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Background: The authors developed a framework for estimating and comparing the risks of various long-term complications on a common scale and applied it to 3 different techniques for craniospinal irradiation in patients with pediatric medulloblastoma.Methods: Radiation dose-response parameters related to excess hazard ratios for secondary breast, lung, stomach, and thyroid cancer; heart failure, and myocardial infarction were derived from large published clinical series. Combined with age-specific and sex-specific hazards in the US general population, the dose-response analysis yielded excess hazards of complications for a cancer survivor as a function of attained age. After adjusting for competing risks of death, life years lost (LYL) were estimated based on excess hazard and prognosis of a complication for 3-dimensional conformal radiotherapy (3D CRT), volumetric modulated arc therapy (VMAT), and intensity-modulated proton therapy (IMPT).Results: Lung cancer contributed most to the estimated LYL, followed by myocardial infarction, and stomach cancer. The estimates of breast or thyroid cancer incidence were higher than those for lung and stomach cancer incidence, but LYL were lower because of the relatively good prognosis. Estimated LYL ranged between 1.90 years for 3D CRT to 0.28 years for IMPT. In a paired comparison, IMPT was associated with significantly fewer LYL than both photon techniques.Conclusions: Estimating the risk of late complications is associated with considerable uncertainty, but including prognosis and attained age at an event to obtain the more informative LYL estimate added relatively little to this uncertainty. [ABSTRACT FROM AUTHOR]

Purpose: A Pediatric Normal Tissue Effects in the Clinic (PENTEC) analysis of published investigations of central nervous system (CNS) subsequent neoplasms (SNs), subsequent sarcomas, and subsequent lung cancers in childhood cancer survivors who received radiation therapy (RT) was performed to estimate the effect of RT dose on the risk of SNs and the modification of this risk by host and treatment factors., Methods and Materials: A systematic literature review was performed to identify data published from 1975 to 2022 on SNs after prior RT in childhood cancer survivors. After abstract review, usable quantitative and qualitative data were extracted from 83 studies for CNS SNs, 118 for subsequent sarcomas, and 10 for lung SNs with 4 additional studies (3 for CNS SNs and 1 for lung SNs) later added. The incidences of SNs, RT dose, age, sex, primary cancer diagnosis, chemotherapy exposure, and latent time from primary diagnosis to SNs were extracted to assess the factors influencing risk for SNs. The excess relative ratio (ERR) for developing SNs as a function of dose was analyzed using inverse-variance weighted linear regression, and the ERR/Gy was estimated. Excess absolute risks were also calculated., Results: The ERR/Gy for subsequent meningiomas was estimated at 0.44 (95% CI, 0.19-0.68); for malignant CNS neoplasms, 0.15 (95% CI, 0.11-0.18); for sarcomas, 0.045 (95% CI, 0.023-0.067); and for lung cancer, 0.068 (95% CI, 0.03-0.11). Younger age at time of primary diagnosis was associated with higher risk of subsequent meningioma and sarcoma, whereas no significant effect was observed for age at exposure for risk of malignant CNS neoplasm, and insufficient data were available regarding age for lung cancer. Females had a higher risk of subsequent meningioma (odds ratio, 1.46; 95% CI, 1.22-1.76; P < .0001) relative to males, whereas no statistically significant sex difference was seen in risk of malignant CNS neoplasms, sarcoma SNs, or lung SNs. There was an association between chemotherapy receipt (specifically alkylating agents and anthracyclines) and subsequent sarcoma risk, whereas there was no clear association between specific chemotherapeutic agents and risk of CNS SNs and lung SNs., Conclusions: This PENTEC systematic review shows a significant radiation dose-response relationship for CNS SNs, sarcomas, and lung SNs. Given the linear dose response, improved conformality around the target volume that limits the high dose volume might be a promising strategy for reducing the risk of SNs after RT. Other host- and treatment-related factors such as age and chemotherapy play a significant contributory role in the development of SNs and should be considered when estimating the risk of SNs after RT among childhood cancer survivors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: A PENTEC review of childhood cancer survivors who received brain radiation therapy (RT) was performed to develop models that aid in developing dose constraints for RT-associated central nervous system (CNS) morbidities., Methods and Materials: A comprehensive literature search, through the PENTEC initiative, was performed to identify published data pertaining to 6 specific CNS toxicities in children treated with brain RT. Treatment and outcome data on survivors were extracted and used to generate normal tissue complication probability (NTCP) models., Results: The search identified investigations pertaining to 2 of the 6 predefined CNS outcomes: neurocognition and brain necrosis. For neurocognition, models for 2 post-RT outcomes were developed to (1) calculate the risk for a below-average intelligence quotient (IQ) (IQ <85) and (2) estimate the expected IQ value. The models suggest that there is a 5% risk of a subsequent IQ <85 when 10%, 20%, 50%, or 100% of the brain is irradiated to 35.7, 29.1, 22.2, or 18.1 Gy, respectively (all at 2 Gy/fraction and without methotrexate). Methotrexate (MTX) increased the risk for an IQ <85 similar to a generalized uniform brain dose of 5.9 Gy. The model for predicting expected IQ also includes the effect of dose, age, and MTX. Each of these factors has an independent, but probably cumulative effect on IQ. The necrosis model estimates a 5% risk of necrosis for children after 59.8 Gy or 63.6 Gy (2 Gy/fraction) to any part of the brain if delivered as primary RT or reirradiation, respectively., Conclusions: This PENTEC comprehensive review establishes objective relationships between patient age, RT dose, RT volume, and MTX to subsequent risks of neurocognitive injury and necrosis. A lack of consistent RT data and outcome reporting in the published literature hindered investigation of the other predefined CNS morbidity endpoints., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Due to cancer survivors living longer and morbidity associated with cancer treatments, it is necessary to understand symptoms experienced by cancer survivors. This study will analyze the symptom burden among a large cohort of survivors across multiple cancer sites., Methods: Data from the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study were used to examine the symptom burden of older cancer survivors. Poisson regression with robust standard errors was utilized to determine differences in symptoms by cancer site, treatment, and other covariates., Results: The most frequently reported symptoms among cancer survivors were fatigue (15.8%) and feeling sad or depressed (14.1%). Multivariable analyses indicated that more symptoms were reported among survivors who were younger (p = 0.002), divorced or separated (p = 0.03), and had a combination of public and private insurance (p = 0.01). Survivors who received chemotherapy (p < 0.001), radiation (p = 0.01), or hormone therapy (p = 0.02) reported more symptoms than survivors who did not receive these treatments. Survivors diagnosed with cancer < 5 years ago reported fewer symptoms than longer-term survivors, particularly those diagnosed > 10 years ago (p = 0.02)., Conclusions: Results indicate that common physical and psychological symptoms are reported across cancer types. Cancer survivors diagnosed with cancer 10 or more years ago reported more symptoms than those recently diagnosed. This suggests that symptoms may remain a problem for some survivors decades after their diagnosis., Implications for Cancer Survivors: Future research should focus on implementing active surveillance of cancer survivors. Healthcare providers and those who care for cancer survivors should understand that the symptom burden associated with cancer may persist even decades following diagnosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: Hippocampus is a central component for neurocognitive function and memory. We investigated the predicted risk of neurocognitive impairment of craniospinal irradiation (CSI) and the deliverability and effects of hippocampal sparing. The risk estimates were derived from published NTCP models. Specifically, we leveraged the estimated benefit of reduced neurocognitive impairment with the risk of reduced tumor control., Material and Methods: For this dose planning study, a total of 504 hippocampal sparing intensity modulated proton therapy (HS-IMPT) plans were generated for 24 pediatric patients whom had previously received CSI. Plans were evaluated with respect to target coverage and homogeneity index to target volumes, maximum and mean dose to OARs. Paired t-tests were used to compare hippocampal mean doses and normal tissue complication probability estimates., Results: The median mean dose to the hippocampus could be reduced from 31.3 Gy RBE to 7.3 Gy RBE ( p  < .001), though 20% of these plans were not considered clinically acceptable as they failed one or more acceptance criterion. Reducing the median mean hippocampus dose to 10.6 Gy RBE was possible with all plans considered as clinically acceptable treatment plans. By sparing the hippocampus to the lowest dose level, the risk estimation of neurocognitive impairment could be reduced from 89.6%, 62.1% and 51.1% to 41.0% ( p  < .001), 20.1% ( p  < .001) and 29.9% ( p  < .001) for task efficiency, organization and memory, respectively. Estimated tumor control probability was not adversely affected by HS-IMPT, ranging from 78.5 to 80.5% for all plans., Conclusions: We present estimates of potential clinical benefit in terms of neurocognitive impairment and demonstrate the possibility of considerably reducing neurocognitive adverse effects, minimally compromising target coverage locally using HS-IMPT.

Background: To evaluate the change in parotid glands at mid-treatment during IMRT and the association between radiation dose to the parotid gland stem cell (PGSC) region and patient-reported xerostomia for patients with head and neck cancer (HNC)., Material and Methods: Patients who were treated from 2006-2012 at our institution with patient-reported xerostomia outcomes available at least 9 months following RT were included. PG and PGSC regions were delineated and the dose was estimated from the treatment plan dose distribution, using contours from pre- and mid-treatment CT scans. The association between radiation dose and volumetric changes was assessed using linear regression. Univariable logistic regression, logistic dose-response curves, and receiver operating characteristics (ROC) were used to examine the relationship between radiation dose and patient-reported xerostomia., Results: Sixty-three patients were included, most treated with 70 Gy in 33 fractions; 34 patients had mid-treatment CT scans. Both contralateral and ipsilateral PGs had considerable volume reduction from baseline to mid-treatment (25% and 27%, respectively, both p  < .001), significantly associated with mean PG dose (-0.44%/Gy, p  = .008 and -0.54%/Gy, p  < .001, respectively). There was a  > 5 Gy difference in mean PG and PGSC dose for 8/34 patients at mid-treatment, with 6/8 (75%) reporting severe xerostomia. Xerostomia prediction based on whole PG or PGSC region dose showed similar performance (ROC AUC 0.754 and 0.749, respectively). The corresponding dose-response models also predicted similar risk of patient-reported xerostomia with mean dose to the contralateral PG (32.5%) or PGSC region (31.4%) at the 20 Gy QUANTEC-recommended sparing level., Conclusions: The radiation dose to the PGSC region did not show stronger association with patient-reported xerostomia compared to that of whole PG, possibly due to considerable anatomical changes identified at mid-treatment. This shift in the size and position of the PG warrants adaptive planning strategies to evaluate the true benefit of parotid stem cell sparing.

Radionuclide irradiators (137Cs and 60Co) are commonly used in preclinical studies ranging from cancer therapy to stem cell biology. Amidst concerns of radiological terrorism, there are institutional initiatives to replace radionuclide sources with lower energy X-ray sources. As researchers transition, questions remain regarding whether the biological effects of γ-rays may be recapitulated with orthovoltage X-rays because different energies may induce divergent biological effects. We therefore sought to compare the effects of orthovoltage X-rays with 1-mm Cu or Thoraeus filtration and 137Cs γ-rays using mouse models of acute radiation syndrome. Following whole-body irradiation, 30-day overall survival was assessed, and the lethal dose to provoke 50% mortality within 30-days (LD50) was calculated by logistic regression. LD50 doses were 6.7 Gy, 7.4 Gy, and 8.1 Gy with 1-mm Cu-filtered X-rays, Thoraeus-filtered X-rays, and 137Cs γ-rays, respectively. Comparison of bone marrow, spleen, and intestinal tissue from mice irradiated with equivalent doses indicated that injury was most severe with 1-mm Cu-filtered X-rays, which resulted in the greatest reduction in bone marrow cellularity, hematopoietic stem and progenitor populations, intestinal crypts, and OLFM4+ intestinal stem cells. Thoraeus-filtered X-rays provoked an intermediate phenotype, with 137Cs showing the least damage. This study reveals a dichotomy between physical dose and biological effect as researchers transition to orthovoltage X-rays. With decreasing energy, there is increasing hematopoietic and intestinal injury, necessitating dose reduction to achieve comparable biological effects., Significance: Understanding the significance of physical dose delivered using energetically different methods of radiation treatment will aid the transition from radionuclide γ-irradiators to orthovoltage X-irradiators., (©2022 American Association for Cancer Research.)

Purpose: Liver-directed therapy after transarterial chemoembolization (TACE) can lead to improvement in survival for selected patients with unresectable hepatocellular carcinoma (HCC). However, there is uncertainty in the appropriate application and modality of therapy in current clinical practice guidelines. The aim of this study was to develop a proof-of-concept, machine learning (ML) model for treatment recommendation in patients previously treated with TACE and select patients who might benefit from additional treatment with combination stereotactic body radiotherapy (SBRT) or radiofrequency ablation (RFA)., Methods: This retrospective observational study was based on data from an urban, academic hospital system selecting for patients diagnosed with stage I-III HCC from January 1, 2008, to December 31, 2018, treated with TACE, followed by adjuvant RFA, SBRT, or no additional liver-directed modality. A feedforward, ML ensemble model provided a treatment recommendation on the basis of pairwise assessments evaluating each potential treatment option and estimated benefit in survival., Results: Two hundred thirty-seven patients met inclusion criteria, of whom 54 (23%) and 49 (21%) received combination of TACE and SBRT or TACE and RFA, respectively. The ML model suggested a different consolidative modality in 32.7% of cases among patients who had previously received combination treatment. Patients treated in concordance with model recommendations had significant improvement in progression-free survival (hazard ratio 0.5; P = .007). The most important features for model prediction were cause of cirrhosis, stage of disease, and albumin-bilirubin grade (a measure of liver function)., Conclusion: In this proof-of-concept study, an ensemble ML model was able to provide treatment recommendations for HCC who had undergone prior TACE. Additional treatment in line with model recommendations was associated with significant improvement in progression-free survival, suggesting a potential benefit for ML-guided medical decision making., Competing Interests: Nitin OhriConsulting or Advisory Role: Merck, GenentechResearch Funding: Merck (Inst), RefleXion Medical (Inst), AstraZeneca Shalom KalnickiTravel, Accommodations, Expenses: Elekta Chandan GuhaConsulting or Advisory Role: Johnson & Johnson, Varian Medical Systems, Focused Ultrasound FoundationResearch Funding: Celldex, Johnson & Johnson, Myelo Therapeutics GmbH (Inst)Patents, Royalties, Other Intellectual Property: Montefiore Medical CenterOpen Payments Link: https://openpaymentsdata.cms.gov/physician/480201 N. Patrik BrodinResearch Funding: Varian Medical Systems (Inst)No other potential conflicts of interest were reported.

Objective: To quantify the clinical performance of a machine learning (ML) algorithm for organ-at-risk (OAR) dose prediction for lung stereotactic body radiation therapy (SBRT) and estimate the treatment planning benefit from having upfront access to these dose predictions., Methods: ML models were trained using multi-center data consisting of 209 patients previously treated with lung SBRT. Two prescription levels were investigated, 50 Gy in five fractions and 54 Gy in three fractions. Models were generated using a gradient-boosted regression tree algorithm using grid searching with fivefold cross-validation. Twenty patients not included in the training set were used to test OAR dose prediction performance, ten for each prescription. We also performed blinded re-planning based on OAR dose predictions but without access to clinically delivered plans. Differences between predicted and delivered doses were assessed by root-mean square deviation (RMSD), and statistical differences between predicted, delivered, and re-planned doses were evaluated with one-way analysis of variance (ANOVA) tests., Results: ANOVA tests showed no significant differences between predicted, delivered, and replanned OAR doses (all p ≥ 0.36). The RMSD was 2.9, 3.9, 4.3, and 1.7Gy for max dose to the spinal cord, great vessels, heart, and trachea, respectively, for 50 Gy in five fractions. Average improvements of 1.0, 1.4, and 2.0 Gy were seen for spinal cord, esophagus, and trachea max doses in blinded replans compared to clinically delivered plans with 54 Gy in three fractions, and 1.8, 0.7, and 1.5 Gy, respectively, for the esophagus, heart and bronchus max doses with 50 Gy in five fractions. Target coverage was similar with an average PTV V100% of 94.7% for delivered plans compared to 97.3% for blinded re-plans for 50 Gy in five fractions, and respectively 98.4% versus 99.2% for 54 Gy in three fractions., Conclusion: This study validated ML-based OAR dose prediction for lung SBRT, showing potential for improved OAR dose sparing and more consistent plan quality using dose predictions for patient-specific planning guidance., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Purpose: Although fatigue is a known side effect in patients with head and neck cancer (HNC) receiving radiation therapy, knowledge regarding long-term fatigue and dose-response relationships to organs at risk is scarce. The aim of this prospective study was to analyze patient-reported fatigue in patients with HNC receiving radiation therapy and to explore any possible association with organ-at-risk doses., Methods and Materials: Patients with HNC referred for curative radiation therapy were eligible for inclusion in the study. To assess patient-reported fatigue, quality of life questionnaires (European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-FA12) were distributed before treatment and 1, 3, 6, 12, 24, and 60 months after the start of treatment. Mean dose (D mean ) and near maximum dose (D2%) of the cerebellum and brain stem were evaluated in relation to baseline-adjusted fatigue scores at 3 months., Results: One hundred twenty-six patients treated with intensity modulated radiation therapy between 2008 and 2010 were available for final analysis. Female sex and age <60 years were associated with higher fatigue at baseline, whereas patients also treated with chemotherapy had reduced physical and emotional fatigue at 6 months. Physical fatigue (QLQ-FA12 scale) increased from baseline up to 3 months (29 vs 59; P < .0001) but showed no difference compared with baseline from 1 to 5 years. Emotional fatigue was significantly lower at 5 years compared with baseline (14 vs 28; P < .0001). Patients with cerebellum D mean > 3.5 Gy had higher mean physical fatigue scores at 3 months (38 vs 27; P  = .036)., Conclusions: Although there is a significant increase in fatigue scores for patients with HNC up to 1 year after radiation therapy, this study showed a return to baseline levels at 5 years. A possible association was found between physical fatigue and a higher mean dose to the cerebellum., (© 2022 The Authors.)

Background and Purpose: Disease recurrence and distant metastases (DM) are major concerns for oropharyngeal cancer (OPC) patients receiving definitive chemo-radiotherapy. Here, we investigated whether pre-treatment primary tumor positron emission tomography (PET) features could predict progression-free survival (PFS) or DM., Methods and Materials: Primary tumors were delineated on pre-treatment PET scans for patients treated between 2005 and 2018 using gradient-based segmentation. Radiomic image features were extracted, along with SUV metrics. Features with zero variance and strong correlation to tumor volume, stage, p16 status, age or smoking were excluded. A random forest model was used to identify features associated with PFS. Kaplan-Meier methods, Cox regression and logistic regression with receiver operating characteristics (ROC) and 5-fold cross-validated areas-under-the-curve (CV-AUCs) were used., Results: A total of 114 patients were included. With median follow-up 40 months (range: 3-138 months), 14 patients had local recurrence, 21 had DM and 38 died. Two-year actuarial local control, distant control, PFS and overall survival was 89%, 84%, 70% and 84%, respectively. The wavelet&#95;LHL&#95;GLDZM&#95;LILDE feature slightly improved PFS prediction compared to clinical features alone (CV-AUC 0.73 vs. 0.71). Age > 65 years (HR = 2.64 (95%CI: 1.36-5.2), p = 0.004) and p16-negative disease (HR = 3.38 (95%CI: 1.72-6.66), p < 0.001) were associated with poor PFS. A binary radiomic classifier strongly predicted DM with multivariable HR = 3.27 (95%CI: 1.15-9.31), p = 0.027, specifically for patients with p16-negative disease with 2-year DM-free survival 83% for low-risk vs. 38% for high-risk patients (p = 0.004)., Conclusions: A radiomics signature strongly associated with DM risk could provide a tool for improved risk stratification, potentially adding adjuvant immunotherapy for high-risk patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Purpose: Immunotherapy is now a first-line treatment for metastatic non-small cell lung cancer (NSCLC) and melanomaQuery. It is important to understand the relationship between immunotherapy and radiation to the brain. The aim of this study was to assess the role of stereotactic radiosurgery (SRS) or WBRT in addition to immunotherapy in patients with melanoma or NSCLC metastatic to the brain., Methods/patients: Using the National Cancer Database, 2951 patients with NSCLC and 936 patients with melanoma treated with immunotherapy were identified. Patients were classified as having received immunotherapy alone, immunotherapy with SRS, or immunotherapy with whole-brain radiation therapy (WBRT). Kaplan-Meier, multivariate Cox regression analyses, and propensity matching were performed to evaluate the impact of adding SRS to immunotherapy on overall survival (OS). Immortal survival bias was accounted for by only including patients who received radiation before immunotherapy and time zero was defined as the start of immunotherapy., Results: 205(6.9%) and 75(8.0%) patients received immunotherapy with no radiation, 822(27.9%) and 326(34.8%) received SRS and immunotherapy, and 1924(65.2%) and 535(57.2%) received WBRT and immunotherapy for NSCLC and melanoma, respectively. Adding SRS to immunotherapy was associated with improved OS in multivariate analyses (NSCLC HR = 0.81, 95% CI 0.66-0.99, p = 0.044; melanoma HR = 0.63, 95% CI 0.45-0.90, p = 0.011). The addition of WBRT to immunotherapy did not improve OS in patients with melanoma nor NSCLC., Conclusions: This analysis suggests that treatment with SRS and immunotherapy is associated with improved OS compared to immunotherapy alone for patients with melanoma or NSCLC metastatic to the brain., (© 2021. Federación de Sociedades Españolas de Oncología (FESEO).)

Objectives This study aimed to evaluate quantitative and qualitative screening measures for anomalous computed tomography (CT) scans in cancer patients with potential coronavirus disease 2019 (COVID-19) as an automated detection tool in a radiation oncology treatment setting. Methods We identified a non-COVID-19 cohort and patients with suspected COVID-19 with chest CT scans from February 1, 2020 to June 30, 2020. Lungs were segmented, and a mean normal Hounsfield Unit (HU) histogram was generated for the non-COVID-19 CT scans; these were used to define thresholds for designating the COVID-19-suspected histograms as normal or abnormal. Statistical measures were computed and compared to the threshold levels, and density maps were generated to examine the difference between lungs with and without COVID-19 qualitatively. Results The non-COVID-19 cohort consisted of 70 patients with 70 CT scans, and the cohort of suspected COVID-19 patients consisted of 59 patients with 80 CT scans. Sixty-two patients were positive for COVID-19. The mean HUs and skewness of the intensity histogram discriminated between COVID-19 positive and negative cases, with an area under the curve of 0.948 for positive and 0.944 for negative cases. Skewness correctly identified 57 of 62 positive cases, whereas mean HUs correctly identified 17 of 18 negative cases. Density maps allowed for visualization of the temporal evolution of COVID-19 disease. Conclusions The statistical measures and density maps evaluated here could be employed in an automated screening algorithm for COVID-19 infection. The accuracy is high enough for a simple and rapid screening tool for early identification of suspected infection in patients treated with chemotherapy and radiation therapy already receiving CT scans as part of clinical care. This screening tool could also identify other infections that present critical risks for patients undergoing chemotherapy and radiation therapy, such as pneumonitis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Tomé et al.)

Purpose: Adolescent young adults (AYA) with Hodgkin lymphoma (HL) are treated according to either pediatric or adult protocols, however, the best strategy has yet to be established. We describe the AYA patients referred for radiotherapy and quantify the risk of radiation-induced late effects and the corresponding life years lost (LYL) following pediatric and adult regimens., Methods: Patients ≤24 years irradiated for HL were included. For each patient, organs at risk (OARs) were contoured and dosimetric parameters were extracted. Estimated excess hazard ratios of radiation-induced late effects were calculated from dose-response models and LYL attributable to various late effects were estimated., Results: In total, 77 patients were analyzed (pediatric regimen: 15; adult regimen: 62). Age, clinical stage, and the number of patients enrolled in protocols were significantly different between the groups. Pediatric patients had more advanced disease, which resulted in larger target volumes and higher doses to most OARs, despite a lower prescribed dose compared to adult regimens. LYL estimates were all higher with the pediatric regimens. Total LYL with pediatric and adult treatment regimens were 3.2 years and 2.3 years, respectively. Due to the clinical stage variation and heterogeneity in disease location, a direct comparison of the estimated risks of late effects was only exploratory., Conclusion: Pediatric regimens selected patients with more advanced disease to radiotherapy resulting in larger target volumes and higher doses to the OARs. Target volume rather than prescribed dose impacted OAR exposure. Consequently, the estimated risk of radiation-induced late effects and corresponding LYL was increased when compared to adult regimens., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

The prostate is a hormone-responsive organ where testicular androgens drive the proliferation and survival of prostatic cells, ensuring the development and functioning of this gland throughout life. Androgen deprivation therapy leads to apoptosis of prostatic cells and organ regression, and is a cornerstone of prostate cancer and benign prostatic hypertrophy treatment. For several decades, androgen deprivation has been used as an adjuvant to external beam radiotherapy, however, emerging data suggests that the low rates of epithelial proliferation in the castrated prostate imparts radio-resistance. As proliferating cells exhibit increased sensitivity to radiation, we hypothesized that short bursts of synchronized epithelial proliferation, which can be achieved by exogeneous testosterone supplementation prior to targeted high-dose radiation, would maximize sustained prostate ablation, while minimizing damage to surrounding tissues. To test this hypothesis, we designed a novel computed-tomography (CT)-guided stereotactic prostate radiation therapy (CT-SPRT) technique to deliver a single high-dose 25 Gy fraction of X-ray radiation. Sustained prostatic cell ablation was assessed post CT-SPRT by measuring prostate weight, epithelial cell number, and relative contributions of luminal and basal epithelial populations in control and testosterone-pretreated glands. CT-SPRT was safely delivered with no observed damage to surrounding rectal and bladder tissues. Importantly, castrated mice that received a pulse of testosterone to induce synchronous cell proliferation prior to CT-SPRT exhibited significant sustained gland ablation compared to control mice. These results provide new insights in stereotactic radiotherapy sensitivity to maximize prostatic cell ablation and improve our understanding of prostate gland regeneration that can potentially lead to improved non-invasive therapies for benign prostatic hypertrophy and prostate cancer.

Background: Proton therapy is a promising advancement in radiation oncology especially in terms of reducing normal tissue toxicity, although it is currently expensive and of limited availability. Here we estimated the individual quality of life benefit and cost-effectiveness of proton therapy in patients with oropharyngeal cancer treated with definitive radiation therapy (RT), as a decision-making tool for treatment individualization., Methods and Materials: Normal tissue complication probability models were used to estimate the risk of dysphagia, esophagitis, hypothyroidism, xerostomia and oral mucositis for 33 patients, comparing delivered photon intensity-modulated RT (IMRT) plans to intensity-modulated proton therapy (IMPT) plans. Quality-adjusted life years (QALYs) lost were calculated for each complication while accounting for patient-specific conditional survival probability and assigning quality-adjustment factors based on complication severity. Cost-effectiveness was modeled based on upfront costs of IMPT and IMRT, and the cost of acute and/or long-term management of treatment complications. Uncertainties in all model parameters and sensitivity analyses were included through Monte Carlo sampling., Results: The incremental cost-effectiveness ratios (ICERs) showed considerable variability in the cost of QALYs spared between patients, with median $361,405/QALY for all patients, varying from $54,477/QALY to $1,508,845/QALY between individual patients. Proton therapy was more likely to be cost-effective for patients with p16-positive tumors ($234,201/QALY), compared to p16-negative tumors ($516,297/QALY). For patients with p16-positive tumors treated with comprehensive nodal irradiation, proton therapy is estimated to be cost-effective in ≥ 50% of sampled cases for 8/9 patients at $500,000/QALY, compared to 6/24 patients who either have p16-negative tumors or receive unilateral neck irradiation., Conclusions: Proton therapy cost-effectiveness varies greatly among oropharyngeal cancer patients, and highlights the importance of individualized decision-making. Although the upfront cost, societal willingness to pay and healthcare administration can vary greatly among different countries, identifying patients for whom proton therapy will have the greatest benefit can optimize resource allocation and inform prospective clinical trial design.

Purpose: Analyses from the ACRIN6668/RTOG0235 trial data identified the SumMean textural feature, calculated from 18-fluorodeoxyglucose positron emission tomography for tumors with a metabolic tumor volume >93 cm 3 , as a predictor of overall survival (OS) for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy. Here, we validated that finding in a completely independent patient cohort from a single institution., Methods and Materials: We identified patients with LA-NSCLC who underwent staging 18-fluorodeoxyglucose positron emission tomography and received definitive chemoradiation therapy at our institution between 2007 and 2018. Primary tumors were segmented semiautomatically, and SumMean score was calculated for each tumor and categorized according to the previously proposed cutoff of 0.018. In patients with metabolic tumor volume >93 cm 3 , SumMean was evaluated as a predictor of progression-free survival (PFS) and OS using log rank and Cox proportional hazards testing., Results: One hundred forty-eight patients met inclusion criteria, and 34 had large tumors (>93 cm 3 ). Twelve (35%) had high SumMean, and 22 (65%) had low SumMean. SumMean was not significantly associated with other clinical variables. Median PFS for patients with large tumors and low SumMean was 5.8 months, compared with 41.1 months for patients with large tumors and high SumMean (log rank P = .022). Median OS for patients with large tumors and low SumMean was 15.0 months; median OS was not reached for patients with large tumors and high SumMean (log rank P = .014). In multivariable analysis, high SumMean was an independent predictor of improved OS (hazard ratio, 0.26; 95% confidence interval, 0.07-0.94; P = .041) and PFS (hazard ratio, 0.30; 95% confidence interval, 0.10-0.86; P = .026)., Conclusions: We externally validated SumMean as a prognostic marker for patients with LA-NSCLC treated with chemoradiation therapy in an independent patient cohort. Future studies will explore potential mechanisms for this association and how textural features may help guide treatment decisions., (Copyright © 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Importance: Hepatocellular carcinoma (HCC) is a heterogeneous disease with many available treatment modalities. Transarterial chemoembolization (TACE) is a valuable treatment modality for HCC lesions. This article seeks to evaluate the utility of additional ablative therapy in the management of patients with HCC who received an initial TACE procedure., Objective: To compare the overall survival (OS) and freedom from local progression (FFLP) outcomes after TACE alone with TACE that is followed by an ablative treatment regimen using stereotactic body radiation therapy, radiofrequency ablation, or microwave ablation for patients with HCC., Design, Setting, and Participants: This cohort study of 289 adults at a single urban medical center examined survival outcomes for patients with nonmetastatic, unresectable HCC who received ablative therapies following TACE or TACE alone from January 2010 through December 2018. The Lee, Wei, Amato common baseline hazard model was applied for within-patient correlation with robust variance and Cox regression analysis was used to assess the association between treatment group (TACE vs TACE and ablative therapy) and failure time events (FFLP per individual lesion and OS per patient), respectively. In both analyses, the treatment indication was modeled as a time-varying covariate. Landmark analysis was used as a further sensitivity test for bias by treatment indication., Exposures: TACE alone vs TACE followed by ablative therapy., Main Outcomes and Measures: Freedom from local progression and overall survival. Hypotheses were generated before data collection., Results: Of the 289 patients identified, 176 (60.9%) received TACE only and 113 (39.1%) received TACE plus ablative therapy. Ablative therapy included 45 patients receiving stereotactic body radiation therapy, 39 receiving microwave ablation, 20 receiving radiofrequency ablation, and 9 receiving a combination of these following TACE. With a median (interquartile range) follow-up of 17.4 (9.5-29.5) months, 242 of 512 (47.3%) lesions progressed, 211 in the group with TACE alone and 31 in the group with TACE plus ablative therapy (P < .001). Over 3 years, FFLP was 28.1% for TACE alone vs 67.4% for TACE with ablative therapy (P < .001). The 1-year and 3-year OS was 87.5% and 47.1% for patients with lesions treated with TACE alone vs 98.7% and 85.3% for patients where any lesion received TACE plus ablative therapy, respectively (P = .01), and this benefit remained robust on landmark analyses at 6 and 12 months. The addition of ablative therapy was independently associated with OS on multivariable analysis for all patients (hazard ratio, 0.26; 95% CI, 0.13-0.49; P < .001) and for patients with Barcelona clinic liver cancer stage B or C disease (hazard ratio, 0.31; 95% CI, 0.14-0.69; P = .004)., Conclusions and Relevance: Adding ablative therapy following TACE improved FFLP and OS among patients with hepatocellular carcinoma. This study aims to guide the treatment paradigm for HCC patients until results from randomized clinical trials become available.

Importance: As of May 11, 2020, there have been more than 290 000 deaths worldwide from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). Risk-adjusted differences in outcomes among patients of differing ethnicity and race categories are not well characterized., Objectives: To investigate whether presenting comorbidities in patients with COVID-19 in New York City differed by race/ethnicity and whether case fatality rates varied among different ethnic and racial groups, controlling for presenting comorbidities and other risk factors., Design, Setting, and Participants: This cohort study included 5902 patients who presented for care to the Montefiore Medical Center, a large urban academic medical center in the Bronx, New York, between March 14 and April 15, 2020, and tested positive for SARS-CoV-2 on reverse transcription quantitative polymerase chain reaction assay. Final data collection was April 27, 2020., Exposures: Patient characteristics, including self-identified ethnicity/race, age, sex, socioeconomic status, and medical comorbidities, were tabulated., Main Outcomes and Measures: Overall survival. Associations between patient demographic characteristics, comorbidities, and race/ethnicity were examined using χ2 tests, and the association with survival was assessed using univariable and multivariable Cox proportional hazards regression, based on time from positive COVID-19 test., Results: Of 9268 patients who were tested, 5902 ethnically diverse patients (63.7%) had SARS-CoV-2. Of these, 3129 patients (53.0%) were women, and the median (interquartile range) age was 58 (44-71) years. A total of 918 patients (15.5%) died within the study time frame. Overall, 1905 patients (32.3%) identified as Hispanic; 1935 (32.8%), non-Hispanic Black; 509 (8.6%), non-Hispanic White; and 171 (2.9%), Asian; the death rates were 16.2% (309), 17.2% (333), 20.0% (102), and 17.0% (29), respectively (P = .25). Hispanic and non-Hispanic Black patients had a higher proportion of more than 2 medical comorbidities with 654 (34.3%) and 764 (39.5%), respectively, compared with 147 (28.9%) among non-Hispanic White patients (P < .001). Hispanic and non-Hispanic Black patients were also more likely to test positive for COVID-19 than White patients, with 1905 of 2919 Hispanic patients (65.3%), 1935 of 2823 non-Hispanic Black patients (68.5%), and 509 of 960 non-Hispanic White patients (53.0%) having positive test results for SARS-CoV-2 (P < .001). While controlling for age, sex, socioeconomic status and comorbidities, patients identifying as Hispanic (hazard ratio, 0.77; 95% CI, 0.61-0.98; P = .03) or non-Hispanic Black (hazard ratio, 0.69; 95% CI, 0.55-0.87; P = .002) had slightly improved survival compared with non-Hispanic White patients., Conclusions and Relevance: In this cohort study of patients with COVID-19 who presented for care at the same urban medical center, non-Hispanic Black and Hispanic patients did not experience worse risk-adjusted outcomes compared with their White counterparts. This finding is important for understanding the observed population differences in mortality by race/ethnicity reported elsewhere.

Background: Optimal alignment is of utmost importance when treating pediatric patients with craniospinal irradiation (CSI), especially with regards to field junctions and multiple isocenters and techniques applying high dose gradients. Here, we investigated the setup errors and uncertainties for pediatric CSI using different setup verification protocols., Methods: A total of 38 pediatric patients treated with CSI were identified for whom treatment records and setup images were available. The setup images were registered retrospectively to the reference image using an automated tool and matching on bony anatomy, subsequently, the impact of different correction protocols was simulated., Results: For an action-level (AL)-protocol and a non-action level (NAL)-protocol, the translational residual setup error can be as large as 24 mm for an individual patient during a single fraction, and the rotational error as large as 6.1°. With daily IGRT, the maximum setup errors were reduced to 1 mm translational and 5.4° rotational versus 1 mm translational and 2.4° rotational for 3- and 6- degrees of freedom (DoF) couch shifts, respectively. With a daily 6-DoF IGRT protocol for a wide field junction irradiation technique, the residual positioning uncertainty was below 1 mm and 1° for translational and rotational directions, respectively. The largest rotational uncertainty was found for the patients' roll even though this was the least common type of rotational error, while the largest translational uncertainty was found in the patients' anterior-posterior-axis., Conclusions: These results allow for informed margin calculation and robust optimization of treatments. Daily IGRT is the superior choice for setup of pediatric patients treated with CSI, although centers that do not have this option could use the results presented here to improve their margins and uncertainty estimates for a more accurate treatment alignment.

Bone marrow (BM) mesenchymal stem and progenitor cells (MSPCs) are a critical constituent of the hematopoietic stem cell (HSC) niche. Previous studies have suggested that the zinc-finger epithelial-mesenchymal transition transcription factor Snai2 (also known as Slug) regulated HSCs autonomously. Here, we show that Snai2 expression in the BM is restricted to the BM stromal compartment where it regulates the HSC niche. Germline or MSPC-selective Snai2 deletion reduces the functional MSPC pool and their mesenchymal lineage output and impairs HSC niche function during homeostasis and after stress. RNA sequencing analysis revealed that Spp1 (osteopontin) expression is markedly upregulated in Snai2-deficient MSPCs. Genetic deletion of Spp1 in Snai2-deficient mice rescues MSPCs' functions. Thus, SNAI2 is a critical regulator of the transcriptional network maintaining MSPCs by the suppression of osteopontin expression., Competing Interests: Declaration of Interests P.S.F. has served as consultant for Pfizer, received research funding from Ironwood Pharmaceuticals, and owns stock options of Cygnal Therapeutics., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: To describe the incidental detection of COVID-19 disease on positron-emission tomography/computed tomography (PET/CT) in a patient with cancer despite initial negative swab by polymerase chain reaction (PCR)., Case Report: Clinical and radiographic data were obtained from the electronic medical record. Nasopharyngeal swabs were obtained and evaluated for COVID-19 by the Food and Drug Administration-approved reverse transcription-PCR assays. On radiographic examination, PET/CT was consistent with COVID-19-related pneumonia not seen on prior imaging. Initial nasopharyngeal swab 2 days after PET/CT imaging was negative for COVID-19. Subsequent repeat swab 10 days later was positive for COVID-19, while the patient was febrile on screening assessment. The patient remained COVID-19-positive until 1 month after abnormal PET/CT imaging., Conclusion: PET/CT can be sensitive for early COVID-19 detection, even in the setting of a negative confirmatory PCR test. This highlights the importance of continued patient surveillance and use of appropriate personal protective equipment to minimize COVID-19 transmission., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: There have been nearly 200,000 deaths worldwide so far from coronavirus disease 2019 (COVID-19), which is caused by a coronavirus called SARS-CoV-2. Cancer history appears to be a poor prognostic factor for COVID-19 patients, although the reasons for this are unclear. In this report, we assess whether extent of prior lung irradiation is a risk factor for death as a result of COVID-19 infection., Methods and Materials: Patients who tested positive for COVID-19 between March 14 and April 15, 2020, at our institution and who previously received radiation therapy for cancer in our department were included in this analysis. Patient characteristics and metrics describing the extent of lung irradiation were tabulated. Cox regression models were used to identify predictors of death after COVID-19 diagnosis. A logistic model was used to characterize the association between mean lung radiation therapy dose and 14-day mortality risk after COVID-19 diagnosis., Results: For the study, 107 patients met the inclusion criteria. With a median follow-up of 7 days from COVID-19 diagnosis for surviving patients, 24 deaths have been observed. The actuarial survival rate 14 days after COVID-19 testing is 66%. Increasing mean lung dose (hazard ratio [HR] per Gy = 1.1, P = .002), lung cancer diagnosis (HR = 3.0, P = .034), and receiving radiation therapy between 1 month and 1 year before COVID-19 testing (HR = 3.4, P = .013) were associated with increased risk of death. Our survival model demonstrates a near linear relationship between mortality risk after COVID-19 diagnosis and mean lung radiation therapy dose., Conclusions: COVID-19 patients with a history of radiation therapy for cancer have a poor prognosis, and mortality risk appears to be associated with extent of lung irradiation. Validation of these findings will be critical as the COVID-19 pandemic continues., (© 2020 The Authors.)

Purpose: Image-guided small animal irradiators (IGSAI) are increasingly being adopted in radiation biology research. These animal irradiators, designed to deliver radiation with submillimeter accuracy, exhibit complexity similar to that of clinical radiation delivery systems, including image guidance, robotic stage motion, and treatment planning systems. However, physics expertise and resources are scarcer in radiation biology, which makes implementation of conventional prescriptive QA infeasible. In this study, we apply the failure modes and effect analysis (FMEA) popularized by the AAPM task group 100 (TG-100) report to IGSAI and radiation biological research., Methods: Radiation biological research requires a change in paradigm where small errors to large populations of animals are more severe than grievous errors that only affect individuals. To this end, we created a new adverse effects severity table adapted to radiation biology research based on the original AAPM TG-100 severity table. We also produced a process tree which outlines the main components of radiation biology studies performed on an IGSAI, adapted from the original clinical IMRT process tree from TG-100. Using this process tree, we created and distributed a preliminary survey to eight expert IGSAI operators in four institutions. Operators rated proposed failure modes for occurrence, severity, and lack of detectability, and were invited to share their own experienced failure modes. Risk probability numbers (RPN) were calculated and used to identify the failure modes which most urgently require intervention., Results: Surveyed operators indicated a number of high (RPN >125) failure modes specific to small animal irradiators. Errors due to equipment breakdown, such as loss of anesthesia or thermal control, received relatively low RPN (12-48) while errors related to the delivery of radiation dose received relatively high RPN (72-360). Errors identified could either be improved by manufacturer intervention (e.g., electronic interlocks for filter/collimator) or physics oversight (errors related to tube calibration or treatment planning system commissioning). Operators identified a number of failure modes including collision between the collimator and the stage, misalignment between imaging and treatment isocenter, inaccurate robotic stage homing/translation, and incorrect SSD applied to hand calculations. These were all relatively highly rated (90-192), indicating a possible bias in operators towards reporting high RPN failure modes., Conclusions: The first FMEA specific to radiation biology research was applied to image-guided small animal irradiators following the TG-100 methodology. A new adverse effects severity table and a process tree recognizing the need for a new paradigm were produced, which will be of great use to future investigators wishing to pursue FMEA in radiation biology research. Future work will focus on expanding scope of user surveys to users of all commercial IGSAI and collaborating with manufacturers to increase the breadth of surveyed expert operators., (© 2020 American Association of Physicists in Medicine.)

PET using 18-fluorodeoxyglucose (FDG) has become an important part of the work-up for non-small cell lung cancer (NSCLC). This article summarizes advancements in using FDG-PET for patients with locally advanced NSCLC treated with definitive radiation therapy (RT). This article discusses prognostication of outcome based on pretreatment or midtreatment PET metrics, using textural image features to predict treatment outcomes, and using PET to define RT target volumes and inform RT dose modifications. The role of PET is evolving and is moving toward using quantitative image information, with the overarching goal of individualizing therapy to improve outcomes for patients with NSCLC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To determine if anal cancer patients with HPV positive disease have different overall survival (OS) compared to those with HPV negative disease, and to elucidate differences in the association between radiation dose and OS. Patients and methods: We utilized the National Cancer Database (NCDB) registry to identify a cohort of non-metastatic anal cancer patients treated with curative intent between 2008 and 2014. Propensity score matching was used to account for potential selection bias between patients with HPV positive and negative disease. Multivariable Cox regression was used to determine the association between HPV status and OS. Kaplan-Meier methods were used to compare actuarial survival estimates. Results: We identified 5927 patients with tumor HPV status for this analysis, 3523 (59.4%) had HPV positive disease and 2404 (40.6%) had HPV negative disease. Propensity-matched analysis demonstrated that patients with HPV positive locally advanced (T3-4 or node positive) anal cancer had better OS (HR = 0.81 (95%CI: 0.68-0.96), p =.018). For patients with early stage disease (T1-2 and node negative) there was no difference in OS (HR = 1.11 (95%CI: 0.86-1.43), p =.43). In the unmatched cohort, we found a significant improvement in OS with increasing radiation dose only for patients with locally advanced, HPV negative disease ( p <.001). In those patients, significant improvement in OS compared to the group receiving 30-45 Gy was seen for increasing doses up to 55-60 Gy, but not beyond 60 Gy. Conclusion: We found HPV to be a significant prognostic marker in anal tumors, especially for locally advanced disease. We further found that higher radiation dose up to 55-60 Gy was associated with better OS, but only for patients with locally advanced, HPV negative disease.

Radiation therapy (RT) has traditionally not been widely used in the management of hepatic malignancies for fear of toxicity in the form of radiation-induced liver disease (RILD). Pre-clinical hepatic irradiation models can provide clinicians with better understanding of the radiation tolerance of the liver, which in turn may lead to the development of more effective cancer treatments. Previous models of hepatic irradiation are limited by either invasive laparotomy procedures, or the need to irradiate the whole or large parts of the liver using external skin markers. In the setting of modern-day radiation oncology, a truly translational animal model would require the ability to deliver RT to specific parts of the liver, through non-invasive image guidance methods. To this end, we developed a targeted hepatic irradiation model on the Small Animal Radiation Research Platform (SARRP) using contrast-enhanced cone-beam computed tomography image guidance. Using this model, we showed evidence of the early development of region-specific RILD through functional single photon emission computed tomography (SPECT) imaging.

Background: There is recent interest in treating locally advanced rectal cancer (LARC) patients with total neoadjuvant therapy (TNT). However, whether TNT is associated with improved overall survival (OS) remains unknown. This study compares outcomes following TNT and following neoadjuvant chemoradiation therapy (nCRT) in patients with LARC, clinically defined cT3/4 or node positive disease, using the National Cancer Database., Methods: LARC patients diagnosed between 2004-2015 were included. TNT was defined as multi-agent chemotherapy given at least 2 months before RT followed by pre-operative chemoradiation therapy and definitive surgery without adjuvant chemotherapy. nCRT was defined as pre-operative RT and chemotherapy started within 2 weeks from each other followed by definitive surgery with or without adjuvant chemotherapy. Kaplan-Meier curve with logrank test and multivariable Cox proportional hazards regression modelling were used to analyse the primary endpoint of overall survival (OS). Multivariable logistic regression modelling was used for secondary outcomes to determine if TNT is associated with pathological complete response (pCR), defined as ypT0N0, and negative circumferential resection margin (CRM)., Findings: Data from 372 TNT patients and 707 nCRT patients were analysed after a 2:1 propensity matching with replacement. Kaplan-Meier curve showed that OS with TNT was comparable to that with nCRT ( p  = 0•16). The 5-year OS rates for TNT and nCRT were 73•6% vs. 78•5% ( p  = 0•20). Multivariable Cox proportional hazards regression modelling confirmed no difference in OS between TNT and nCRT (HR = 1•21, p  = 0•25). With TNT, 16•9% patients achieved pCR, whereas 13•1% patients achieved pCR with nCRT ( p  = 0•12). TNT was not found to be significantly associated with pCR (OR = 1•36, p  = 0•13) or negative CRM (OR = 1•77, p  = 0•19) in multivariable logistic regression modelling., Interpretation: With results from current clinical trials pending, our data suggested that TNT and nCRT resulted in similar survival, while TNT led to higher pCR and CRM negative rate, albeit not statistically significant., Competing Interests: NO receives research support from Merck and receive consulting fees from Merck and AstraZeneca unrelated to this manuscript., (© 2019 Published by Elsevier Ltd.)

Background: Patients with lower socioeconomic status (SES), ethnic minorities and elevated neutrophil-lymphocyte ratio (NLR) have been suggested to have worse outcomes in hepatocellular carcinoma (HCC). However, how changes in NLR after intervention relate to survival has not been elucidated., Objectives: We evaluated the association of NLR with overall survival (OS) and progression-free survival (PFS) in a large institutional cohort of HCC., Methods: We reviewed all patients diagnosed with HCC between 2005-2016. The association between elevated NLR (> 4) and survival was examined with univariable and multivariable Cox regression., Results: We identified 991 patients diagnosed with HCC. Lower SES and Hispanic and non-Hispanic Black ethnicity were significantly associated with lower NLR (p = 0.015 and 0.019, respectively). Elevated NLR, but not SES or ethnicity, was an independent predictor of worse OS (HR = 1.66, p < 0.001) and PFS (HR = 1.25, p = 0.032). The median OS in patients with elevated NLR was 8 months, compared to 42 months in patients with normal NLR. Patients with elevated NLR unresponsive to treatment and those with NLR that became elevated after treatment had significantly worse 3-year OS (47% and 44%, respectively), compared to patients whose NLR remained normal or normalized after treatment (72% and 80%, respectively; p < 0.01)., Conclusions: Our study showed that elevated NLR, but not SES or ethnicity, is an independent prognostic marker for OS and PFS in patients with HCC. NLR trends following intervention were highly predictive of outcome. NLR is easy to obtain and would provide valuable information to clinicians in evaluating prognosis and monitoring response after procedures.

Purpose: Using in vivo measurements from optically stimulated luminescence dosimeters (OSLDs) to develop and validate a prediction model for estimating the skin dose received by patients undergoing breast intraoperative radiation therapy (IORT)., Methods and Materials: IORT was performed using INTRABEAM-600 with spherical applicators placed in the lumpectomy cavity. Ultrasound skin bridge measurements were used to determine the applicator-to-skin distance, with OSLDs placed to measure the skin surface dose at the corresponding points. The OSLD response was calibrated for the 50 kVp INTRABEAM-600 output. Models were fit to describe the dose fall-off with increasing applicator-to-skin distance and the best fitting model was chosen for estimating skin dose., Results: Twenty four patients with 25 lumpectomy cavities were included, and the average skin dose recorded was 1.18 Gy ± 0.88 Gy, ranging from 0.17 Gy to 4.77 Gy, with an average applicator-to-skin distance of 19.9 mm ± 5.1 mm. An exponential-plateau model was found to best describe the dose fall-off with a root-mean-square error of 0.73. This model was then validated prospectively using skin dose measurements from five consecutive patients. Validation measurements were well within the 95% prediction limits of the model, with a root-mean-square error of 0.52, showing that the prediction model accurately estimates skin dose using ultrasound skin bridge measurements., Conclusions: This prediction model constitutes a useful tool for estimating the skin dose received during breast lumpectomy IORT. The model and accompanying 95% confidence intervals can be used to establish a minimum allowable skin bridge distance, effectively limiting the maximum allowable skin dose., (Copyright © 2019 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Developing a quantitative decision-support strategy estimating the impact of normal tissue complications from definitive radiation therapy (RT) for head and neck cancer (HNC). We developed this strategy to identify patients with oropharyngeal HNC who may benefit most from receiving proton RT., Methods and Materials: Recent normal tissue complication probability (NTCP) models for dysphagia, esophagitis, hypothyroidism, xerostomia, and oral mucositis were used to estimate NTCP for 33 patients with oropharyngeal HNC previously treated with photon intensity modulated radiation therapy (IMRT). Comparative proton therapy plans were generated using clinical protocols for HNC RT at a collaborating proton center. Organ-at-risk (OAR) doses from photon and proton RT plans were used to calculate NTCPs; Monte Carlo sampling 10,000 times was used for each patient to account for model parameter uncertainty. The latency and duration of each complication were modeled from calculated NTCP, accounting for age-, sex-, smoking- and p16-specific conditional survival probability. Complications were then assigned quality-adjustment factors based on severity to calculate quality-adjusted life years (QALYs) lost from each complication., Results: Based on our institutional-delivered photon IMRT doses and the achievable proton therapy doses, the average QALY reduction from all HNC RT complications for photon and proton therapy was 1.52 QALYs versus 1.15 QALYs, with proton therapy sparing 0.37 QALYs on average (composite 95% confidence interval, 0.27-2.53 QALYs). Long-term complications (dysphagia and xerostomia) contributed most to the QALY reduction. The QALYs spared with proton RT varied considerably among patients, ranging from 0.06 to 0.84 QALYs. Younger patients with p16-positive tumors who smoked ≤10 pack-years may benefit most from proton therapy, although this finding should be validated using larger patient series. A sensitivity analysis reducing photon IMRT doses to all OARs by 20% resulted in no overall estimated benefit with proton therapy with -0.02 QALYs spared, although some patients still had an estimated benefit in this scenario, ranging from -0.50 to 0.43 QALYs spared., Conclusions: This quantitative decision-support strategy allowed us to identify patients with oropharyngeal cancer who might benefit the most from proton RT, although the estimated benefit of proton therapy ultimately depends on the OAR doses achievable with modern photon IMRT solutions. These results can help radiation oncologists and proton therapy centers optimize resource allocation and improve quality of life for patients with HNC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: The aim of our study was to report on patterns of failure using detailed information from follow-up positron emission tomography-computed tomography (PET/CT) scans for patients with laryngeal squamous cell carcinoma (SCCA) treated with definitive radiation therapy using intensity-modulated radiation therapy (IMRT)., Methods: One hundred and sixty-eight patients with laryngeal SCCA treated with definitive IMRT using a simultaneous integrated boost were included. The point of recurrence origin on follow-up PET/CT was determined using two separate data-driven methods. The first method, the mathematical epicenter point of origin (PO Epi ), calculated the mathematical focal epicenter point for which the maximum distance to the surface of the surrounding volume was smaller than for any other point. The second method, maximum standardized uptake value point of origin (PO Max ), calculated the voxel with maximum standardized uptake value (SUV) uptake within the recurrence volume. The failure pattern was then determined by whether the point of recurrence origin fell within the low, intermediate, or high-risk target volumes in the original treatment planning CT., Results: Thirty-five primary/nodal recurrences in 33 patients were included in the analysis. In the PO Epi method, 94% (33/35) of all recurrences originated either within the high-risk gross tumor volume (GTV High-risk ) or within an average of 0.9 ± 1.3 mm from it. In the PO Max method, 91% (32/35) of all recurrences originated either within the GTV High-risk or within an average of 1.8 ± 1.7 mm from it. There were no recurrences outside the low-risk planning target volume (PTV Low-risk ) for the PO Epi method but there was one for the PO Max method, which was 19.8 mm away from the edge of the gross tumor volume receiving 70 Gy (GTV 70 ). Increasing distance between the two different origin points was strongly correlated with the size of the recurrence volume., Conclusion: The majority of recurrences for laryngeal cancer patients treated with definitive IMRT originated from within the high-dose treatment region. This can have implications for reducing clinical target volumes while using a risk-adaptive treatment approach to both constrain dose to critical areas and further escalate the dose to the gross tumor to improve locoregional control rates., Competing Interests: The authors have declared that no competing interests exist.

Surgical cavity sizing applicators were developed for utilization prior to intraoperative radiation therapy (IORT) of the breast lumpectomy cavity with the Zeiss INTRABEAM (Carl Zeiss Meditec AG, Jena, Germany) device. The use of these applicators minimizes the number of sterilizations of the treatment applicator, which is currently limited to 100 sterilizations per applicator. This maximizes the number of patients who can be treated with each applicator, resulting in cost savings for the treating institution., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To evaluate whether a response assessment using mid-treatment computed tomography (CT) scans during definitive radiation therapy (RT) for oropharyngeal head and neck cancer can predict for locoregional recurrence (LRR)., Methods and Materials: Head and neck cancer patients who receive RT at our institution undergo CT repeat scans at the 15th fraction, with treatment replanning in the case of an inadequate dose to gross disease or an increased dose to organs at risk. A retrospective cohort analysis was performed of 96 consecutive patients with oropharyngeal cancer treated from 2007 to 2015 with mid-treatment repeat CT scans available. The primary disease volume and involved lymph node volume were delineated on the pre- and mid-treatment CT scans. Univariable and multivariable Cox proportional hazards regression analyses were used to evaluate the efficacy of the mid-treatment reduction in tumor volume as a predictor of LRR. Risk stratification was performed by dichotomizing the patients into high- and low-risk groups according to the mid-treatment response and p16 status and smoking history., Results: With a median follow-up of 34 months, 14 patients experienced LRR. The median reduction in the total tumor volume was 18.7% (interquartile range 8.4%-30.9%). A reduction in total tumor volume greater than the median was an independent predictor of LRR (hazard ratio 0.22, 95% confidence interval 0.05-0.89; P = .020). The reduction in primary tumor volume was an even stronger predictor of LRR (hazard ratio 0.11, 95% confidence interval 0.02-0.57; P = .002). Stratifying patients into a high-risk group for those with a reduction in the total tumor volume at mid-treatment at or less than the median, p16 negative status, and smoking status of >10 pack-years and a low-risk group for those without these factors, we found a clear separation in Kaplan-Meier curves, with actuarial 3-year locoregional control, progression-free survival, and overall survival rates for the high-risk patients of 45.7%, 38.2%, and 71.8% compared with 90.7%, 70.6%, and 89.8% for low-risk patients, respectively (P ≤ .021 for all)., Conclusions: Our results have shown that the treatment response from an early assessment using mid-treatment CT scans is an independent predictor of LRR and can be used to effectively distinguish high- and low-risk patients, allowing for risk-adaptive treatment stratification at the midway point., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Head and neck cancer poses a particular challenge in radiation therapy, whilst being an effective treatment modality it requires very high doses of radiation to provide effective therapy. This is further complicated by the fact that the head and neck region contains a large number of radiosensitive tissues, often resulting in patients experiencing debilitating normal tissue complications. In the era of intensity-modulated radiation therapy (IMRT) treatments can be delivered using non-uniform dose distributions selectively aimed at reducing the dose to critical organs-at-risk while still adequately covering the tumor target. Dose-volume constraints for the different risk organs play a vital role in one's ability to devise the best IMRT treatment plan for a head and neck cancer patient. To this end, it is pivotal to have access to the latest and most relevant dose constraints available and as such the goal of this review is to provide a summary of suggested dose-volume constraints for head and neck cancer RT that have been published after the QUANTEC reports were made available in early 2010., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Purpose: The purpose of this study was to investigate whether treatment information from medical records can be used to estimate radiation doses to heart and lungs retrospectively in pediatric patients receiving spinal irradiation with conventional posterior fields., Material and Methods: An algorithm for retrospective dosimetry in children treated with spinal irradiation was developed in a cohort of 21 pediatric patients with available CT-scans and treatment plans. We developed a multivariable linear regression model with explanatory variables identifiable in case note review for retrospective estimation of minimum, maximum, mean and V 10% -V 80% doses to the heart and lungs. Doses were estimated for both linear accelerator (Linac) and 60 Co radiation therapy modalities., Results: Age and spinal field width were identified as statistically significant predictors of heart and lung doses in multivariable analyses (p < 0.01 in all models). Models showed excellent predictive performance with R 2  = 0.70 for mean heart dose and 0.79 for mean lung dose, for Linac plans. In leave-one-out cross-validation analysis the average difference between predicted and actual mean heart dose was 6.7% and 7.6% of the prescription dose for Linac and 60 Co plans, respectively, and 5.2% and 4.9% for mean lung dose. Due to the small sample size and large inter-patient variation in heart and lung dose, prospective studies validating these findings are highly warranted., Conclusions: The models presented here provide retrospective estimates of heart and lung doses for historical cohorts of pediatric patients, thus facilitating studies of long-term adverse effects of radiation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To investigate whether photon or proton-based stereotactic body radiation therapy (SBRT is the preferred modality for high dose hypofractionation prostate cancer treatment. Achievable dose distributions were compared when uncertainties in target positioning and range uncertainties were appropriately accounted for., Methods: 10 patients with prostate cancer previously treated at our institution (Montefiore Medical Center) with photon SBRT using volumetric modulated arc therapy (VMAT) were identified. MRI images fused to the treatment planning CT allowed for accurate target and organ at risk (OAR) delineation. The clinical target volume was defined as the prostate gland plus the proximal seminal vesicles. Critical OARs include the bladder wall, bowel, femoral heads, neurovascular bundle, penile bulb, rectal wall, urethra and urogenital diaphragm. Photon plan robustness was evaluated by simulating 2 mm isotropic setup variations. Comparative proton SBRT plans employing intensity modulated proton therapy (IMPT) were generated using robust optimization. Plan robustness was evaluated by simulating 2 mm setup variations and 3% or 1% Hounsfield unit (HU) calibration uncertainties., Results: Comparable maximum OAR doses are achievable between photon and proton SBRT, however, robust optimization results in higher maximum doses for proton SBRT. Rectal maximum doses are significantly higher for Robust proton SBRT with 1% HU uncertainty compared to photon SBRT (p = 0.03), whereas maximum doses were comparable for bladder wall (p = 0.43), urethra (p = 0.82) and urogenital diaphragm (p = 0.50). Mean doses to bladder and rectal wall are lower for proton SBRT, but higher for neurovascular bundle, urethra and urogenital diaphragm due to increased lateral scatter. Similar target conformality is achieved, albeit with slightly larger treated volume ratios for proton SBRT, >1.4 compared to 1.2 for photon SBRT., Conclusion: Similar treatment plans can be generated with IMPT compared to VMAT in terms of target coverage, target conformality, and OAR sparing when range and HU uncertainties are neglected. However, when accounting for these uncertainties during robust optimization, VMAT outperforms IMPT in terms of achievable target conformity and OAR sparing. Advances in knowledge: Comparison between achievable dose distributions using modern, robust optimization of IMPT for high dose per fraction SBRT regimens for the prostate has not been previously investigated.

There has recently been an increasing interest in model-based evaluation and comparison of different treatment options in radiation oncology studies. This is partly driven by the considerable technical advancements in radiation therapy of the last decade, leaving radiation oncologists with a multitude of options to consider. In lieu of randomized trials comparing all of these different treatment options for varying indications, which is unfeasible, treatment evaluations based on normal tissue complication probability (NTCP) models offer a practical alternative. The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) effort, culminating in a number of reports published in 2010, provided a basis for many of the since-implemented dose-response models and dose-volume constraints and was a key component for model-based treatment evaluations. Given that 7 years have passed since the QUANTEC publications and that patient-reported outcomes have emerged as an important consideration in recent years, an updated summary of the published radiation dose-response literature, which includes a focus on patient-reported quality of life outcomes, is warranted. Here we provide a systematic review of quantitative dose-response models published after January 1, 2010 for endpoints relevant to radiation therapy for head and neck cancer, because these patients are typically at risk for a variety of treatment-induced normal tissue complications., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Currently, interactions between voxels are neglected in the tumor control probability (TCP) models used in biologically-driven intensity-modulated radiotherapy treatment planning. However, experimental data suggests that this may not always be justified when bystander effects are important. We propose a model inspired by the Ising model, a short-range interaction model, to investigate if and when it is important to include voxel to voxel interactions in biologically-driven treatment planning. This Ising-like model for TCP is derived by first showing that the logistic model of tumor control is mathematically equivalent to a non-interacting Ising model. Using this correspondence, the parameters of the logistic model are mapped to the parameters of an Ising-like model and bystander interactions are introduced as a short-range interaction as is the case for the Ising model. As an example, we apply the model to study the effect of bystander interactions in the case of radiation therapy for prostate cancer. The model shows that it is adequate to neglect bystander interactions for dose distributions that completely cover the treatment target and yield TCP estimates that lie in the shoulder of the dose response curve. However, for dose distributions that yield TCP estimates that lie on the steep part of the dose response curve or for inhomogeneous dose distributions having significant hot and/or cold regions, bystander effects may be important. Furthermore, the proposed model highlights a previously unexplored and potentially fruitful connection between the fields of statistical mechanics and tumor control probability/normal tissue complication probability modeling., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: Due to the long life expectancy after treatment, the risk of late effects after radiotherapy (RT) is of particular importance for patients with Hodgkin lymphoma (HL). Both deep inspiration breath hold (DIBH) and proton therapy have been shown to reduce the dose to normal tissues for mediastinal HL, but the impact of these techniques in combination is unknown. The purpose of this study was to compare the life years lost (LYL) attributable to late effects after RT for mediastinal HL using intensity modulated radiation therapy (IMRT) in free breathing (FB) and DIBH, and proton therapy in FB and DIBH., Materials and Methods: Plans for each technique were created for 22 patients with HL. Doses were extracted and the risk of late effects and LYL were estimated., Results: We found that the use of DIBH, proton therapy, and the combination significantly reduced the LYL compared to IMRT in FB. The lowest LYL was found for proton therapy in DIBH. However, when IMRT in DIBH was compared to proton therapy in FB, no significant difference was found., Conclusions: Patient-specific plan comparisons should be used to select the optimal technique when comparing IMRT in DIBH and proton therapy in FB., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Currently, no readily available mitigators exist for acute abdominal radiation injury. Here, we present an animal model for precise and homogenous limb-sparing abdominal irradiation (LSAIR) to study the radiation-induced gastrointestinal syndrome (RIGS)., Materials and Methods: The LSAIR technique was developed using the small animal radiation research platform (SARRP) with image guidance capabilities. We delivered LSAIR at doses between 14 and 18 Gy on 8- to 10-week-old male C57BL/6 mice. Histological analysis was performed to confirm that the observed mortality was due to acute abdominal radiation injury., Results: A steep dose-response relationship was found for survival, with no deaths seen at doses below 16 Gy and 100% mortality at above 17 Gy. All deaths occurred between 6 and 10 days after irradiation, consistent with the onset of RIGS. This was further confirmed by histological analysis showing clear differences in the number of regenerative intestinal crypts between animals receiving sublethal (14 Gy) and 100% lethal (18 Gy) radiation., Conclusion: The developed LSAIR technique provides uniform dose delivery with a clear dose response, consistent with acute abdominal radiation injury on histological examination. This model can provide a useful tool for researchers investigating the development of mitigators for accidental or clinical high-dose abdominal irradiation., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

WNT/β-catenin signalling is crucial for intestinal homoeostasis. The intestinal epithelium and stroma are the major source of WNT ligands but their origin and role in intestinal stem cell (ISC) and epithelial repair remains unknown. Macrophages are a major constituent of the intestinal stroma. Here, we analyse the role of macrophage-derived WNT in intestinal repair in mice by inhibiting their release using a macrophage-restricted ablation of Porcupine, a gene essential for WNT synthesis. Such Porcn-depleted mice have normal intestinal morphology but are hypersensitive to radiation injury in the intestine compared with wild-type (WT) littermates. Porcn-null mice are rescued from radiation lethality by treatment with WT but not Porcn-null bone marrow macrophage-conditioned medium (CM). Depletion of extracellular vesicles (EV) from the macrophage CM removes WNT function and its ability to rescue ISCs from radiation lethality. Therefore macrophage-derived EV-packaged WNTs are essential for regenerative response of intestine against radiation.

Purpose: Tissue-mimicking thermal therapy phantoms that coagulate at specific temperatures are valuable tools for developing and evaluating treatment strategies related to thermal therapy. Here, the authors propose a simple and efficient method for determining the coagulation threshold temperature of transparent thermal therapy gel phantoms., Methods: The authors used a previously published gel phantom recipe with 2% (w/v) of bovine serum albumin as the temperature-sensitive protein. Using the programmable heating settings of a polymerase chain reaction (PCR) machine, the authors heated 50 μl gel samples to various temperatures for 3 min and then imaged them using the BioRad Gel Doc system to determine the coagulation temperature using an opacity quantification method. The estimated coagulation temperatures were then validated for gel phantoms prepared with different pH levels using high-intensity focused ultrasound (HIFU) heating and magnetic resonance imaging (MRI) thermometry methods on a clinical MR-HIFU system., Results: The PCR heating method produced consistent and reproducible coagulation of gel samples in precise correlation with the set incubation temperatures. The resulting coagulation threshold temperatures for gel phantoms of varying pH levels were found to be 44.1 ± 0.1, 53.4 ± 0.9, and 60.3 ± 0.9 °C for pH levels of 4.25, 4.50, and 4.75, respectively. This corresponded well with the coagulation threshold temperatures determined by MR-thermometry, with coagulation defined as a 95% decrease in T2 relaxation time, which were estimated at 53.6 ± 1.9 and 62.9 ± 2.4 °C for a pH of 4.50 and 4.75, respectively., Conclusions: The opacity quantification method provides a fast and reproducible estimate of the coagulation threshold temperature of transparent temperature-sensitive gel phantoms. The temperatures determined using this method were well within the range of temperatures estimated using MR-thermometry. Due to the specific heating capabilities of the PCR machine, and the robust determination of coagulation threshold temperatures based on the statistically significant increase in the opacity of gel samples, coagulation temperatures can be determined more precisely and with less variability compared to MRI-based methods.

Shielded Cs irradiators are routinely used in pre-clinical radiation research to perform in vitro or in vivo investigations. Without appropriate dosimetry and irradiation protocols in place, there can be large uncertainty in the delivered dose of radiation between irradiated subjects that could lead to inaccurate and possibly misleading results. Here, a dosimetric evaluation of the JL Shepard Mark I-68A Cs irradiator and an irradiation technique for whole-body irradiation of small animals that allows one to limit the between subject variation in delivered dose to ±3% are provided. Mathematical simulation techniques and Gafchromic EBT film were used to describe the region within the irradiation cavity with homogeneous dose distribution (100% ± 5%), the dosimetric impact of varying source-to-subject distance, and the variation in attenuation thickness due to turntable rotation. Furthermore, an irradiation protocol and dosimetry formalism that allows calculation of irradiation time for whole-body irradiation of small animals is proposed that is designed to ensure a more consistent dose delivery between irradiated subjects. To compare this protocol with the conventional irradiation protocol suggested by the vendor, high-resolution film dosimetry measurements evaluating the dose difference between irradiation subjects and the dose distribution throughout subjects was performed using phantoms resembling small animals. Based on these results, there can be considerable variation in the delivered dose of > ± 5% using the conventional irradiation protocol for whole-body irradiation doses below 5 Gy. Using the proposed irradiation protocol this variability can be reduced to within ±3% and the dosimetry formalism allows for more accurate calculation of the irradiation time in relation to the intended prescription dose.

We reviewed the literature for studies pertaining to impaired adult neurogenesis leading to neurocognitive impairment following cranial irradiation in rodent models. This compendium was compared with respect to radiation dose, converted to equivalent dose in 2 Gy fractions (EQD2) to allow for direct comparison between studies. The effects of differences between animal species and the dependence on animal age as well as for time after irradiation were also considered. One of the major sites of de novo adult neurogenesis is the hippocampus, and as such, this review also focuses on assessing evidence related to the expression and potential effects of inflammatory cytokines on neural stem cells in the subgranular zone of the dentate gyrus and whether this correlates with neurocognitive impairment. This review also discusses potential strategies to mitigate the detrimental effects on neurogenesis and neurocognition resulting from cranial irradiation, and how the rationale for these strategies compares with the current outcome of pre-clinical studies.

Modern pre-clinical radiation therapy (RT) research requires high precision and accurate dosimetry to facilitate the translation of research findings into clinical practice. Several systems are available that provide precise delivery and on-board imaging capabilities, highlighting the need for a quality management program (QMP) to ensure consistent and accurate radiation dose delivery. An ongoing, simple, and efficient QMP for image-guided robotic small animal irradiators used in pre-clinical RT research is described. Protocols were developed and implemented to assess the dose output constancy (based on the AAPM TG-61 protocol), cone-beam computed tomography (CBCT) image quality and object representation accuracy (using a custom-designed imaging phantom), CBCT-guided target localization accuracy and consistency of the CBCT-based dose calculation. To facilitate an efficient read-out and limit the user dependence of the QMP data analysis, a semi-automatic image analysis and data representation program was developed using the technical computing software MATLAB. The results of the first 6-mo experience using the suggested QMP for a Small Animal Radiation Research Platform (SARRP) are presented, with data collected on a bi-monthly basis. The dosimetric output constancy was established to be within ±1 %, the consistency of the image resolution was within ±0.2 mm, the accuracy of CBCT-guided target localization was within ±0.5 mm, and dose calculation consistency was within ±2 s (±3%) per treatment beam. Based on these results, this simple quality assurance program allows for the detection of inconsistencies in dosimetric or imaging parameters that are beyond the acceptable variability for a reliable and accurate pre-clinical RT system, on a monthly or bi-monthly basis.

Cancer patients undergoing cranial irradiation are at risk of developing neurocognitive impairments. Recent evidence suggests that radiation-induced injury to the hippocampi could play an important role in this cognitive decline. As a tool for studying the mechanisms of hippocampal-dependent cognitive decline, we developed a mouse model replicating the results of the recent clinical RTOG 0933 study of hippocampal sparing whole-brain irradiation. We irradiated 16-week-old female C57BL/6J mice to a single dose of 10 Gy using either whole-brain irradiation (WBRT) or hippocampal sparing irradiation (HSI). These animals, as well as sham-irradiated controls, were subjected to behavioral/cognitive assessments distinguishing between hippocampal-dependent and hippocampal-independent functions. Irradiation was well tolerated by all animals and only limited cell death of proliferating cells was found within the generative zones. Animals exposed to WBRT showed significant deficits compared to sham-irradiated controls in the hippocampal-dependent behavioral task. In contrast, HSI mice did not perform significantly different from sham-irradiated mice (control group) and performed significantly better when compared to WBRT mice. This is consistent with the results from the RTOG 0933 clinical trial, and as such this animal model could prove a helpful tool for exploring new strategies for mitigating cognitive decline in cancer patients receiving cranial irradiation.