Image-guided preplanning workflow for high-dose-rate interstitial brachytherapy for gynecological malignancies.

PURPOSE: To demonstrate image-guided preplan workflows for high-dose-rate (HDR) brachytherapy for advanced gynecological malignancies. METHODS AND MATERIALS: Two different preplanning scenarios are presented: (1) CT- or MRI-based preplan with partial applicator in place; (2) Preplans generated from prior fractions. The first scenario can be applied to Syed-Neblett template-based implants or hybrid brachytherapy applicators, while the second scenario applies to hybrid applicators. Both scenarios use MRI or CT images acquired with the applicator in place to demonstrate tumor and applicator relative locations and therefore, provide the ability to show optimized suggested needle positions including the implant depths before the actual insertion. RESULTS: The preplanning techniques have demonstrated feasibility and shown five areas of potential improvement: (1) shorter procedure time, (2) decreased number of total needles inserted, (3) shorter physician tumor contour time, (4) shorter planning time, and (5) evaluation of appropriateness for brachytherapy. CONCLUSIONS: The use of image-guided brachytherapy preplanning improves clinical efficiency and is recommended for consideration for adaptation into clinical workflows for HDR interstitial and hybrid brachytherapy.

Characterization of an Onboard Transmission Detector for Efficient Linear Accelerator Output Quality Assurance.

Purpose To investigate the potential to perform linear accelerator output quality assurance (QA) with the ScandiDos Delta4 Discover (Discover) onboard transmission detector. Materials and methods Using the ScandiDos Delta4 software (version 8), a conversion factor from raw signal to output was obtained via cross-calibration with an accredited dosimetry calibration laboratory (ADCL) calibrated ionization chamber for each photon energy, including flattening-filter-free (FFF) energies. With the calibration factor for 6 MV (6x) photon energy, output measurements were taken with both the Delta4 Discover and ion chamber and compared for output as a function of gantry angle and dose-rate dependence. Monitor unit (MU) linearity for 6x was measured and compared with ion chamber measurements. Additionally, the Discover was used to take output measurements, for 6x, approximately every hour throughout the course of a treatment day, and compared with ion chamber output measurements at the beginning and end of the treatment day. Results Output measurements for each photon energy were comparable with a maximum difference of -0.57% for flattened beams (6x) and 0.21% for FFF beams (10FFF). Output measurements using the Discover matched ion chamber output measurements at every dose rate within 2%, and within 1% for output as a function of gantry angle. MU linearity test agreed with ion chamber measurements with a maximum difference of 0.41%. Output measurements using the Discover showed a daily drift in output throughout the course of a treatment day of around 2% and correlated very well with ion chamber outputs measured at the beginning and end of the treatment day (within 0.2%). Conclusions The ScandiDos Delta4 Discover onboard transmission detector is able to accurately measure linear accelerator output comparable to ion chamber measurements.

Dosimetric Evaluation of Organs at Risk From SAVE Protocol.

PURPOSE: The objective of this work was to evaluate dosimetric characteristics to organs at risk (OARs) from short-course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared with standard of care (SOC) in a multi-institutional prospective randomized trial. METHODS AND MATERIALS: SAVE (Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care) is a prospective, phase 3, multisite randomized trial in which 108 patients requiring VCB were randomized to an experimental short-course arm (11 Gy × 2 fractions [fx] to surface) and SOC arm. Those randomized to the SOC arm were subdivided into treatment groups based on treating physician discretion as follows: 7 Gy × 3 fx to 5 mm, 5 to 5.5 Gy × 4 fx to 5 mm, and 6 Gy × 5 fx to surface. To evaluate doses to OARs of each SAVE cohort, the rectum, bladder, sigmoid, small bowel, and urethra were contoured on planning computed tomography, and doses to OARs were compared by treatment arm. Absolute doses for each OAR and from each fractionation scheme were converted to 2 Gy equivalent dose (EQD23). Each SOC arm was compared with the experimental arm separately using 1-way analysis of variance, followed by pairwise comparisons using Tukey's honestly significant difference test. RESULTS: The experimental arm had significantly lower doses for rectum, bladder, sigmoid, and urethra compared with the 7 Gy × 3 and 5 to 5.5 Gy × 4 fractionation schemes; however, the experimental arm did not differ from the 6 Gy × 5 fractionation scheme. For small bowel doses, none of the SOC fractionation schemes were statistically different than the experimental. The highest EQD23 doses to the examined OARs were observed to come from the most common dose fractionation scheme of 7 Gy × 3 fx. With a short median follow-up of 1 year, there have been no isolated vaginal recurrences. CONCLUSIONS: Experimental short-course VCB of 11 Gy × 2 fx to the surface provides a comparable biologically effective dose to SOC courses. Experimental short-course VCB was found to reduce or be comparable to D2cc and D0.1cc EQD23 doses to rectum, bladder, sigmoid, small bowel, and urethra critical structures. This may translate into a comparable or lower rate of acute and late adverse effects.

A novel approach for Venezia ovoid commissioning with a comprehensive analysis of source positions in high-dose-rate brachytherapy.

PURPOSE: The lunar design of a Venezia ovoid makes commissioning of the applicator very challenging with traditional autoradiography. In this study, we propose a novel solution to ovoid commissioning and a quality assurance (QA) workflow to effectively assess the entire source path. METHODS AND MATERIALS: A two-step commissioning process, using electron radiation and radiochromic films, was developed to verify the most distal source position. The ovoid was first attached to a film and was irradiated with a 12 MeV linac beam. This process was repeated on a separate, unexposed film, followed by irradiating it with a HDR source at the most distal position. Two lengths, including the ovoid thickness and the distance between the irradiated spot and the ovoid's outer surface, were obtained from the films' intensity maps. The offset value was calculated from the subtraction of the two measured lengths. Besides acquiring the offset, a source positional simulator (SPS) and a series of planar x-rays from two orthogonal orientations were used to characterize source movement within the ovoid. RESULTS: Compared to x-ray-based autoradiography, the electron exposure significantly improved the ovoid's visibility on film. Our approach did not use surrogate, which further improved measurement outcomes by decreasing inherent uncertainties. The SPS results suggested the source movement was complex within the cervicovaginal area, but it was predictable with the proposed QA workflow. CONCLUSION: We introduced a novel, surrogate-free method to commission the Venezia ovoid, which facilitated a manual applicator reconstruction. Additionally, we recommended QA multiple source positions to safely use the ovoid in clinical settings.

Clinical Validation of Artificial Intelligence-Augmented Pathology Diagnosis Demonstrates Significant Gains in Diagnostic Accuracy in Prostate Cancer Detection.

CONTEXT.­: Prostate cancer diagnosis rests on accurate assessment of tissue by a pathologist. The application of artificial intelligence (AI) to digitized whole slide images (WSIs) can aid pathologists in cancer diagnosis, but robust, diverse evidence in a simulated clinical setting is lacking. OBJECTIVE.­: To compare the diagnostic accuracy of pathologists reading WSIs of prostatic biopsy specimens with and without AI assistance. DESIGN.­: Eighteen pathologists, 2 of whom were genitourinary subspecialists, evaluated 610 prostate needle core biopsy WSIs prepared at 218 institutions, with the option for deferral. Two evaluations were performed sequentially for each WSI: initially without assistance, and immediately thereafter aided by Paige Prostate (PaPr), a deep learning-based system that provides a WSI-level binary classification of suspicious for cancer or benign and pinpoints the location that has the greatest probability of harboring cancer on suspicious WSIs. Pathologists' changes in sensitivity and specificity between the assisted and unassisted modalities were assessed, together with the impact of PaPr output on the assisted reads. RESULTS.­: Using PaPr, pathologists improved their sensitivity and specificity across all histologic grades and tumor sizes. Accuracy gains on both benign and cancerous WSIs could be attributed to PaPr, which correctly classified 100% of the WSIs showing corrected diagnoses in the PaPr-assisted phase. CONCLUSIONS.­: This study demonstrates the effectiveness and safety of an AI tool for pathologists in simulated diagnostic practice, bridging the gap between computational pathology research and its clinical application, and resulted in the first US Food and Drug Administration authorization of an AI system in pathology.

Impact of detector selection on commissioning of Leipzig surface applicators with improving immobilization in high-dose-rate brachytherapy.

PURPOSE: Commission and treatment setup of Leipzig surface applicators, because of the steep dose gradient and lack of robust immobilization, is challenging. We aim to improve commissioning reliability by investigating the impact of detector choice on percentage depth dose (PDD) verifications, and to enhance accuracy and reproducibility in calibration/treatment setup through a simple and novel immobilization device. METHODS AND MATERIALS: PDD distributions were measured with radiochromic films, optically stimulated luminescent dosimeters (OSLDs), a diode detector, and both cylindrical and parallel plate ionization chambers. The films were aligned to the applicators in parallel and transverse orientations. PDD data from a benchmarking Monte Carlo (MC) study were compared with the measured results, where surface doses were acquired from extrapolation. To improve setup accuracy and reproducibility, a custom-designed immobilization prototype device was made with cost-effective materials using a 3D printer. RESULTS: The measured PDD data with different detectors had an overall good agreement (<±10%). The parallel plate ionization chamber reported unreliable doses for the smallest applicator. There was no remarkable dose difference between the two film setups. The two-in-one prototype device provided a rigid immobilization and a flexible positioning of the applicator. It enhanced accuracy and reproducibility in calibration and treatment setup. CONCLUSION: We recommend using radiochromic films in the transverse orientation for a reliable and efficient PDD verification. The applicator's clinical applicability has been limited by a lack of robust immobilization. We expect this economical, easy-to-use prototype device can promote the use of Leipzig applicators in surface brachytherapy.

Independent real-world application of a clinical-grade automated prostate cancer detection system.

Artificial intelligence (AI)-based systems applied to histopathology whole-slide images have the potential to improve patient care through mitigation of challenges posed by diagnostic variability, histopathology caseload, and shortage of pathologists. We sought to define the performance of an AI-based automated prostate cancer detection system, Paige Prostate, when applied to independent real-world data. The algorithm was employed to classify slides into two categories: benign (no further review needed) or suspicious (additional histologic and/or immunohistochemical analysis required). We assessed the sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs) of a local pathologist, two central pathologists, and Paige Prostate in the diagnosis of 600 transrectal ultrasound-guided prostate needle core biopsy regions ('part-specimens') from 100 consecutive patients, and to ascertain the impact of Paige Prostate on diagnostic accuracy and efficiency. Paige Prostate displayed high sensitivity (0.99; CI 0.96-1.0), NPV (1.0; CI 0.98-1.0), and specificity (0.93; CI 0.90-0.96) at the part-specimen level. At the patient level, Paige Prostate displayed optimal sensitivity (1.0; CI 0.93-1.0) and NPV (1.0; CI 0.91-1.0) at a specificity of 0.78 (CI 0.64-0.89). The 27 part-specimens considered by Paige Prostate as suspicious, whose final diagnosis was benign, were found to comprise atrophy (n = 14), atrophy and apical prostate tissue (n = 1), apical/benign prostate tissue (n = 9), adenosis (n = 2), and post-atrophic hyperplasia (n = 1). Paige Prostate resulted in the identification of four additional patients whose diagnoses were upgraded from benign/suspicious to malignant. Additionally, this AI-based test provided an estimated 65.5% reduction of the diagnostic time for the material analyzed. Given its optimal sensitivity and NPV, Paige Prostate has the potential to be employed for the automated identification of patients whose histologic slides could forgo full histopathologic review. In addition to providing incremental improvements in diagnostic accuracy and efficiency, this AI-based system identified patients whose prostate cancers were not initially diagnosed by three experienced histopathologists. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

FMEA occurrence values for four failure modes occurring using look-up tables for dose calculations.

PURPOSE: For a number of different treatment types [such as Total Body Irradiation (TBI), etc.] most institutions utilize tables from commissioned databooks to perform the dose calculations. Each time one manually looks up data from a large table and then copies the numbers for a manual calculation, there is potential for errors. While a second check effectively mitigates the potential error from such calculations, information regarding the frequency and nature of such mistakes is important to develop protocols and workflows that avoid related errors. METHODS: Five years' worth of TBI calculations were reviewed. Each calculation was re-performed and evaluated against the original calculation and original second check. Any discrepancies were noted and those discrepancies were checked to see if the number was the result of misreading from the look-up table, a typo, copying/skipping partially redundant steps, or rounding/avoiding interpolation. The number of calculations that contained these various types of discrepancies was tallied and percentages representing the frequency of said discrepancies were derived. RESULTS: All of the discrepancies only resulted in a monitor unit (MU) calculation difference of <1.7%. Typos, looking up wrong values from tables, rounding/avoiding interpolation, and skipping steps occurred in 10.4% ( ± 3.1%), 6.3% ( ± 2.5%), 53.1% ( ± 5.1%), and 4.2% ( ± 2.0%) of MU calculations, respectively. CONCLUSIONS: While all of the discrepancies only resulted in a monitor unit (MU) calculation difference of <1.7%, this review shows how frequently various discrepancies can occur. Typos and rounding/avoiding interpolation are the steps most likely to potentially cause a miscalculation of MU. To avoid direct human interaction on such a large repetitive scale, creating forms that calculate MU automatically from initial measurement data would reduce the incidences that numbers are written/transcribed and eliminate the need to look up data in a table, thus reducing the chance for error.

Evaluation of the effects of implementing a diode transmission device into the clinical workflow.

PURPOSE: This work investigated effects of implementing the Delta4 Discover diode transmission detector into the clinical workflow. METHODS: PDD and profile scans were completed with and without the Discover for a number of photon beam energies. Transmission factors were determined for all beam energies and included in Eclipse TPS to account for the attenuation of the Discover. A variety of IMRT plans were delivered to a Delta4 Phantom+ with and without the Discover to evaluate the Discover's effects on IMRT QA. An imaging QA phantom was used to assess the detector's effects on MV image quality. OSLDs placed on the Phantom+ were used to determine the detector's effects on superficial dose. RESULTS: The largest effect on PDDs after dmax was 0.5%. The largest change in beam profile symmetry and flatness was 0.2% and 0.1%, respectively. An average difference in gamma passing rates (2%/2 mm) of 0.2% was observed between plans that did not include the Discover in the measurement and calculation to plans that did include the Discover in the measurement and calculation. The Discover did not significantly change the MV image quality, and the largest observed increase in the relative superficial dose when the Discover was present was 1%. CONCLUSIONS: The effects the Discover has on the linac beam were found to be minimal. The device can be implemented into the clinic without the need to alter the TPS beam modeling, other than accounting for the device's attenuation. However, a careful workflow review to implement the Discover should be completed.

Novel artificial intelligence system increases the detection of prostate cancer in whole slide images of core needle biopsies.

Prostate cancer (PrCa) is the second most common cancer among men in the United States. The gold standard for detecting PrCa is the examination of prostate needle core biopsies. Diagnosis can be challenging, especially for small, well-differentiated cancers. Recently, machine learning algorithms have been developed for detecting PrCa in whole slide images (WSIs) with high test accuracy. However, the impact of these artificial intelligence systems on pathologic diagnosis is not known. To address this, we investigated how pathologists interact with Paige Prostate Alpha, a state-of-the-art PrCa detection system, in WSIs of prostate needle core biopsies stained with hematoxylin and eosin. Three AP-board certified pathologists assessed 304 anonymized prostate needle core biopsy WSIs in 8 hours. The pathologists classified each WSI as benign or cancerous. After ~4 weeks, pathologists were tasked with re-reviewing each WSI with the aid of Paige Prostate Alpha. For each WSI, Paige Prostate Alpha was used to perform cancer detection and, for WSIs where cancer was detected, the system marked the area where cancer was detected with the highest probability. The original diagnosis for each slide was rendered by genitourinary pathologists and incorporated any ancillary studies requested during the original diagnostic assessment. Against this ground truth, the pathologists and Paige Prostate Alpha were measured. Without Paige Prostate Alpha, pathologists had an average sensitivity of 74% and an average specificity of 97%. With Paige Prostate Alpha, the average sensitivity for pathologists significantly increased to 90% with no statistically significant change in specificity. With Paige Prostate Alpha, pathologists more often correctly classified smaller, lower grade tumors, and spent less time analyzing each WSI. Future studies will investigate if similar benefit is yielded when such a system is used to detect other forms of cancer in a setting that more closely emulates real practice.

A systematic evaluation of the error detection abilities of a new diode transmission detector.

Transmission detectors meant to measure every beam delivered on a linear accelerator are now becoming available for monitoring the quality of the dose distribution delivered to the patient daily. The purpose of this work is to present results from a systematic evaluation of the error detection capabilities of one such detector, the Delta4 Discover. Existing patient treatment plans were modified through in-house-developed software to mimic various delivery errors that have been observed in the past. Errors included shifts in multileaf collimator leaf positions, changing the beam energy from what was planned, and a simulation of what would happen if the secondary collimator jaws did not track with the leaves as they moved. The study was done for simple 3D plans, static gantry intensity modulated radiation therapy plans as well as dynamic arc and volumetric modulated arc therapy (VMAT) plans. Baseline plans were delivered with both the Discover device and the Delta4 Phantom+ to establish baseline gamma pass rates. Modified plans were then delivered using the Discover only and the predicted change in gamma pass rate, as well as the detected leaf positions were evaluated. Leaf deviations as small as 0.5 mm for a static three-dimensional field were detected, with this detection limit growing to 1 mm with more complex delivery modalities such as VMAT. The gamma pass rates dropped noticeably once the intentional leaf error introduced was greater than the distance-to-agreement criterion. The unit also demonstrated the desired drop in gamma pass rates of at least 20% when jaw tracking was intentionally disabled and when an incorrect energy was used for the delivery. With its ability to find errors intentionally introduced into delivered plans, the Discover shows promise of being a valuable, independent error detection tool that should serve to detect delivery errors that can occur during radiotherapy treatment.

Aluminum plasmonic nanoshielding in ultraviolet inactivation of bacteria.

Ultraviolet (UV) irradiation is an effective bacterial inactivation technique with broad applications in environmental disinfection. However, biomedical applications are limited due to the low selectivity, undesired inactivation of beneficial bacteria and damage of healthy tissue. New approaches are needed for the protection of biological cells from UV radiation for the development of controlled treatment and improved biosensors. Aluminum plasmonics offers attractive opportunities for the control of light-matter interactions in the UV range, which have not yet been explored in microbiology. Here, we investigate the effects of aluminum nanoparticles (Al NPs) prepared by sonication of aluminum foil on the UVC inactivation of E. coli bacteria and demonstrate a new radiation protection mechanism via plasmonic nanoshielding. We observe direct interaction of the bacterial cells with Al NPs and elucidate the nanoshielding mechanism via UV plasmonic resonance and nanotailing effects. Concentration and wavelength dependence studies reveal the role and range of control parameters for regulating the radiation dosage to achieve effective UVC protection. Our results provide a step towards developing improved radiation-based bacterial treatments.

Rapid detection of drought stress in plants using femtosecond laser-induced breakdown spectroscopy.

Drought stress disrupts the balance of macro- and micronutrients and affects the yield of agriculturally and economically significant plants. Rapid detection of stress-induced changes of relative content of elements such as sodium (Na), potassium (K), calcium (Ca) and iron (Fe) in the field may allow farmers and crop growers to counter the effects of plant stress and to increase their crop return. Unfortunately, the analytical methods currently available are time-consuming, expensive and involve elaborate sample preparation such as acid digestion which hinders routine daily monitoring of crop health on a field scale. We report application of an alternative method for rapid detection of drought stress in plants using femtosecond laser-induced breakdown spectroscopy (LIBS). We demonstrate daily monitoring of relative content of Na, K, Ca and Fe in decorative indoor (gardenia) and cultivated outdoor (wheat) plant species under various degrees of drought stress. The observed differences in spectral and temporal responses indicate different mechanisms of drought resistance. We identify spectroscopic markers of drought stress which allow for distinguishing mild environmental and severe drought stress in wheat and may be used for remote field-scale estimation of plant stress resistance and health.