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Atrial fibrillation (AF) has been associated with prior thoracic radiotherapy. However, AF risk after irradiation of specific cardiac substructures, namely the pulmonary veins (PVs), is still being characterized. We sought to investigate the relationship between PV irradiation and the development of clinically significant (grade≥3) AF (AFG≥3) and determine whether PV dose-volume cutoff values may predict for AFG≥3 risk. We conducted a retrospective study including serial patients who underwent definitive radiotherapy for localized cancers at a single academic institution from 2004-2022, with available dosimetric data. We calculated radiotherapy doses (mean, maximum dose [d max ], and absolute volume receiving ≥15 Gy [V15]) in 2 Gray (Gy) fraction equivalent dose to PVs and other cardiac substructures, including left atrium (LA), sinoatrial node (SAN), and left coronary arteries (LCA tot = left main+left anterior descending+left circumflex). AF incidence was calculated using Fine-Gray with univariable and multivariable analyses clustered by cancer type and adjusted for the competing risk of death to measure adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for AFG≥3 incidence. We used the validated "Mayo AF risk score" ([MAFRS] range, 0-12; greater risk with higher scores) to adjust for clinical factors known to predict for AF. We identified 539 patients with median follow-up time of 58.8 months (range, 0-120). Cancer types included 43% [ n = 230] non-small cell lung cancer, 32% [ n = 174] breast cancer, 22% [ n = 119] Hodgkin lymphoma, and 3% [ n = 16]) esophageal cancer. Baseline factors included a median age of 58 years, 40% male, 52% never-smokers, 59% MAFRS 0-1, 42% PV d max >20 Gy. 35 AFG≥3 events occurred at a median of 22.9 months (range, 0.3-120). AFG≥3 risk was greater among patients with higher PV d max (per Gy; aHR 1.02, 95% CI 1.01-1.03, P<0.001), higher V15 LCAtot (per cm3; aHR 1.14, 95% CI 1.06-1.23, P = 0.001), higher LA volume (per cm3; aHR 1.01, 95% CI 1.00-1.02, P = 0.02). Conversely, AFG≥3 risk was lower among patients with MAFRS 0-1 compared to ≥2 (aHR 0.47, 95% CI 0.23-0.96, P = 0.04) and greater LA d max (per Gy; aHR 0.99, 95% CI 0.98-0.99, P<0.001). The hazard ratio for PV d max remained comparably significant across baseline MAFRS groups (P interaction = 0.14). Higher SAN d max was not associated with AFG≥3 risk (HR 1.01, 95% CI 0.99-1.02, P = 0.36). Finally, in a spline analysis, patients with PV d max >20 Gy (among several potential local maxima identified) had significantly higher risk of AF even when stratified by MAFRS. Pulmonary vein d max , in addition to LCA tot dose, appear to be significant predictors of grade ≥3 AF — regardless of other underlying clinical risk factors. These findings provide new evidence to support the clinical relevance of these cardiac substructures with respect to radiation toxicity, and suggest that PV dose metrics may warrant further validation. [ABSTRACT FROM AUTHOR]

Abstract Background Blood is a complex tissue comprising numerous cell types with distinct functions and corresponding gene expression profiles. We attempted to define the cell type specific gene expression patterns for the major constituent cells of blood, including B-cells, CD4+ T-cells, CD8+ T-cells, lymphocytes and granulocytes. We did this by comparing the global gene expression profiles of purified B-cells, CD4+ T-cells, CD8+ T-cells, granulocytes, and lymphocytes using cDNA microarrays. Results Unsupervised clustering analysis showed that similar cell populations from different donors share common gene expression profiles. Supervised analyses identified gene expression signatures for B-cells (427 genes), T-cells (222 genes), CD8+ T-cells (23 genes), granulocytes (411 genes), and lymphocytes (67 genes). No statistically significant gene expression signature was identified for CD4+ cells. Genes encoding cell surface proteins were disproportionately represented among the genes that distinguished among the lymphocyte subpopulations. Lymphocytes were distinguishable from granulocytes based on their higher levels of expression of genes encoding ribosomal proteins, while granulocytes exhibited characteristic expression of various cell surface and inflammatory proteins. Conclusion The genes comprising the cell-type specific signatures encompassed many of the genes already known to be involved in cell-type specific processes, and provided clues that may prove useful in discovering the functions of many still unannotated genes. The most prominent feature of the cell type signature genes was the enrichment of genes encoding cell surface proteins, perhaps reflecting the importance of specialized systems for sensing the environment to the physiology of resting leukocytes.

Abstract Background Much of the microarray data published at Stanford is based on mouse and human arrays produced under controlled and monitored conditions at the Brown and Botstein laboratories and at the Stanford Functional Genomics Facility (SFGF). Nevertheless, as large datasets based on the Stanford Human array began to accumulate, a small but significant number of discrepancies were detected that required a serious attempt to track down the original source of error. Due to a controlled process environment, sufficient data was available to accurately track the entire process leading to up to the final expression data. In this paper, we describe our statistical methods to detect the inconsistencies in microarray data that arise from process errors, and discuss our technique to locate and fix these errors. Results To date, the Brown and Botstein laboratories and the Stanford Functional Genomics Facility have together produced 40,000 large-scale (10–50,000 feature) cDNA microarrays. By applying the heuristic described here, we have been able to check most of these arrays for misidentified features, and have been able to confidently apply fixes to the data where needed. Out of the 265 million features checked in our database, problems were detected and corrected on 1.3 million of them. Conclusion Process errors in any genome scale high throughput production regime can lead to subsequent errors in data analysis. We show the value of tracking multi-step high throughput operations by using this knowledge to detect and correct misidentified data on gene expression microarrays.

Abstract Background In asthma and other allergic disorders, the activation of mast cells by IgE and antigen induces the cells to release histamine and other mediators of inflammation, as well as to produce certain cytokines and chemokines. To search for new mast cell products, we used complementary DNA microarrays to analyze gene expression in human umbilical cord blood-derived mast cells stimulated via the high-affinity IgE receptor (FcεRI). Results One to two hours after FcεRI-dependent stimulation, more than 2,400 genes (about half of which are of unknown function) exhibited 2–200 fold changes in expression. The transcriptional program included changes in the expression of IL-11 and at least 30 other cytokines and chemokines. Human mast cells secreted 130–529 pg of IL-11/106 cells by 6 h after stimulation with anti-IgE. Conclusion Our initial analysis of the transcriptional program induced in in vitro-derived human mast cells stimulated via the FcεRI has identified many products that heretofore have not been associated with this cell type, but which may significantly influence mast cell function in IgE-associated host responses. We also have demonstrated that mast cells stimulated via the FcεRI can secrete IL-11. Based on the previously reported biological effects of IL-11, our results suggest that production of IL-11 may represent one link between IgE-dependent mast cell activation in subjects with allergic asthma and the development of a spectrum of structural changes in the airways of these individuals; such changes, collectively termed "airway remodeling," can constitute an important long term consequence of asthma.

Several studies have noted an increase in the volume of lung tumors treated with stereotactic ablative radiotherapy (SABR) through the course of treatment. The prevalence of such changes and the effect on disease control have not been well studied. Tumor swelling could improve control through immune effects, or worsen it due to geographic miss of the radiotherapy. This is the first study investigating the association between inter-fraction volume changes during lung SABR and clinical outcomes. Patients with AJCC 7th ed. T1-2N0M0 non-small cell lung cancer (NSCLC), who had 4-5 fraction SABR from 4/2009-7/2019 were included in this retrospective study. A planning target volume (PTV) of 5mm was used with motion management as needed. Using cone-beam CT (CBCT) images obtained before each treatment, we contoured each tumor with a standardized procedure in commercially available software. Tumor volumes were assessed prior to initial, midway (third fraction), and last fraction. To explore the relationships between volumetric changes and baseline characteristics, univariable and multivariable linear regression was used. To assess relationship of volume change with outcomes, Fine-Gray models were used with outcomes of local, regional, and distant recurrence, with death as a competing risk. The analysis plan was specified prior to data collection. 121 patients were included. The median ratio of tumor volume at the middle of treatment to start of treatment (Start-Mid) was 1.18 (IQR 1.08, 1.27); the ratio of end of treatment to start (Start-End) was 1.15 (IQR 1.04, 1.28). There was a negative correlation between initial tumor volume and both Start-Mid and Start-End values (p = 0.004 and 0.005, respectively) on univariable analysis. Tumors treated with 50 Gy in 4 fractions (BED 10 112.5 Gy) exhibited larger Start-Mid values compared to those treated with 50 Gy in 5 fractions (BED 10 100 Gy, p = 0.038). Other examined characteristics had no significant correlation with inter-fraction tumor volume changes. Multivariable linear regression analysis reaffirmed a strong correlation between initial tumor volume and both Start-Mid and Start-End changes (p = 0.004 and 0.009, respectively). Fine-Gray models showed no significant correlation between tumor volume changes and local or regional recurrence but found a negative association between Start-Mid change and distant recurrence (p<0.001). Tumor volume often increases during lung SABR. This phenomenon did not appear to adversely affect locoregional control. Increased tumor volume was correlated with reduced distant recurrence, possibly representing an immune effect. Our findings suggest volume changes are likely a consequence of acute inflammatory reactions rather than tumor growth, and modest PTV expansions may be sufficient for tumor coverage. [ABSTRACT FROM AUTHOR]

Stereotactic ablative radiation therapy (SABR) leads to excellent local control in patients with primary or metastatic lung tumors. While there are multiple strategies for motion management in thoracic SABR, there is limited data to compare the efficacy of different approaches. We compared local tumor control by the extent of tumor motion and the motion management strategy for patients treated on the iSABR clinical trial. This is a secondary analysis of patients treated on the multicenter phase II iSABR clinical trial that utilized an individualized dosing strategy for patients with primary or metastatic lung tumors. We evaluated the extent of tumor motion on 4D CT and the motion management approach used during treatment (free breathing, breath hold [BH], or expiratory gating [EG]). For patients treated with free breathing or EG approaches, an internal target volume (ITV) was contoured based on tumor movement on the 4D CT. Patients were treated on a linear accelerator using Real-time Position Management (RPM) triggering. In-field local control rates were compared using the Kaplan-Meier method. In total, 62 patients with 63 tumors had available data on motion management. Fifteen patients (24.2%) underwent SABR with free breathing, 22 (35.5%) had BH (20 inspiratory, and 2 expiratory), and 26 (41.9%) had EG (24 amplitude based, and 2 phase based). 1-, and 2-year local control rates were 100% and 100% with free breathing, 94.7% and 83.2% with BH, and 90.7% and 78.6% with EG (p = 0.2), respectively. Overall, median maximal tumor motion was 10mm (3.5mm for tumors treated with free breathing vs 14.5mm for tumors treated with BH or EG). There was no association between local control and maximum extent of motion on 4D CT (HR = 1.01, p = 0.75). 1- and 2-year local control rates were 92.9% and 89.1% for tumors with maximal motion <10mm, and 96.3% and 82.5% for tumors with maximal motion >10mm (HR = 0.6, p = 0.53), respectively. Patients on the iSABR trial were treated with a range of motion management strategies including motion inclusive free breathing, BH and EG with no observed association between local control by treatment approach. The similar local control rates between mobile and non-mobile tumors suggests that the RPM approach used on the iSABR trial was effective. Our results will be further analyzed pending motion management data collection for the entire iSABR cohort. [ABSTRACT FROM AUTHOR]

For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects, or address the most threatening tumors while the immunotherapy provides benefit for the remaining disease. In the Radical RADiotherapy and Immunotherapy for metastatic Cancer of the Lung (RRADICAL) trial (NCT03176173), we posited that the addition of high-dose RT to ICI therapy could prolong progression-free survival (PFS). In this non-randomized single arm phase 2 trial, 45 patients with metastatic NSCLC who received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017 to May 2021. Imaging after initiation of ICI had to show partial response or stable disease (per RECIST version 1.1) or modest progression (per investigator). Patients received high-dose RT to 1-4 extracranial tumors and continued the ICI until disease progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks from enrollment, comparing to a historical control rate of 35%. Secondary endpoints included toxicity, overall survival (OS), and local control. The exact binomial and log-rank tests were used. Of 44 evaluable patients, median age was 71 years, 75% had adenocarcinoma, 64% were poly-metastatic, and 82% were on pembrolizumab. Of 81 treated tumors, the most common dose received was 40 Gray in 10 fractions (n = 41). Forty-six percent of patients had one tumor treated; the most common treatment site was lung. All visible tumors were treated in 21 (48%) patients. Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI = 44-75%), higher than the historical control rate (P < 0.001). Median time from enrollment to last dose of the same immunotherapy drug was 6.1 months (IQR = 2.7-12.8 mo). Median PFS was 6.9 months (95% CI = 4.0-13.5 mo) and median OS was 27.4 months (95% CI = 20.4-not reached). Several patients with pre-study disease progression on ICI treatment alone achieved durable responses with addition of radiotherapy, up to 56 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis. Adding high-dose radiotherapy to immunotherapy in metastatic NSCLC improved 24-week PFS compared to historical controls receiving ICI therapy alone, indicating that this is a promising strategy for further study. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease in this setting. However, many patients progressed in other non-radiated sites soon after study RT, highlighting the need for better biomarkers for patient selection for aggressive local therapy. [ABSTRACT FROM AUTHOR]

Circulating tumour DNA (ctDNA) assays conducted on plasma are rapidly developing a strong evidence base for use in patients with cancer. The European Society for Medical Oncology convened an expert working group to review the analytical and clinical validity and utility of ctDNA assays. For patients with advanced cancer, validated and adequately sensitive ctDNA assays have utility in identifying actionable mutations to direct targeted therapy, and may be used in routine clinical practice, provided the limitations of the assays are taken into account. Tissue-based testing remains the preferred test for many cancer patients, due to limitations of ctDNA assays detecting fusion events and copy number changes, although ctDNA assays may be routinely used when faster results will be clinically important, or when tissue biopsies are not possible or inappropriate. Reflex tumour testing should be considered following a non-informative ctDNA result, due to false-negative results with ctDNA testing. In patients treated for early-stage cancers, detection of molecular residual disease or molecular relapse, has high evidence of clinical validity in anticipating future relapse in many cancers. Molecular residual disease/molecular relapse detection cannot be recommended in routine clinical practice, as currently there is no evidence for clinical utility in directing treatment. Additional potential applications of ctDNA assays, under research development and not recommended for routine practice, include identifying patients not responding to therapy with early dynamic changes in ctDNA levels, monitoring therapy for the development of resistance mutations before clinical progression, and in screening asymptomatic people for cancer. Recommendations for reporting of results, future development of ctDNA assays and future clinical research are made. • Validated and sensitive ctDNA assays can be used to genotype advanced cancers and select patients for targeted therapies. • Initial genotyping with ctDNA assays should be considered when rapid results are needed, and tissue is unavailable. • ctDNA assay genotyping is limited by false-negative results, lower sensitivity for fusion events and copy number changes. • Use of ctDNA to detect molecular residual disease is not recommended, due to lack of evidence of its clinical utility. [ABSTRACT FROM AUTHOR]

Trimodality therapy with chemoradiation (CRT) followed by esophagectomy is the standard of care for locally advanced esophageal cancer. An unresolved question is whether pathologic complete response (pCR) can be assessed non-invasively for patients post-CRT. In this study, we assessed whether diffusion-weighted imaging (DWI) with MRI or PET can be used as predictors of pCR and other clinical outcomes after CRT. Patients were enrolled on a single-arm institutional trial (PA13-0380) assessing the role of imaging in predicting outcomes in potentially resectable esophageal patients undergoing trimodality therapy. All patients received neoadjuvant CRT, and 29 patients had subsequent surgery. DWI MRI and PET scans were obtained at baseline, 2 weeks after the start of CRT (interim) and 4 to 6 weeks after completion of CRT (follow up). Apparent diffusion coefficients (ADCs) were calculated based on DWI images. Circulating tumor DNA was obtained for 27 patients post-radiation using CAPP-Seq. Mann-Whitney tests compared imaging changes associated with pCR. Discrimination of pCR by imaging changes was quantified by received operating characteristics. Youden's index was applied to select optimal thresholds. Kaplan-Meier analysis was performed to assess differences in overall survival (OS) and progression-free survival (PFS) by changes in DWI, PET, and ctDNA parameters. Our cohort of 60 patients had a median follow up of 42.7 months, age of 65.4 yrs, and ECOG of 1 at completion of CRT. 90% were male, 58% had a history of smoking, and 85% were white. 83% had adenocarcinoma with the rest squamous cell carcinoma. Stages of the patients ranged from IIA to IIIB. All had moderately (47%) or poorly (53%) differentiated disease. All received 41.4-50.4 Gy in 1.8 Gy fractions with the majority receiving 50.4 Gy (95%). 29 patients underwent surgery after CRT of which 8 (27.6%) had pCR. Mean ΔADC from baseline to mid-treatment was most associated with pCR (AUC = 0.98, p<0.001) for patients undergoing surgery. Max ΔADC from baseline to first follow-up was most associated with OS (p = 0.002) and PFS (p<0.001) for the whole cohort. 27 patients had ctDNA analyzed after RT with the presence of ctDNA significantly associated with worse OS (HR = 0.12, p = 0.05) and PFS (HR = 0.10, p = 0.002). Combining ctDNA and max ΔADC generated a model that was more predictive of OS and PFS than either alone. We found that neither the PET parameters of TLG or SUV max at baseline or changes in these parameters from baseline to mid-treatment or first follow-up were as predictive as DWI. We show that changes in DWI is associated with pCR, OS, and PFS in resectable esophageal cancer patients undergoing CRT. DWI was more predictive than PET and a model combining DWI and ctDNA was the most predictive of clinical outcomes. This study shows the significant promise of using DWI in potentially guiding treatment decisions in esophageal cancer patients and will require validation in a larger cohort. [ABSTRACT FROM AUTHOR]

For patients with locally recurrent thoracic tumors or second primaries within previously irradiated volumes, hyperfractionated reirradiation (re-RT) may mitigate late toxicity compared to conventional fractionation, but clinical outcomes have not been extensively studied. We herein report our institutional experience with thoracic hyperfractionated reirradiation. We identified 26 cases among 23 patients treated with re-RT to either primary or metastatic thoracic tumors, 60 Gy in 50 fractions, twice daily over 5 weeks using highly conformal image guided RT with motion management. Nineteen patients had dosimetry data available. The primary outcome was Grade (G2) or higher toxicity rates per CTCAEv5.0. Secondary endpoints were 12-month local control (LC), progression free survival (PFS)—determined by treating physician and/or multidisciplinary tumor board—and overall survival (OS). Median follow-up was 13 months. Half had non-small cell lung cancer, 95.8% had ultracentral tumors, 57.7% had single prior thoracic RT course; 38.5%, 11.5% and 11.5% received concurrent chemotherapy, immunotherapy, and targeted agents, respectively. Minimum and median intervals between RT courses were 10 and 39.5 months, respectively; 94.7% of re-irradiation plans had overlapping 80% isodose volumes. Median OS and PFS were 13 and 10 months, respectively. Crude 12-month LC was 73.1%. Of those with a recurrence, the first recurrence occurred locally in 6 (54.6%), regionally in 3 (27.3%), and distantly in 8 (72.7%) patients. ≥G2 and ≥G3 toxicity rates were 30.8% and 7.69%, respectively (one G3 atrial fibrillation; one G5 pneumonitis). Using the American Radium Society guidelines for thoracic reirradiation, only 10.5% met all dose volume constraint recommendations. Definitive hyperfractionated thoracic re-RT was well tolerated with promising local control. ≥G3 toxicities were rare. Patients should be counseled on the low but potential risk of life-threatening toxicity. Consensus guidelines for dose constraints may be difficult to meet in reirradiation setting; in this cohort, rates of severe toxicity were low despite exceeding putative constraints in most patients. [ABSTRACT FROM AUTHOR]

Over 500 clinical trials combining radiation (RT) and immune checkpoint blockade (ICB) have been initiated based on preclinical evidence that RT can augment local immunity and improve the efficacy of ICB. However, many recent clinical trials have not found a benefit of combining RT and ICB, raising questions about whether a synergy exists. We examined whether RT and ICB interact to beneficially stimulate the immune response in patients and identified biomarkers of response to RT and ICB. We performed a molecular analysis of 1,740 patients from 3 cohorts. The COSINR dataset is a randomized clinical trial of 22 non-small cell lung cancer (NSCLC) patients treated with concurrent or sequential SBRT and ipilimumab/nivolumab. Paired pre- and on-treatment biopsies of an irradiated metastasis underwent whole exome sequencing and RNA-seq. On-treatment biopsies were obtained after SBRT and prior to ICB (sequential) or after SBRT and one cycle of ICB (concurrent). The UC cohort consisted of targeted DNA sequencing of 58 NSCLC patients treated with ICB alone, sequential RT+ICB, or concurrent RT+ICB. The MSKCC dataset is a pan-cancer cohort of targeted DNA sequencing of 1,660 patients treated with ICB. Aneuploidy score (AS) was defined as the fraction of chromosome arms with arm-level copy number alterations. Survival analyses utilized the Kaplan-Meier method and multivariable Cox proportional hazards models. In the COSINR trial, SBRT+ICB increased, whereas SBRT alone decreased, expression of effector T cell IFN-gamma and adaptive immune signatures (P <0.05). Established biomarkers of ICB response, including IFN-gamma signature, tumor mutational burden (TMB), PD-L1 expression, and neoantigen burden were not associated with survival (P >0.05). However, patients whose tumors exhibited high (≥median) but not low, AS had improved survival when treated with concurrent vs. sequential SBRT+ICB (1-year overall survival [OS] 100% vs. 17%, P = 0.025). Our findings were corroborated in the UC cohort: high AS tumors treated with RT + ICB had superior 1-year OS compared to those treated with ICB alone (59% vs. 31%, P = 0.021). Among those who received RT + ICB, concurrent treatment improved OS relative to sequential (1-year OS 76% vs. 38%). RT did not improve OS in patients with low (

Minimizing cardiac toxicity after thoracic radiation therapy (RT) remains a clinical challenge. Mean heart dose is associated with major adverse cardiac events (MACE) and recent studies suggest RT dose to coronary arteries may better quantify risk after conformal RT. Prior studies have not evaluated RT dose to individual coronary arteries in risk modeling. We therefore sought to develop an integrated dosimetric model accounting for RT doses received by each coronary artery. We performed a retrospective study of a randomly selected representative cohort of patients with locally advanced non-small cell lung cancer. We scored cardiac events as (1) ischemic, (2) constrictive, (3) valvular, or (4) conductive. We contoured and measured doses received by the left circumflex (LCX), left anterior descending (LAD), left main coronary (LMCA), and right coronary arteries (RCA). RT doses were measured as equivalent dose in 2-Gray (Gy) fractions. Dosimetric parameters associated with cardiac toxicity were examined using cumulative incidence, competing risk regression models, receiver operator characteristic (ROC), and log-rank statistics with significance defined as two-tailed P <0.05. We identified 100 patients who received definitive RT (median=66 Gy, range=60-74 Gy) from 2006-2020. Median follow-up was 4.1 years (range, 0-11.0). Median age was 70 years (range, 38-84). Half the cohort was male (50%), a majority had smoking history (81%), and all received chemotherapy (100%). Thirty (30%) experienced MACE at a median of 13 months post-RT. Most events were ischemic (n=17, 57%) or conductive (n=13, 43%), with only 3 cases (10%) of valvular disease. Mean heart, LCX, LAD, and LMCA doses were predictive of cardiac toxicity (AUC=0.59, 0.58, 0.59, and 0.63, respectively) and were each significantly associated with MACE on univariable analysis (P <0.05). For patients with full labs available, 10-year atherosclerotic cardiovascular disease (ASCVD) risk was also associated with MACE (HR=1.31, P =0.04). Chemotherapy, age, diabetes, hypertension, prior cardiac event, and mean RCA dose were not associated with MACE. Using the log-rank statistic, we identified threshold mean doses of 1.82, 12.71, 15.45, and 31.29 Gy for the heart, LCX, LAD, and LMCA, respectively. Patients exceeding all three threshold doses to the LCX, LAD, and LMCA had a two-year rate of MACE of 57.1% versus 15.9% (P =0.005). On multivariable analysis after adjusting for ASCVD, patients exceeding all identified doses to the LCX, LAD, and LMCA were at nearly 5 times the risk of MACE (HR=4.76, P =0.0005). Our results suggest that patients receiving doses above our identified thresholds to all of the left coronary arteries (LCX, LAD, and LMCA) are at highest risk of MACE. If validated, our findings may inform RT treatment planning, where sparing of at least one vessel may lead to lower risk of MACE. [ABSTRACT FROM AUTHOR]

Recent randomized trials have supported the existence of a limited metastatic disease state that may benefit from definitive local therapy in patients with non-small cell lung cancer (NSCLC). Due to limits of current staging systems, it is not possible to evaluate the spectrum of metastatic disease with commonly used cancer registries. The purpose of this study is to evaluate the extent and burden of metastatic disease in NSCLC patients presenting to an academic medical center and determine the incidence of patients meet existing criteria for 'oligometastatic' disease. An observational cohort of patients with de novo or recurrent metastatic NSCLC diagnosed from 2016 to 2019 were randomly sampled from a tumor registry. Patients were excluded if they did not receive any tumor directed therapy. Baseline demographic, staging, and treatment data were obtained from the registry and structured electronic health record (EHR) data. Manual chart review was performed to obtain details on metastatic presentation, local therapy, and progression. Definitions for oligometastatic disease were obtained from NRG LU002, MDACC Gomez et al., SINDAS and SABR COMET clinical trials. One hundred eight patients were evaluated with a median age of 68 years (range, 22 – 92) at initial diagnosis and median follow up of 23.5 months. 75% of patients (n=81) presented with de novo metastatic disease, while 25% (n=27) presented with recurrence. Histologies included adenocarcinoma (66%, n=71), squamous cell carcinoma (9%, n=10), and 'other' (20%, n=22). Targetable mutations were present in 31% (n=34) of patients including EGFR (n=27) and ALK (n=2) and MET (n=6). 41% (n=48) of patients had a suspected malignant effusion present at the time of diagnosis. Common sites of metastases included lymph nodes (n=85, 79%), lungs (n=60, 56%), brain (n=49, 45%), and bone (n=48, 44%). 19% (n=21) presented with only one total metastatic tumor, 29% (n=31) with 2-3, 17% (n=18) with 4-5, 19% (n=21) with 6-10, and 16% (n=17) with 10+ tumors. 28% (n=30) of all patients were eligible for at least one oligometastatic NSCLC clinical trial, with 16% meeting eligibility for LU-002 (n=17), 19% for MDACC (n=22), 16% for SABR COMET (n=17), and 5% for SINDAS (n=5). Among those that met trial criteria for oligometastatic disease 40% (n=12) were treated with local therapy including surgery or radiation. Most patients presenting with metastatic NSCLC to our institution had initial de novo metastatic presentation, multi-organ involvement, and adenocarcinoma histology. Roughly one third of patients were classified as oligometastatic using existing trial criteria. A minority of oligometastatic patients were treated with local therapy after metastatic diagnosis during the study period. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Stereotactic ablative radiotherapy (SABR) is an effective treatment for lung tumors, but can result in toxicity such as chest wall pain and life-threatening damage to central lung structures. We hypothesized that while larger tumors require higher dose, small tumors up to 10cc in volume can be controlled with biologically effective dose < 100Gy. In this phase II single-arm trial, we tested the hypothesis that individualizing lung SABR dose and fractionation to tumor size, location, and histology would result in excellent local control with acceptable toxicity. The trial was conducted at two centers in the United States and Japan (NCT# redacted for blinded review).Materials/methods: Patients in three groups were enrolled: initial diagnosis of non-small cell lung cancer (NSCLC), AJCC 7th edition stage T1-3 N0 M0 (group 1); new primary NSCLC with history of NSCLC, or multiple synchronously diagnosed NSCLCs (group 2); and lung metastases from NSCLC or another primary site (group 3). Up to four tumors could be treated with once-daily SABR. There were six dose/fractionation schedules used, depending on gross tumor volume (≤10cc, 10-30cc, > 30cc) and location (peripheral vs. central). Larger tumors received higher dose and central tumors generally received lower dose per fraction. Dose ranged from 25Gy in one fraction for 0-10cc peripheral tumors to 60Gy in 8 fractions for > 30cc central tumors. Colorectal cancer metastases were treated to higher dose, at least 50Gy in 4 fractions. The primary endpoint was per-group cumulative incidence of local recurrence at 1 year (recurrence of treated tumor within same lobe), with distant recurrence and death as competing risks. Treated tumor recurrence (recurrence with epicenter within 1cm of PTV) and toxicity were also analyzed.Results: A total of 217 patients were enrolled from 2011-2018 (some patients were enrolled multiple times). Median age was 72, 59% were male, and 69% were current/former smokers. There were 240 treatment courses and 285 tumors treated (range 1-3 tumors per course). 211 tumors were peripheral and 74 were central. Tumor size distribution was: ≤10cc, 74%; 10-30cc, 19%; > 30cc, 7%. The most common dose was 25Gy in one fraction (158 tumors). Median follow-up was 30 months (range 2-95). Median overall survival was 57 months. Local recurrence data are currently being updated and will be presented at the meeting. The rate of grade 2 or higher pneumonitis was 16/217 (7%) and grade 3 or higher pneumonitis was 3/217 (1%). The rate of grade 2 or higher chest wall pain was 13/217 (6%). One patient had a grade 5 adverse event, developing pulmonary hemorrhage that was possibly related to radiotherapy, 17 months after treatment of a large central NSCLC.Conclusion: Individualized SABR to lung cancers resulted in excellent local control and favorable toxicity profile. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Prior research suggests that radiation oncologist provider experience may influence outcomes for radiation treatment modalities requiring greater technical expertise for given disease sites. We investigated whether institution treatment volume (TV) for SABR technique impacted survival outcomes for patients with NSCLC.Materials/methods: We conducted a retrospective cohort study using the Veteran's Affairs Informatics and Computing Infrastructure (VINCI) database to identify patients who underwent treatment for NSCLC between 2012 and 2017 at Veteran's Health Administration Medical Centers (VHAMCs). Patients were included in the cohort if they had tumor (T) stage 1 or 2 disease, node negative (N0) disease, and underwent SABR radiation treatment based on associated Current Procedural Terminology codes. We conducted univariate and multivariate analyses for overall survival (OS) and cause-specific survival (CSS) using Cox regression models accounting for age, sex, race, histology, T stage, tobacco history, ECOG status, and VHAMC facility TV. TV was calculated as the total number of SABR treatments performed per facility over the study period and was categorized into high and low volume groups based on a median TV cutoff.Results: The observational cohort included N = 433 patients with early-stage NSCLC who underwent treatment with SABR across 25 VHAMC facilities. Most patients (83.1%) had T stage 1 disease, and nearly equal proportions had SCC (31.2%) and adenocarcinoma (32.5%) histologies, with the remaining having clinical diagnoses of NSCLC. Median facility TV was 29 SABR treatments (interquartile range 19-33). Median follow up was 657 days. Estimated 2-year overall and cause-specific survival rates were 78.4% (95% CI: 73.9% - 82.1%) and 87.0% (95% CI: 83.2% - 90.0%), respectively. On univariate analysis, high versus low facility TV was not significantly associated with OS (hazard ratio (HR) 1.08, 95% CI: 0.74-1.58) or CSS (HR 1.06, 95% CI: 0.65 - 1.73). Similarly, facility volume was not associated with OS or CSS on multivariate analysis. In a sensitivity analysis, facility volume was not associated with survival outcomes when treated as a continuous variable. Covariates associated with decreased OS included male sex (HR 4.5, P < 0.05), age over 65 (HR 1.77, P < 0.05), ECOG status 2 or greater (HR 1.94, P < 0.05), SCC histology (HR 1.66, P < 0.05), and T stage 2 disease (HR 1.68, P < 0.05).Conclusion: In this observational cohort of patients treated at VHAMCs, facility TV was not associated with survival outcomes for early-stage NSCLC radiation treatment using SABR technique. Research is ongoing to account for factors including baseline pulmonary function, comorbidities, and variations in institutional treatment patterns such as propensity for treatment with surgery versus radiation. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) have high rates of local control but may be at increased risk of nodal recurrence compared to those who undergo surgical resection with more invasive nodal evaluation. The optimal treatment for patients with isolated nodal recurrence (INR) is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and describe patterns of care and treatment outcomes for patients that experience INR.Materials/methods: This retrospective cohort study included 342 patients with stage T1-3N0 NSCLC treated with definitive SABR. We evaluated the estimated rate of INR using the cumulative incidence function with death as a competing risk and compared baseline factors among patients who did or did not experience INR. Among patients that experienced INR, we describe patterns of treatment and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method. OS and PFS outcomes were compared between treatment groups using the log-rank test.Results: Of the 342 patients treated with SABR from 2003-2018, 34 developed INR and 19 developed any nodal recurrence. Patients were treated with definitive SABR for T1 (62.6%, n = 214), T2 (25.4%, n = 87) and T3 (12.0%, n = 41) NSCLC with a median BED10 of 87.5. The 3- and 5-year cumulative incidence of INR was 9.3 (95% CI 6.1 - 12.4) and 10.1 (6.8 -13.4) %, respectively. Pathologic nodal staging prior to SBRT was 9.1 and 13.3 % (P = 0.68) for patients who did or did not experience INR, respectively. The median number of involved nodes at the time of recurrence was one with a maximum of four. Among the 30 patients with a known treatment course after INR, patients were treated with RT alone (26.7 %, n = 8), chemotherapy and RT (CRT) (43.3 %, n = 13), chemotherapy alone (13.3%, n = 4) or observation (16.7%, n = 5). RT regimens included standard fractionation (38.0%, n = 8), hypofractionation (52.4%, n = 11) or SABR (9.5%, n = 2). The estimated two-year OS and PFS for patients experiencing INR were 48.0 (32.6 - 70.7) % and 27.6 (14.7 - 52.8) %, respectively. Treatment with CRT was associated with improved OS (2 year est: 91.7 vs 16.7 %, P < 0.01) and PFS (2 year est: 63.9 vs 0 %, P < 0.01) over RT alone. Similarly, CRT was associated with improved OS (91.7 vs 25.0 %, P < 0.01) and PFS (63.9 vs 0%, P < 0.01) over chemotherapy alone. Median follow-up time after INR was 21.7 months.Conclusion: INR occurred in approximately 10% of patients treated for early-stage NSCLC with SABR. Treatment paradigms for post-SABR INR varied significantly at our institution and included combined chemotherapy and radiation, chemotherapy alone, SABR and hypofractionated RT. The highest rates of survival in patients with post-SABR INR were observed in those treated with combined chemotherapy and radiation. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Hemoptysis is a rare but potentially fatal toxicity associated with thoracic stereotactic ablative radiotherapy (SABR). Prior studies have suggested that vascular endothelial growth factor inhibitors (VEGFI) may potentiate the risk for pulmonary hemorrhage in patients treated with SABR for centrally located lung tumors. To what degree the risk of toxicity varies by timing of therapies or tumor location is uncertain. The purpose of this study is to evaluate the combined toxicity of VEGFIs and SABR for peripheral, central, or ultra-central tumors.Materials/methods: We evaluated patients with primary or metastatic lung tumors treated with SABR between 2008 and 2018 at a single institution. Baseline patient, tumor and treatment characteristics were evaluated. Pulmonary bleeding events were graded using CTCAE version 5.0. Rates of a grade three or higher (G3+) or any ipsilateral pulmonary hemorrhage at three years were estimated using the Kaplan-Meier method. We compared rates of bleeding by tumor location, treatment with a VEGFI, sequence of therapy and VEGFI within 90 days of SABR using the log-rank test.Results: This retrospective cohort study included a total of 925 pulmonary tumors treated with SABR in 691 patients. There were 44 patients treated with a VEGFI (bevacizumab, sorafenib, pazopanib, sunitinib or ramucirumab), with the majority receiving bevacizumab (n = 38, 86.3%). Among those treated with a VEGFI, the median interval between VEGFI therapy and SABR was 16 weeks, ranging from zero days to 3.7 years, with 15 (34.0%) patients treated within 90 days of SABR. Patients were treated with SABR to peripheral (738, 79.8%), central (137, 14.8%) and ultra-central (50, 5.4%) locations with a median BED10 of 87.5 Gy. Median follow-up was 32.2 months for the overall cohort and 46.4 months for VEGFI patients. The rate of G3+ hemorrhage was significantly higher in patients treated with a VEGFI (7.3 vs 0.8%, P < 0.01). The rate of any grade hemorrhage did not significantly vary between groups (9.4 vs 2.7%, P = 0.1). When stratified by location, both central/ultra-central tumors (21.1 vs 3.2%, P = 0.03) and peripheral tumors (3.4 vs 0.1%, P = 0.03) had increased rates of G3+ hemorrhage when treated with a VEGFI. Among patients treated with SABR and VEGFI, there was no significant difference in rates of hemorrhage when the interval was > or ≤ 90 days (12.0 vs 0.0%, P = 0.17). Similarly, there was no significant difference between rates of G3+ hemorrhage when VEGFI was given before (12.9%), after (8.3%), or before and after SABR (0.0%).Conclusion: VEGFI therapy was associated with an increased rate of high-grade hemorrhage in patients undergoing SABR to pulmonary tumors. Rates of high-grade hemorrhage were increased with VEGFI for both central/ultra-central and peripheral tumors although the absolute rate was low for peripheral tumors. While limited by low sample size and event rate, there was no correlation observed between interval or sequence of VEGFI and SABR and rate of high-grade hemorrhage. [ABSTRACT FROM AUTHOR]

Introduction: The current standard of care for patients with inoperable stage III non-small cell lung cancer includes chemoradiotherapy (CRT) followed by 1 year of checkpoint inhibitor (CPI) therapy. Nevertheless, the optimal duration of consolidation CPI remains unknown. Here, we characterized the relationship between circulating tumor DNA (ctDNA) minimal residual disease (MRD) and clinical outcomes of patients with unresectable locally advanced non-small cell lung cancer treated on a phase 2 trial of short-course consolidation immunotherapy after CRT, with the goal of testing whether ctDNA may be able to identify patients who do not require a full year of treatment., Methods: Plasma samples for ctDNA analysis were collected from patients on the Big Ten Cancer Research Consortium LUN 16-081 trial after completion of CRT, before day 1 of cycle 2 (C2D1) of CPI (i.e., 1 mo after treatment start), and at the end of up to 6 months of treatment. Tumor-informed ctDNA MRD analysis was performed using cancer personalized profiling by deep sequencing. Levels of ctDNA at each time point were correlated with clinical outcomes., Results: Detection of ctDNA predicted significantly inferior progression-free survival after completion of CRT (24-mo 29% versus 65%, p = 0.0048), before C2D1 of CPI (24-mo 0% versus 72%, p < 0.0001) and at the end of CPI (24-mo 15% versus 67%, p = 0.0011). In addition, patients with decreasing or undetectable ctDNA levels after 1 cycle of CPI had improved outcomes compared with patients with increasing ctDNA levels (24-mo progression-free survival 72% versus 0%, p < 0.0001). Progression of disease occurred within less than 12 months of starting CPI in all patients with increasing ctDNA levels at C2D1., Conclusions: Detection of ctDNA before, during, or after 6 months of consolidation CPI is strongly associated with inferior outcomes. Our findings suggest that analysis of ctDNA MRD may enable personalizing the duration of consolidation immunotherapy treatment., Competing Interests: Disclosure Dr. Durm receives support from Bristol-Myers Squibb; grants or contracts from AstraZeneca, Merck, and Mirati; consulting fees from Cook Biotech; payments or honoraria from Curio Science, DAVA Oncology, and AstraZeneca; and participates on an advisory board for Curio Science, DAVA oncology, and AstraZeneca. Dr. Ganti receives research grants or contracts from VA Office of Research and Development, Merck, TAB Biosciences, NEKTAR Therapeutics, Mirati Therapeutics, IOVANCE Therapeutics, and Apexigen; royalties or licenses from Oxford University Press; consulting fees from AstraZeneca, Flagship Biosciences, G1 Therapeutics, Jazz Pharmaceuticals, Cardinal Health, Mirati Therapeutics, Beigene Ltd., Sanofi Genzyme, Blueprint Medicines, and Regeneron Pharmaceuticals; payments or honoraria from MedLearning Group and Plexus Communications; participates on a data safety monitoring board for YmAbs Therapeutics; holds leadership or fiduciary roles at Academic and Community Cancer Research United and A Breath of Hope for Lung Cancer; and has received equipment or materials from Takeda Pharmaceuticals and Chimerx. Dr. Alizadeh receives research grants or contracts from the National Cancer Institute, National Heart, Lung and Blood Institute, National Institutes of Health, Celgene, Bristol-Myers Squibb, and Pfizer; consulting fees from ADCT, Celgene, Chugai, Genentech, Gilead, Janssen, Pharmacyclics, and Roche; has patents planned, issued, or pending with FortySeven Inc., Foresight Diagnostics, CiberMed Inc., and Roche; participates on a data safety monitoring board for Lymphoma Research Foundation; holds leadership or fiduciary roles at the American Society of Hematology, American Society of Clinical Oncology, American Society of Clinical Investigation, and Leukemia & Lymphoma Society; and has equity ownership interests in CiberMed Inc., Foresight Diagnostics, FortySeven Inc., and CARGO Therapeutics. Dr. Hanna receives grants or contracts from Merck, Genentech, Bristol-Myers Squibb, and Natera. Dr. Diehn receives grants or contracts from AstraZeneca and Varian Medical Systems; royalties or licenses from Roche and Foresight Diagnostics; consulting fees from AstraZeneca, Boehringer Ingelheim, Genentech, Illumina, Gritstone Bio, and Regeneron; payments or honoraria from Bristol-Myers Squibb, Japan, and Novartis; support for attending meetings or travel from Foresight Diagnostics and Regeneron; has patents planned, issued, or pending with Stanford University; holds leadership or fiduciary roles at Foresight Diagnostics; and holds stock or stock options in CiberMed Inc., Foresight Diagnostics, and Gritstone Bio. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Only a subset of patients with severe emphysema qualify for lung volume reduction surgery or endobronchial valves. We previously demonstrated that stereotactic ablative radiation therapy of lung tumors reduces lung volume in treated lobes by creating localized lung fibrosis. We aimed to determine the safety and secondarily explore the efficacy of stereotactic irradiation for lung volume reduction (SILVR) over 18 months after intervention in patients with severe emphysema., Methods and Materials: We conducted a single-arm, prospective clinical trial in eligible patients with severe emphysema treated with unilateral stereotactic ablative radiation therapy (45 Gy in 3 fractions) to a target within the most emphysematous region. The primary outcome was safety in terms of incidence of grade ≥3 adverse events, and the secondary outcome was efficacy., Results: Eight patients received the intervention. Median (range) baseline characteristics were age 73 years (63-78); forced expiratory volume in 1 second percent of predicted value (FEV 1 %) 28.5% (19.0-42.0); diffusing capacity of the lungs for carbon monoxide percent of predicted value 40% (24.0-67.0); and body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index 5.5 (5-9). The incidence of grade ≥3 adverse events was 3 of 8 (37.5%). The relative change in target lobe volume was -23.1% (-1.6 to -41.5) and -26.5% (-20.6 to -40.8) at 6 and 18 months, respectively. The absolute ΔFEV 1 % was greater in patients with a BODE index ≤5 versus ≥6 (+12.0% vs -2.0%). The mean baseline lung density (in Hounsfield units, reflecting the amount of preserved parenchyma) within the intermediate dose volume (V 60BED3 ) correlated with the absolute change in target lobe volume at 18 months., Conclusions: SILVR appears to be safe, with a signal for efficacy as a novel therapeutic alternative for patients with severe emphysema. SILVR may be most safe and effective in patients with a lower BODE index and/or less parenchymal destruction., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hypothesis: For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects and address the most threatening tumors. We posited that the addition of high-dose RT to ICI could prolong progression-free survival (PFS)., Methods: In this single arm phase 2 trial, 45 patients with metastatic NSCLC who had received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017-May 2021. Patients received high-dose RT to 1-4 extracranial tumors and continued ICI until progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks, comparing to a historical control rate of 35%., Results: Of 44 evaluable patients, median age was 71, 75% had adenocarcinoma, 64% had polymetastatic disease, and 85% of cancers with known PD-L1 percentage were PD-L1 positive. Median number of treated tumors was two and most common dose was 40 Gy in 10 fractions (41/81 tumors). Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI 44-75%), higher than the historical control rate (p<0.001). Median PFS was 6.9 months (95% CI 4.0-13.5 mo) and median OS was 27.4 months (95% CI 20.4-not reached). Several patients with pre-study disease progression on ICI treatment achieved durable responses to study treatment, up to 53 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis., Conclusions: The strategy improved 24-week PFS compared to historical controls receiving ICI alone. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease., Competing Interests: Declaration of competing interest AC reports consulting fees from TibaRay. BL reports consulting fees from Beigene, honoraria from Mevion, leadership role in TibaRay. MD reports honoraria from AstraZeneca, Illumina, Genentech, Novartis, Griftstone oncology, Boehringer Ingelheim, Bristol Myers Squibb, leadership role in CiberMed and Foresight Diagnostics, stock in Griftstone Oncology. HW reports honoraria from IOBiotech and Mirati., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Small cell lung cancer (SCLC) is characterized by rapid progression after platinum resistance. Circulating tumor (ctDNA) dynamics early in treatment may help determine platinum sensitivity., Materials and Methods: Serial plasma samples were collected from patients receiving platinum-based chemotherapy for SCLC on the first 3 days of cycle one and on the first days of subsequent cycles with paired samples collected both before and again after infusions. Tumor-informed plasma analysis was carried out using CAncer Personalized Profiling by deep Sequencing (CAPP-Seq). The mean variant allele frequency (VAF) of all pretreatment mutations was tracked in subsequent blood draws and correlated with radiologic response., Results: ctDNA kinetics were assessed in 122 samples from 21 patients. Pretreatment VAF did not differ significantly between patients who did and did not respond to chemotherapy (mean 22.5% v 4.6%, P = .17). A slight increase in ctDNA on cycle 1, day 1 immediately post-treatment was seen in six of the seven patients with available draws (fold change from baseline: 1.01-1.44), half of whom achieved a response. All patients who responded had a >2-fold decrease in mean VAF on cycle 2 day 1 (C2D1). Progression-free survival (PFS) and overall survival (OS) were significantly longer in patients with a >2-fold decrease in mean VAF after one treatment cycle (6.8 v 2.6 months, log-rank P = .0004 and 21.7 v 6.4 months, log rank P = .04, respectively)., Conclusion: A >2-fold decrease in ctDNA concentration was observed by C2D1 in all patients who were sensitive to platinum-based therapy and was associated with longer PFS and OS.

Background and Purpose: Concerns over chest wall toxicity has led to debates on treating tumors adjacent to the chest wall with single-fraction stereotactic ablative radiotherapy (SABR). We performed a secondary analysis of patients treated on the prospective iSABR trial to determine the incidence and grade of chest wall pain and modeled dose-response to guide radiation planning and estimate risk., Materials and Methods: This analysis included 99 tumors in 92 patients that were treated with 25 Gy in one fraction on the iSABR trial which individualized dose by tumor size and location. Toxicity events were prospectively collected and graded based on the CTCAE version 4. Dose-response modeling was performed using a logistic model with maximum likelihood method utilized for parameter fitting., Results: There were 22 grade 1 or higher chest wall pain events, including five grade 2 events and zero grade 3 or higher events. The volume receiving at least 11 Gy (V 11Gy ) and the minimum dose to the hottest 2 cc (D 2cc ) were most highly correlated with toxicity. When dichotomized by an estimated incidence of ≥ 20 % toxicity, the D 2cc  > 17 Gy (36.6 % vs. 3.7 %, p < 0.01) and V 11Gy  > 28 cc (40.0 % vs. 8.1 %, p < 0.01) constraints were predictive of chest wall pain, including among a subset of patients with tumors abutting or adjacent to the chest wall., Conclusion: For small, peripheral tumors, single-fraction SABR is associated with modest rates of low-grade chest wall pain. Proximity to the chest wall may not contraindicate single fractionation when using highly conformal, image-guided techniques with sharp dose gradients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B.L., Y.F.W., S.C., J.F., S.J., P.D., H.G., V.M., S.E., H.S., and A.L.C. report no disclosures. L.S. reports US patent: 16/809427. D.P. reports disclosures including a grant with RefleXion Medical Research. H.T. reports a contract with the Global Center for Biomedical Science and Engineering at Hokkaido University. M.F.G. reports disclosures including grants with Varian Medical Systems and stock holdings with Roche. M.Diehnreports disclosures including research support from AstraZeneca and Varian Medical Systems, royalties for patent licenses from Roche and Foresight Diagnostics, consulting fees from AstraZeneca, Boehringer Ingelheim, Genentech, Gritstone Bio, Illumina, and Regeneron, honoraria from Bristol Myers Squibb and Novartis, leadership as a board member of Foresight Diagnostics, and stock/options for CiberMed, Gritstone Bio, and Foresight Diagnostics. B.W.L. reports disclosures including grants with Varian Medical Systems, leadership as a board member of TibaRay, and stock holdings in TibaRay. L.K.V. reports disclosures including grants from RefleXion Medical., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti-PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non-small cell lung cancer. Patients who failed to respond to initial anti-PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti-PD-1 alone that improved after JAK inhibition. Itacitinib promoted CD8 T cell plasticity and therapeutic responses of exhausted and effector memory-like T cell clonotypes. Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti-PD-1 immunotherapy by pivoting T cell differentiation dynamics.

Background: The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern., Methods: We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient., Results: A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques., Conclusions: Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.)., (Copyright © 2024 Massachusetts Medical Society.)

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., (© 2024. The Author(s).)

The integration of cancer biomarkers into oncology has revolutionized cancer treatment, yielding remarkable advancements in cancer therapeutics and the prognosis of cancer patients. The development of personalized medicine represents a turning point and a new paradigm in cancer management, as biomarkers enable oncologists to tailor treatments based on the unique molecular profile of each patient's tumor. In this review, we discuss the scientific milestones of cancer biomarkers and explore future possibilities to improve the management of patients with solid tumors. This progress is primarily attributed to the biological characterization of cancers, advancements in testing methodologies, elucidation of the immune microenvironment, and the ability to profile circulating tumor fractions. Integrating these insights promises to continually advance the precision oncology field, fostering better patient outcomes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Heterogeneity in the tumor microenvironment (TME) of follicular lymphomas (FLs) can affect clinical outcomes. Current immunotherapeutic strategies, including antibody- and cell-based therapies, variably overcome pro-tumorigenic mechanisms for sustained disease control. Modeling the intact FL TME, with its native, syngeneic tumor-infiltrating leukocytes, is a major challenge. Here, we describe an organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME. We define the robustness of this method by successfully culturing cryopreserved FL specimens from diverse patients and demonstrate the stability of TME cellular composition, tumor somatic mutations, gene expression profiles, and B/T cell receptor dynamics over 3 weeks. PDLOs treated with CD3:CD19 and CD3:CD20 therapeutic bispecific antibodies showed B cell killing and T cell activation. This stable system offers a robust platform for advancing precision medicine efforts in FL through patient-specific modeling, high-throughput screening, TME signature identification, and treatment response evaluation., Competing Interests: Declaration of interests J.M.K., J.G.S.-M., B.J.S., M.D., L.E.W., and A.A.A. have submitted a provisional patent application (filed by Stanford University on 06/12/2023 with application number 63/507,692) on the development and applications of PDLOs. A.A.A. reports ownership interest in CiberMed, FortySeven Inc., and Foresight Diagnostics; patent filings related to cancer biomarkers; research funding from Bristol Myers Squibb and Celgene; and paid consultancy from Genentech, Karyopharm, Roche, Chugai, Gilead, and Celgene. L.E.W. reports research funding (unrelated to this study) from F. Hoffman La Roche., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Prior attempts to escalate radiation dose for non-small cell lung cancer (NSCLC) have not improved survival. Given the high risk for cardiopulmonary toxicity with treatment and heterogenous presentation of locally advanced NSCLC, it is unlikely that a single dose regimen is optimal for all patients. This phase I/II trial aims to evaluate a novel treatment approach where the level of accelerated hypofractionation is determined by the predicted toxicity from dose to organs at risk (OARs)., Methods: Patients ≥ 18 years old with lung cancer planned for fractionated radiotherapy to the lung with concurrent chemotherapy will be eligible. Radiation therapy (RT) will be delivered to a total dose of 60 to 66 Gy in 30, 25, or 20 fractions depending on the ability to meet constraints to key organs at risk including the lungs, heart, and esophagus. The primary endpoint is high grade pulmonary, esophageal, or cardiac toxicity. A Bayesian optimized design is used to determine stopping boundaries and evaluate the primary endpoint., Conclusion: PACER will evaluate the safety and feasibility of personalized accelerated chemoradiotherapy for lung cancer., Competing Interests: Disclosure Billy W Loo: co-founder and board member of TibaRay and a consultant on a clinical trial steering committee of Beigene, and has received lecture honorarium from Mevion; Joel W Neal: ASCO; Millie Das: consulting with Genentech and Eurofins; participation on the advisory board for AstraZeneca, Beigene, Sanofi/Genzyme, and Janssen; and research with Merck, Genentech, CellSight, Novartis, AbbVie, United Therapeutics, Verily, Varian Medical Systems and Celgene. Heather Wakelee: grants with ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bristol-Myers Squibb, Clovis Oncology, Genentech/Roche, Merck, Novartis, SeaGen, Xcovery, and Helsinn; participation on the advisory board for AstraZeneca, Blueprint, Mirati, Merck, and Genentech/Roche; and leadership with International Association for the Study of Lung Cancer and ECOG-ACRIN; Maximilian Diehn: grants with Varian, Genentech, and AstraZeneca; royalties for patent license with Roche and Foresight Diagnostics; consulting fees with Roche Sequencing Solutions, Varian, BioNTech, RefleXion, Novartis, Illumina, Genentech, BioNTech, Boehringer Ingelheim, and Gritstone Oncology; patents with Roche, Foresight Diagnostics, and Celgene; participation on the advisory board for AstraZeneca, Genentech, Boehringer Ingel- heim, Illumina, and Gritstrone; leadership as a board member of Foresight Diagnostics; stock holdings with Foresight Diagnostics and CiberMed; and in-kin research from Illumina; Lucas Vitzthum: grants from RefleXion Medical; Mohona Roy: Speakers' Bureau: MJH Life Sciences; Research Funding: Varian Medical Systems (Inst); Nathaniel Myall: Honoraria: Patient Power; Kavitha Ramchandran: Consulting or Advisory Role: Drishti, GroupWell, Varian Medical Systems. The remaining authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose/objectives: Adoption of hypofractionated accelerated radiation therapy (HART) with concurrent chemotherapy has been limited by toxicity concerns. We aimed to describe outcomes of patients treated with HART and concurrent chemotherapy and to evaluate dosimetry to organs at risk to guide patient selection., Materials/methods: We evaluated a retrospective cohort of NSCLC patients treated with concurrent chemotherapy with HART (>2.2 Gy per fraction) or standard fractionated radiation therapy (SFRT; 2-2.2 Gy fractions). Dosimetric parameters to key organs at risk were compared, and toxicity, patterns of recurrence and survival were calculated for the cohorts., Results: Fifty-three patients treated with HART were compared with 100 patients treated with SFRT. Median dose per fraction for the HART cohort was 2.75 Gy (range 2.4-3 Gy). HART patients had significantly lower doses to the lung, heart, and esophagus due to patient selection. The HART group and had rates of grade 2+ pneumonitis (9.4 vs. 19%, P = .16) and grade 2+ esophagitis (20.8 vs. 45%, P < .01) that compared favorably to SFRT. Cumulative incidence of in-field recurrence trended lower in the HART cohort (7.6% vs. 23.1%, P = .058). Among the HART group, 88.7% (47/53) met the newly proposed lung constraints based on the degree of hypofractionation CONCLUSION: In select patients with favorable dosimetry to organs at risk, definitive HART with concurrent chemotherapy achieved excellent local control with low toxicity. These results are being used to inform a prospective study on the safety and efficacy of HART with concurrent chemotherapy for select NSCLC patients., Competing Interests: Disclosure Billy W Loo: co-founder and board member of TibaRay and a consultant on a clinical trial steering committee of Beigene, and has received lecture honorarium from Mevion; Joel W Neal: ASCO; Millie Das: consulting with Genentech and Eurofins; participation on the advisory board for AstraZeneca, Beigene, Sanofi/Genzyme, and Janssen; and research with Merck, Genentech, CellSight, Novartis, AbbVie, United Therapeutics, Verily, Varian Medical Systems and Celgene; Heather Wakelee: grants with ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bristol-Myers Squibb, Clovis Oncology, Genentech/Roche, Merck, Novartis, SeaGen, Xcovery, and Helsinn; participation on the advisory board for AstraZeneca, Blueprint, Mirati, Merck, and Genentech/Roche; and leadership with International Association for the Study of Lung Cancer and ECOG-ACRIN; Maximilian Diehn: grants with Varian, Genentech, and AstraZeneca; royalties for patent license with Roche and Foresight Diagnostics; consulting fees with Roche Sequencing Solutions, Varian, BioNTech, RefleXion, Novartis, Illumina, Genentech, BioNTech, Boehringer Ingelheim, and Gritstone Oncology; patents with Roche, Foresight Diagnostics, and Celgene; participation on the advisory board for AstraZeneca, Genentech, Boehringer Ingel- heim, Illumina, and Gritstrone; leadership as a board member of Foresight Diagnostics; stock holdings with Foresight Diagnostics and CiberMed; and in-kin research from Illumina; Lucas Vitzthum: grants from RefleXion Medical; Mohona Roy: Speakers' Bureau: MJH Life Sciences; Research Funding: Varian Medical Systems (Inst) Nathaniel Myall: Honoraria: Patient Power The remaining authors declare no conflict of interest., (Published by Elsevier Inc.)

Background: Central nervous system lymphomas (CNSL) display remarkable clinical heterogeneity, yet accurate prediction of outcomes remains challenging. The IPCG criteria are widely used in routine practice for the assessment of treatment response. However, the value of the IPCG criteria for ultimate outcome prediction is largely unclear, mainly due to the uncertainty in delineating complete from partial responses during and after treatment., Methods: We explored various MRI features including semi-automated 3D tumor volume measurements at different disease milestones and their association with survival in 93 CNSL patients undergoing curative-intent treatment., Results: At diagnosis, patients with more than 3 lymphoma lesions, periventricular involvement, and high 3D tumor volumes showed significantly unfavorable PFS and OS. At first interim MRI during treatment, the IPCG criteria failed to discriminate outcomes in responding patients. Therefore, we randomized these patients into training and validation cohorts to investigate whether 3D tumor volumetry could improve outcome prediction. We identified a 3D tumor volume reduction of ≥97% as the optimal threshold for risk stratification (=3D early response, 3D&#95;ER). Applied to the validation cohort, patients achieving 3D&#95;ER had significantly superior outcomes. In multivariate analyses, 3D&#95;ER was independently prognostic of PFS and OS. Finally, we leveraged prognostic information from 3D MRI features and circulating biomarkers to build a composite metric that further improved outcome prediction in CNSL., Conclusions: We developed semi-automated 3D tumor volume measurements as strong and independent early predictors of clinical outcomes in CNSL patients. These radiologic features could help improve risk stratification and help guide future treatment approaches., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)