late toxicity.

Characterization of Dosimetric Differences in Strut-Adjusted Volume Implant Treatment Plans Calculated With TG-43 Formalism and a Model-Based Dose Calculation Algorithm.

PURPOSE: To comprehensively characterize dosimetric differences between calculations with a commercial model-based dose calculation algorithm (MBDCA) and the TG-43 formalism in application to accelerated partial breast irradiation (APBI) with the strut-adjusted volume implant (SAVI) applicator. METHODS: Dose for 100 patients treated with the SAVI applicator was recalculated with an MBDCA for comparison to dose calculated via TG-43. For every pair of dose calculations, dose-volume histogram (DVH) metrics including V90%, V95%, V100%, V150%, and V200% for the PTV_EVAL were compared. Features were defined for each case including (1) applicator size, (2) ratio between PTV_EVAL contour and 1-cm rind surrounding SAVI applicator, (3) ratio between dwell time in central catheter and total dwell time, and (4) mean computed tomography (CT) number within the lumpectomy cavity. Wilcoxon rank sum tests were performed to test whether treatment plans could be stratified according to feature values into groups with statistically significant dosimetry differences between MBDCA and TG-43. RESULTS: For all DVH metrics, differences between TG-43 and MBDCA calculations were statistically significant (P < .05). Minimum (maximum) relative percent differences between the MBDCA and TG-43 for V90%, V95%, and V100% were -2.1% (0.1%), -3.1% (-0.1%), and -5.0% (-0.5%), respectively. The median relative percent difference in mean PTV_EVAL dose between the MBDCA and TG-43 was -3.9%, with minimum (maximum) difference of -6.5% (-1.8%). For V90%, V95%, and V100%, plan quality worsened beyond defined thresholds in 26, 23, and 31 cases with no instances of coverage improvement. Features 1, 2, and 4 were shown to be able to stratify treatment plans into groups with statistically significant differences in dosimetry metrics between MBDCA and TG-43. CONCLUSIONS: Investigated dose metrics for SAVI treatments were found to be systematically lower with MBDCA calculation in comparison to TG-43. Plans could be stratified according to several features by the magnitude of dosimetric differences between these calculations.

Initial experience and lessons learned with implementing Lutetium-177-dotatate radiopharmaceutical therapy in a radiation oncology-based program.

PURPOSE: To assist radiation oncology centers in implementing Lutetium-177-dotatate (177Lu) radiopharmaceutical therapy for midgut neuroendocrine tumors. Here we describe our workflow and how it was revised based on our initial experience on an expanded access protocol (EAP). METHODS: A treatment team/area was identified. An IV-pump-based infusion technique was implemented. Exposure-based techniques were implemented to determine completion of administration, administered activity, and patient releasability. Acute toxicities were assessed at each fraction. A workflow failure modes and effects analysis (FMEA) was performed. RESULTS: A total of 22 patients were treated: 11 patients during EAP (36 administrations) and 11 patients after EAP (44 administrations). Mean 177Lu infusion time was 37 min (range 26-65 min). Mean administered activity was 97% (range 90-99%). Mean patient exposures at 1 m were 1.9 mR/h (range 1.0-4.1 mR/h) post-177Lu and 0.9 mR/h (range 0.4-1.8 mR/h) at discharge, rendering patients releasable with instructions. Treatment area was decontaminated and released same day. All patients in the EAP experienced nausea, and nearly half experienced emesis despite premedication with antiemetics. Peripheral IV-line complications occurred in six treatments (16.7%), halting administration in 2 cases (5.6%). We transitioned to peripherally inserted central catheter (PICC)-lines and revised amino acid formulary after the EAP. The second cohort of 11 patients after EAP were analyzed for PICC-line complications and acute toxicity. Nausea and emesis rates decreased (nausea G1+ 61%-27%; emesis G1+ 23%-7%), and no PICC complications were observed. FMEA revealed that a failure in amino acid preparation was the highest risk. CONCLUSION: 177Lu-dotatate can be administered safely in an outpatient radiation oncology department.

NOTCH3 signaling is essential for NF-κB activation in TLR-activated macrophages.

Macrophage activation by Toll receptors is an essential event in the development of the response against pathogens. NOTCH signaling pathway is involved in the control of macrophage activation and the inflammatory processes. In this work, we have characterized NOTCH signaling in macrophages activated by Toll-like receptor (TLR) triggering and determined that DLL1 and DLL4 are the main ligands responsible for NOTCH signaling. We have identified ADAM10 as the main protease implicated in NOTCH processing and activation. We have also observed that furin, which processes NOTCH receptors, is induced by TLR signaling in a NOTCH-dependent manner. NOTCH3 is the only NOTCH receptor expressed in resting macrophages. Its expression increased rapidly in the first hours after TLR4 activation, followed by a gradual decrease, which was coincident with an elevation of the expression of the other NOTCH receptors. All NOTCH1, 2 and 3 contribute to the increased NOTCH signaling detected in activated macrophages. We also observed a crosstalk between NOTCH3 and NOTCH1 during macrophage activation. Finally, our results highlight the relevance of NOTCH3 in the activation of NF-κB, increasing p65 phosphorylation by p38 MAP kinase. Our data identify, for the first time, NOTCH3 as a relevant player in the control of inflammation.

Single fraction high-dose-rate brachytherapy as monotherapy for low and intermediate risk prostate cancer: toxicities and early outcomes from a single institutional experience.

PURPOSE: High-dose-rate brachytherapy (HDR-BT) delivered in a single fraction as monotherapy is a potential treatment modality for low- and intermediate-risk prostate cancer (LIR-PC); however, outcome data with this technique remain limited. Here we describe our institutional HDR monotherapy experience and report the efficacy and toxicity of this treatment. MATERIAL AND METHODS: LIR-PC patients who received a definitive single fraction HDR-BT during 2013-2017 were retrospectively identified. The intended HDR monotherapy dose was 19 Gy in one fraction. Acute (< 90 days) and late (≥ 90 days) toxicity was assessed using CTCAE version 4.03. Trends in prostate-specific antigen (PSA) and American Urological Association (AUA) symptom scores after treatment were assessed using Bayesian linear mixed models. The Kaplan-Meier method was used to evaluate biochemical failure-free survival (BFFS). RESULTS: 28 patients with median follow-up of 23.6 months were identified. The median age at treatment was 65 years (48-83). The NCCN risk groups were low in 14, favorable intermediate in 10, and unfavorable intermediate in 4 patients. There were 5 (18%) and 0 (0%) acute grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities, respectively, and one (4%) acute grade 3 GU toxicity. There were no late grade 3 toxicities, and 5 (18%) and 0 (0%) late grade 2 GU and GI toxicities respectively. PSA values and AUA symptom scores decreased significantly after treatment. There were 3 biochemical failures with the two- and three-year BFFS of 90.7% and 80.6%, respectively. CONCLUSIONS: Early results from a single institution suggest that single fraction HDR-BT with 19 Gy has limited toxicity, although with suboptimal biochemical control.

Concurrent chemoradiation for cervical cancer: Comparison of LDR and HDR brachytherapy.

PURPOSE: To compare clinical outcomes between low-dose-rate (LDR) brachytherapy and high-dose-rate (HDR) brachytherapy for cervical cancer patients. METHODS AND MATERIALS: All consecutive newly diagnosed cervical cancer patients undergoing pretreatment 18-fluorodeoxyglucose positron emission tomography imaging and treated with curative-intent definitive chemoradiation from 1997 to 2016 at a U.S. academic center were included. Brachytherapy boost was LDR or HDR 2D treatment planning from 1997 to 2005 and HDR with MR-based 3D planning from 2005 to 2016. Local control (LC), cancer-specific survival (CSS), and late bowel/bladder complications were evaluated. RESULTS: Tumor stages were International Federation of Gynecology and Obstetrics IB1-IIB (n = 457; 75%) and III-IVA (n = 152; 25%). Brachytherapy was LDR for 104 patients and HDR for 505 patients. Concurrent weekly cisplatin was administered to 536 patients (88%). With median followup of 9.4 years, there was no difference in LC (p = 0.24) or CSS (p = 0.50) between LDR and HDR brachytherapy. Cox multivariable regression showed that only International Federation of Gynecology and Obstetrics stage III-IVA (HR=2.4, p = 0.004) was associated with worse LC. A propensity-matched cohort (90 LDR vs. 90 HDR) was created, and the 5-year LC rates were 88% LDR and 82% HDR, p = 0.26; 5-year CSS rates were 66% LDR and 58% HDR, p = 0.19; 5-year grade ≥3 bowel/bladder toxicities were 23% LDR and 16% HDR, p = 0.44. For all patients, the 5-year late toxicity in stage III-IVA patients was higher with LDR 47% vs. HDR 15%, p = 0.03, with no difference in LC, 86% and 75%, respectively (p = 0.09). CONCLUSIONS: There was no difference in LC with either LDR or HDR brachytherapy. The late complication rate was reduced with HDR and 3D-planned brachytherapy compared to LDR and 2D-planned brachytherapy.

MRI safety risks in the obese: The case of the disposable lighter stored in the pannus.

Obese patients constitute 40% of the adult population. MRIs of obese patients are typically challenging because of the effects of a large field of view on image quality and the increased risk of thermal burns from contact with the bore. In this case report, the impacts of obesity on MRI procedures and safety are introduced. Then a case is presented of a 30-year old female cervical cancer patient who received an MRI simulation to verify the placement of a titanium tandem and colpostats for brachytherapy. A large magnetic susceptibility artifact was detected near the right pelvis during the MRI scout indicating the presence of ferrous material. The source of the artifact turned out to be a disposable lighter that was stored inside the patient's pannus. The finding highlights an unanticipated risk to MRI safety and image quality associated with large body habitus.

Validation of post-treatment PET-based dosimetry software for hepatic radioembolization of Yttrium-90 microspheres.

PURPOSE: Yttrium-90 (90 Y) microsphere radioembolization enables selective internal radiotherapy for hepatic malignancies. Currently, there is no standard postdelivery imaging and dosimetry of the microsphere distribution to verify treatment. Recent studies have reported utilizing the small positron yield of 90 Y (32 ppm) with positron emission tomography (PET) to perform treatment verification and dosimetry analysis. In this study, we validated a commercial dosimetry software, MIM SurePlan™ LiverY90 (MIM Software Inc., Cleveland, OH), for clinical use. METHODS: A MATLAB-based algorithm for 90 Y PET-based dosimetry was developed in-house and validated for the purpose of commissioning the commercial software. The algorithm is based on voxel S values and dosimetry formalism reported in MIRD Pamphlet 17. We validated the in-house algorithm to establish it as the ground truth by comparing results from a digital point phantom and a digital uniform cylinder to manual calculations. Once we validated our in-house MATLAB-based algorithm, we used it to perform acceptance testing and commissioning of the commercial dosimetry software, MIM SurePlan, which uses the same dosimetry formalism. A 0.4 cm/5% gamma test was performed on PET-derived dose maps from each algorithm of uniform digital and nonuniform physical phantoms filled with 90 Y chloride solution. Average dose (Davg ) and minimum dose to 70% (D70 ) of a given volume of interest (VOI) were compared for the digital phantom, the physical phantom, and five patient cases (27 tumor VOIs), representing different clinical scenarios. RESULTS: The gamma-pass rates were 97.26% and 97.66% for the digital and physical phantoms, respectively. The differences between Davg and D70 were 0.076% and 0.10% for the digital phantom, respectively, and <5.2% for various VOIs in the physical phantom. In the clinical cases, 96.3% of the VOIs had a difference <5% for Davg , and 88.9% of the VOIs had a difference <5% for D70 . CONCLUSIONS: Dose calculation results from MIM SurePlan were found to be in good agreement with our in-house algorithm. This indicates that MIM SurePlan performs as it should and, hence, can be deemed accepted and commissioned for clinical use for post-implant PET-based dosimetry of 90 Y radioembolization.

Standardization and automation of quality assurance for high-dose-rate brachytherapy planning with application programming interface.

PURPOSE: To standardize and automate the high-dose-rate (HDR) brachytherapy planning quality assurance (QA) process utilizing scripting with application programming interface (API) in a commercially available treatment planning system (TPS). METHODS AND MATERIALS: Site- and applicator-dependent plan quality (PQ) evaluation criteria and plan integrity (PI) checklists were established based on published guidelines, clinical protocols, and institutional experience. User designed C# programs ("scripts") were created and executed through the API to access planning information in TPS. A set of standardized quality control reports, focusing on PQ evaluations and PI checks, were automatically generated. Information derived from the TPS was compared against predetermined QA metrics with color-coded pass/fail indicators to aid and enhance the efficiency of plan evaluation. Five independent, blinded observers reviewed mock plans with simulated errors to validate the scripts and to quantify the improvement of plan review efficiency. RESULTS: Scripts were developed for HDR prostate and breast. Forty-one parameters were reported/checked in the PI report; the PQ report returned dose-volume indices and an independent check of dwell time. All simulated errors were detected by the PI scripts with appropriate warning messages displayed, and any values failing to meet the planning constraints were red-flagged successfully in the PQ report. An average time reduction of 16 min for plan review was observed when using the scripts. CONCLUSIONS: API scripting-based automated planning QA for HDR brachytherapy including PI checks and PQ evaluations was designed and implemented. The simulated error study showed promising results in terms of error catching and efficiency improvement.

Efficiency of using the day-of-implant CT for planning of SAVI APBI.

PURPOSE: The purpose of the study was to develop an optimized, efficient workflow for using the day-of-implant (DOI) CT for treatment planning of accelerated partial breast irradiation brachytherapy using the strut-adjusted volume implant (SAVI) device. METHODS AND MATERIALS: For 62 consecutive SAVI patients, a DOI CT was acquired and used for treatment planning. A "verification" CT was acquired 24-72 h after implant and immediately before the first fraction, then registered to the DOI CT. If the DOI CT-based plan was no longer optimal, a replan was performed. An array of metrics describing the geometry of the device and its relative position in the patient from the DOI CTs for these patients was collected. These metrics from the DOI CT were evaluated to determine what features could predict for the need to replan before the first treatment fraction. Logistical regression analysis including χ2 tests was used to determine if different factors correlated with replanning. RESULTS: Twenty-two of 62 patients (35%) required replanning. Only the presence of splayed struts, where splay was toward the skin, and the use of a nine strut ("8-1") SAVI were significantly correlated (p < 0.05) with replanning. Within these individual populations, no additional factors showed a significant statistical correlation for requiring replanning. CONCLUSIONS: For strut-based accelerated partial breast irradiation brachytherapy, it was feasible to treat with a plan based on the DOI CT for a majority (65%) of patients. Some factors correlate to needing replanning; recognizing these could be used to optimize treatment workflow for certain patients, increasing clinical efficiency while enhancing the quality of patient care.

MRI-based treatment planning and dose delivery verification for intraocular melanoma brachytherapy.

PURPOSE: Episcleral plaque brachytherapy (EPB) planning is conventionally based on approximations of the implant geometry with no volumetric imaging following plaque implantation. We have developed an MRI-based technique for EPB treatment planning and dose delivery verification based on the actual patient-specific geometry. METHODS AND MATERIALS: MR images of 6 patients, prescribed 85 Gy over 96 hours from Collaborative Ocular Melanoma Study-based EPB, were acquired before and after implantation. Preimplant and postimplant scans were used to generate "preplans" and "postplans", respectively. In the preplans, a digital plaque model was positioned relative to the tumor, sclera, and nerve. In the postplans, the same plaque model was positioned based on the imaged plaque. Plaque position, point doses, percentage of tumor volume receiving 85 Gy (V100), and dose to 100% of tumor volume (Dmin) were compared between preplans and postplans. All isodose plans were computed using TG-43 formalism with no heterogeneity corrections. RESULTS: Shifts and tilts of the plaque ranged from 1.4 to 8.6 mm and 1.0 to 3.8 mm, respectively. V100 was ≥97% for 4 patients. Dmin for preplans and postplans ranged from 83 to 118 Gy and 45 to 110 Gy, respectively. Point doses for tumor apex and base were all found to decrease from the preimplant to the postimplant plan, with mean differences of 16.7 ± 8.6% and 30.5 ± 11.3%, respectively. CONCLUSIONS: By implementing MRI for EPB, we eliminate reliance on approximations of the eye and tumor shape and the assumption of idealized plaque placement. With MRI, one can perform preimplant as well as postimplant imaging, facilitating EPB treatment planning based on the actual patient-specific geometry and dose-delivery verification based on the imaged plaque position.

Magnetic resonance imaging metal artifact reduction for eye plaque patient with dental braces.

PURPOSE: To determine if metal artifact reduction can minimize magnetic susceptibility artifacts in the orbits for an eye plaque brachytherapy patient with metallic dental braces. MATERIAL AND METHODS: A 62-year-old female patient with a choroidal melanoma in the right eye received a 1.5 T magnetic resonance imaging (MRI) simulation for 3D eye plaque brachytherapy planning. The protocol included conventional 3D T1-weighted and 2D T2-weighted MRIs. A vendor-supplied T2-weighted metal artifact reduction sequence was added to the protocol to reduce magnetic susceptibility artifacts from the metallic dental braces. The metal artifact reduction sequence combined turbo spin echo acquisitions, high RF excitation and readout bandwidths, and view angle tilting and slice encoding for metal artifact correction with z-shimming to correct in-plane and through-plane image distortions, respectively. RESULTS: Dental braces caused significant signal loss and image distortion in the orbits on the conventional T1-weighted and T2-weighted MRIs, and the MRIs were unusable for treatment planning. The metal artifact reduction sequence with 13 z-phase encodes minimized distortion and signal loss in the orbits, allowing the tumor to be clearly delineated. CONCLUSIONS: T2-weighted MRI with metal artifact reduction was successfully applied to minimize artifacts in the orbits resulting from the dental braces, thus allowing the MRIs to be used in 3D brachytherapy treatment planning.