Purpose: The objective of this work is to test the validity of the Gaussian approximation for prostate motion through characterization of its spatial distribution. Methods and Materials: Real-time intrafraction prostate motion was observed using Calypso 4-dimensional (4D) nonradioactive electromagnetic tracking system. We report the results from a total of 1024 fractions from 31 prostate cancer patients. First, the correlation of prostate motion in right/left (RL), anteroposterior (AP), and superoinferior (SI) direction were determined using Pearson's correlation of coefficient. Then the spatial distribution of prostate motion was analyzed for individual fraction, individual patient including all fractions, and all patients including all fractions. The displacement in RL, AP, SI, oblique, or total direction is fitted into a Gaussian distribution, and a Lilliefors test was used to evaluate the validity of the hypothesis that the displacement is normally distributed. Results: There is high correlation in AP/SI direction (61% of fractions with medium or strong correlation). This is consistent with the longitudinal oblique motion of the prostate, and likely the effect from respiration on an organ confined within the genitourinary diaphragm with the rectum sitting posteriorly and bladder sitting superiorly. In all directions, the non-Gaussian distribution is more common for individual fraction, individual patient including all fractions, and all patients including all fractions. The spatial distribution of prostate motion shows an elongated shape in oblique direction, indicating a higher range of motion in the AP and SI directions. Conclusions: Our results showed that the prostate motion is highly correlated in AP and SI direction, indicating an oblique motion preference. In addition, the spatial distribution of prostate motion is elongated in an oblique direction, indicating that the organ motion dosimetric modeling using Gaussian kernel may need to be modified to account for the particular organ motion character of prostate.

Abstract: The role of consolidative radiotherapy (RT) in patients ≥60 years old with DLBCL in the rituximab era is controversial. We examined the impact on disease control and overall survival by the addition of consolidative RT after completion of chemotherapy, while adjusting for known adverse risk factors. Retrospective chart review from 2004 to 2012 of 83 consecutive patients ≥60 years old with DLBCL treated in the rituximab era, 68 of which had a complete response to chemotherapy, was performed. Amongst patients with a complete response, consolidative RT use was associated with 100% 5-year local control, improved progression-free survival (p = 0.047), and a trend for overall survival (p =.098) on multivariate analysis. Amongst all patients, the use of consolidative RT was associated with improved overall survival (p = 0.03). The use of consolidative RT should be considered for patients ≥60 years old independent of stage and response to chemotherapy.

We retrospectively compared the outcomes and toxicities of melanoma brain metastases (MBM) patients treated with BRAF inhibitors (BRAFi) and stereotactic radiosurgery (SRS) with SRS alone. We identified 87 patients with 157 MBM treated with SRS alone from 2005 to 2013. Of these, 15 (17.2%) patients with 32 MBM (21.4%) received BRAFi therapy: three (20.0%) before SRS, two (13.3%) concurrent, and 10 (66.7%) after SRS. Overall survival (OS) was compared between cohorts using the product limit method. Intracranial outcomes were compared using cumulative incidence with competing risk for death. Baseline patient characteristics were similar between groups, except for the SRS cohort, which had higher rates of chemotherapy and more recent year of diagnosis. Radiation characteristics, including dose per fraction, total dose, gross tumor volume size, and prescription isodose, were also similar between cohorts. One-year outcomes-OS (64.3 vs. 40.4%, P=0.205), local failure (3.3 vs. 9.6%, P=0.423), and distant intracranial failure (63.9 vs. 65.1%, P=0.450) were not statistically different between the SRS+BRAFi and SRS-alone groups, respectively. The SRS+BRAFi group showed higher rates of radiographic radiation necrosis (RN) (22.2 vs. 11.0% at 1 year, P<0.001) and symptomatic radiation necrosis (SRN) (28.2 vs. 11.1% at 1 year, P<0.001). Multivariable analysis showed that BRAFi predicted an increased risk of both radiographic and SRN. SRS and BRAFi predicted for an increased risk of radiographic and SRN compared with SRS alone. Approaches to mitigate RN for patients receiving SRS and BRAFi should be considered until the clinical trial (http//:www.clinicaltrials.gov: NCT01721603) evaluating this treatment regimen is completed.

Background Radiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (abscopal effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) stimulated antitumor immune response. Here, we investigated whether the LN is also important in mediating a RT alone stimulated abscopal response. Methods We used a subcutaneous modified B16F10 flank tumor model injected bilaterally. Our B16F10 cell line has an inserted viral glycoprotein which facilitated identification of tumor-specific T-cells. RT was directed at one flank tumor alone or one flank tumor and the tumor-draining LN. We evaluated response by tumor growth measurements and flow cytometry of both tumor-infiltrating and LN T-cells. Results We show that local tumor irradiation improves distant tumor control (abscopal effect). Depletion of CD8 + T-cells significantly reduced this abscopal response. We have previously shown, in a chronic lymphocytic choriomeningitis virus (LCMV) infection, that the T-cell proliferative burst following blockade of PD-1/L1 is provided by a 'stem-like' CD8 + T-cell subset which then differentiate into terminally differentiated effectors. These terminally differentiated effectors have the potential to kill virally infected or tumor cells following PD-1/L1 blockade. In the chronic LCMV infection, stem-like CD8 + T-cells were found exclusively in secondary lymphoid organs. Similarly, here we found these cells at high frequencies in the tumor-draining LN, but at low frequencies within the tumor. The effect of RT on this T-cell subset in unknown. Interestingly, tumor irradiation stimulated total CD8 + and stem-like CD8 + T-cell proliferation in the LN. When the LN and the tumor were then targeted with RT, the abscopal effect was reduced, and we found a concomitant reduction in the number of total tumor-specific CD8 + T-cells and stem-like CD8 + T-cells in both the irradiated and unirradiated tumor. Conclusions These correlative results suggest the tumor-draining LN may be an important mediator of the abscopal effect by serving as a stem-like CD8 + T-cell reservoir, a site for stem-like T-cell expansion, and a site from which they can populate the tumor.

Background and purpose: Antibodies against programmed cell death protein 1 (PD-1) are standard treatments for advanced melanoma. Palliative radiation therapy (RT) is commonly administered for this disease. Safety and optimal timing for this combination for melanoma has not been established. Materials and methods: In this retrospective cohort study, records for melanoma patients who received anti-PD-1 therapy at Duke University or Emory University (1/1/2013–12/30/2015) were reviewed. Patients were categorized by receipt of RT and RT timing relative to anti-PD-1. Results: 151 patients received anti-PD-1 therapy. Median follow-up was 12.9 months. Patients receiving RT (n = 85) had worse baseline prognostic factors than patients without RT (n = 66). One-year overall survival (OS) was lower for RT patients than patients without RT (66%, 95% CI: 55–77% vs 83%, 95% CI: 73–92%). One-year OS was 61% for patients receiving RT before anti-PD-1 (95% CI: 46−76%), 78% for RT during anti-PD-1 (95% CI: 60–95%), and 58% for RT after anti-PD-1 (95% CI: 26–89%). On Cox regression, OS for patients without RT did not differ significantly from patients receiving RT during anti-PD-1 (HR 1.07, 95% CI: 0.41–2.84) or RT before anti-PD-1 (HR 0.56, 95% CI: 0.21–1.45). RT and anti-PD-1 therapy administered within 6 weeks of each other was well tolerated. Conclusion: RT can be safely administered with anti-PD-1 therapy. Despite worse baseline prognostic characteristics for patients receiving RT, OS was similar for patients receiving concurrent RT with anti-PD-1 therapy compared to patients receiving anti-PD-1 therapy alone.

Low-dose radiation therapy (LD-RT) has historically been a successful treatment for pneumonia and is clinically established as an immunomodulating therapy for inflammatory diseases. The ongoing COVID-19 pandemic has elicited renewed scientific interest in LD-RT and multiple small clinical trials have recently corroborated the historical LD-RT findings and demonstrated preliminary efficacy and immunomodulation for the treatment of severe COVID-19 pneumonia. The present review explicates archival medical research data of LD-RT and attempts to translate this into modernized evidence, relevant for the COVID-19 crisis. Additionally, we explore the putative mechanisms of LD-RT immunomodulation, revealing specific downregulation of proinflammatory cytokines that are integral to the development of the COVID-19 cytokine storm induced hyperinflammatory state. Radiation exposure in LD-RT is minimal compared to radiotherapy dosing standards in oncology care and direct toxicity and long-term risk for secondary disease are expected to be low. The recent clinical trials investigating LD-RT for COVID-19 confirm initial treatment safety. Based on our findings we conclude that LD-RT could be an important treatment option for COVID-19 patients that are likely to progress to severity. We advocate the further use of LD-RT in carefully monitored experimental environments to validate its effectiveness, risks and mechanisms of LD-RT.

Background: Radiotherapy-induced lymphopenia may be limiting the success of therapy and could also negatively affect the ability of immune system in mediating the bystander (BE) and abscopal effects (AE). A novel SBRT-based PArtial Tumor irradiation of HYpoxic clonogenic cells (SBRT-PATHY) for induction of the tumoricidal BE and AE by sparing the peritumoral immune microenvironment and regional circulating lymphocytes has been developed to enhance the radiotherapy therapeutic ratio of advanced lung cancer. The aim of this retrospective review of prospectively collected mono-institutional phase 2 study was to compare the outcomes between unconventional SBRT-PATHY and standard of care in unresectable stage IIIB/IV bulky NSCLC. Materials and methods: Sixty patients considered inoperable or unsuitable for radical radio-chemotherapy were enrolled and treated using the following 3 regimens: SBRT-PATHY (group I, n = 20 patients), recommended standard of care chemotherapy (group II, n = 20 patients), and institutional conventional palliative radiotherapy (group III, n = 20 patients). Results: Median follow-up was 13 months. The 1-year overall survival was 75, 60, and 20% in groups 1, 2 and 3, respectively (p = 0.099). The 1-year cancer specific survival was 90, 60, and 20% in groups 1, 2, and 3, respectively (p = 0.049). Bulky tumor control rate was 95% for SBRT-PATHY compared with 20% in the other two groups. BE and AE were seen by SBRT-PATHY in 95 and 45% of patients, respectively. Multi-variate analysis for cancer specific survival was significant for treatment effect with SBRT-PATHY (p < 0.001) independent of age, sex, performance status, histology, stage, treated bulky site and tumor diameter. SBRT-PATHY resulted in lower toxicity (p = 0.026), and improved symptom control (p = 0.018) when compared to other two treatment options. Conclusion: SBRT-PATHY improved treatment outcomes in unresectable NSCLC and should be investigated in larger trials. Present study has been retrospectively registered on 8th of August 2019 by the ethic committee for Austrian region .,Kärnten "in Klagenfurt (AUT), under study number A 31/19.

Spatially Fractionated Radiation therapy (SFRT) has a history of over 100 years. The principle of SFRT is distinctive from the standard radiation approaches, as it treats the total tumor with a non-uniform dose, effectively treating the tumor while staying within normal tissue tolerance of the surrounding structures. Historically, SFRT is frequently used to treat bulky malignant tumors with a high radiation dose in the stereotactic radiosurgery (SRS)/stereotactic body radiotherapy (SBRT) dose range (10–20 Gy per fraction) using megavoltage x-ray beams. The application of SFRT, historically known as GRID therapy, has produced dramatic relief of severe symptoms, significant objective regression, above average local control rates and minimal toxicity in palliative settings [1]. The advancement of physics and technology has provided more techniques to deliver SFRT. Some understandings of radiobiology and immunology have been generated from studies of SFRT. These promising clinical results have generated a renewed interest in this technique at many centers in the United States and internationally. A series of novel application of SFRT in clinical trials are being anticipated in the near future. Here, we summarize the history, the present and the future of SFRT. As current reviews of SFRT are lacking, we present a comprehensive review of SFRT and its clinical implications.

Aim. To determine absorbed radiation dose (ARD) in radiosensitive organs during prospective and full phase dose modulation using ECG-gated MDCTA scanner under 64- and 320-row detector modes. Methods. Female phantom was used to measure organ radiation dose. Five DP-3 radiation detectors were used to measure ARD to lungs, breast, and thyroid using the Aquilion ONE scanner in 64- and 320-row modes using both prospective and dose modulation in full phase acquisition. Five measurements were made using three tube voltages: 100, 120, and 135 kVp at 400 mA at heart rate (HR) of 60 and 75 bpm for each protocol. Mean acquisition was recorded in milligrays (mGy). Results. Mean ARD was less for 320-row versus 64-row mode for each imaging protocol. Prospective EKG-gated imaging protocol resulted in a statistically lower ARD using 320-row versus 64-row modes for midbreast (6.728 versus 19.687 mGy, P < 0.001), lung (6.102 versus 21.841 mGy, P < 0.001), and thyroid gland (0.208 versus 0.913 mGy; P < 0.001). Retrospective imaging using 320- versus 64-row modes showed lower ARD for midbreast (10.839 versus 43.169 mGy, P < 0.001), lung (8.848 versus 47.877 mGy, P < 0.001), and thyroid gland (0.057 versus 2.091 mGy; P < 0.001). ARD reduction was observed at lower kVp and heart rate. Conclusions. Dose reduction to radiosensitive organs is achieved using 320-row compared to 64-row modes for both prospective and retrospective gating, whereas 64-row mode is equivalent to the same model 64-row MDCT scanner.

There has yet to be any clinical case studies demonstrating the efficacy, safety, and response of combined therapy with 4-1BB agonists and radiation. This report provides the first case of immune costimulatory directed therapy potentially augmented with RT after progression of disease despite several treatments with immunotherapy. Based on preclinical data and results presented in this case, radiation combined with 4-1BB agonists may have a unique and potent effect in addition to other therapies.