Receive coil quality assurance procedure and automated analysis for ViewRay MRIdian MR-Linac.

PURPOSE: Regular receiving coil quality assurance (QA) is required to ensure image quality of an MRIdian Linac system. The manufacturer provides a spherical phantom and positioning tube for single-slice signal-to-noise ratio (SNR) and uniformity assessments. We aimed to improve imaging setup and coverage and eliminate inter-scan variability by employing multi-slice imaging of a stable phantom. Additionally, we strived to expedite analysis by developing objective, automated analysis software. METHODS: A 5300 mL cylindrical plastic bottle placed in plastic bins was scanned at isocenter using a spin-echo sequence with NEMA-recommended parameters and 18 axial slices, avoiding phantom repositioning. Acquisition was repeated with and without prescan normalization filtering and by saving uncombined element images. Obtained data were analyzed using custom open-source MATLAB code. Signal and noise images were automatically assigned, and ROIs for SNR and uniformity calculations were defined using image thresholding. SNR and uniformity pass/fail decisions were made using baseline comparisons. RESULTS: The proposed method was successfully implemented as monthly coil QA for 3.5 years. Setup and scanning took 41 min on average for a coil set. Automated image analysis was completed in a few minutes. Signal intensity peaked around +90 or -90 mm for Torso or Head/Neck coil unfiltered images. Noise peaked and minimized SNR inside ±30 mm from isocenter, while maximizing it around ±130 mm. Prescan normalization smoothed signal response, reduced SNR and increased uniformity. Individual coil element image analysis identified their position, signal or noise response and SNR. SNR and uniformity pass/fail thresholds were set for already tested and new coils. Conspicuous and subtle Torso coil malfunctions were detected considering baseline deviations of combined and individual element results. CONCLUSIONS: Our QA method eliminated observer bias and provided insights into coil function, image filtering performance and coil element location. It provided SNR and uniformity thresholds and identified faulty coil elements.

Widening the therapeutic window for central and ultra-central thoracic oligometastatic disease with stereotactic MR-guided adaptive radiation therapy (SMART).

BACKGROUND/PURPOSE: Central/ultra-central thoracic tumors are challenging to treat with stereotactic radiotherapy due potential high-grade toxicity. Stereotactic MR-guided adaptive radiation therapy (SMART) may improve the therapeutic window through motion control with breath-hold gating and real-time MR-imaging as well as the option for daily online adaptive replanning to account for changes in target and/or organ-at-risk (OAR) location. MATERIALS/METHODS: 26 central (19 ultra-central) thoracic oligoprogressive/oligometastatic tumors treated with isotoxic (OAR constraints-driven) 5-fraction SMART (median 50 Gy, range 35-60) between 10/2019-10/2022 were reviewed. Central tumor was defined as tumor within or touching 2 cm around proximal tracheobronchial tree (PBT) or adjacent to mediastinal/pericardial pleura. Ultra-central was defined as tumor abutting the PBT, esophagus, or great vessel. Hard OAR constraints observed were ≤ 0.03 cc for PBT V40, great vessel V52.5, and esophagus V35. Local failure was defined as tumor progression/recurrence within the planning target volume. RESULTS: Tumor abutted the PBT in 31 %, esophagus in 31 %, great vessel in 65 %, and heart in 42 % of cases. 96 % of fractions were treated with reoptimized plan, necessary to meet OAR constraints (80 %) and/or target coverage (20 %). Median follow-up was 19 months (27 months among surviving patients). Local control (LC) was 96 % at 1-year and 90 % at 2-years (total 2/26 local failure). 23 % had G2 acute toxicities (esophagitis, dysphagia, anorexia, nausea) and one (4 %) had G3 acute radiation dermatitis. There were no G4-5 acute toxicities. There was no symptomatic pneumonitis and no G2 + late toxicities. CONCLUSION: Isotoxic 5-fraction SMART resulted in high rates of LC and minimal toxicity. This approach may widen the therapeutic window for high-risk oligoprogressive/oligometastatic thoracic tumors.

Stereotactic MR-guided on-table adaptive radiation therapy (SMART) for borderline resectable and locally advanced pancreatic cancer: A multi-center, open-label phase 2 study.

BACKGROUND AND PURPOSE: Radiation dose escalation may improve local control (LC) and overall survival (OS) in select pancreatic ductal adenocarcinoma (PDAC) patients. We prospectively evaluated the safety and efficacy of ablative stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for borderline resectable (BRPC) and locally advanced pancreas cancer (LAPC). The primary endpoint of acute grade ≥ 3 gastrointestinal (GI) toxicity definitely related to SMART was previously published with median follow-up (FU) 8.8 months from SMART. We now present more mature outcomes including OS and late toxicity. MATERIALS AND METHODS: This prospective, multi-center, single-arm open-label phase 2 trial (NCT03621644) enrolled 136 patients (LAPC 56.6 %; BRPC 43.4 %) after ≥ 3 months of any chemotherapy without distant progression and CA19-9 ≤ 500 U/mL. SMART was delivered on a 0.35 T MR-guided system prescribed to 50 Gy in 5 fractions (biologically effective dose10 [BED10] = 100 Gy). Elective coverage was optional. Surgery and chemotherapy were permitted after SMART. RESULTS: Mean age was 65.7 years (range, 36-85), induction FOLFIRINOX was common (81.7 %), most received elective coverage (57.4 %), and 34.6 % had surgery after SMART. Median FU was 22.9 months from diagnosis and 14.2 months from SMART, respectively. 2-year OS from diagnosis and SMART were 53.6 % and 40.5 %, respectively. Late grade ≥ 3 toxicity definitely, probably, or possibly attributed to SMART were observed in 0 %, 4.6 %, and 11.5 % patients, respectively. CONCLUSIONS: Long-term outcomes from the phase 2 SMART trial demonstrate encouraging OS and limited severe toxicity. Additional prospective evaluation of this novel strategy is warranted.

Ablative radiotherapy improves survival but does not cure autochthonous mouse models of prostate and colorectal cancer.

BACKGROUND: Genetically engineered mouse models (GEMMs) of cancer are powerful tools to study mechanisms of disease progression and therapy response, yet little is known about how these models respond to multimodality therapy used in patients. Radiation therapy (RT) is frequently used to treat localized cancers with curative intent, delay progression of oligometastases, and palliate symptoms of metastatic disease. METHODS: Here we report the development, testing, and validation of a platform to immobilize and target tumors in mice with stereotactic ablative RT (SART). Xenograft and autochthonous tumor models were treated with hypofractionated ablative doses of radiotherapy. RESULTS: We demonstrate that hypofractionated regimens used in clinical practice can be effectively delivered in mouse models. SART alters tumor stroma and the immune environment, improves survival in GEMMs of primary prostate and colorectal cancer, and synergizes with androgen deprivation in prostate cancer. Complete pathologic responses were achieved in xenograft models, but not in GEMMs. CONCLUSIONS: While SART is capable of fully ablating xenografts, it is unable to completely eradicate disease in GEMMs, arguing that resistance to potentially curative therapy can be modeled in GEMMs.

Mice can be used to model the types of cancer seen in people to investigate the effects of cancer therapies, such as radiation. Here, we apply radiation therapy treatments that are able to cure cancer in humans to mice that have cancer of the prostate or colorectum. We show that the mice do not experience many side effects and that the tumours reduce in size, but in some cases show progression after treatment. Our study demonstrates that mice can be used to better understand how human cancers respond to radiation treatment, which can lead to the development of improved treatments and treatment schedules.

A Multi-Institutional Phase 2 Trial of Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided On-Table Adaptive Radiation Therapy for Borderline Resectable and Locally Advanced Pancreatic Cancer.

PURPOSE: Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted a prospective study evaluating the safety of 5-fraction Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC). METHODS AND MATERIALS: Patients with LAPC or BRPC were eligible for this multi-institutional, single-arm, phase 2 trial after ≥3 months of systemic therapy without evidence of distant progression. Fifty gray in 5 fractions was prescribed on a 0.35T MR-guided radiation delivery system. The primary endpoint was acute grade ≥3 gastrointestinal (GI) toxicity definitely attributed to SMART. RESULTS: One hundred thirty-six patients (LAPC 56.6%, BRPC 43.4%) were enrolled between January 2019 and January 2022. Mean age was 65.7 (36-85) years. Head of pancreas lesions were most common (66.9%). Induction chemotherapy mostly consisted of (modified)FOLFIRINOX (65.4%) or gemcitabine/nab-paclitaxel (16.9%). Mean CA19-9 after induction chemotherapy and before SMART was 71.7 U/mL (0-468). On-table adaptive replanning was performed for 93.1% of all delivered fractions. Median follow-up from diagnosis and SMART was 16.4 and 8.8 months, respectively. The incidence of acute grade ≥3 GI toxicity possibly or probably attributed to SMART was 8.8%, including 2 postoperative deaths that were possibly related to SMART in patients who had surgery. There was no acute grade ≥3 GI toxicity definitely related to SMART. One-year overall survival from SMART was 65.0%. CONCLUSIONS: The primary endpoint of this study was met with no acute grade ≥3 GI toxicity definitely attributed to ablative 5-fraction SMART. Although it is unclear whether SMART contributed to postoperative toxicity, we recommend caution when pursuing surgery, especially with vascular resection after SMART. Additional follow-up is ongoing to evaluate late toxicity, quality of life, and long-term efficacy.

Hyperextended telomeres promote formation of C-circle DNA in telomerase positive human cells.

Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). Currently, the primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. We investigated C-circle formation in the human cen3tel cell line, a long-telomere, telomerase+ (LTT+) cell line with progressively hyper-elongated telomeres (up to ∼100 kb). cECTR signal was observed in 2D gels and C-circle assays but not t-circle assays, which also detect circular DNA with extrachromosomal telomere repeats. Telomerase activity and C-circle signal were not separable in the analysis of clonal populations, consistent with C-circle production occurring within telomerase+ cells. We observed similar cECTR results in two other LTT+ cell lines, HeLa1.3 (∼23 kb telomeres) and HeLaE1 (∼50 kb telomeres). In LTT+ cells, telomerase activity did not directly impact C-circle signal; instead, C-circle signal correlated with telomere length. LTT+ cell lines were less sensitive to hydroxyurea than ALT+ cell lines, suggesting that ALT status is a stronger contributor to replication stress levels than telomere length. Additionally, the DNA repair-associated protein FANCM did not suppress C-circles in LTT+ cells as it does in ALT+ cells. Thus, C-circle formation may be driven by telomere length, independently of telomerase and replication stress, highlighting limitations of C-circles as a stand-alone ALT biomarker.

Hyperextended telomeres promote C-circle formation in telomerase positive human cells.

Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). The primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. To investigate C-circle formation in telomerase+ cells, we studied the human cen3tel cell line, in which telomeres progressively hyper-elongated post TERT -immortalization. cECTR signal was observed in 2D gels and C-circle assays but not t-circle assays, which also detect cECTRs. Telomerase activity and C-circle signal were not separable in the analysis of clonal populations, consistent with C-circle production occurring within telomerase+ cells. Two other long telomere, telomerase+ (LTT+) cell lines, HeLa1.3 (~23 kb telomeres) and HeLaE1 (~50 kb telomeres), had similar cECTR properties. Telomerase activity did not directly impact C-circle signal in LTT+ cells; instead, C-circle signal correlated with telomere length. LTT+ lines were less sensitive to hydroxyurea than an ALT+ cell line, suggesting that ALT status is a stronger contributor to replication stress levels than telomere length. Additionally, FANCM did not suppress C-circles in LTT+ cells as it does in ALT+ cells. Thus, C-circle formation may be driven by telomere length, independently of telomerase and replication stress, highlighting limitations of C-circles as a stand-alone ALT biomarker.

Cybersecurity and Information Assurance for the Clinical Laboratory.

BACKGROUND: Network-connected medical devices have rapidly proliferated in the wake of recent global catalysts, leaving clinical laboratories and healthcare organizations vulnerable to malicious actors seeking to ransom sensitive healthcare information. As organizations become increasingly dependent on integrated systems and data-driven patient care operations, a sudden cyberattack and the associated downtime can have a devastating impact on patient care and the institution as a whole. Cybersecurity, information security, and information assurance principles are, therefore, vital for clinical laboratories to fully prepare for what has now become inevitable, future cyberattacks. CONTENT: This review aims to provide a basic understanding of cybersecurity, information security, and information assurance principles as they relate to healthcare and the clinical laboratories. Common cybersecurity risks and threats are defined in addition to current proactive and reactive cybersecurity controls. Information assurance strategies are reviewed, including traditional castle-and-moat and zero-trust security models. Finally, ways in which clinical laboratories can prepare for an eventual cyberattack with extended downtime are discussed. SUMMARY: The future of healthcare is intimately tied to technology, interoperability, and data to deliver the highest quality of patient care. Understanding cybersecurity and information assurance is just the first preparative step for clinical laboratories as they ensure the protection of patient data and the continuity of their operations.

Stereotactic Magnetic Resonance-Guided Adaptive Radiation Therapy (SMART) for Abdominopelvic Oligometastases.

PURPOSE: Stereotactic body radiation therapy can be an effective treatment for oligometastases. However, safe delivery of ablative radiation is frequently limited by the proximity of mobile organs sensitive to high radiation doses. The goal of this study was to determine the feasibility, safety, and disease control outcomes of stereotactic magnetic resonance-guided adaptive radiation therapy (SMART) in patients with abdominopelvic oligometastases. METHODS AND MATERIALS: We identified 101 patients with abdominopelvic oligometastases, including 20 patients enrolled on phase 1 protocols, who were consecutively treated with SMART on a 0.35T magnetic resonance linear accelerator (MR linac) at a single institution from October 2019 to September 2021. Local control and overall survival were analyzed using the Kaplan-Meier method. RESULTS: Overall, 114 tumors were treated. The most common histology was prostate adenocarcinoma (60 tumors [53.5%]), and 65 sites (57.0%) were centered in the pelvis. Ninety-one sites (79.8%) were treated to 8 Gy × 5, and 49 (43.0%) were treated with breath-hold respiratory gating. Online adaptation resulted in a clinically significant improvement in coverage or organ sparing in 86.6% of delivered fractions. The median time required for adaptation was 24 minutes, and the median time in the treatment room was 58 minutes. With median follow-up of 11.4 months, the 12-month local control was 93% and was higher for prostate adenocarcinoma versus other histologies (100% vs 84%; P = .009). The 12-month overall survival was 96% and was higher for prostate adenocarcinoma versus other histologies (100% vs 91%; P = .046). Three patients (3.0%) developed grade 3 toxic effects (colonic hemorrhage at 3.4 months and urinary tract obstructions at 10.1 and 18.4 months, respectively). CONCLUSIONS: In this study, SMART was feasible, safe, and effective for delivering ablative radiation therapy to abdominopelvic metastases. Adaptive planning was necessary in the large majority of cases. The advantages of SMART warrant its further investigation as a standard option for the treatment of abdominopelvic oligometastases.

Understanding unidentified human remains investigations through the United States census data.

Each year, thousands of unidentified human remains (UHR) cases are reported in the U.S. Technological advances have greatly enhanced the forensic community's capacity and capability to solve UHR cases, but little is known about the extent to which these resources are used by medical examiners and coroners (MECs). Using public datasets, the study purpose is to describe the current state MEC system with respect to UHR cases, the resources used to investigate these cases, and the evidence retention polices in place. There was an overall decline in UHR cases reported between 2004 and 2018. Less than half of MECs in both study years reported having established written final disposition and evidence retention policies for UHR cases. National missing persons databases were underused. This study provides an important window into the present state of UHRs being handled by our Nation's MEC offices and the resources available to solve these difficult cases.

A pyrosequencing protocol for rapid identification of SARS-CoV-2 variants.

Next-generation sequencing (NGS) is the primary method used to monitor the distribution and emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants around the world; however, it is costly and time-consuming to perform and is not widely available in low-resourced geographical regions. Pyrosequencing has the potential to augment surveillance efforts by providing information on specific targeted mutations for rapid identification of circulating and emerging variants. The current study describes the development of a reverse transcription (RT)-PCR-pyrosequencing assay targeting >65 spike protein gene (S) mutations of SARS-CoV-2, which permits differentiation of commonly reported variants currently circulating in the United States with a high degree of confidence. Variants typed using the assay included B.1.1.7 (Alpha), B.1.1.529 (Omicron), B.1.351 (Beta), B.1.375, B.1.427/429 (Epsilon), B.1.525 (Eta), B.1.526.1 (Iota), B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.621 (Mu), P1 (Gamma), and B.1.1 variants, all of which were confirmed by the NGS data. An electronic typing tool was developed to aid in the identification of variants based on mutations detected by pyrosequencing. The assay could provide an important typing tool for rapid identification of candidate patients for monoclonal antibody therapies and a method to supplement SARS-CoV-2 surveillance efforts by identification of circulating variants and novel emerging lineages.

Technical note: Toward implementation of MR-guided radiation therapy for laryngeal cancer with healthy volunteer imaging and a custom MR-CT larynx phantom.

PURPOSE: Internal motion of the larynx can cause normal tissue toxicity and/or tumor underdosage during radiotherapy. MR-guided radiation therapy (MRgRT) provides improved soft-tissue contrast for patient setup and real-time gating of radiation based on cine imaging of tumor motion, potentially making it an advantageous modality for laryngeal treatments. However, there are potential concerns regarding the small target size, proximity to heterogeneous tissue interfaces in the airway that may cause dosimetric errors in the presence of the magnetic field, and uncertainty about the ability of MR-linear accelerator (MR-Linac) systems to visualize and track laryngeal motion. To date, there have been no reports of the use of MRgRT for laryngeal treatments. METHODS: A healthy volunteer was imaged on a ViewRay MRIdian MR-Linac. Organs-at-risk and a laryngeal pseudo target were contoured and used to generate a stereotactic body radiotherapy plan. A custom phantom was created using 3D-printing based on structures delineated on the volunteer images to construct an enclosure containing the target and airway anatomy, with a gap for radiochromic film, and filled with gelatin . The treatment plan was mapped onto the phantom and delivered dose assessed on radiochromic film with global normalization and a 10% dose threshold. A cine MR of the volunteer was acquired to assess the magnitude of larynx motion with speaking and swallowing, and system's ability to gate radiation. RESULTS: A clinically acceptable laryngeal treatment plan and larynx phantom that was MR and computed tomography-visible were successfully created. The delivered dose had good agreement with the treatment plan with a gamma passing rate of 96.5% (3%/2 mm). The MR-Linac was able to visualize, track, and gate larynx motion. CONCLUSIONS: The MRgRT workflow for laryngeal treatments was assessed and performed in preparation for clinical implementation on the MR-Linac, demonstrating that it is feasible to treat laryngeal cancer patients on the MR-Linac.

Dosimetric Planning Tradeoffs to Reduce Heart Dose Using Machine Learning-Guided Decision Support Software in Patients with Lung Cancer.

PURPOSE: Cardiac toxicity is a well-recognized risk after radiation therapy (RT) in patients with non-small cell lung cancer (NSCLC). However, the extent to which treatment planning optimization can reduce mean heart dose (MHD) without untoward increases in lung dose is unknown. METHODS AND MATERIALS: Retrospective analysis of RT plans from 353 consecutive patients with locally advanced NSCLC treated with intensity modulated RT (IMRT) or 3-dimensional conformal RT. Commercially available machine learning-guided clinical decision support software was used to match RT plans. A leave-one-out predictive model was used to examine lung dosimetric tradeoffs necessary to achieve a MHD reduction. RESULTS: Of all 232 patients, 91 patients (39%) had RT plan matches showing potential MHD reductions of >4 to 8 Gy without violating the upper limit of lung dose constraints (lung volume [V] receiving 20 Gy (V20 Gy) <37%, V5 Gy <70%, and mean lung dose [MLD] <20 Gy). When switching to IMRT, 75 of 103 patients (72.8%) had plan matches demonstrating improved MHD (average 2.0 Gy reduction, P < .0001) without violating lung constraints. Examining specific lung dose tradeoffs, a mean ≥3.7 Gy MHD reduction was achieved with corresponding absolute increases in lung V20 Gy, V5 Gy, and MLD of 3.3%, 5.0%, and 1.0 Gy, respectively. CONCLUSIONS: Nearly 40% of RT plans overall, and 73% when switched to IMRT, were predicted to have reductions in MHD >4 Gy with potentially clinically acceptable tradeoffs in lung dose. These observations demonstrate that decision support software for optimizing heart-lung dosimetric tradeoffs is feasible and may identify patients who might benefit most from more advanced RT technologies.

COVID-19 Pandemic Spurs Evolution of an Academic Pathology Department and Laboratory.

The COVID-19 pandemic has caused much suffering through disease and death, disruption of daily life, and economic havoc. Global health infrastructure has been challenged, in some cases failing. In the United States, the inability of laboratories to provide adequate testing for the causative pathogen, severe acute respiratory syndrome coronavirus 2, has been the subject of negative press and national debate. Even so, these challenges have prompted pathology practices and clinical labs to change their organizations and operations for the better. The natural positive evolution of the University of Oklahoma Department of Pathology and OU Health Laboratories has been greatly accelerated by the global pandemic. While developing a substantial COVID testing response, our department of pathology and laboratories have evolved a much nimbler organizational structure, established an important research partnership, built a translational research resource, created a significant reference lab capability, and completed many key hires against a national background of hiring freezes and pay cuts. Also, the high visibility of the clinical lab and pathologists during the outbreak has reinforced the value of lab medicine to patient care across our health system. In the midst of significant ongoing changes to the structure and financing of our underlying organizations, high trust among departmental, hospital, health system, and medical school leadership during the pandemic has promoted these positive changes, allowing us to emerge much stronger from this crisis.

Identification and characterization of novel ACD variants: modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length.

Telomere biology disorders, largely characterized by telomere lengths below the first centile for age, are caused by variants in genes associated with telomere replication, structure, or function. One of these genes, ACD, which encodes the shelterin protein TPP1, is associated with both autosomal dominantly and autosomal recessively inherited telomere biology disorders. TPP1 recruits telomerase to telomeres and stimulates telomerase processivity. Several studies probing the effect of various synthetic or patient-derived variants have mapped specific residues and regions of TPP1 that are important for interaction with TERT, the catalytic component of telomerase. However, these studies have come to differing conclusions regarding ACD haploinsufficiency. Here, we report a proband with compound heterozygous novel variants in ACD (NM_001082486.1)-c.505_507delGAG, p.(Glu169del); and c.619delG, p.(Asp207Thrfs*22)-and a second proband with a heterozygous chromosomal deletion encompassing ACD: arr[hg19] 16q22.1(67,628,846-67,813,408)x1. Clinical data, including symptoms and telomere length within the pedigrees, suggested that loss of one ACD allele was insufficient to induce telomere shortening or confer clinical features. Further analyses of lymphoblastoid cell lines showed decreased nascent ACD RNA and steady-state mRNA, but normal TPP1 protein levels, in cells containing heterozygous ACD c.619delG, p.(Asp207Thrfs*22), or the ACD-encompassing chromosomal deletion compared to controls. Based on our results, we conclude that cells are able to compensate for loss of one ACD allele by activating a mechanism to maintain TPP1 protein levels, thus maintaining normal telomere length.

Frequency-dependent optimal weighting approach for megavoltage multilayer imagers.

Multi-layer imaging (MLI) devices improve the detective quantum efficiency (DQE) while maintaining the spatial resolution of conventional mega-voltage (MV) x-ray detectors for applications in radiotherapy. To date, only MLIs with identical detector layers have been explored. However, it may be possible to instead use different scintillation materials in each layer to improve the final image quality. To this end, we developed and validated a method for optimally combining the individual images from each layer of MLI devices that are built with heterogeneous layers. Two configurations were modeled within the GATE Monte Carlo package by stacking different layers of a terbium doped gadolinium oxysulfide Gd2O2S:Tb (GOS) phosphor and a LKH-5 glass scintillator. Detector response was characterized in terms of the modulation transfer function (MTF), normalized noise power spectrum (NNPS) and DQE. Spatial frequency-dependent weighting factors were then analytically derived for each layer such that the total DQE of the summed combination image would be maximized across all spatial modes. The final image is obtained as the weighted sum of the sub-images from each layer. Optimal weighting factors that maximize the DQE were found to be the quotient of MTF and NNPS of each layer in the heterogeneous MLI detector. Results validated the improvement of the DQE across the entire frequency domain. For the LKH-5 slab configuration, DQE(0) increases between 2%-3% (absolute), while the corresponding improvement for the LKH-5 pixelated configuration was 7%. The performance of the weighting method was quantitatively evaluated with respect to spatial resolution, contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) of simulated planar images of phantoms at 2.5 and 6 MV. The line pair phantom acquisition exhibited a twofold increase in CNR and SNR, however MTF was degraded at spatial frequencies greater than 0.2 lp mm-1. For the Las Vegas phantom, the weighting improved the CNR by around 30% depending on the contrast region while the SNR values are higher by a factor of 2.5. These results indicate that the imaging performance of MLI systems can be enhanced using the proposed frequency-dependent weighting scheme. The CNR and SNR of the weighted combined image are improved across all spatial scales independent of the detector combination or photon beam energy.

Statin Use, Heart Radiation Dose, and Survival in Locally Advanced Lung Cancer.

PURPOSE: Patients with locally advanced non-small cell lung cancer (LA-NSCLC) have a high prevalence of pre-existing coronary heart disease and face excess cardiac risk after thoracic radiation therapy. We sought to assess whether statin therapy is a predictor of overall survival (OS) after thoracic radiation therapy. METHODS AND MATERIALS: We performed a retrospective analysis of 748 patients with LA-NSCLC treated with thoracic radiation therapy, using Kaplan-Meier OS estimates and Cox regression. RESULTS: Statin use among high cardiac risk patients (Framingham risk ≥20% or pre-existing coronary heart disease; n = 496) was 51.2%. After adjustment for baseline cardiac risk and other prognostic factors, statin therapy was associated with a significantly increased risk of all-cause mortality (adjusted hazard ratio, 1.39; 95% confidence interval [CI], 1.00-1.91; P = .048) but not major adverse cardiac events (adjusted hazard ratio, 1.18; 95% CI, 0.52-2.68; P = .69). Among statin-naïve patients, mean heart dose ≥10 Gy versus <10 Gy was associated with a significantly increased risk of all-cause mortality (hazard ratio, 1.32; 95% CI, 1.04-1.68; P = .022), with 2-year OS estimates of 46.9% versus 60.0%, respectively. However, OS did not differ by heart dose among patients on statin therapy (hazard ratio, 1.00; 95% CI, 0.76-1.32; P = 1.00; P-interaction = .031), with 2-year OS estimates of 46.9% versus 50.3%, respectively. CONCLUSIONS: Among patients with LA-NSCLC, only half of statin-eligible high cardiac risk patients were on statin therapy, reflecting the highest cardiac risk level of our cohort. Statin use was an independent predictor of all-cause mortality but not major adverse cardiac events. Elevated mean heart dose (≥10 Gy) was associated with increased risk of all-cause mortality in statin-naïve patients but not among those on statin therapy, identifying a group of patients in which early intervention with statins may mitigate the deleterious effects of high heart radiation therapy dose. This warrants evaluation in prospective trials.

Association of Left Anterior Descending Coronary Artery Radiation Dose With Major Adverse Cardiac Events and Mortality in Patients With Non-Small Cell Lung Cancer.

IMPORTANCE: Radiotherapy accelerates coronary heart disease (CHD), but the dose to critical cardiac substructures has not been systematically studied in lung cancer. OBJECTIVE: To examine independent cardiac substructure radiotherapy factors for major adverse cardiac events (MACE) and all-cause mortality in patients with locally advanced non-small cell lung cancer (NSCLC). DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort analysis of 701 patients with locally advanced NSCLC treated with thoracic radiotherapy at Harvard University-affiliated hospitals between December 1, 2003, and January 27, 2014, was performed. Data analysis was conducted between January 12, 2019, and July 22, 2020. Cardiac substructures were manually delineated. Radiotherapy dose parameters (mean, maximum, and the volume [V, percentage] receiving a specific Gray [Gy] dose in 5-Gy increments) were calculated. Receiver operating curve and cut-point analyses estimating MACE (unstable angina, heart failure hospitalization or urgent visit, myocardial infarction, coronary revascularization, and cardiac death) were performed. Fine and Gray and Cox regressions were adjusted for preexisting CHD and other prognostic factors. MAIN OUTCOMES AND MEASURES: MACE and all-cause mortality. RESULTS: Of the 701 patients included in the analysis, 356 were men (50.8%). The median age was 65 years (interquartile range, 57-73 years). The optimal cut points for substructure and radiotherapy doses (highest C-index value) were left anterior descending (LAD) coronary artery V15 Gy greater than or equal to 10% (0.64), left circumflex coronary artery V15 Gy greater than or equal to 14% (0.64), left ventricle V15 Gy greater than or equal to 1% (0.64), and mean total coronary artery dose greater than or equal to 7 Gy (0.62). Adjusting for baseline CHD status and other prognostic factors, an LAD coronary artery V15 Gy greater than or equal to 10% was associated with increased risk of MACE (adjusted hazard ratio, 13.90; 95% CI, 1.23-157.21; P = .03) and all-cause mortality (adjusted hazard ratio, 1.58; 95% CI, 1.09-2.29; P = .02). Among patients without CHD, associations with increased 1-year MACE were noted for LAD coronary artery V15 Gy greater than or equal to 10% (4.9% vs 0%), left circumflex coronary artery V15 Gy greater than or equal to 14% (5.2% vs 0.7%), left ventricle V15 Gy greater than or equal to 1% (5.0% vs 0.4%), and mean total coronary artery dose greater than or equal to 7 Gy (4.8% vs 0%) (all P ≤ .001), but only a left ventricle V15 Gy greater than or equal to 1% increased the risk among patients with CHD (8.4% vs 4.1%; P = .046). Among patients without CHD, 2-year all-cause mortality was increased with an LAD coronary artery V15 Gy greater than or equal to 10% (51.2% vs 42.2%; P = .009) and mean total coronary artery dose greater than or equal to 7 Gy (53.2% vs 40.0%; P = .01). CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that optimal cardiac dose constraints may differ based on preexisting CHD. Although the LAD coronary artery V15 Gy greater than or equal to 10% appeared to be an independent estimator of the probability of MACE and all-cause mortality, particularly in patients without CHD, left ventricle V15 Gy greater than or equal to 1% appeared to confer an increased risk of MACE among patients with CHD. These constraints are worthy of further study because there is a need for improved cardiac risk stratification and aggressive risk mitigation strategies.

Display Characteristics and Their Impact on Digital Pathology: A Current Review of Pathologists' Future "Microscope".

Digital displays (monitors) are an indispensable component of a pathologists' daily workflow, from writing reports, viewing whole-slide images, or browsing the Internet. Due to a paucity of literature and experience surrounding display use and standardization in pathology, the Food and Drug Administration's (FDA) has currently restricted FDA-cleared whole-slide imaging systems to a specific model of display for each system, which at this time consists of only medical-grade (MG) displays. Further, given that a pathologists' display will essentially become their new surrogate "microscope," it becomes exceedingly important that all pathologists have a basic understanding of fundamental display properties and their functional consequences. This review seeks to: (a) define and summarize the current and emerging display technology, terminology, features, and regulation as they pertain to pathologists and review the current literature on the impact of different display types (e.g. MG vs. consumer off the shelf vs. professional grade) on pathologists' diagnostic performance and (b) discuss the impact of the recent digital pathology device componentization and the coronavirus disease 2019 public emergency on the pixel pathway and display use for remote digital pathology. Display technology has changed dramatically over the past 20 years and continues to change at a rapid rate. There is a paucity of published studies to date that investigate how display type affects pathologist performance, with more research necessary in order to develop standards and minimum specifications for displays in digital pathology. Given the complexity of modern displays, pathologists must become better informed regarding display technology if they wish to have more choice over their future "microscopes."

Expansion of germline RPS20 mutation phenotype to include Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a ribosomopathy of variable expressivity and penetrance characterized by red cell aplasia, congenital anomalies, and predisposition to certain cancers, including early-onset colorectal cancer (CRC). DBA is primarily caused by a dominant mutation of a ribosomal protein (RP) gene, although approximately 20% of patients remain genetically uncharacterized despite exome sequencing and copy number analysis. Although somatic loss-of-function mutations in RP genes have been reported in sporadic cancers, with the exceptions of 5q-myelodysplastic syndrome (RPS14) and microsatellite unstable CRC (RPL22), these cancers are not enriched in DBA. Conversely, pathogenic variants in RPS20 were previously implicated in familial CRC; however, none of the reported individuals had classical DBA features. We describe two unrelated children with DBA lacking variants in known DBA genes who were found by exome sequencing to have de novo novel missense variants in RPS20. The variants affect the same amino acid but result in different substitutions and reduce the RPS20 protein level. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. These findings expand the phenotypic spectrum of RPS20 mutation beyond familial CRC to include DBA, which itself is associated with increased risk of CRC.