Radiation Survival Research Articles

Cytotoxic and Radiosensitizing Effects of European and African Propolis in 3D Lung Carcinoma Cell Cultures.

Natural compounds such as propolis have gained wide popularity in the last decades. While its antibacterial, antiviral, and antifungal properties are well known, the anticancer properties of propolis are just beginning to be appreciated. Herein, we comparatively investigate the cytotoxic and radiosensitizing potential of four different ethanolic propolis extracts originating from three different countries (Germany, Ireland, South Africa) in human lung cancer cell models. Liquid chromatography-mass spectrometry (LC-MS/MS) was applied to characterize the four different propolis extracts. Cytotoxicity and radiation survival were determined by 3D matrix-based clonogenic assays and autophagy was examined by western blotting. We found cytotoxicity in a propolis type-, time- and cell model- dependent manner. In the four ethanolic propolis extracts, Coumaric acid, Caffeic acid phenethyl ester, Pinocembrin and Chrysin presented the major compounds identified. Examining the induction of autophagy using the marker LC3B and autophagy inhibition with chloroquine suggested autophagy to be part of the survival mechanisms upon propolis treatment in a cell model-dependent manner. Combining propolis with X-ray irradiation showed the radiosensitizing potential of propolis in human lung cancer cell models, which clearly presented in a manner dependent on the incubation time of propolis and the cell model treated. Propolis treatment showed cytotoxic and radiosensitizing effects of propolis on human lung cancer cells. Since these effects differ greatly between the four propolis extracts studied and originating from different regions, further studies are urgently needed to differentiate propolis species and their anticancer properties in more detail.

MICROBIOME AND INFLAMMASOME ALTERATIONS FOUND DURING RADIATION DOSE FINDING IN A SINCLAIR MINIPIG MODEL OF GASTROINTESTINAL ACUTE RADIATION SYNDROME.

Both abdominal radiotherapy and a nuclear event can result in gastrointestinal symptoms, including acute radiation syndrome (GI-ARS). GI-ARS is characterized by compromised intestinal barrier integrity increasing the risk for infectious complications. Physiologically relevant animal models are crucial for elucidating host responses and therapeutic targets. We aimed to determine the radiation dose requirements for creating GI-ARS in the Sinclair minipig. Male, sexually mature swine were randomly divided into sham (n = 6) and three lower hemibody radiation dosage groups of 8, 10, and 12 Gy (n = 5/group) delivered using linear accelerator-derived x-rays (1.9 Gy/min). Animals were monitored for GI-ARS symptoms for 14 days with rectal swab and blood collection at days 0-3, 7, 10, and 14 followed by necropsy for western blotting and histology. Dose-dependent increases in weight loss, diarrhea severity, and mortality (log-rank test, P = 0.041) were seen. Villi length was significantly reduced in all irradiated animals compared to controls ( P < 0.001). Serum citrulline decreased and bacterial translocation increased after irradiation compared to controls. Increased NLRP3 levels in post-mortem jejunum were seen ( P = 0.0043) as well as increased IL-1β levels in the 12 Gy group ( P = 0.041). Radiation dose and survival were associated with significant gut microbial community shifts in beta diversity. Moreover, decedents had increased Porphyromonas, Campylobacter, Bacteroides , Parvimonas , and decreased Fusobacterium and decreased Aerococcus, Lactobacillus, Prevotella, and Streptococcus . Our novel Sinclair minipig model showed dose-dependent clinical symptoms of GI-ARS. These findings provide invaluable insights into the intricate interplay between GI-ARS, intestinal inflammation, and gut microbiota alterations offering potential targets for therapeutic and diagnostic interventions after radiation exposure.

Prognostic nomogram of overall survival for radiation therapy in hepatocellular carcinoma: a population study based on the SEER database and an external cohort.

Radiotherapy (RT) plays an important role in the treatment of hepatocellular carcinoma (HCC). To screen patients who benefit most from RT, a nomogram for survival prediction of RT based on a large sample of patients with HCC was created and validated. A total of 2,252 cases collected from the Surveillance, Epidemiology, and End Results (SEER) database were separated into a training or an internal validation cohort in a 7:3 ratio (n = 1,565:650). An external validation cohort of cases from our institute was obtained (n = 403). LASSO regression and Cox analyses were adopted to develop a nomogram for survival prediction. The decision curve analysis (DCA), calibration curve, and time-dependent receiver operating characteristic curves (TROCs) demonstrated the reliability of the predictive model. For patients with HCC who received RT, the analyses revealed that the independent survival prediction factors were T stage {T2 vs. T1, hazard ratio (HR) =1.452 [95% CI, 1.195-1.765], p < 0.001; T3 vs. T1, HR = 1.469 [95% CI, 1.168-1.846], p < 0.001; T4 vs. T1, HR = 1.291 [95% CI, 0.951-1.754], p = 0.101}, N stage (HR = 1.555 [95% CI, 1.338-1.805], p < 0.001), M stage (HR = 3.007 [95% CI, 2.645-3.418], p < 0.001), max tumor size (>2 and ≤5 vs. ≤2 cm, HR = 1.273 [95% CI, 0.992-1.633], p = 0.057; >5 and ≤10 vs. ≤2 cm, HR = 1.625 [95% CI, 1.246-2.118], p < 0.001; >10 vs. ≤2 cm, HR = 1.784 [95% CI, 1.335-2.385], p < 0.001), major vascular invasion (MVI) (HR = 1.454 [95% CI, 1.028-2.057], p = 0.034), alpha fetoprotein (AFP) (HR = 1.573 [95% CI, 1.315-1.882], p < 0.001), and chemotherapy (HR = 0.511 [95% CI, 0.454-0.576], p < 0.001). A nomogram constructed with these prognostic factors demonstrated outstanding predictive accuracy. The area under the curve (AUC) in the training cohort for predicting overall survival (OS) at 6, 12, 18, and 24 months was 0.824 (95% CI, 0.803-0.846), 0.824 (95% CI, 0.802-0.845), 0.816 (95% CI, 0.792-0.840), and 0.820 (95% CI, 0.794-0.846), respectively. The AUCs were similar in the other two cohorts. The DCA and calibration curve demonstrated the reliability of the predictive model. For patients who have been treated with RT, a nomogram constructed with T stage, N stage, M stage, tumor size, MVI, AFP, and chemotherapy has good survival prediction ability.

Fluorescence capturing behaviour of cyanobacterial resilience: Insights into UV-exposed ecosystems and its environmental applications.

Cyanobacteria are resilient microorganisms and thrive in environments exposed to UV radiation, ranging from ocean surfaces to scorching hot springs and dry expanses. 'Cyanobacterial Resilience' refers to their ability to withstand UV radiation, revealing intricate genomic secrets and adaptive mechanisms ensuring survival. These mechanisms include metabolic adaptations, robust DNA repair systems and UV-protective compounds such as Scytonemin and Mycosporine, vital for shielding against UV radiation survival. Cyanobacteria are crucial pioneers in UV-exposed ecosystems, highlighting their resilience and adaptability. Some cyanobacteria exhibit luminescence, emitting blue-green light due to phycobiliproteins, while bioluminescence in cyanobacteria, if it occurs, involves different compounds rather than luciferins and luciferase enzymes. This luminescence holds promise for various biotechnological applications, such as biosensors, imaging probes and carbon sequestration, for participating in photocatalytic processes for water purification and CO2 conversion, and contributes to solar simulation studies to advance photosynthesis and renewable energy technologies. The versatile applications of these materials highlight their ecological importance and potential in addressing global challenges. In conclusion, 'Cyanobacterial Resilience' highlights the remarkable adaptation strategies of cyanobacteria in UV-exposed environments. It emphasises their role as pioneers and innovators in biological and technological domains, providing insights into their enduring impact on ecosystems and scientific advancement.

The structural complexity of pyomelanin impacts UV shielding in Pseudomonas species with different lifestyles.

Pyomelanin, a polymeric pigment in Pseudomonas, arises mainly from alterations in tyrosine degradation. The chemical structure of pyomelanin remains elusive due to its heterogeneous nature. Here, we report strain-specific differences in pyomelanin structural features across Pseudomonas using PAO1 and PA14 reference strains carrying mutations in hmgA (a gene involved in pyomelanin synthesis), a melanogenic P. aeruginosa clinical isolate (PAM), and a melanogenic P. extremaustralis (PexM). UV spectra showed dual peaks for PAO1 and PA14 mutants and single peaks for PAM and PexM. FTIR phenol : alcohol ratio changes and complex NMR spectra indicated non-linear polymers. UVC radiation survival increased with pyomelanin addition, correlating with pigment absorption attenuation. P. extremaustralis UVC survival varied with melanin source, with PAO1 pyomelanin being the most protective. These findings delineate structure-based pyomelanin subgroups, having distinct physiological effects.

Myoferlin: A Potential Marker of Response to Radiation Therapy and Survival in Locally Advanced Rectal Cancer

PurposePatients with locally advanced rectal cancer often require neo-adjuvant chemoradiotherapy to downstage the disease, but the response is variable with no predictive biomarkers. We have previously revealed through proteomic profiling that myoferlin is associated with response to radiotherapy. The aims of this study were to further validate this finding and explore the potential for myoferlin to act as a prognostic and/or therapeutic target. Materials and MethodsImmunohistochemical analysis of a tissue microarray for 111 patients was used to validate the initial proteomic findings. Manipulation of myoferlin was achieved using siRNA, a small molecular inhibitor (wj460) and a CRISPR-Cas9 knockout cell line. Radiosensitisation following treatment was assessed using 2D clonogenic assays, 3D spheroid models and patient derived organoids. Underlying mechanisms were investigated using electrophoresis, immunofluorescence and immunoblotting. ResultsAnalysis of both the diagnostic biopsy and tumour resection samples confirmed that low myoferlin expression correlated with a good response to neoadjuvant LCRT. High myoferlin expression was associated with spread to local lymph nodes and worse 5-year survival (p = 0.01, HR 3.5, 95%CI [1.27, 10.04]). This was externally validated using the S:CORT database. Quantification of myoferlin using immunoblotting in immortalised colorectal cancer cell lines and organoids demonstrated that high myoferlin expression was associated with increased radioresistance. Biological and pharmacological manipulation of myoferlin resulted in significantly increased radiosensitivity across all cell lines in 2D and 3D models. Following irradiation, myoferlin knockdown cells had a significantly impaired ability to repair DNA double strand breaks. This appeared to be mediated via non-homologous end-joining. ConclusionsWe have confirmed that high expression of myoferlin in rectal cancer is associated with poor response to neoadjuvant therapy and worse long-term survival. Furthermore, the manipulation of myoferlin led to increased radiosensitivity in vitro. This suggests that myoferlin could be targeted to enhance the sensitivity of rectal cancer patients to radiotherapy and further work is required.

Abstract PO1-22-05: Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis

Abstract Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis Rayan Bensenane1 MD, Arnaud Beddok1,2,3 MD, Nadine Andrieu4 PhD, Fabienne Lesueur4 PhD, Eve Cavaciuti 4 MSc, Dorothee Le Gal4 MSc, Eon-Marchais Severine4 PhD, Dominique Stoppa Lyonnet 5MD PhD, Youlia Kirova1 MD 1. Institut Curie, PSL Research University, Radiation Oncology Department, Paris/Saint-Cloud/Orsay, France. 2. Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, 125 Nashua St., Boston, MA, 02114, USA 3. Institut Curie, PSL Research University, University Paris Saclay, Inserm LITO U1288 Orsay, France 4. Inserm, U900, Institut Curie, PSL Research University, Mines ParisTech, Paris, France Abstract (characters: 2952; max 3400 characters, not include spaces) Background: The Ataxia-Telangiectasia Mutated (ATM) gene, involved in the repair of DNA double-strand breaks, can contribute to radiosensitivity when a bi-allelic variant is present and lead to Ataxia-Telangiectasia syndrome. Moreover, monoallelic ATM pathologic variant (PV) carriers, especially women, has an estimated occurrence rate of 0.5-1% globally and face a 2 to 3-fold increased risk of developing breast cancer. Despite evidence of in vitro radiosensitivity in cells derived from monoallelic variant carriers, there is a dearth of patient studies examining the risk of radiation-induced toxicity. This study aims to explore radiation therapy (RT) toxicities in non-metastatic breast cancer women carrying a germline monoallelic ATM variant, compared to non-carriers. Methods: A retrospective study was conducted on patients treated at Institut Curie, Paris from 1999 to 2014 and participating to CoF-AT (a French national study) and GENESIS database. ATM variant screenings encompassed both PV and non-PV, with toxicities evaluated using CTCAE v.5. Variants were classified as pathogenic, variant of unknown significance (VUS), or benign. Follow-up started from age/date at breast cancer to acute, late toxicities, disease recurrence or last news. Survival and toxicity comparisons were made using Kaplan-Meier survival analysis and Chi-square tests, respectively, with a significance level of α set at 0.05. Results: Among 50 patients, nine were ATM variant carriers (3 PV/5 VUS/1 benign), and 41 were non-carriers. Most patients had no smoking history (68%), and invasive ductal carcinoma was the predominant diagnosis (82%). The majority underwent breast-conservative surgery (80%), and the dominant RT techniques were 3D-Conformational Radiation Therapy (70%) and Isocentric Lateral Decubitus (30%). The median RT dose was 50 Gy over an average period of 36.5 days. With a median follow-up of 12 years post-diagnosis, no significant difference in acute dermatitis, esophagitis, lymphedema, cutaneous fibrosis, telangiectasia, or heart disease was observed between the groups. Analysis of overall survival (OS) showed a 5-year OS of 98%, decreasing to 89% at 10 years. For ATM variant carriers, the OS at 5, 10, and 15 years was 100%, 89%, and 89%, respectively, similar to non-carriers. Kaplan-Meier analysis revealed no significant differences in 5, 10, and 15-year overall survival, progression-free survival, local failure-specific survival, and contralateral breast cancer rates between the groups. Conclusion: In non-metastatic breast cancer patients, monoallelic ATM variant carrier status does not significantly influence acute or late RT toxicities and survival outcomes. These findings, derived from a small cohort, highlight the need for prospective studies for further validation. Table: Acute and Late Toxicities Post-Radiation Therapy in Monoallelic ATM Variant Carriers vs Non-Carriers * Pearson/Chi2 test ; NS: non significant at α=0.05; ATM +/+: wild type for ATM; ATM +/- : ATM monoallelic germline variant carrier Citation Format: Rayan BENSENANE, Youlia Kirova, Arnaud BEDDOK, Andine ANDRIEU, Fabienne Lesueur, Eve CAVACIUTI, Dorothée Le GAL, Severine EON-MARCHAIS, Dominique STOPPA LYONNET. Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-22-05.

Abstract 2872: GLUT3 promotes metabolic plasticity that drives radiation resistance in glioblastoma

Abstract Glioblastomas (GBM) are the most common and malignant brain tumors in adults. While radiation therapy (RT) offers a significant advantage for GBM patients, improving long-term survival remains elusive largely due to the remarkable resistant nature of these tumors. We have shown that metabolic plasticity, especially rewiring of glucose metabolism, promotes radiation survival in GBM. In this study, we investigate the role of glucose transporter 3 (GLUT3) translocation to the cell surface in radiation resistance of GBM. The effect of radiation on GLUT3 total protein levels was determined in patient-derived gliomaspheres via westerns blots, while cellular localization of GLUT3 was determined via immunofluorescence, flow cytometry and cell fractionation assays. The role of the AMPK and αvβ3 integrin in the radiation-induced GLUT3 translocation to the cell membrane was probed via small molecule inhibitors and activators. To determine the role of GLUT3 in radiation survival, GLUT3 levels were knocked down via siRNA and shRNA, followed by functional in vitro and in vivo assays. We provide evidence that irradiated gliomaspheres translocate GLUT3 to the plasma membrane, in a radiation-induced oxidative stress-dependent manner, effectively increasing their glucose uptake and promoting radiation survival. Our data also suggest that GLUT3 translocation to the cell surface contributes to RT resistance. AMPK and αvβ3 integrin are linked to radiation-induced translocation of GLUT3 to the cell membrane, suggesting that targeting these pathways is a potential approach to sensitize GBM tumors to radiation therapy. Citation Format: Lobna Abdulrahman, Justine Bailleul, Hanna Hoang, Aaron Tang, Erina Vlashi. GLUT3 promotes metabolic plasticity that drives radiation resistance in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2872.

Compound Taxus exerts marked anti-tumor activity and radiosensitization effect on hepatocellular carcinoma cells

BackgroundCompound Taxus capsule, as an antineoplastic Chinese patent drug, has been increasingly applied as an adjunctive treatment for the management of non-small-cell lung cancer (NSCLC) and some other malignancies, but research about its antitumor activity and radiosensitization effect on hepatocellular carcinoma (HCC) cells is very rare. PurposeTo investigate the antitumor activity and radiosensitization effect of Compound Taxus on HCC cells and to preliminarily explore the possible molecule mechanisms involved. MethodsCell viability, cell cycle distribution, apoptosis, DNA damage repair and protein expression levels were detected by CCK-8 assay, flow cytometry, immunofluorescence staining, western blotting analysis and immunohistochemical staining, respectively. The migration and invasion activities and vasculogenic mimicry (VM) formation and angiogenesis were evaluated by tube formation and VM formation assay. Radiation survival curves were obtained from the colony formation assay in human HCC cell lines, Smmc7721 and Bel7402 cells, pretreated with or without Compound Taxus before receiving X-ray irradiation. A Bel7402 tumor-bearing mouse model was established and the radiosensitization effect of Compound Taxus in vivo was evaluated by analyzing tumor volume and tumor weight in different groups receiving different treatments. ResultsCompound Taxus decreased viability, induced G2/M arrest, promoted apoptosis, suppressed migration and invasion, and inhibited VM formation and angiogenesis in Smmc7721 and Bel7402 cells. Furthermore, Compound Taxus inhibited irradiation-induced DNA damage repair, enhanced the radiosensitivity of Smmc7721 and Bel7402 cells and improved the anti-tumor therapeutic efficacy of irradiation in Bel7402 tumor-bearing mice. Radiotherapy in combination with Compound Taxus showed the best tumor inhibition compared to that of Compound Taxus alone or irradiation alone. In addition, Compound Taxus significantly down-regulated NF-κB p65, p–NF–κB p65 and Bcl-2, and up-regulated Bax in vitro and in vivo, yet NF-κB p65 overexpression reversed the proapoptotic effect of Taxus on HCC cells, indicating that the NF-κB signaling pathway might be an important signal mediator in the Compound-Taxus-modulated biological responses. ConclusionOur findings suggest that Compound Taxus shows marked antitumor activity and significant radiosensitization effect on HCC cells, making it possible for Compound Taxus to become a promising auxiliary modality for HCC management and a potential radiosensitizer of HCC in the future.

Serum microRNA profile of rhesus macaques following ionizing radiation exposure and treatment with a medical countermeasure, Ex-Rad

Exposure to ionizing radiation (IR) presents a formidable clinical challenge. Total-body or significant partial-body exposure at a high dose and dose rate leads to acute radiation syndrome (ARS), the complex pathologic effects that arise following IR exposure over a short period of time. Early and accurate diagnosis of ARS is critical for assessing the exposure dose and determining the proper treatment. Serum microRNAs (miRNAs) may effectively predict the impact of irradiation and assess cell viability/senescence changes and inflammation. We used a nonhuman primate (NHP) model—rhesus macaques (Macaca mulatta)—to identify the serum miRNA landscape 96 h prior to and following 7.2 Gy total-body irradiation (TBI) at four timepoints: 24, 36, 48, and 96 h. To assess whether the miRNA profile reflects the therapeutic effect of a small molecule ON01210, commonly known as Ex-Rad, that has demonstrated radioprotective efficacy in a rodent model, we administered Ex-Rad at two different schedules of NHPs; either 36 and 48 h post-irradiation or 48 and 60 h post-irradiation. Results of this study corroborated our previous findings obtained using a qPCR array for several miRNAs and their modulation in response to irradiation: some miRNAs demonstrated a temporary increased serum concentration within the first 24–36 h (miR-375, miR-185-5p), whereas others displayed either a prolonged decline (miR-423-5p) or a long-term increase (miR-30a-5p, miR-27b-3p). In agreement with these time-dependent changes, hierarchical clustering of differentially expressed miRNAs showed that the profiles of the top six miRNA that most strongly correlated with radiation exposure were inconsistent between the 24 and 96 h timepoints following exposure, suggesting that different biodosimetry miRNA markers might be required depending on the time that has elapsed. Finally, Ex-Rad treatment restored the level of several miRNAs whose expression was significantly changed after radiation exposure, including miR-16-2, an miRNA previously associated with radiation survival. Taken together, our findings support the use of miRNA expression as an indicator of radiation exposure and the use of Ex-Rad as a potential radioprotectant.

CPNE1, A Potential Therapeutic Target in Nasopharyngeal Carcinoma, Affects Cell Growth and Radiation Resistance.

The increased expression of Copine 1 (CPNE1) has been observed in various cancers, which promotes cell proliferation, apoptosis, and radio resistance. However, the potential mechanism of CPNE1 in nasopharyngeal carcinoma (NPC) remains elusive. Consequently, our objective was to investigate the role of CPNE1 in regulating proliferation and radio resistance of NPC. CPNE1 expression in NPC and normal patients were obtained from Cancer Genome Atlas (TCGA) database. An elevated CPNE1 was observed in NPC patients and cells (C666-1, SUNE-1, and HNE-1). Then, C666-1 and SUNE-1 cells were subjected to si-CPNE1 under different radiations (0-8 Gy). Cell growth and proliferation were measured by CCK8 and EDU assays, which demonstrated si-CPNE1 suppressed proliferation. Colony formation was performed to detect cell viability under different radiation therapy and survival curve of cell was plotted, which indicated that CPNE1 knockdown improved cell radiosensitivity. Additionally, flow cytometry showed silence of CPNE1 enhanced apoptosis rate in radiated cells. To further investigate the mechanisms of CPNE1 regulating NPC, the expression of activated phosphate Akt (p-Akt) was assessed through western blotting. We observed elevated p-Akt in si-CPNE1 transfected C666-1 and SUNE-1 cells. In conclusion, these results demonstrated that CPNE1 expression is elevated in nasopharyngeal carcinoma cells, and its silencing could attenuate nasopharyngeal carcinoma advancement and improve radiosensitivity to radiation therapy by controlling Akt activation.

Surgery combined with adjuvant radiation and chemotherapy prolonged overall survival in stage IVC anaplastic thyroid cancer: a SEER-based analysis.

Anaplastic thyroid carcinoma (ATC) is a rare but aggressive malignancy, which accounts for only 1-2% of all thyroid cancers. The median overall survival (OS) time for all stages patients is at about 5 months. The benefit of surgery combined with adjuvant radiation and chemotherapy in stage IVC anaplastic thyroid cancer is still controversial. The aim of this study is to investigating surgery combined with adjuvant radiation and chemotherapy and survival outcomes in stage IVC ATC patients. Anaplastic thyroid carcinoma patients from the Surveillance, Epidemiology, and End Results database from 2004 to 2016 were used to conduct a cross-sectional study in the analysis. The endpoint of this study was overall survival. The median OS of the overall population was 2.0 months. Multivariate analysis showed that age (<67 vs. ≥67 years old, P = 0.017, HR = 1.355, 95% CI: 1.057-1.738), tumor size (<7 cm vs. ≥7 cm, P = 0.001, HR = 1.579, 95% CI: 1.202-2.073), Surgery (thyroidectomy vs. non-surgery, P < 0.001, HR = 0.554, 95% CI: 0.401-0.766), radiation therapy (P < 0.001, HR = 0.571, 95% CI: 0.445-0.733) and chemotherapy (P = 0.003, HR = 0.684, 95% CI: 0.531-0.881) were independent prognostic factor for worse OS in stage IVC ATC patients. Surgery combined with adjuvant radiation and chemotherapy exhibited the better overall survival time for 4 months. Surgery combined with adjuvant radiation and chemotherapy can improve overall survival in stage IVC ATC patients. We recommend surgical approach with fully evaluation combined with radiation therapy and chemotherapy for selected stage IVC ATC patients.

Different benefits of adaptive radiotherapy for different histologies of NSCLC

Background Adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the most frequent histological subtypes of non-small cell lung cancer (NSCLC). The aim of this study was to investigate how patients with AC and SCC benefit from image-guided adaptive radiotherapy (ART) with tumour match. Material and methods Consecutive patients diagnosed with AC or SCC of the lung treated with definitive chemo-radiotherapy before and after the implementation of ART and tumour match were retrospectively included for analyses. Data collection included baseline patient and treatment characteristics in addition to clinical data on radiation pneumonitis (RP), failure, and survival. Patients were divided into four categories based on their histology and treatment before (n = 173 [89 AC and 84 SCC]) and after implementation of ART (n = 240 [141 AC and 99 SCC]). Results Median follow-up was 5.7 years for AC and 6.3 years for SCC. Mean lung dose decreased for both histologies with ART, whereas mean heart dose only decreased for patients with AC. Incidences of grade 3 and 5 RP decreased for both histologies with ART. Loco-regional failure (LRF) rates decreased significantly for patients with SCC after ART (p = .04), no significant difference was observed for AC. Overall survival (OS) increased significantly for SCC after ART (p < .01): the 2-year OS increased from 31.0% (95% confidence interval [CI] [22.5–42.6]) to 54.5% (95% CI [45.6–65.3]). No significant effect on OS was observed for patients with AC. Conclusion ART and tumour match in the radiotherapeutic treatment of patients with locally advanced NSCLC primarily led to decreased LRF and improved OS for patients with SCC.

Relationship of Sarcopenia to Tolerance of Chemotherapy During Definitive Treatment of Primary Anal Squamous Cell Carcinoma

Primary therapy for anal squamous cell carcinoma consists of definitive radiation with concurrent chemotherapy, most commonly 5-fluorouracil and mitomycin-C. This regimen is associated with significant cutaneous, hematologic, and gastrointestinal toxicity. Sarcopenia, or low skeletal muscle mass, has been described as an adverse prognostic factor and predictor of poor tolerance to therapy across a range of malignancies, including breast, gynecologic and head and neck cancers. Here, we sought to determine if the presence of sarcopenia at the initiation of therapy is associated with increased rates of toxicity and poorer tolerance of definitive treatment for primary anal squamous cell carcinoma. This was a review of patients treated with curative intent for anal squamous cell carcinoma at a single academic medical center between 2007 and 2017, median follow up was 38 months. Analysis was limited to patients receiving definitive radiation with concurrent chemotherapy. Sarcopenia was objectively defined, using previously validated methods, as a skeletal muscle index (SMI) <41 cm2/m2 for female patients regardless of body mass index (BMI); for male patients sarcopenia was defined as SMI<43cm2/m2 for BMI<25 and <53 cm2/m2 for BMI >25. SMI calculations were performed using the average skeletal muscle cross sectional areas of two sequential axial CT slices at the L3 vertebral level obtained from radiation planning computed tomography scans. The image analysis was performed by a single trained observer using Sliceomatic software with a Hounsfield unit threshold of -29 to 150 to define skeletal muscle. Sarcopenia as a predictor for treatment toxicity was analyzed using Chi-Square testing. Overall survival and progression free survival were compared with 2-sample t tests. Sixty-one patients were included in the analysis with 49% meeting criteria for sarcopenia. Stage did not differ although sarcopenic patients were significantly more elderly than those without sarcopenia (mean 72 vs 58 years, p<0.001). Patients with sarcopenia were significantly more likely to have chemotherapy breaks, chemotherapy dose reductions, and incomplete chemotherapy courses compared to non-sarcopenic patients (33.3% vs 9.7%; p = 0.02). Sarcopenia was not predictive of more radiation treatment breaks, hematologic toxicity, progression free survival or overall survival. Sarcopenia is predictive of reduced tolerance to chemotherapy among patients receiving definitive combined modality therapy for primary anal carcinoma. We found no association between sarcopenia and tolerance of radiation therapy or survival outcomes.

Radiation Necrosis following SRS or FSRT with Higher BED for Brain Metastases >20 mm

In the RTOG 90-05 study, the maximum tolerated dose of single-fraction radiosurgery (SRS) for lesions 21-30 mm was 18 Gy (BED 45 Gy12). However, patients of the RTOG study were previously irradiated with median 60 Gy (brain tumors) or 30 Gy (brain metastasis). Thus, the max. tolerated BED for lesions not irradiated before may be >45 Gy12. This study investigated safety and efficacy of SRS or fractionated stereotactic radiotherapy (FSRT) with BED >49 Gy12 for radiotherapy-naive brain metastases >20 mm. Data of 169 patients who received SRS or FSRT alone with BED >49 Gy12 for 1-4 brain metastases (2011-2022) were retrospectively analyzed. Thirty-two patients had lesions >20 mm (21-30 mm, n = 27; 21-40 mm, n = 4; >40 mm, n = 1). SRS was performed with 20 Gy (n = 9; 53.3 Gy12) or 19 Gy (n = 2; 49.1 Gy12), prescribed to the 60-80% isodose line (PTV = GTV). FSRT was Linac-based delivering 3 x 10 Gy (n = 3; 55 Gy12), 3 x 11 Gy (n = 4; 63.3 Gy12), 7 x 6 Gy (n = 1; 63 Gy12), 9 x 5 Gy (n = 1; 63.8 Gy12), 10 x 4 Gy (n = 11; 53.3 Gy12), or 12 x 4 Gy (n = 1; 64 Gy12), prescribed to the 80% isodose line (PTV = GTV+1-2 mm). SRS and FSRT were compared for grade ≥2 radiation necrosis (RN), local control (LC) and survival (OS). Fractionation [SRS (n = 89) vs FSRT (n = 48)] and lesion size (≤20 vs >20 mm) were studied in terms of RN rates. Kaplan-Meier method and log-rank test were used for univariate analyses and the Cox proportional hazards model for multivariate analyses. In patients with lesions >20 mm, SRS and FSRT were compared (Fisher's exact/Chi square test) for age, gender, KPS, year of SRS/FSRT, primary tumor, number/site of lesions, systemic treatment, and extracranial metastases. In patients with lesions >20 mm, significantly more patients receiving SRS had a KPS >80 than patients treated with FSRT (91% vs 29%, p = 0.002); otherwise, distributions of patient characteristics were balanced. In patients with lesions >20 mm, SRS was associated with significantly higher RN rates at 1 year (50% vs 9%) and 2 years (50% vs 9%) on univariate analysis (p = 0.012), which remained on multivariate analysis (HR: 0.10; 95% CI: 0.01-0.94, p = 0.044). No significant differences were found for LC (p = 0.21) at 1 year (75% vs 70%) and 2 years (75% vs 53%), and OS (p = 0.09) at 1 year (36% vs 59%) and 2 years (27% vs 46%). In patients with lesions ≤20 mm, 1- and 2-year RN rates following SRS were both 4%, compared to 0% and 15% respectively after FSRT (p = 0.60). In the SRS group, RN rates were significantly higher with lesions >20 mm (vs ≤20 mm) on univariate (p<0.001) and multivariate (HR: 3.82, 95% CI: 1.70-8.58, p = 0.001) analyses. In the FSRT group, max. diameter had no significant impact on RN rates (p = 0.93). Given the limitations of this study, FSRT with BED >49 Gy12 appears associated with a low risk of RN when used for brain metastases >20 mm. SRS with 1x19-20 Gy may not be optimal for metastases >20 mm but appears safe for lesions ≤20 mm. Prospective trials are warranted.

256 Patient-Specific Pre-Treatment Nuclei Size Distribution is of Significance for Post Radiation Therapy Locoregional Recurrence and Survival Outcomes

256 Patient-Specific Pre-Treatment Nuclei Size Distribution is of Significance for Post Radiation Therapy Locoregional Recurrence and Survival Outcomes

Delayed time to radiation and overall survival in Merkel cell carcinoma.

Clinically localized Merkel cell carcinoma (MCC) is commonly treated with surgical excision and radiotherapy. The relationship between time to adjuvant radiotherapy and overall survival (OS) remains understudied. This retrospective study used data from the National Cancer Database (2006-2019). Patients with clinically localized MCC who received surgical excision and adjuvant radiotherapy were included. Multivariate regressions were used to account for various patient and tumor factors. The primary outcome was 5-year OS, and the secondary outcome was time from diagnosis to adjuvant radiation (TTR). Of the 1965 patients included, most were male (n = 1242, 63.2%) and white (n = 1915, 97.5%), and the median age was 74 years (interquartile range [IQR]: 66-81). The median TTR was 83 days (IQR: 65-106). A total of 83.6% of patients received radiotherapy to the primary site, 21.3% to the draining nodal basin, 17.1% to both, and 12.2% whose target location of radiotherapy was not recorded in the data. TTR of ≥79 days (the 45th percentile) was associated with worse OS on both univariate and multivariate analyses (log-rank p = 0.0014; hazard ratio [HR]: 1.258, 95% confidence interval [CI]: 1.055-1.500, p = 0.010). This persisted on sub-analyses of patients <80 years old (n = 1407; HR: 1.380, 95% CI: 1.080-1.764, p = 0.010) and of patients with Charlson comorbidity index (CCI) of 0 (n = 1411; HR: 1.284, 95% CI: 1.034-1.595, p = 0.024). Factors associated with delayed TTR included greater age (p = 0.039), male sex (p = 0.04), CCI > 1 (p = 0.036), academic facility (p < 0.001), rural county (p = 0.034), AJCC T2 stage (p = 0.010), negative margins (p = 0.017), 2+ pathologically positive regional nodes (p = 0.011), and margin size >2 cm (p = 0.015). Delayed radiotherapy (≥79 days) was associated with worse OS of MCC patients. Further study in controlled cohorts is needed to ascertain this relationship.

Radiation Facility Volume and Survival for Men With Very High-Risk Prostate Cancer Treated with Radiation and Androgen Deprivation Therapy

Very high-risk (VHR) prostate cancer is an aggressive substratum of high-risk prostate cancer, characterized by high prostate-specific antigen levels, high Gleason score, and/or advanced T category. Contemporary management paradigms involve advanced molecular imaging and multimodal treatment with intensified prostate-directed or systemic treatment-resources more readily available at high-volume centers. To examine radiation facility case volume and overall survival (OS) in men with VHR prostate cancer. A retrospective cohort study was performed from November 11, 2022, to March 4, 2023, analyzing data from US facilities reporting to the National Cancer Database. Patients included men diagnosed with nonmetastatic VHR prostate cancer by National Comprehensive Cancer Network criteria (clinical T3b-T4 category, primary Gleason pattern 5, >4 cores with grade group 4-5, and/or 2-3 high-risk features) and treated with curative-intent radiotherapy and androgen deprivation therapy between January 1, 2004, to December 31, 2016. Treatment at high- vs low-average cumulative facility volume (ACFV), defined as the total number of prostate radiotherapy cases at an individual patient's treatment facility from 2004 until the year of their diagnosis. The nonlinear association between a continuous ACFV and OS was examined through a Martingale residual plot; an optimal ACFV cutoff was identified that maximized the separation between high vs low ACFV via a bias-adjusted log rank test. Overall survival was assessed between high vs low ACFV using Kaplan-Meier analysis with and without inverse probability score weighted adjustment and multivariable Cox proportional hazards. A total of 25 219 men (median age, 71 [IQR, 64-76] years; 78.7% White) with VHR prostate cancer were identified, 6438 (25.5%) of whom were treated at high ACFV facilities. Median follow-up was 57.4 (95% CI, 56.7-58.1) months. Median OS for patients treated at high ACFV centers was 123.4 (95% CI, 116.6-127.4) months vs 109.0 (95% CI, 106.5-111.2) months at low ACFV centers (P < .001). On multivariable analysis, treatment at a high ACFV center was associated with lower risk of death (hazard ratio, 0.89; 95% CI, 0.84-0.95; P < .001). These results were also significant after inverse probability score weighted-based adjustment. In this cohort study of patients with VHR prostate cancer who underwent definitive radiotherapy and androgen deprivation therapy, facility case volume was independently associated with longer OS. Further studies are needed to identify which factors unique to high-volume centers may be responsible for this benefit.

Prediction of Cancer Treatment Effectiveness and Patient Outcomes using Machine Learning Classification Approaches - A Review

This study systematically reviews the Machine Learning methods developed to help predict the patient outcome and treatment effectiveness in cancer treatment. This research paper has been drafted from several other similar papers and with the help of a few topics related websites providing information regarding the radiation toxicity, survival rate and tumor response. Which are the main classification criteria for the patients. The use of ANN, DT, SVM and BNs has proved to be very beneficial in the classification of any given dataset, the accuracy of the model will be high with the use of all these ML methods.

Single Fraction and Hypofractionated Radiation Cause Cochlear Damage, Hearing Loss, and Reduced Viability of Merlin-Deficient Schwann Cells.

Vestibular schwannomas (VS) are benign intracranial tumors caused by loss of function of the merlin tumor suppressor. We tested three hypotheses related to radiation, hearing loss (HL), and VS cell survival: (1) radiation causes HL by injuring auditory hair cells (AHC), (2) fractionation reduces radiation-induced HL, and (3) single fraction and equivalent appropriately dosed multi-fractions are equally effective at controlling VS growth. We investigated the effects of single fraction and hypofractionated radiation on hearing thresholds in rats, cell death pathways in rat cochleae, and viability of human merlin-deficient Schwann cells (MD-SC). Adult rats received cochlear irradiation with single fraction (0 to 18 Gray [Gy]) or hypofractionated radiation. Auditory brainstem response (ABR) testing was performed for 24 weeks. AHC viabilities were determined using immunohistochemistry. Neonatal rat cochleae were harvested after irradiation, and gene- and cell-based assays were conducted. MD-SCs were irradiated, and viability assays and immunofluorescence for DNA damage and cell cycle markers were performed. Radiation caused dose-dependent and progressive HL in rats and AHC losses by promoting expression of apoptosis-associated genes and proteins. When compared to 12 Gy single fraction, hypofractionation caused smaller ABR threshold and pure tone average shifts and was more effective at reducing MD-SC viability. Investigations into the mechanisms of radiation ototoxicity and VS radiobiology will help determine optimal radiation regimens and identify potential therapies to mitigate radiation-induced HL and improve VS tumor control.