Commissioning considerations for the Bravos high-dose-rate afterloader: Towards improving treatment delivery accuracy.

BACKGROUND AND PURPOSE: The upgrade of major equipment can be disruptive to clinical operations and introduce risk as policy and procedures need to adapt to new technical possibilities and constraints. We describe here the transition from GammaMedPlus-iX to Bravos in a busy brachytherapy clinic, involving four afterloaders across two sites. MATERIAL AND METHODS: Our clinic employs three high-dose-rate remote afterloaders in four dedicated treatment vaults at the main site and a fourth afterloader at a regional location. Of more than 600 new HDR treatment plans performed annually, most are planned and treated intraoperatively. Most treatments are for prostate cancer, followed by GYN, intraoperative brachytherapy, GI, and other sites. Applicators used include vendor-provided applicators as well as third party applicators and in-house 3D-printed devices to provide interstitial, intracavitary, intraluminal, and surface treatments. All applicators were commissioned according to recommended guidelines. The choice of tolerances and the design of new procedures were informed by current guidelines and leveraged new HDR afterloader functionalities. A review of clinical operations in the 4 months postupgrade was conducted to evaluate the feasibility of new tolerances and the effectiveness of new procedures. RESULTS: The procedures outlined improved and standardized afterloader QA and treatment protocols with clear actionable steps for staff to follow to ensure treatments are delivered as planned. Re-commissioning of applicators yielded results similar to those previously reported by other investigators. A review of initial treatment data revealed that in one case, due to the implementation of tight tolerances, obstruction near the tip of the channel was detected and corrected prior to treatment. It confirms that the implementation of the tolerances adopted is feasible and effective in flagging treatment deviations. CONCLUSION: Enhanced procedures and QA processes were implemented successfully. We established clear actionable steps to follow by staff to ensure that treatments are delivered accurately.

Extended Follow-Up Outcomes from Pooled Prospective Studies Evaluating Efficacy of Interstitial Alpha Radionuclide Treatment for Skin and Head and Neck Cancers.

The initial favorable efficacy and safety profile for Alpha DaRT have been demonstrated (NCT04377360); however, the longer-term safety and durability of the treatment are unknown. This pooled analysis of four prospective trials evaluated the long-term safety and efficacy of Alpha DaRT for the treatment of head and neck or skin tumors. A total of 81 lesions in 71 patients were treated across six international institutions, with a median follow-up of 14.1 months (range: 2-51 months). Alpha DaRT sources were delivered via a percutaneous interstitial technique and placed to irradiate the tumor volume with the margin. The sources were removed two to three weeks following implantation. A complete response was observed in 89% of treated lesions (n = 72) and a partial response in 10% (n = 8). The two-year actuarial local recurrence-free survival was 77% [95% CI 63-87]. Variables, including recurrent versus non-recurrent lesions, baseline tumor size, or histology, did not impact long-term outcomes. Twenty-seven percent of patients developed related acute grade 2 or higher toxicities, which resolved with conservative measures. No grade 2 or higher late toxicities were observed. These data support the favorable safety profile of Alpha DaRT, which is currently being explored in a pivotal US trial.

Cancer mutational signatures identification in clinical assays using neural embedding-based representations.

While mutational signatures provide a plethora of prognostic and therapeutic insights, their application in clinical-setting, targeted gene panels is extremely limited. We develop a mutational representation model (which learns and embeds specific mutation signature connections) that enables prediction of dominant signatures with only a few mutations. We predict the dominant signatures across more than 60,000 tumors with gene panels, delineating their landscape across different cancers. Dominant signature predictions in gene panels are of clinical importance. These included UV, tobacco, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) signatures that are associated with better survival, independently from mutational burden. Further analyses reveal gene and mutation associations with signatures, such as SBS5 with TP53 and APOBEC with FGFR3S249C. In a clinical use case, APOBEC signature is a robust and specific predictor for resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Our model provides an easy-to-use way to detect signatures in clinical setting assays with many possible clinical implications for an unprecedented number of cancer patients.

AAPM Task Group 334: A guidance document to using radiotherapy immobilization devices and accessories in an MR environment.

Use of magnetic resonance (MR) imaging in radiation therapy has increased substantially in recent years as more radiotherapy centers are having MR simulators installed, requesting more time on clinical diagnostic MR systems, or even treating with combination MR linear accelerator (MR-linac) systems. With this increased use, to ensure the most accurate integration of images into radiotherapy (RT), RT immobilization devices and accessories must be able to be used safely in the MR environment and produce minimal perturbations. The determination of the safety profile and considerations often falls to the medical physicist or other support staff members who at a minimum should be a Level 2 personnel as per the ACR. The purpose of this guidance document will be to help guide the user in making determinations on MR Safety labeling (i.e., MR Safe, Conditional, or Unsafe) including standard testing, and verification of image quality, when using RT immobilization devices and accessories in an MR environment.

Impact of Dietary Fat and Oral Delivery System on Cannabigerol Pharmacokinetics in Adults.

Background and Aims: Cannabigerol (CBG) is a nonintoxicating cannabinoid synthesized in the Cannabis sativa plant that is incorporated into dietary supplements. This study investigated the influence of dietary fat and an emulsified delivery vehicle on CBG pharmacokinetics (PKs) after oral ingestion by adults. Materials and Methods: Consented participants were enrolled in a double-crossover pilot study and were blinded to the delivery vehicle type (isolate or emulsification) and isocaloric meal condition (low-fat=<5 g fat/meal or high-fat [HF]=>30 g fat/meal). The concentration of CBG in human plasma was measured after a single 25 mg dose of CBG using liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK parameters were calculated using noncompartmental analysis. Results: The PKs of the two delivery systems (emulsified vs. non-emulsified) were significantly impacted by the HF meal condition. Participants in the HF meal group exhibited significantly higher area under the plasma concentration time curve from time 0 to last quantifiable value, maximum concentration, and terminal half-life. Participants in the HF meal group also had a significantly lower terminal elimination rate constant and time to maximum concentration (Tmax), in addition to decreased Tmax variation. The threshold for bioequivalence between conditions was not met. An exploratory aim correlated anthropometric measures and previous day's dietary intake on PK parameters which yielded inconsistent results across dietary fat conditions. Conclusions: In aggregate, dietary fat had a greater effect on CBG PKs than the emulsified delivery vehicle. This supports accounting for dietary intake in development of therapeutics and administration guidelines for orally delivered CBG.

Sucrose Concentration and Fermentation Temperature Impact the Sensory Characteristics and Liking of Kombucha.

Kombucha is a fermented tea beverage consumed for its probiotics and functional properties. It has a unique sensory profile driven by the properties of tea polyphenols and fermentation products, including organic acids. Fermentation temperature and sucrose content affect the fermentation process and the production of organic acids; yet less is known about their impacts on the sensory profile and consumer acceptance. Thus, we aimed to examine the impact of sucrose concentration and fermentation temperature on sensory attributes and liking. For this study, kombucha tea was fermented at three different concentrations of sucrose and fermented at two temperatures for 11 days. Fermentation was monitored by pH, brix, and titratable acidity, and consumers (n = 111) evaluated the kombucha for sensory attributes and overall liking. The fermentation temperature resulted in significant differences in titratable acidity, with higher temperatures producing more organic acids, resulting in higher astringency, and suppressed sweetness. The lower fermentation was reported as significantly more liked, with no difference in liking between the 7.5% and 10% sucrose kombucha samples. Fermentation temperature had the greatest impact on the sensory profile rather than sucrose concentration, which had a greater effect on the fermentation rate and production organic acids.

Feasibility and Safety of Diffusing Alpha-Emitter Radiation Therapy for Recurrent or Unresectable Skin Cancers.

Importance: Patients with recurrent or unresectable skin cancers have limited treatment options. Diffusing alpha-emitter radiation therapy (DaRT), a novel solid tumor management strategy using alpha-particle interstitial brachytherapy, may address this challenge. Objective: To evaluate the feasibility and safety of using DaRT to manage recurrent or unresectable skin cancers. Design, Setting, and Participants: This prospective cohort study of patients who received a 2-week to 3-week treatment course and were followed up for 24 weeks after treatment during 2021 and 2022 at 2 sites in the US. Patients with malignant skin tumors or soft tissue tumors were recruited if they had limited treatment options for tumors recurrent after prior surgery or external beam radiotherapy or unresectable tumors. Intervention: Patients underwent DaRT to deliver a physical dose of 10 Gy (equivalent weighted dose of 200 CGE) to the tumor. Main Outcomes and Measures: Feasibility of the DaRT procedure was evaluated based on the ability of investigators to successfully deliver radiation to the tumor. Patients were followed up for adverse events (AEs) for 24 weeks and for tumor response by physicians' physical examination and imaging 12 weeks after device removal. Results: This study included 10 participants with recurrent or unresectable skin cancer (median [IQR] age, 72 [68-75] years; 6 males [60%]; 4 females [40%]). Six patients (60%) had recurrent disease, and 4 (40%) had tumors that were deemed unresectable. Tumors were located on the nose, chin, eyelid, scalp, neck, trunk, and extremities. Median (range) tumor volume before treatment was 2.1 cm3 (0.65-12.65 cm3). The mean (SD) prescription dose coverage of the gross tumor volume was 91% (2.8%) with all tumors having coverage of 85% or more. No device-related grade 3 AEs were noted. Common AEs were grade 1 to 2 erythema, edema, and pruritus. At 12 weeks following treatment, there was a 100% complete response rate. Nine of 10 complete responses (90%) were confirmed by CT imaging. Conclusions and Relevance: This cohort study suggests the feasibility and preliminary safety of DaRT in the management of recurrent or unresectable skin cancers. The favorable safety profile and high response rates are promising. A US trial for marketing approval based on this pilot study is under way. Trial Registration: ClinicalTrials.gov Identifier: NCT04377360.

Breaking water carbon nexus by the natural biological system: ultimate solution for ESG challenges.

Clean water supply has become an enormous challenge in pursuance of the global warming process. Water technologies have traditionally created carbon emissions and chemical reactions that pollute the landscape, aquifers, and the air. The need for carbon footprint reduction and corporate ESG consideration has led to adopt a more environmentally friendly water treatment and management system. The Natural Biological System (NBS) is a nature-based technology for sewage and waste stream treatment and management, rehabilitating affected water bodies, reducing greenhouse gas (GHG) emissions, and rebalancing eco-systems. The NBS is a patent-tailored solution with the ability of large-scale water treatment and a negative carbon footprint promoting the user ESG rating. From Chile to India, the NBS is changing the global water-energy equation, reducing dependence on energy and maintenance, freeing up valuable water resources for on-site usage, and restoring nature's ability to preserve and protect itself and to stop the escalating climate change effects.

AAPM medical physics practice guideline 13.a: HDR brachytherapy, part A.

The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8000 members and is the principal organization of medical physicists in the United States. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines (MPPGs) will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized. The following terms are used in the AAPM practice guidelines: (1) Must and must not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline. (2) Should and should not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances. Approved by AAPM's Executive Committee April 28, 2022.

Concordance between cancer gene alterations in tumor and circulating tumor DNA correlates with poor survival in a real-world precision-medicine population.

Genomic analysis, performed on tumoral tissue DNA and on circulating tumor DNA (ctDNA) from blood, is the cornerstone of precision cancer medicine. Herein, we characterized the clinical prognostic implications of the concordance of alterations in major cancer genes between tissue- and blood-derived DNA in a pan-cancer cohort. The molecular profiles of both liquid (Guardant Health) and tissue (Foundation Medicine) biopsies from 433 patients were analyzed. Mutations and amplifications of cancer genes scored by these two tests were assessed. In 184 (42.5%) patients, there was at least one mutual gene alteration. The mean number of mutual gene-level alterations in the samples was 0.67 per patient (range: 0-5). A higher mutual gene-level alteration number correlated with shorter overall survival (OS). As confirmed in multivariable analysis, patients with ≥2 mutual gene-level alterations in blood and tissue had a hazard ratio (HR) of death of 1.49 (95% confidence interval [CI]=1-2.2; P=0.047), whereas patients with ≥3 mutual gene-level alterations had an HR of death 2.38 (95% CI=1.47-3.87; P=0.0005). Together, our results show that gene-level concordance between tissue DNA and ctDNA analysis is prevalent and is an independent factor predicting significantly shorter patient survival.

ESG risks and corporate survival.

This research is the first attempt to examine the impact of corporate sustainability risks factors on its financial stability. By using S&P500 stocks data from 2019 to 2021 and calculating Altman's Z-score, we examined the influence of ESG (Environmental, Social, and Corporate Governance) risks score on the company survival chances. We documented diminishing total ESG scores of S&P500 stocks in recent years pointing out that companies pay attention to sustainability issues and invest resources to reduce them. We documented that Altman's Z-score is negatively influenced by E and S and not by G. These findings are very important since they prove for the first time that high environmental and social risks may reduce corporates' financial stability and rise their default risks incurring default costs. Moreover, high sensitivity of Altman's Z-score changes to S changes was found especially for relatively smaller firms. The result of this study emphasizes the importance of sustainability risk and especially social risk to a firm's survival chances and therefore mitigating those risks can dramatically improve corporates' financial stability.

Shared Cancer Dataset Analysis Identifies and Predicts the Quantitative Effects of Pan-Cancer Somatic Driver Variants.

Driver mutations endow tumors with selective advantages and produce an array of pathogenic effects. Determining the function of somatic variants is important for understanding cancer biology and identifying optimal therapies. Here, we compiled a shared dataset from several cancer genomic databases. Two measures were applied to 535 cancer genes based on observed and expected frequencies of driver variants as derived from cancer-specific rates of somatic mutagenesis. The first measure comprised a binary classifier based on a binomial test; the second was tumor variant amplitude (TVA), a continuous measure representing the selective advantage of individual variants. TVA outperformed all other computational tools in terms of its correlation with experimentally derived functional scores of cancer mutations. TVA also highly correlated with drug response, overall survival, and other clinical implications in relevant cancer genes. This study demonstrates how a selective advantage measure based on a large cancer dataset significantly impacts our understanding of the spectral effect of driver variants in cancer. The impact of this information will increase as cancer treatment becomes more precise and personalized to tumor-specific mutations. SIGNIFICANCE: A new selective advantage estimation assists in oncogenic driver identification and relative effect measurements, enabling better prognostication, therapy selection, and prioritization.

A Multicenter Prospective Trial of Electronic Skin Surface Brachytherapy for Keratinocyte Carcinoma: Early Cosmesis, Quality of Life, and Adverse Events.

PURPOSE: Keratinocyte carcinomas are amenable to many treatments, including radiation therapy (RT). Electronic skin surface brachytherapy (ESSB) enables the precise delivery of radiation without radioisotopes. In this prospective multicenter clinical trial, we characterized early outcomes of ESSB prospectively through both patient- and clinician-reported measures. To corroborate the cosmesis observations, we also assessed patient-reported quality of life (QoL) and adverse events. METHODS AND MATERIALS: Patients ≥60 years old with stage T1N0M0 keratinocyte carcinoma were treated with ESSB. At 2-, 6-, and 12-weeks post-treatment, cosmesis from ESSB was assessed by both the patient and a clinician study investigator as either "good," "fair," or "bad." The Skindex-16 and the Skin Cancer Index (SCI) were used to assess patient QoL before and after treatment. Adverse events were assessed using the Common Toxicity Criteria for Adverse Events, version 4.0. RESULTS: Cosmesis and QoL were collected at 97% (99/102) of possible patient follow-up times. By 12 weeks post-treatment, 93.9% (31/33) of patient-reported and 96.9% (31/32) of clinician-reported cosmesis outcomes were "good." Compared with baseline, total Skindex-16 score significantly deteriorated at 2 weeks post-treatment (10.5 vs 24.5, P <.001), but significantly improved at 6 weeks (10.5 vs 4.7, P = .014) and 12 weeks (10.5 vs 2.1, P = .001) post-treatment. The total SCI score significantly improved from baseline to 6 weeks (78.4 vs 89.0, P = .001) post-treatment. The most frequent adverse events were radiation dermatitis, skin pain, and pruritus. All adverse events resolved to Grade ≤1 by 12 weeks post-treatment. CONCLUSIONS: This prospective, multicenter study demonstrated that ESSB is associated with a high rate of "good" early patient-reported cosmesis and increasing QoL and satisfaction with time. Validated assessments demonstrated a significant improvement in quality of life and resolution of moderate early adverse events by 6 to 12 weeks after treatment and corroborate the observation of favorable cosmesis.

Salvage resection plus cesium-131 brachytherapy durably controls post-SRS recurrent brain metastases.

BACKGROUND: Salvage of recurrent previously irradiated brain metastases (rBrM) is a significant challenge. Resection without adjuvant re-irradiation is associated with a high local failure rate, while reirradiation only partially reduces failure but is associated with greater radiation necrosis risk. Salvage resection plus Cs131 brachytherapy may offer dosimetric and biologic advantages including improved local control versus observation, with reduced normal brain dose versus re-irradiation, however data are limited. METHODS: A prospective registry of consecutive patients with post-stereotactic radiosurgery (SRS) rBrM undergoing resection plus implantation of collagen-matrix embedded Cs131 seeds (GammaTile, GT Medical Technologies) prescribed to 60 Gy at 5 mm from the cavity was analyzed. RESULTS: Twenty patients underwent 24 operations with Cs131 implantation in 25 tumor cavities. Median maximum preoperative diameter was 3.0 cm (range 1.1-6.3). Gross- or near-total resection was achieved in 80% of lesions. A median of 16 Cs131 seeds (range 6-30), with a median air-kerma strength of 3.5 U/seed were implanted. There was one postoperative wound dehiscence. With median follow-up of 1.6 years for survivors, two tumors recurred (one in-field, one marginal) resulting in 8.4% 1-year progression incidence (95%CI = 0.0-19.9). Radiographic seed settling was identified in 7/25 cavities (28%) 1.9-11.7 months post-implantation, with 1 case of distant migration (4%), without clinical sequelae. There were 8 cases of radiation necrosis, of which 4 were symptomatic. CONCLUSIONS: With > 1.5 years of follow-up, intraoperative brachytherapy with commercially available Cs131 implants was associated with favorable local control and toxicity profiles. Weak correlation between preoperative tumor geometry and implanted tiles highlights a need to optimize planning criteria.

AAPM task group report 303 endorsed by the ABS: MRI implementation in HDR brachytherapy-Considerations from simulation to treatment.

The task group (TG) on magnetic resonance imaging (MRI) implementation in high-dose-rate (HDR) brachytherapy (BT)-Considerations from simulation to treatment, TG 303, was constituted by the American Association of Physicists in Medicine's (AAPM's) Science Council under the direction of the Therapy Physics Committee, the Brachytherapy Subcommittee, and the Working Group on Brachytherapy Clinical Applications. The TG was charged with developing recommendations for commissioning, clinical implementation, and on-going quality assurance (QA). Additionally, the TG was charged with describing HDR BT workflows and evaluating practical consideration that arise when implementing MR imaging. For brevity, the report is focused on the treatment of gynecologic and prostate cancer. The TG report provides an introduction and rationale for MRI implementation in BT, a review of previous publications on topics including available applicators, clinical trials, previously published BT-related TG reports, and new image-guided recommendations beyond CT-based practices. The report describes MRI protocols and methodologies, including recommendations for the clinical implementation and logical considerations for MR imaging for HDR BT. Given the evolution from prescriptive to risk-based QA, an example of a risk-based analysis using MRI-based, prostate HDR BT is presented. In summary, the TG report is intended to provide clear and comprehensive guidelines and recommendations for commissioning, clinical implementation, and QA for MRI-based HDR BT that may be utilized by the medical physics community to streamline this process. This report is endorsed by the American Brachytherapy Society.

TP53_PROF: a machine learning model to predict impact of missense mutations in TP53.

Correctly identifying the true driver mutations in a patient's tumor is a major challenge in precision oncology. Most efforts address frequent mutations, leaving medium- and low-frequency variants mostly unaddressed. For TP53, this identification is crucial for both somatic and germline mutations, with the latter associated with the Li-Fraumeni syndrome (LFS), a multiorgan cancer predisposition. We present TP53_PROF (prediction of functionality), a gene specific machine learning model to predict the functional consequences of every possible missense mutation in TP53, integrating human cell- and yeast-based functional assays scores along with computational scores. Variants were labeled for the training set using well-defined criteria of prevalence in four cancer genomics databases. The model's predictions provided accuracy of 96.5%. They were validated experimentally, and were compared to population data, LFS datasets, ClinVar annotations and to TCGA survival data. Very high accuracy was shown through all methods of validation. TP53_PROF allows accurate classification of TP53 missense mutations applicable for clinical practice. Our gene specific approach integrated machine learning, highly reliable features and biological knowledge, to create an unprecedented, thoroughly validated and clinically oriented classification model. This approach currently addresses TP53 mutations and will be applied in the future to other important cancer genes.

Protocol for the measurement of the absorbed dose rate to water for a planar 32P beta emitting brachytherapy source: A multi-institutional validation.

PURPOSE: This is a multi-institutional report on inter-observer and inter-instrument variation in the calibration of the absorbed dose rate for a planar 32P beta emitting brachytherapy source. Measurement accuracy is essential since the dose profile is steep and the source is used for the treatment of tumors that are located in close proximity to healthy nervous system structures. METHODS AND MATERIALS: An RIC-100 32P source was calibrated by three institutions using their own equipment and following their standard procedures. The first institution calibrated the source with an electron diode and EBT3 film. The second institution used an electron diode. The third institution used HD810 film. Additionally, each institution was asked to calibrate the source using an electron diode and procedure that was shared among all institutions and shipped along with the radiation source. The dose rate was reported in units of cGy*min-1 at a water equivalent depth of 1 mm. RESULTS: Close agreement was observed in the measurements from different users and equipment. The variation across all diode detectors and institutions had a standard deviation of 1.8% and maximum difference of 4.6%. The observed variation among two different diode systems used within the same institution had a mean difference of 1.6% and a maximum variation of 1.8%. The variations among film and diode systems used within the same institution had a mean difference of 2.9% and a maximum variation of 4.3% CONCLUSIONS: The absorbed dose rate measurement protocol of the planar beta-emitting 32P source permits consistent dosimetry across three institutions and five different electron diode and radiochromic film systems. The methodologies presented herein should enable measurement consistency among other clinical users, which will help ensure high quality patient treatments and outcomes analysis.

The Information Conveyed in a SPAC's Offering.

The popularity of SPACs (Special Purpose Acquisition Companies) has grown dramatically in recent years as a substitute for the traditional IPO (Initial Public Offer). We modeled the average annual return for SPAC investors and found that this financial tool produced an annual return of 17.3%. We then constructed an information model that examined a SPAC's excess returns during the 60 days after a potential merger or acquisition had been announced. We found that the announcement had a major impact on the SPAC's share price over the 60 days, delivering on average 0.69% daily excess returns over the IPO portfolio and 31.6% cumulative excess returns for the entire period. Relative to IPOs, the cumulative excess returns of SPACs rose dramatically in the next few days after the potential merger or acquisition announcement until the 26th day. They then declined but rose again until the 48th day after the announcement. Finally, the SPAC's structure reduced the investors' risk. Thus, if investors buy a SPAC stock immediately after a potential merger or acquisition has been announced and hold it for 48 days, they can reap substantial short-term returns.