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Item Prognostic Significance of Tumor-Associated Macrophages in Chondroblastoma and Their Association with Response to Adjuvant Radiotherapy(Dovepress, 2021-05-17) Zheng, Bo-Wen; Yang, Min-Liang; Huang, Wei; Zheng, Bo-Yv; Zhang, Tao-Lan; Li, Jing; Lv, Guo-Hua; Yan, Yi-Guo; Zou, Ming-Xiang; Radiation Oncology, School of MedicineObjective: Chondroblastoma (CB) is a rare and locally growing cartilage-derived tumor. Currently, clinical implications of tumor-associated macrophages (TAMs) in CB remain unclear. In this study, we sought to analyze the relationship between TAM parameters (including densities of CD68+ and CD163+ cells as well as the CD163+/CD68+ ratio) and clinicopathological characteristics and survival of patients. Methods: Immunohistochemistry was used to assess TAM subtypes for CD68 and CD163, as well as the expression levels of p53, CD34, and Ki-67 on tumor cells in 132 tissue specimens retrieved between July 2002 and April 2020. Then, TAM parameters were retrospectively analyzed for their associations with patient outcomes (local recurrence-free survival [LRFS] and overall survival [OS]) and clinicopathological features. Results: TAM densities were significantly higher in axial chondroblastoma tissue than in extra-axial chondroblastoma tissue. Moreover, the number of CD163+ TAMs was positively correlated with tumor invasion of surrounding tissues and high expression of CD34 and Ki-67 on tumor cells, whereas CD163+ cell density and the CD163/CD68 ratio were negatively associated with patient response to adjuvant radiotherapy. Univariate Kaplan-Meier analysis revealed that the number of CD68+ and CD163+ lymphocytes was significantly associated with both LRFS and OS. Multivariate Cox regression analysis showed that CD163+ and CD68+ cell levels were independent prognostic factors of LRFS, while TAM data independently predicted OS. More importantly, in subgroup analysis based on three significant factors in univariate survival analysis (including tumor location, adjuvant radiotherapy, and surrounding tissue invasion by tumors), the TAM parameters still displayed good prognostic performance. Conclusion: These data suggest that TAM may significantly affect the biological behavior of CB. We hypothesize that modulating the TAM level or polarization status in the microenvironment may be an effective approach for CB treatment.Item β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation(Frontiers, 2021) Zhao, Wenxiu; Jiang, Lingxiang; Fang, Ting; Fang, Fei; Liu, Yingchun; Zhao, Ye; You, Yuting; Zhou, Hao; Su, Xiaolin; Wang, Jiangwei; Liu, Sheng; Chen, Yaomin; Wan, Jun; Huang, Xiumei; Radiation Oncology, School of MedicineHepatocellular carcinoma (HCC) is the second leading cause of cancer-related death globally. Currently there is a lack of tumor-selective and efficacious therapies for hepatocellular carcinoma. β-Lapachone (ARQ761 in clinical form) selectively kill NADPH: quinone oxidoreductase 1 (NQO1)-overexpressing cancer cells. However, the effect of β-Lapachone on HCC is virtually unknown. In this study, we found that relatively high NQO1 and low catalase levels were observed in both clinical specimens collected from HCC patients and HCC tumors from the TCGA database. β-Lapachone treatment induced NQO1-selective killing of HCC cells and caused ROS formation and PARP1 hyperactivation, resulting in a significant decrease in NAD+ and ATP levels and a dramatic increase in double-strand break (DSB) lesions over time in vitro. Administration of β-Lapachone significantly inhibited tumor growth and prolonged survival in a mouse xenograft model in vivo. Our data suggest that NQO1 is an ideal potential biomarker, and relatively high NQO1:CAT ratios in HCC tumors but low ratios in normal tissues offer an optimal therapeutic window to use β-Lapachone. This study provides novel preclinical evidence for β-Lapachone as a new promising chemotherapeutic agent for use in NQO1-positive HCC patients.Item National trends in management of adult myxopapillary ependymomas(Elsevier, 2020-03) Scarpelli, Daphne B.; Turina, Claire B.; Kelly, Patrick D.; Khudanyan, Arpine; Jaboin, Jerry J.; McClelland, Shearwood, III.; Radiation Oncology, School of MedicineMyxopapillary ependymomas (MPE) are WHO Grade I ependymomas that annually occur in 0.05–0.08 per 100,000 people. Surgical resection is the recommended first line therapy. Due to the rarity of the disease, there is a relatively poor understanding of the use of radiotherapy (RT) in managing this disease. The National Cancer Database (NCDB) was analyzed for patterns of care for adult MPE diagnosed between 2002 and 2016. Of 753 qualifying cases, the majority of patients underwent resection (n = 617, 81.9%). A relatively small portion received RT (n = 103, 13.3%) with most receiving RT post-operatively (n = 98, 95.1%). The likelihood of patients to undergo resection and RT was associated with patient age at diagnosis (p = 0.002), tumor size (p < 0.001), and race (p = 0.017). Chemotherapy was not widely utilized (0.27% of patients). One limitation of our analysis is that there was no data on progression free survival (PFS), an important outcome given the high survival rate in this disease. Surgery remains the primary means to manage adult MPE. For spinal MPE, it is understood that gross total resection (GTR) should be attempted whenever possible as GTR has been associated with improved PFS in several studies. The impact of RT on overall survival (OS) is indeterminate given the 1.6% death rate in the cohort. Analyses of the impact of RT on PFS in a larger database would be beneficial for determining an algorithm for post-operative and definitive RT in this disease entity.Item Patient-Specific Lymphocyte Loss Kinetics as Biomarker of Spleen Dose in Patients Undergoing Radiation Therapy for Upper Abdominal Malignancies(Elsevier, 2020-08-10) Yalamanchali, Anirudh; Zhang, Hong; Huang, Ke Colin; Mohan, Radhe; Lin, Steven H.; Zhu, Cong; Grossman, Stuart A.; Jin, Jian-Yue; Ellsworth, Susannah G.; Radiation Oncology, School of MedicinePurpose: Radiation therapy (RT)-induced lymphopenia (RIL) is linked with inferior survival in esophageal and pancreatic cancers. Previous work has demonstrated a correlation between spleen dose and RIL risk. The present study correlates spleen dose-volume parameters with fractional lymphocyte loss rate (FLL) and total percent change in absolute lymphocyte count (%ΔALC) and suggests spleen dose constraints to reduce RIL risk. Methods and materials: This registry-based study included 140 patients who underwent RT for pancreatic (n = 67), gastroesophageal (n = 61), or biliary tract (n = 12) adenocarcinoma. Patient-specific parameters of lymphocyte loss kinetics, including FLL and %ΔALC, were calculated based on serial ALCs obtained during RT. Spearman's rho was used to correlate spleen dose-volume parameters with %ΔALC, end-treatment ALC, and FLL. Multivariable logistic regression was used to identify predictors of ≥grade 3 and grade 4 RIL. Results: Spleen dose-volume parameters, including mean spleen dose (MSD), all correlated with %ΔALC, end-treatment ALC, and FLL. Controlling for baseline ALC and planning target volume (PTV), an increase in any spleen dose-volume parameter increased the odds of developing ≥grade 3 lymphopenia. Each 1-Gy increase in MSD increased the odds of ≥grade 3 RIL by 18.6%, and each 100-cm3 increase in PTV increased the odds of ≥grade 3 lymphopenia by 20%. Patients with baseline ALC < 1500 cells/μL had a high risk of ≥grade 3 RIL regardless of MSD or PTV. FLL was an equally good predictor of ≥grade 3 lymphopenia as any spleen dose-volume parameter. Conclusions: In patients undergoing RT for upper abdominal malignancies, higher spleen dose is associated with higher per-fraction lymphocyte loss rates, higher total %ΔALC, and increased odds of severe lymphopenia. Spleen dose constraints should be individualized based on baseline ALC and PTV size to minimize RIL risk, although our findings require validation in larger, ideally prospective data sets.Item Radiation oncology should be a partner to medical oncology in end-of-life care(Elsevier, 2020) McClelland, Shearwood, III.; Mitin, Timur; Radiation Oncology, School of MedicineItem FLASH Irradiation Results in Reduced Severe Skin Toxicity Compared to Conventional-Dose-Rate Irradiation(BioOne, 2020-12-01) Soto, Luis A.; Casey, Kerriann M.; Wang, Jinghui; Blaney, Alexandra; Manjappa, Rakesh; Breitkreutz, Dylan; Skinner, Lawrie; Dutt, Suparna; Ko, Ryan B.; Bush, Karl; Yu, Amy S.; Melemenidis, Stavros; Strober, Samuel; Englemann, Edgar; Maxim, Peter G.; Graves, Edward E.; Loo, Billy W., Jr.; Radiation Oncology, School of MedicineRadiation therapy, along with surgery and chemotherapy, is one of the main treatments for cancer. While radiotherapy is highly effective in the treatment of localized tumors, its main limitation is its toxicity to normal tissue. Previous preclinical studies have reported that ultra-high dose-rate (FLASH) irradiation results in reduced toxicity to normal tissues while controlling tumor growth to a similar extent relative to conventional-dose-rate (CONV) irradiation. To our knowledge this is the first report of a dose-response study in mice comparing the effect of FLASH irradiation vs. CONV irradiation on skin toxicity. We found that FLASH irradiation results in both a lower incidence and lower severity of skin ulceration than CONV irradiation 8 weeks after single-fraction hemithoracic irradiation at high doses (30 and 40 Gy). Survival was also higher after FLASH hemithoracic irradiation (median survival >180 days at doses of 30 and 40 Gy) compared to CONV irradiation (median survival 100 and 52 days at 30 and 40 Gy, respectively). No ulceration was observed at doses 20 Gy or below in either FLASH or CONV. These results suggest a shifting of the dose-response curve for radiation-induced skin ulceration to the right for FLASH, compared to CONV irradiation, suggesting the potential for an enhanced therapeutic index for radiation therapy of cancer.Item Evaluating the Reproducibility of Mouse Anatomy under Rotation in a Custom Immobilization Device for Conformal FLASH Radiotherapy(BioOne, 2020-12-01) Ko, Ryan B.; Soto, Luis A.; von Eyben, Rie; Melemenidis, Stavros; Rankin, Erinn B.; Maxim, Peter G.; Graves, Edward E.; Loo, Billy W., Jr.; Radiation Oncology, School of MedicineThe observation of an enhanced therapeutic index for FLASH radiotherapy in mice has created interest in practical laboratory-based FLASH irradiators. To date, systems capable of 3D conformal FLASH irradiation in mice have been lacking. We are developing such a system, incorporating a high-current linear accelerator to produce a collimated X-ray beam in a stationary beamline design, rotating the mouse about a longitudinal axis to achieve conformal irradiation from multiple beam directions. The purpose of this work was to evaluate the reproducibility of mouse anatomy under rotation at speeds compatible with conformal FLASH delivery. Three short-hair mice and two hairless mice were immobilized under anesthesia in body weight-specific contoured plastic molds, and subjected to three rotational (up to 3 revolutions/s) and two non-rotational movement interventions. MicroCT images were acquired before and after each intervention. The displacements of 11 anatomic landmarks were measured on the image pairs. The displacement of the anatomical landmarks with any of the interventions was 0.5 mm or less for 92.4% of measurements, with a single measurement out of 275 (11 landmarks × 5 interventions × 5 mice) reaching 1 mm. There was no significant difference in the displacements associated with rotation compared to those associated with moving the immobilized mouse in and out of a scanner or with leaving the mouse in place for 5 min with no motion. There were no significant differences in displacements between mice with or without hair, although the analysis is limited by small numbers, or between different anatomic landmarks. These results show that anatomic reproducibility under rotation speed corresponding to FLASH irradiation times appears to be compatible with conformal/stereotactic irradiation in mice.Item Initial Steps Towards a Clinical FLASH Radiotherapy System: Pediatric Whole Brain Irradiation with 40 MeV Electrons at FLASH Dose Rates(BioOne, 2020-12-01) Breitkreutz, Dylan Yamabe; Shumail, Muhammad; Bush, Karl K.; Tantawi, Sami G.; Maxim, Peter G.; Loo, Billy W., Jr.; Radiation Oncology, School of MedicineIn this work, we investigated the delivery of a clinically acceptable pediatric whole brain radiotherapy plan at FLASH dose rates using two lateral opposing 40-MeV electron beams produced by a practically realizable linear accelerator system. The EGSnrc Monte Carlo software modules, BEAMnrc and DOSXYZnrc, were used to generate whole brain radiotherapy plans for a pediatric patient using two lateral opposing 40-MeV electron beams. Electron beam phase space files were simulated using a model of a diverging beam with a diameter of 10 cm at 50 cm SAD (defined at brain midline). The electron beams were collimated using a 10-cm-thick block composed of 5 cm of aluminum oxide and 5 cm of tungsten. For comparison, a 6-MV photon plan was calculated with the Varian AAA algorithm. Electron beam parameters were based on a novel linear accelerator designed for the PHASER system and powered by a commercial 6-MW klystron. Calculations of the linear accelerator's performance indicated an average beam current of at least 6.25 µA, providing a dose rate of 115 Gy/s at isocenter, high enough for cognition-sparing FLASH effects. The electron plan was less homogenous with a homogeneity index of 0.133 compared to the photon plan's index of 0.087. Overall, the dosimetric characteristics of the 40-MeV electron plan were suitable for treatment. In conclusion, Monte Carlo simulations performed in this work indicate that two lateral opposing 40-MeV electron beams can be used for pediatric whole brain irradiation at FLASH dose rates of >115 Gy/s and serve as motivation for a practical clinical FLASH radiotherapy system, which can be implemented in the near future.Item Clinical application and mechanism of traditional Chinese medicine in treatment of lung cancer(Wolters Kluwer, 2020-12) Su, Xiao-Lin; Wang, Jiang-Wei; Che, Hui; Wang, Chang-Fu; Jiang, Hai; Lei, Xia; Zhao, Wan; Kuang, Hai-Xue; Wang, Qiu-Hong; Radiation Oncology, School of MedicineLung cancer is a malignant tumor characterized by a rapid proliferation rate, less survivability, high mortality, and metastatic potential. This review focuses on updated research about the clinical application of traditional Chinese medicine (TCM) as an adjuvant therapy to lung cancer treatment and the mechanisms of TCM effect on lung cancer in vitro and in vivo. We summarized the recent 5 years of different research progress on clinical applications and antitumor mechanisms of TCM in the treatment of lung cancer. As a potent adjuvant therapy, TCM could enhance conventional treatments (chemotherapy, radiation therapy, and epidermal growth factor receptors [EGFRs] tyrosine kinase inhibitors [TKIs]) effects as well as provide synergistic effects, enhance chemotherapy drugs chemosensitivity, reverse drug resistance, reduce adverse reactions and toxicity, relieve patients’ pain and improve quality of life (QOL). After treating with TCM, lung cancer cells will induce apoptosis and/or autophagy, suppress metastasis, impact immune reaction, and therapeutic effect of EGFR-TKIs. Therefore, TCM is a promisingly potent adjuvant therapy in the treatment of lung cancer and its multiple mechanisms are worthy of an in-depth study.Item Improving the Clinical Treatment of Vulnerable Populations in Radiation Oncology(Elsevier, 2020-08-06) McClelland, Shearwood, III.; Petereit, Daniel G.; Zeitlin, Ross; Takita, Cristiane; Suneja, Gita; Miller, Robert C.; Deville, Curtiland; Siker, Malika L.; Radiation Oncology, School of MedicineThe increasing role of radiation oncology in optimal cancer care treatment brings to mind the adage that power is never a gift, but a responsibility. A significant part of the responsibility we in radiation oncology bear is how to ensure optimal access to our services. This article summarizes the discussion initiated at the 2019 American Society for Radiation Oncology Annual Meeting educational panel entitled "Improving the Clinical Treatment of Vulnerable Populations in Radiation Oncology: Latin, African American, Native American, and Gender/Sexual Minority Communities." By bringing the discussion to the printed page, we hope to continue the conversation with a broader audience to better define the level of responsibility our field bears in optimizing cancer care to the most vulnerable patient populations within the United States.