Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition.

Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.

Integrating genomic features for non-invasive early lung cancer detection.

Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

Patient motion tracking for non-isocentric and non-coplanar treatments via fixed frame-of-reference 3D camera.

PURPOSE: As C-arm linac radiation therapy evolves toward faster, more efficient delivery, and more conformal dosimetry, treatments with increasingly complex couch motions are emerging. Monitoring the patient motion independently of the couch motion during non-coplanar, non-isocentric, or dynamic couch treatments is a key bottleneck to their clinical implementation. The goal of this study is to develop a prototype real-time monitoring system for unconventional beam trajectories to ensure a safe and accurate treatment delivery. METHODS: An in-house algorithm was developed for tracking using a couch-mounted three-dimensional (3D) depth camera. The accuracy of patient motion detection on the couch was tested on a 3D printed phantom created from the body surface contour exported from the treatment planning system. The technique was evaluated against a commercial optical surface monitoring system with known phantom displacements of 3, 5, and 7 mm in lateral, longitudinal, and vertical directions by placing a head phantom on a dynamic platform on the treatment couch. The stability of the monitoring system was evaluated during dynamic couch trajectories, at speeds between 10.6 and 65 cm/min. RESULTS: The proposed monitoring system agreed with the ceiling mounted optical surface monitoring system in longitudinal, lateral, and vertical directions within 0.5 mm. The uncertainty caused by couch vibration increased with couch speed but remained sub-millimeter for speeds up to 32 cm/min. For couch speeds of 10.6, 32.2, and 65 cm/min, the uncertainty ranges were 0.27- 0.73 mm, 0.15-0.87 mm, and 0.28-1.29 mm, respectively. CONCLUSION: By mounting a 3D camera in the same frame-of-reference as the patient and eliminating dead spots, this proof of concept demonstrates real-time patient monitoring during couch motion. For treatments with non-coplanar beams, multiple isocenters, or dynamic couch motion, this provides additional safety without additional radiation dose and avoids some of the complexity and limitations of room mounted systems.

Pulmonary interstitial lymphography: A prospective trial with potential impact on stereotactic ablative radiotherapy planning for early-stage lung cancer.

This prospective feasibility trial investigated pulmonary interstitial lymphography to identify thoracic primary nodal drainage (PND). A post-hoc analysis of nodal recurrences was compared with PND for patients with early-stage lung cancer; larger studies are needed to establish correlation. Exploratory PND-inclusive stereotactic ablative radiotherapy plans were assessed for dosimetric feasibility.

Quantification of cerebrospinal fluid tumor DNA in lung cancer patients with suspected leptomeningeal carcinomatosis.

Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman's ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.

Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiation Therapy for Non-Small Cell Lung Cancer.

PURPOSE: Stereotactic ablative radiation therapy (SABR) results in high rates of primary tumor control for early-stage non-small cell lung cancer (NSCLC). For patients with isolated hilar or mediastinal nodal recurrence (INR) after SABR, the optimal salvage treatment strategy is unclear. The purpose of this study was to determine the rate of INR after SABR for early-stage NSCLC and to describe patterns of care and treatment outcomes after salvage therapy. METHODS AND MATERIALS: This retrospective cohort study included 342 patients with stage T1-3N0M0 NSCLC treated with definitive SABR from 2003 to 2018. We evaluated the incidence of INR and baseline factors between patients who did and did not experience INR. Among patients who experienced INR, we described treatment patterns and outcomes including overall survival (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method. RESULTS: With a median follow-up of 3.3 years, the 3-year INR rate was 10.6% (95% CI, 6.6%-13.4%). Among the 34 patients experiencing INR, the 3-year rates of OS and PFS were 39.3% (24.4%-63.3%) and 26.7% (14.1%-0.3%), respectively. The 34 patients with INR were treated with radiation therapy alone (26.7%), concurrent chemoradiation therapy (43.3%), chemotherapy alone (13.3%), or observation (16.7%). Patients treated with concurrent chemoradiation therapy had the best survival outcomes, with a 3-year OS and PFS of 81.5% (61.1%-100.0%) and 63.9% (40.7%-100.0%), respectively. Of the patients treated with salvage radiation therapy or concurrent chemoradiation therapy, 14.3% experienced grade 3 toxic effects, and no patients had grade ≥4 toxic effects. CONCLUSIONS: In this study, INR occurred in approximately 10% of patients treated with SABR for early-stage NSCLC. The highest rates of OS and PFS among patients with INR were observed in those treated with salvage chemoradiation therapy.

Real-world risk of brain metastases in stage III non-small cell lung cancer in the era of PET and MRI staging.

Objective: The 2-year incidence of brain metastases (BrMs) in stage III non-small lung cell cancer (NSCLC) has been estimated to be around 30%. However, recent clinical trials have demonstrated considerably lower BrMs rates in this patient population. In this study, we aimed to review the real-world incidence, surveillance, and treatment patterns of BrMs in stage III NSCLC. Materials and methods: Using a retrospective single-center study design, we identified patients with stage III NSCLC who received radiation with curative intent over a 10-year period. Outcome variables included BrMs incidence, overall survival (OS), and survival from date of BrMs. Additionally, we assessed patterns of BrMs surveillance in stage III NSCLC and treatment. Results: We identified a total of 279 stage III NSCLC patients, of which 160 with adequate records were included in the final analyses [adenocarcinoma (n = 96), squamous cell carcinoma (n = 53), other histology subtype (n = 11)]. The median OS for the entire cohort was 41 months (95% CI, 28-53), while the median time from BrMs to death was 19 months (95% CI, 9-21). Twenty-three patients (14.4%) received planned surveillance brain MRIs at 6, 12, and 24 months after completion of treatment. The remaining 137 patients (85.6%) received brain MRIs at systemic recurrence (restaging) or when neurologically symptomatic. A total of 37 patients (23%) developed BrMs, with a 2-year cumulative BrMs incidence of 17% (95% CI, 11-23). A higher incidence of BrMs was identified in patients with adenocarcinoma relative to those with squamous cell carcinoma (p < 0.01). Similarly, a higher 2-year BrMs incidence was observed in patients who received planned surveillance brain MRI relative to those who did not, although statistical significance was not reached. Stereotactic radiosurgery (SRS) treated 29 of BrMs patients (78.4%) and was preferred over WBRT, which treated only 3 patients (8.1%). Conclusions: At our center, BrMs incidence in stage III NSCLC patients was lower than historically reported but notably higher than the incidence described in recent clinical trials. Routine BrMs surveillance potentially allows earlier detection of asymptomatic BrMs. However, asymptomatic BrMs were mostly detected on restaging MRI at the time of recurrence.

Pulmonary Hemorrhage in Patients Treated With Thoracic Stereotactic Ablative Radiotherapy and Antiangiogenic Agents.

INTRODUCTION: Severe pulmonary hemorrhage can occur in patients treated with thoracic stereotactic ablative radiotherapy (SABR) and vascular endothelial growth factor inhibitors (VEGFis). There is limited understanding of which patients are at risk for toxicity with the combination of thoracic SABR and VEGFis or how the risk differs over either therapy alone. METHODS: We evaluated a prospectively maintained cohort of 690 patients with 818 pulmonary tumors treated with highly conformal SABR. Rates of any-grade and grade 3 plus (G3+) pulmonary hemorrhage were compared between patients treated with or without VEGFi therapy across tumor locations. Outcomes were compared between patients treated with SABR plus VEGFi and a propensity-matched cohort of those treated with VEGFi therapy alone. RESULTS: Treatment with VEGFi plus SABR was associated with higher rates of G3+ pulmonary hemorrhage compared with those treated with SABR alone for the overall cohort (3-y incidence: 7.9% versus 0.6%, p < 0.01) and those with central tumors (19.1% versus 3.3%, p = 0.04). When further subdivided, there were significantly higher toxicity rates with VEGFi for the ultracentral (9.0% versus 45.0%, p = 0.044), but not central nonabutting tumors (0.0% versus 1.3%, p = 0.69). There was an increased incidence of G3+ hemorrhage in patients treated with VEGFi plus SABR compared with VEGFi alone (9.6% versus 1.3%, p = 0.04). CONCLUSIONS: The combination of VEGFi and SABR was associated with an increased risk of high-grade pulmonary hemorrhage over either therapy alone. Low rates of toxicity were observed when excluding patients with SABR to ultracentral tumors and applying highly conformal SABR techniques.

Vaping-Related Clotting Phenomena Presenting As Central Retinal Vein Occlusion.

Central retinal vein occlusion (CRVO) typically manifests as unilateral vision loss from thrombosis and occlusion of the central retinal vein in patients with thrombophilic risk factors. Here we report a case of a 23-year-old male with three weeks of intermittent left-sided eye pressure and vision loss, who was found to have decreased visual acuity, retinal hemorrhages, and an impending CRVO in his left eye. Upon further evaluation, infectious disease and autoimmune labs were normal, but he had mildly increased right heart pressures and hypercoagulable changes in the right middle cerebral artery. He denied any personal or family history of clotting disorders but noted a four-year history of vaping. He was started on anticoagulation and discharged. Outpatient genetic testing for Factor V Leiden, protein C, protein S, and prothrombin G20210 was normal. His visual acuity returned to normal in the left eye and the retinal hemorrhages resolved. After the exclusion of organic causes, significant vaping history was considered the likely etiology of his hypercoagulable state and resultant CRVO. Vaping-related clotting phenomena may explain the etiology of an otherwise unexplained CRVO, but further investigation of the long-term health consequences of electronic cigarette use is still needed.

Acute and Late Esophageal Toxicity After SABR to Thoracic Tumors Near or Abutting the Esophagus.

PURPOSE: Our purpose was to evaluate the incidence of acute and late esophageal toxicity in patients with thoracic tumors near or abutting the esophagus treated with SABR. METHODS AND MATERIALS: Among patients with thoracic tumors treated with SABR, we identified those with tumors near or abutting the esophagus. Using the linear-quadratic model with an α/ß ratio of 10, we determined the correlation between dosimetric parameters and esophageal toxicity graded using the Common Terminology Criteria for Adverse Events, version 5.0. RESULTS: Out of 2200 patients treated with thoracic SABR, 767 patients were analyzable for esophageal dosimetry. We identified 55 patients with tumors near the esophagus (52 evaluable for esophagitis grade) and 28 with planning target volume (PTV) overlapping the esophagus. Dose gradients across the esophagus were consistently sharp. Median follow-up and overall survival were 16 and 23 months, respectively. Thirteen patients (25%) developed temporary grade 2 acute esophageal toxicity, 11 (85%) of whom had PTV overlapping the esophagus. Symptoms resolved within 1 to 3 months in 12 patients and 6 months in all patients. No grade 3 to 5 toxicity was observed. Only 3 patients (6%) developed late or persistent grade 2 dysphagia or dyspepsia of uncertain relationship to SABR. The cumulative incidence of acute esophagitis was 15% and 25% at 14 and 60 days, respectively. Acute toxicity correlated on univariate analysis with esophageal Dmax, D1cc, D2cc, Dmax/Dprescription, and whether the PTV was overlapping the esophagus. Esophageal Dmax (BED10) <62 Gy, D1cc (BED10) <48 Gy, D2cc (BED10) <43 Gy, and Dmax/Dprescription <85% were associated with <20% risk of grade 2 acute esophagitis. Only 2 local recurrences occurred. CONCLUSIONS: Although 25% of patients with tumors near the esophagus developed acute esophagitis (39% of those with PTV overlapping the esophagus), these toxicities were all grade 2 and all temporary. This suggests the safety and efficacy of thoracic SABR for tumors near or abutting the esophagus when treating with high conformity and sharp dose gradients.

Local Recurrence Outcomes of Colorectal Cancer Oligometastases Treated With Stereotactic Ablative Radiotherapy.

PURPOSE: The aim of this study was to report local failure (LF) outcomes and associated predictors in patients with oligometastatic colorectal cancer (CRC) treated with stereotactic ablative radiotherapy (SABR). MATERIALS AND METHODS: We retrospectively reviewed patients with CRC metastases to the brain, liver, spine, or lung treated with SABR between 2001 and 2016. Time to LF was summarized using cumulative incidence of LF curves with death as a competing risk. RESULTS: The analysis included a total of 130 patients and 256 lesions. Of the metastases treated, 129 (50%) were brain, 50 (20%) liver, 49 (19%) spine, and 28 (11%) lung. Median gross tumor volume was 24 mL for liver metastases, 2 mL for brain metastases, 4 mL for spine metastases, and 1 mL for lung metastases. The overall 1, 2, and 3-year cumulative incidence of LF rates were 21.6% (16.5, 27.1), 28.2% (22.3, 34.4), and 31.5% (25.2, 38.0), respectively. LF was highest among the liver metastases (1 y: 26.0%, 2 y: 38.5%), followed by spine (1 y: 25.1%, 2 y: 31.1%), brain (1 y: 20%, 2 y: 25.2%), and lung (1 y: 13.7%, 2 y: insufficient data). Metastases from right-sided primary CRC were significantly more likely to have LF (P=0.0146, HR=2.23). Biologically effective dose>70 Gy, defined using a standard linear quadratic model using α/ß ratio of 10 on the individual lesion level, and pre-SABR chemotherapy were also significant predictors of LF (P= 0.0009 and 0.018, respectively). CONCLUSIONS: CRC metastases treated with SABR had significantly higher rates of LF if they originated from right-sided primary CRC, compared with left-sided. Liver metastases had the highest rates of LF compared with other metastatic sites. Thus, CRC liver metastases and metastases from right-sided CRC may benefit from more aggressive radiotherapy.

Paclitaxel-eluting stents for chronically occluded saphenous vein grafts (EOS) study.

OBJECTIVES: The aim of this study was to report the feasibility, short- and medium-term results of percutaneous coronary intervention (PCI) on saphenous vein graft (SVG) chronic total occlusions (CTO) using paclitaxel-eluting stents (PES). BACKGROUND: In postbypass patients, PCI on SVG CTO, rather than native vessel CTO, is another treatment option. However, the acute procedural and medium-term outcomes are unknown. METHODS: Twenty-two consecutive, symptomatic postbypass patients underwent PCI on SVG CTO; angiographic success was seen in 16 patients (73%). The successful cases were evaluated at 1 year; restudy angiography was performed at 11 +/- 5 months in 15 patients (94%). RESULTS: The patients had a mean age of 73 years with predominance of male (68%); the mean SVG age was 14 years. On average, patients received 3.4 PESs per lesion; the stent size was 3.5 +/- 0.4 mm with a total stent length of 98 +/- 34 mm. The use of embolic protection devices and glycoprotein IIb/ IIIa inhibitors was observed in 6 (38%) and 5 (31%) patients, respectively. The in-hospital major adverse cardiac event (MACE) was 13%, accountable by 2 patients with postprocedure myocardial infarction. At follow-up, 6 patients had angiographic restenosis (40%); there was 1 noncardiac death and 3 target vessel revascularizations. The 1-year MACE was 25%; the graft survival free of occlusion and revascularization was 56%. CONCLUSIONS: PCI on SVG CTO is a feasible approach with a fairly high success and low in-hospital complication. However, it is associated with a relatively high angiographic restenosis and MACE at 1 year.

Paclitaxel-Eluting Stents for Chronically Occluded Saphenous Vein Grafts (EOS) Study.

Objectives:The aim of this study was to report the feasibility, short- and medium-term results of percutaneous coronary intervention (PCI) on saphenous vein graft (SVG) chronic total occlusions (CTO) using paclitaxel-eluting stents (PES). Background:In postbypass patients, PCI on SVG CTO, rather than native vessel CTO, is another treatment option. However, the acute procedural and medium-term outcomes are unknown. Methods:Twenty-two consecutive, symptomatic postbypass patients underwent PCI on SVG CTO; angiographic success was seen in 16 patients (73%). The successful cases were evaluated at 1 year; restudy angiography was performed at 11 +/- 5 months in 15 patients (94%). Results:The patients had a mean age of 73 years with predominance of male (68%); the mean SVG age was 14 years. On average, patients received 3.4 PESs per lesion; the stent size was 3.5 +/- 0.4 mm with a total stent length of 98 +/- 34 mm. The use of embolic protection devices and glycoprotein IIb/ IIIa inhibitors was observed in 6 (38%) and 5 (31%) patients, respectively. The in-hospital major adverse cardiac event (MACE) was 13%, accountable by 2 patients with postprocedure myocardial infarction. At follow-up, 6 patients had angiographic restenosis (40%); there was 1 noncardiac death and 3 target vessel revascularizations. The 1-year MACE was 25%; the graft survival free of occlusion and revascularization was 56%. Conclusions:PCI on SVG CTO is a feasible approach with a fairly high success and low in-hospital complication. However, it is associated with a relatively high angiographic restenosis and MACE at 1 year. (J Interven Cardiol 2010;**:1-6).

Virtual histology by intravascular ultrasound study on degenerative aortocoronary saphenous vein grafts.

Data of virtual histology (VH) acquired by intravascular ultrasound (IVUS) on saphenous vein graft (SVG) lesions is lacking. This study sought to report the VH IVUS findings in degenerative aortocoronary SVG lesions and correlate various types of plaque compositions (fibrous, fibro-fatty, dense calcium, and necrotic core) with different clinical and lesion characteristics. Virtual histology IVUS was performed on SVG in 38 symptomatic patients with a history of coronary artery bypass grafting, who underwent percutaneous coronary intervention on either native vessels or SVG. Measurements were made at the image slice with the smallest lumen. A total of 54 SVG lesions were analyzed; the mean graft age was 13.7 +/- 4.0 years. The mean vessel size was 5.0 +/- 1.0 mm; plaque area was 13.4 +/- 7.3 mm(2), and plaque burden was 63.0% +/- 15.0%. Fibrous tissue represented the major plaque component (62.1% +/- 17.1%). Lesions with a plaque burden of >or=70% were associated with positive remodeling, larger vessel size, higher percentage of fibro-fatty tissue, but lower percentage of dense calcium. Plaque burden was found to be positively correlated with remodeling index (r = 0.37, P = 0.01) and % fibro-fatty tissue (r = 0.49, P < 0.001) but negatively correlated with % dense calcium (r= -0.31, P = 0.03). The severity of SVG atherosclerosis paralleled with a proportional increase in fibro-fatty tissue. Unstable plaques in SVG were associated with positive remodeling, lipid-rich atheroma, and less calcium deposition, similar to the VH IVUS findings in native coronary arteries.

General Data Protection Regulation (GDPR) in Healthcare: Hot Topics and Research Fronts.

General Data Protection Regulation came into effect across the European Union in May 2018 but its implications in healthcare are yet to be fully understood. The aim of this study was to identify the fronts and hot topics in research on GDPR in healthcare. We analyzed the relevant records in Scopus through bibliometric and scientometric approach and visualization techniques. A set of 155 records was obtained and processed for co-occurrence analysis of key terms and concept mapping. The number of published papers showed a steep rise in the past two years, mainly by European countries. Analysis of the abstract of the papers showed that data protection, privacy, and big data were the most frequently used terms. Three dominant research fronts of GDPR are 1) general implications of GDPR, 2) technology aspects of GDPR, and 3) GDPR in healthcare service. Blockchain and machine learning are among the remerging topics of GDPR research.

Evaluating the Reproducibility of Mouse Anatomy under Rotation in a Custom Immobilization Device for Conformal FLASH Radiotherapy.

The observation of an enhanced therapeutic index for FLASH radiotherapy in mice has created interest in practical laboratory-based FLASH irradiators. To date, systems capable of 3D conformal FLASH irradiation in mice have been lacking. We are developing such a system, incorporating a high-current linear accelerator to produce a collimated X-ray beam in a stationary beamline design, rotating the mouse about a longitudinal axis to achieve conformal irradiation from multiple beam directions. The purpose of this work was to evaluate the reproducibility of mouse anatomy under rotation at speeds compatible with conformal FLASH delivery. Three short-hair mice and two hairless mice were immobilized under anesthesia in body weight-specific contoured plastic molds, and subjected to three rotational (up to 3 revolutions/s) and two non-rotational movement interventions. MicroCT images were acquired before and after each intervention. The displacements of 11 anatomic landmarks were measured on the image pairs. The displacement of the anatomical landmarks with any of the interventions was 0.5 mm or less for 92.4% of measurements, with a single measurement out of 275 (11 landmarks × 5 interventions × 5 mice) reaching 1 mm. There was no significant difference in the displacements associated with rotation compared to those associated with moving the immobilized mouse in and out of a scanner or with leaving the mouse in place for 5 min with no motion. There were no significant differences in displacements between mice with or without hair, although the analysis is limited by small numbers, or between different anatomic landmarks. These results show that anatomic reproducibility under rotation speed corresponding to FLASH irradiation times appears to be compatible with conformal/stereotactic irradiation in mice.

FLASH Irradiation Results in Reduced Severe Skin Toxicity Compared to Conventional-Dose-Rate Irradiation.

Radiation therapy, along with surgery and chemotherapy, is one of the main treatments for cancer. While radiotherapy is highly effective in the treatment of localized tumors, its main limitation is its toxicity to normal tissue. Previous preclinical studies have reported that ultra-high dose-rate (FLASH) irradiation results in reduced toxicity to normal tissues while controlling tumor growth to a similar extent relative to conventional-dose-rate (CONV) irradiation. To our knowledge this is the first report of a dose-response study in mice comparing the effect of FLASH irradiation vs. CONV irradiation on skin toxicity. We found that FLASH irradiation results in both a lower incidence and lower severity of skin ulceration than CONV irradiation 8 weeks after single-fraction hemithoracic irradiation at high doses (30 and 40 Gy). Survival was also higher after FLASH hemithoracic irradiation (median survival >180 days at doses of 30 and 40 Gy) compared to CONV irradiation (median survival 100 and 52 days at 30 and 40 Gy, respectively). No ulceration was observed at doses 20 Gy or below in either FLASH or CONV. These results suggest a shifting of the dose-response curve for radiation-induced skin ulceration to the right for FLASH, compared to CONV irradiation, suggesting the potential for an enhanced therapeutic index for radiation therapy of cancer.

Circulating Tumor DNA Dynamics Predict Benefit from Consolidation Immunotherapy in Locally Advanced Non-Small Cell Lung Cancer.

Circulating tumor DNA (ctDNA) molecular residual disease (MRD) following curative-intent treatment strongly predicts recurrence in multiple tumor types, but whether further treatment can improve outcomes in patients with MRD remains unclear. We applied CAPP-Seq ctDNA analysis to 218 samples from 65 patients receiving chemoradiation therapy (CRT) for locally advanced NSCLC, including 28 patients receiving consolidation immune checkpoint inhibition (CICI). Patients with undetectable ctDNA after CRT had excellent outcomes whether or not they received CICI. Among such patients, one died from CICI-related pneumonitis, highlighting the potential utility of only treating patients with MRD. In contrast, patients with MRD after CRT who received CICI had significantly better outcomes than patients who did not receive CICI. Furthermore, the ctDNA response pattern early during CICI identified patients responding to consolidation therapy. Our results suggest that CICI improves outcomes for NSCLC patients with MRD and that ctDNA analysis may facilitate personalization of consolidation therapy.

KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition.

Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in tumors with KEAP1/NFE2L2 mutations, indicating that they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1-mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations. SIGNIFICANCE: This study shows that mutations in KEAP1 and NFE2L2 predict for LR after radiotherapy but not surgery in patients with NSCLC. Approximately half of all LRs are associated with these mutations and glutaminase inhibition may allow personalized radiosensitization of KEAP1/NFE2L2-mutant tumors.This article is highlighted in the In This Issue feature, p. 1775.

Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice.

Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.