International Journal of Radiation Oncology Biology Physics最新文献

{"title":"A Prospective Interventional Clinical Trial (MC1732): Characterization of Thoracic Chemoradiotherapy-Related Cardiac Changes Using an Implantable Cardiac Monitor (ICM)","authors":"","doi":"10.1016/j.ijrobp.2024.07.024","DOIUrl":"10.1016/j.ijrobp.2024.07.024","url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>Real-time cardiac side effects due to thoracic radiotherapy (RT) have never been previously characterized in patients (pts) with lung and esophageal cancers. We specifically designed and completed a prospective clinical trial to address this.</div></div><div><h3>Materials/Methods</h3><div>A planned cohort of 24 pts were accrued from Dec 2019 to Jan 2023. Two (8%) pts withdrew their consent prior to ICM insertion. All pts met eligibility criteria, which included ≥ 18 years; non-metastatic, <em>de novo</em> lung or esophageal cancer diagnosis; receiving standard-of-care curative RT or chemoRT with an anticipated heart dose V40 Gy ≥ 20 cc; and planned RT dose ≥ 40 Gy. Pts with <em>any</em> prior RT to the heart were excluded. The ICM provided continuous outpatient arrhythmia monitoring (24/7), and all cardiac rhythms were captured prior to RT, and 4 weeks, 3, 9, and 12 months after RT. The ICM was explanted at 12-month follow-up. The ICM automatically captured and alerted clinicians to the following cardiac events: bradycardia ≤ 40 bpm; asystole with pauses ≥ 3 seconds (s); high degree AV block ≤ 30 bpm lasting ≥ 8 seconds; symptomatic tachycardia ≥ 150 bpm for any duration; and atrial fibrillation. Clinical events such as heart failure were also recorded. The primary endpoint was pts’ 12-month cardiac event rate (both clinically and by ICM) after RT completion. Clopper-Pearson confidence intervals were used in the analysis.</div></div><div><h3>Results</h3><div>The final analysis included all 22 pts. Average age was 67 years; 13 pts were male. Eighteen pts finished 12-mo follow-up per protocol, 1 died during treatment, and 3 died during follow-up. At baseline, 4 (19%) reported arrhythmia, 2 (10%) had coronary artery disease, and 1 (5%) with prior myocardial infarction; 15 (68%) were past smokers. Seventeen (77%) received proton beam therapy, and 5 (23%) received photon therapy. The median RT dose was 50 Gy in 2 Gy/fraction. RT was interrupted in 2 (9%) pts, due to needing an ablation for atrial flutter and hospitalization. Cardiac changes as defined in the study were seen in 15 (68%) pts. ICMs detected events in 14 (64%) pts: 10 with atrial arrhythmias (fibrillation/flutter), 2 transient asystoles, 1 non-sustained ventricular tachycardia, and 1 paroxysmal 3rd degree AV block. These events led to 4 interventions including 2 atrial ablations, 1 pacemaker insertion, 1 aortic valve replacement (18% of pts, 95% CI = 5-40%).</div></div><div><h3>Conclusion</h3><div>With real-time cardiac monitoring, cardiac events were detected in 64% of pts within 12 months post-RT, leading to timely medical diagnoses and interventions, with potentially improved outcomes. This novel prospective data highlighted the possible benefits of close cardiac surveillance. Further prospective studies are warranted to study the broad impact of ICM-based cardiac evaluation in better characterizing the intricate effects of thoracic RT on the hear","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Examining the Impact of Combined P53 Status and PD-L1 Expression on Vulvar Cancer Outcomes","authors":"","doi":"10.1016/j.ijrobp.2024.07.043","DOIUrl":"10.1016/j.ijrobp.2024.07.043","url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>Vulvar cancer (VC) has a heterogeneous microenvironment with complex cellular and molecular interactions, which poses a challenge to predict clinical outcomes. VC is commonly known to associated with 2 pathways: HPV dependent, and independent pathway. Little is known about the combined impact of p53 and PD-L1 expression on VC prognosis. We aimed to examine the combined impact of p53 status and PD-L1 expression on treatment outcomes for vulvar cancer.</div></div><div><h3>Materials/Methods</h3><div>A single institutional retrospective study of 90 VC patients treated from 2010 to 2021 was conducted. P53 status was evaluated for wild-type (p53wt) versus aberrant (p53a) by immunohistochemical (IHC) expression. Positive PD-L1 status (PD-L1+) was defined as a Combined Positive score of ≥ 1. The VCs were classified into a 4-category scheme based on PD-L1 and p53 status (PD-L1/p53): PD-L1+/p53a; PD-L1+/p53wt; PD-L1-/p53a; and PD-L1-/p53wt. Associations with outcomes including overall survival (OS), disease-free survival (DFS), local control (LC), and regional control (RC) were assessed via log-rank tests and multivariable Cox regression analyses.</div></div><div><h3>Results</h3><div>The median age was 72 years (IOR = 62–80 years). Most cases (<em>n</em> = 88) were squamous cell carcinoma, 48% of FIGO I-II, 35% were positive for p16, and close to half (44%) were PD-L1+/p53a (see Table 1). Most (74%) received as initial treatment surgery± postoperative radio± chemotherapy (S+POT), versus 26% received upfront definitive chemoradiotherapy (DCRT). Median follow-up: 38 months (IQR = 17–66). The p53a VC showed a statistically significantly worse 5-yr OS (45%, 95 CI = 27–63) than the p53wt VCs (85%, 95 CI = 72–97, <em>P</em> = 0.01) as with DFS, LC, and RC. We observed a significant difference in 5yr OS when patients were stratified by initial treatments received (Table 1) and with 5-yr DFS, and RC as outcomes of measures. On multivariable analysis, PD-L1-/p53a status was associated with worse OS (HR = 3.6, 95% CI = 1.1–11.3) after controlling for p16 status, age, FIGO stage, and other clinicopathologic factors. Other PD-L1/p53 status groups were not found to be independent predictors of clinical outcomes.</div></div><div><h3>Conclusion</h3><div>These results suggest that PD-L1-/p53a VCs as a subtype are prognostic for worse OS. This classification suggests the complex interaction between p53 and PD-L1 and the potential prognostic significance for oncological outcomes. The PD-L1/p53 classification could help risk-stratify VCs in routine practice and potentially guide personalized therapy.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MORF4L1-Mediated DNA Damage Repair Modulates cGAS-STING Activation and Radiosensitivity in Hepatocellular Carcinoma","authors":"","doi":"10.1016/j.ijrobp.2024.07.037","DOIUrl":"10.1016/j.ijrobp.2024.07.037","url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with poor prognosis. Radiotherapy (RT) is one of the main treatments for patients with unresectable HCC, but its efficacy has been limited due to inherent or acquired radiation resistance. However, the regulatory mechanisms of radiation resistance in HCC remain unclear.</div></div><div><h3>Materials/Methods</h3><div>Key DDR genes in HCC were identified by single-cell RNA sequencing (GSE149614). In vitro experiments confirmed that the expression level of MORF4L1 regulates DNA damage repair and susceptibility to radiotherapy of HCC cells. Immunoprecipitation-mass spectrometry was used to explore the core mechanism of MORF4L1 mediating DNA damage repair. Mechanisms of MORF4L1 antagonist combined with radiotherapy to enhance anti-tumor immune response was demonstrated by in vitro cell co-culture model, small molecule inhibitor and genetically engineered mice.</div></div><div><h3>Results</h3><div>In this study, MORF4L1 was identified as a key DDR gene in HCC by single-cell RNA sequencing (GSE149614). High expression of MORF4L1 mediates poor prognosis and poor RT efficacy in patients with HCC. The expression level of MORF4L1 regulates DNA damage repair and susceptibility to radiation therapy in liver cancer cells. Mechanistically, MORF4L1 mediates acetylation of histone H3 at lysine 4 to promote DNA damage repair. Knocking out MORF4L1 or inhibiting histone acetylation reduced recruitment of PALB2, BRCA2, and RAD51 at sites of DNA damage. Using in vitro cell co-culture models and genetically engineered mice, we demonstrated that the FDA-approved drug argatroban (MORF4L1 antagonist) combined with RT can enhance the anti-tumor immune response by activating the cGAS-STING signaling pathway.</div></div><div><h3>Conclusion</h3><div>This work highlights the mechanism of MORF4L1 as a key gene in HCC DNA damage repair. RT combined with argatroban enhances anti-tumor immune response by activating cGAS-STING signaling pathway, providing new insights for improving the efficacy of RT for HCC.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP15 and Radiation-Induced DNA Damage Repair of Intestinal Epithelial Cells by Deubiquitinating and Stabilizing ATM","authors":"","doi":"10.1016/j.ijrobp.2024.07.042","DOIUrl":"10.1016/j.ijrobp.2024.07.042","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Purpose/Objective(s)&lt;/h3&gt;&lt;div&gt;The intestine is vulnerable to structural and functional damage caused by exposure to radiation. Unfortunately, there is currently no effective prophylactic or therapeutic strategy available to mitigate radiation-induced intestinal injury (RIII). Deubiquitinating enzymes (DUBs) play a crucial role in repairing DNA breaks. Therefore, we conducted a new study on the pathogenesis of RIII by examining the role of DUBs, in order to identify potential directions for therapeutic or preventive measures in this area.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Materials/Methods&lt;/h3&gt;&lt;div&gt;The effects of 14 Gy whole abdominal irradiation (WAI) on DUB levels in the intestine of C57BL/6J mice were investigated by RNA-seq analysis. In vivo and in vitro experiments were conducted using the ubiquitin-specific proteases 15 (USP15) inhibitor (USP15-IN-1). The impact of USP15 on the radiosensitization of HIEC-6 cells was observed. The survival and body weight of mice in each irradiated group were recorded, and the severity of radiation-induced intestinal injury (RIII) was evaluated through HE staining, immunohistochemistry (IHC), and the TUNEL method. USP15-bound proteins were identified and validated through mass spectrometry analysis. The role of USP15 in ataxia-telangiectasia mutated (ATM) deubiquitination and stability was determined by constructing a USP15 mutant (C298A). Finally, the potential reversal of USP15 knockdown’s promotional effects on radiosensitizing effect in HIEC-6 cells by ATM was investigated.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;USP15 is one of the top 20 highly expressed genes in the intestinal tissue of mice after exposure to 14Gy of WAI. Inhibition of USP15 resulted in increased radiosensitivity of HIEC-6 cells, as evidenced by a decrease in colony-forming ability and an increase in the formation of micronuclei and apoptotic cells, as well as an increase in 8-OHdG fluorescence intensity. Comet assay and γ-H2AX staining revealed more DNA damage in irradiated HIEC-6 cells treated with USP15-IN-1. In vivo, USP15 was found to modulate apoptosis and DNA damage in the small intestine of mice exposed to WBI. Mass spectrometry analysis showed that USP15 interacts with the protein kinase ATM, a key regulator of DNA double-strand break (DSB) signaling and stress response. By creating a mutant form of USP15(C298A), it was discovered that USP15 directly interacts with ATM, independent of its DUB activity, and can regulate the stability of ATM protein. Furthermore, USP15 was found to specifically disassemble K48-linked polyubiquitination of ATM but had no significant effect on monoubiquitination or other types of polyubiquitination. The radiosensitizing effect produced by knockdown of USP15 in HIEC-6 cells can be reversed by ATM.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Our findings demonstrate that USP15 plays a crucial role in repairing radiation damage in intestinal epithelial cells by counteracting ATM ubiquitination and degradation, w","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Moderated Hypofractionated Online Adaptive Radiotherapy in Locally Advanced Cervical Cancer: A Prospective 1 Clinical Trial","authors":"","doi":"10.1016/j.ijrobp.2024.07.014","DOIUrl":"10.1016/j.ijrobp.2024.07.014","url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>To assess the safety and efficacy of moderated hypofractionated online adaptive radiotherapy (oART) in combination with high-dose-rate (HDR) brachytherapy in patients with locally advanced cervical cancer (LACC).</div></div><div><h3>Materials/Methods</h3><div>Patients with histologically confirmed LACC were enrolled in a prospective, regulatory-approved phase 1 trial (NCT05994300). Participants received daily oART via intensity-modulated radiation therapy with 43.35 Gy in 17 fractions to the whole pelvis and a simultaneous integrated boost of 54.40 Gy in 17 fractions to gross lymph nodes. Clinical target volumes were contoured separately with 5-10mm margins. HDR brachytherapy began after external beam radiation therapy (EBRT). Concurrent weekly cisplatin chemotherapy was administered to all participants. Treatment response was evaluated approximately one month after treatment was complete. Toxicity was graded using CTCAE version 5.0, while the EORTC-QLQ-C30 questionnaire evaluated quality of life, and urinary and bowel symptoms were accessed according to the EORTC-QLQ-CX24.</div></div><div><h3>Results</h3><div>A total of 26 patients have completed treatment with moderated hypofractionated oART and HDR brachytherapy. All patients (100%) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging and computed tomography. Acute gastrointestinal toxicity was Grade 1 or Grade 2 in 15 patients and Grade 3 severity in 3 patients; all Grade 3 toxicities resolved within one week. Acute genitourinary toxicity of Grade 1 or Grade 2 was seen in 8 patients, and no patients had Grade 3 toxicity. Grade 3 acute hematologic toxicity was observed in 9 patients. The mean duration of EBRT was 23 days (ranging from 22 to 28 days). Quality of life and urinary and bowel scores during follow-up were comparable to baseline levels.</div></div><div><h3>Conclusion</h3><div>Moderated hypofractionated oART with HDR brachytherapy appears to be a very promising treatment in LACC, leading to high response rates and limited side effects. Longer follow-up is needed to assess the duration of response. The treatment time of EBRT was shortened compared with conventional therapy.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142359558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tribute to May Abdel-Wahab","authors":"","doi":"10.1016/j.ijrobp.2024.06.023","DOIUrl":"10.1016/j.ijrobp.2024.06.023","url":null,"abstract":"","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Initial Clinical Experience of Cherenkov Imaging in Sub-Total Total Skin Electron Therapy Identifies Opportunities to Improve Daily Set-Up QA","authors":"","doi":"10.1016/j.ijrobp.2024.07.019","DOIUrl":"10.1016/j.ijrobp.2024.07.019","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Purpose/Objective(s)&lt;/h3&gt;&lt;div&gt;Total skin electron therapy (TSET) is a prevalent treatment modality for patients with cutaneous T-cell lymphomas. However, patient-specific QA measures for these TSET patients are lacking. Unlike isocentric treatments, there are no prior CT scans to utilize for planning, nor are there automated motion-management systems in place to ensure consistent and accurate patient positioning from day-to-day and while the patient is standing for treatment. To add additional variability, sub-total skin electron therapy patient treatments are commonly performed without treatment planning systems available to simulate and verify field edges.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Materials/Methods&lt;/h3&gt;&lt;div&gt;To address this unmet need for patient-specific QA, we deployed a clinical Cherenkov imaging system which utilizes three cameras to capture the Cherenkov emission on the patient’s skin surface from one frontal and two lateral directions. There were 52 TSET subjects enrolled under an ongoing IRB-approved clinical Cherenkov imaging study. Amongst the 52 enrolled subjects, 7 patients were withdrawn, 7 subjects were repeat study enrollments, imaged in two separate TSET study cases, and 24 of 52 (46%) treatments were sub-total skin electron therapy cases. All 52 TSET Cherenkov study cases were manually examined to identify potential clinically relevant differences between the planned vs. observed treatment fields within the standard Stanford 6-position treatment scheme.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Among the 52 Cherenkov TSET cases examined, two cases exhibited reduced dose to the upper extremities due to partial blocking, and one case saw increased dose in the subject’s left arm due to patient movement during treatment delivery. In four cases involving head blocking in the posteroanterior (PA) position, the subjects’ forearms were suboptimally aligned, parallel to the beam, rather than perpendicular to it. These specific observations were corroborated by Monte Carlo simulations, which also found reduced dose in a patient’s forearm region after accumulating skin dose from all 6 positions. Lastly, in one subject, Cherenkov imaging detected suboptimal hand positioning in the right anterior oblique (RAO) position, which was subsequently corrected for in the left anterior oblique (LAO) position. Notably, all instances of dose discrepancies or suboptimal patient positions occurred in cases with partial body blocking planned as part of the treatment, i.e. sub-total skin electron therapy.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;When blocking is clinically indicated, modifications to the standard Stanford 6-position treatment are often required. As shown in this analysis, these modifications may increase the difference in planned vs. delivered dose to specific blocked or unblocked anatomic regions. To address these challenges, Cherenkov imaging represents a highly useful record-and-verify tool for ensuring proper patient positioning and field","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Honorary Member Thevenot Tribute","authors":"","doi":"10.1016/j.ijrobp.2024.06.026","DOIUrl":"10.1016/j.ijrobp.2024.06.026","url":null,"abstract":"","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Longitudinal Study to Correlate Neurocognitive Changes of IDH-Mutant and IDH-Wildtype Glioma Patients after Chemoradiotherapy with Changes on Resting-State MRI","authors":"","doi":"10.1016/j.ijrobp.2024.07.059","DOIUrl":"10.1016/j.ijrobp.2024.07.059","url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>This prospective observational study investigates mechanisms behind neurocognitive function (NCF) decline after partial-brain irradiation in malignant glioma patients. We aim to use resting-state functional MRI (RS-fMRI) to identify the dominant network-level disturbances post-radiation therapy (RT) that correlate with NCF changes.</div></div><div><h3>Materials/Methods</h3><div>Adult patients with IDH-wildtype or IDH-mutant gliomas underwent NCF test using the NIH Toolbox Cognitive Function Battery at baseline and 6 months post RT. The battery includes fluid cognition tests: dimension change card sort test (executive function), flanker test (attention), picture sequence test (episodic memory), list sorting test (working memory), and pattern comparison test (processing speed). The five test scores were then combined into an age-normalized composite score, from which the percent change of composite (PCC) was calculated relative to the baseline. To determine a potential correlation between NCF and changes in brain functional connectivity (FC), we used seed-based FC analysis from a 12-minute RS-fMRI scan. A split-sample approach was used for analysis, with a 26-patient training set and a 6-patient validation set, iterated 200 times. Within each run, connectivity-regression analysis within the training set was first used to identify which intra- or inter-network FC change was most significantly associated with PCC, and a linear regression was used to predict FC change of the selected networks using the validation set. Permutation test was used to evaluate the significance of network selection, and R² value was used to evaluate the predictive performance.</div></div><div><h3>Results</h3><div>From September 2020 to December 2023, there were 43 patients who had baseline data, while 32 patients completed 6-month follow-ups and were evaluable. The mean NCF composite changed from 88.8 (±16.2) at baseline to 91.1 (±19.4) at 6 months. The mean PCC was 2.9 (±13.7), including 12 patients with negative PCC (Decline cohort) and 20 patients with positive PCC (Non-decline cohort). The clinical, treatment, and dosimetric characteristics between two cohorts were not significantly different among 24 variables examined. The mean R2 was 0.36 (±0.27). The most significant correlations with PCC were consistently observed in the inter-network FC changes between Default Mode Network to Medial Temporal Lobe (DMN-MTL, <em>P</em> = 0.005) and Parietal Memory Network to MTL (PMN-MTL, <em>P</em> = 0.02). Sensitivity analyses using only FC maps from the contra-lateral side of the tumor confirmed the same finding.</div></div><div><h3>Conclusion</h3><div>RS-fMRI changes post RT correlated with NCF decline, suggesting its potential as an imaging biomarker. Specifically, disruption of inter-network FC between DMN-MTL and PMN-MTL may be key mechanism underlying RT-induced NCF decline, warranting further investigation.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142359157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety Profile of Durvalumab (D) as Consolidation Treatment (tx) in Limited-Stage Small-Cell Lung Cancer (LS-SCLC) in ADRIATIC: Focus on Pneumonitis and Immune-Mediated Adverse Events (imAEs)","authors":"","doi":"10.1016/j.ijrobp.2024.08.024","DOIUrl":"10.1016/j.ijrobp.2024.08.024","url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>In the phase 3 ADRIATIC study (NCT03703297) in patients (pts) with LS-SCLC without progression after concurrent chemoradiotherapy (cCRT), D as consolidation tx significantly improved OS and PFS vs placebo (P) at the first planned interim analysis. D was well tolerated and AEs were consistent with the known safety profile. Here we present pneumonitis/radiation pneumonitis and imAEs.</div></div><div><h3>Materials/Methods</h3><div>530 eligible pts with stage I–III LS-SCLC (stage I/II inoperable), WHO PS 0/1, and no progression after cCRT, were randomized 1–42 days after cCRT to D 1500 mg or P every 4 weeks until investigator-determined progression or intolerable toxicity, or for a maximum of 24 months. Safety was a secondary endpoint. Given the similar clinical presentation of pneumonitis resulting from prior RT (radiation pneumonitis) or immunotherapy (immune-mediated pneumonitis), these events were analyzed as a grouped term to better estimate their frequency. imAEs were also assessed.</div></div><div><h3>Results</h3><div>262 pts received D and 265 received P. Pneumonitis/radiation pneumonitis (preferred terms of immune-mediated lung disease, interstitial lung disease, pneumonitis, radiation fibrosis–lung, and radiation pneumonitis) occurred in 38% (n=100) vs 30% (n=80) of pts in the D vs P arm (maximum grade 3/4 3% vs 3%; grade 5 0.4% vs 0%; leading to tx discontinuation 9% vs 3%). Median time from first study drug dose to onset (mTTO) of pneumonitis/radiation pneumonitis was 56 days (range 1–594) vs 56 days (2–228) in the D vs P arm; 40/100 events in the D arm and 23/80 in the P arm had resolved at data cutoff (Jan 15, 2024). imAEs occurred in 32% vs 10% of pts in the D vs P arm (maximum grade 3/4 5% vs 2%; grade 5 0.4% vs 0%; leading to tx discontinuation 7% vs 3%). 14% vs 6% of pts in the D vs P arms received high-dose steroids and 1% vs 0.4% received immunosuppressants to manage imAEs. The table shows mTTO, resolution, and median time to resolution (mTTR) for the most common imAEs.</div></div><div><h3>Conclusion</h3><div>In ADRIATIC, pneumonitis/radiation pneumonitis was common in both arms in this population who had received prior RT, and imAEs were as expected in the D arm; these events were mainly low grade and led to low rates of tx discontinuation, supporting the favorable benefit-risk profile for consolidation D after cCRT in LS-SCLC.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}