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Highlights • This review summarizes the current state of cardiac radioablation (CRA) for ventricular tachycardia. • Clinical data and radiobiologic principles supporting CRA are reviewed. • An example workflow, including guidance for interpreting cardiac mapping, is provided., Cardiac radioablation with SBRT is a very promising non-invasive modality for the treatment of refractory VT and potentially other cardiac arrhythmias. Initial reports indicate that it is relatively safe and associated with excellent responses, particularly in reduction of ICD-related events, need for anti-arrhythmic medications, and resulting in significantly improved quality of life for patients. Establishment of objective criteria for candidates for cardiac radioablation will accelerate the adoption of this important radiation therapy modality in the treatment of refractory VT and other cardiac arrhythmias in the coming years. In addition, in order to develop more prospective safety and efficacy data, treatment of patients should ideally be performed in the context of clinical trials or prospective registries at, or in collaboration with, experienced centers. Taken together, the future of cardiac radioablation is rich and worthy of further investigation to become a standard treatment in the armamentarium against refractory VT.

Purpose Cardiac radioablation using stereotactic body radiation therapy is gaining popularity as a noninvasive treatment for otherwise refractory ventricular arrhythmias. As radiation oncologists might be unaccustomed to the lexicon used by cardiologists to describe the location of arrhythmogenic foci, a preliminary guide to cardiac-specific anatomy and orientation is needed to foster effective communication between the radiation oncologist and cardiology team. Methods and Materials Electrocardiogram-gated and respiratory-gated computed tomography imaging was acquired per institutional protocol. Additional relevant imaging modalities are described. The American Heart Association 17-segment model is described in detail because this framework is used frequently by cardiologists to describe the location left ventricular abnormalities. Results A step-by-step guide is provided for properly rotating the heart from standard orthogonal views obtained during radiation simulation to the cardiac-specific orientation needed to appreciate the 17-segment model. Once the proper configuration is achieved, the location of each segment is defined in detail. Conclusions This atlas serves as an introduction to the relevant anatomy and principles, and it provides a suggested approach to help delineate cardiac radioablation targets using the established American Heart Association 17-segment model.

Delayed radiation myelopathy is a rare, but significant late side effect from radiation therapy that can lead to paralysis. The cellular and molecular mechanisms leading to delayed radiation myelopathy are not completely understood, but may be a consequence of damage to oligodendrocyte progenitor cells and vascular endothelial cells. Here, we aimed to determine the contribution of endothelial cell damage to the development of radiation-induced spinal cord injury using a genetically defined mouse model in which endothelial cells are sensitized to radiation due to loss of the tumor suppressor p53. Tie2Cre; p53(FL/+) and Tie2Cre; p53(FL/−) mice, which lack one and both alleles of p53 in endothelial cells, respectively, were treated with focal irradiation that specifically targeted the lumbosacral region of the spinal cord. The development of hindlimb paralysis was followed for up to 18 weeks after a single fraction of 26.7 Gy or 28.4 Gy. During 18 weeks of follow-up, 83% and 100% of Tie2Cre; p53(FL/−) mice developed hindlimb paralysis after 26.7 and 28.4 Gy, respectively. In contrast, during this period only 8% of Tie2Cre; p53(FL/+) mice exhibited paralysis after 28.4 Gy. In addition, 8 weeks after 28.4 Gy the irradiated spinal cord from Tie2Cre; p53(FL/−) mice showed a significantly higher fractional area positive for the neurological injury marker glial fibrillary acidic protein (GFAP) compared with the irradiated spinal cord from Tie2Cre; p53(FL/+) mice. Together, our findings show that deletion of p53 in endothelial cells sensitizes mice to the development of delayed radiation myelopathy indicating that endothelial cells are a critical cellular target of radiation that regulates myelopathy.

Some patients elect for self-pay proton radiation therapy (PT) in the United States, but price transparency is a significant concern. The U.S. government recently declared that hospitals must provide a comprehensive list of "standard" charges for all services. Yet, the proportion of compliant proton centers is unknown, as is the extent to which prices vary nationally.We obtained online chargemasters from U.S. proton centers. Technical charges for per fraction delivery of PT of varying complexity were obtained by billing code (77520, 77522, 77523, 77525) and keyword searches. Prices were adjusted for cost-of-living differences using the Medicare geographic cost price index. The relationship between prices for each PT billing code and cost of living was assessed. The interrelationship in cost between codes was examined. The effect of geographic region and other key variables on pricing was explored.Thirty-six proton centers were identified. Twenty-eight (78%) had accessible chargemasters with 20 (56%) listing at least one PT charge. The median prices for billing codes 77520, 77522, 77523, 77525 were $4707, $4712, $5904, and $6690, respectively, with a trend toward greater cost for more complex therapy (77523, 77525; P = .056). Large ranges ($16,863, $16,059, $18,414, $22,143) resulted in ratios of maximum/minimum prices of 5 to 10x. Only prices for code 77522 were associated with cost of living (P = .039). Across institutions, prices for all 4 codes were positively interrelated (all P.0001). Prices differed between regions (P.0001) but not by National Cancer Institute designation.List prices for PT differ dramatically between institutions and regions without obvious explanation, raising the concerning possibility that such variation is largely arbitrary. Policy solutions that promote rationalized pricing would greatly benefit this patient population.

Objectives: Neutrophil-lymphocyte ratio (NLR) has been associated with mortality in non-small cell lung cancer (NSCLC), but its association with recurrence in locally advanced NSCLC (LA-NSCLC), specifically, is less established. We hypothesized pre- and post-treatment NLR would be associated with recurrence and mortality. Methods: We studied the association of pre-treatment NLR (pre-NLR) and post-treatment NLR at 1 (post-NLR1) and 3 months (post-NLR3) with outcomes in patients with LA-NSCLC treated with chemoradiation. Pre-NLR was dichotomized by 5, an a priori cutoff previously shown to be prognostic in LA-NSCLC. Post-NLR1 and post-NLR3 were dichotomized by their medians. Linear and logistic regression were used to correlate thoracic vertebral body dose with post-NLR. Results: We identified 135 patients treated with chemoradiation for LA-NSCLC between 2007 and 2016. Median follow-up for living patients was 61.1 months. On multivariable analysis, pre-NLR ≥ 5 was associated with worse overall survival (HR = 1.82; 95% CI 1.15 – 2.88; p = 0.011), but not with any recurrence, locoregional recurrence, or distant recurrence. Post-NLR1 ≥ 6.3 was not associated with recurrence or survival. Post-NLR3 ≥ 6.6 was associated with worse overall survival (HR = 3.27; 95% CI 2.01– 5.31; p < 0.001), any recurrence (HR = 2.50; 95% CI 1.53 – 4.08; p < 0.001), locoregional recurrence (HR = 2.50; 95% CI 1.40 – 4.46; p = 0.002), and distant recurrence (HR = 2.53; 95% CI 1.49 – 4.30; p < 0.001). Post-NLR3 ≥ 6.6 correlated with thoracic vertebral body volume receiving 5 Gy (p = 0.026), 10 Gy (p = 0.041), and 60 Gy (p = 0.044). Conclusion: Pre-treatment NLR is associated with worse overall survival and post-treatment NLR is associated with worse survival and recurrence. Additionally, post-treatment NLR at 3 months correlates with thoracic vertebral body dose. These findings should be validated independently and prospectively studied.

Background and purpose Late cardiac toxicity is a major side effect of radiation therapy (RT) for breast cancer. We developed and characterized a mouse model of radiation-induced heart disease that mimics the dose, fractionation, and beam arrangement of left breast and chest wall RT. Material and methods Female wild-type (C57BL6/J) and atherosclerosis-prone apolipoprotein E-deficient (ApoE−/−) mice (on a C57BL/6J background) on regular chow were treated with 2 Gy × 25 fractions of partial-heart irradiation via opposed tangential beams to the left chest wall. The changes in myocardial perfusion and cardiac function of C57BL/6J mice were examined by single-photon emission computed tomography (SPECT) and echocardiography, respectively. In addition to SPECT and echocardiography, the formation of calcified plaques and changes in cardiac function of ApoE−/− mice were examined by dual-energy microCT (DE-CT) and pressure–volume (PV) loop analysis, respectively. The development of myocardial fibrosis was examined by histopathology. Results Compared to unirradiated controls, irradiated C57BL/6J mice showed no significant changes by SPECT or echocardiography up to 18 months after 2 Gy × 25 partial-heart irradiation even though irradiated mice exhibited a modest increase in myocardial fibrosis. For ApoE−/− mice, 2 Gy × 25 partial-heart irradiation did not cause significant changes by SPECT, DE-CT, or echocardiography. However, PV loop analysis revealed a significant decrease in load-dependent systolic and diastolic function measures including cardiac output, dV/dtmax and dV/dt min 12 months after RT. Conclusions Following clinically relevant doses of partial-heart irradiation in C57BL/6J and ApoE−/− mice, assessment with noninvasive imaging modalities such as echocardiography, SPECT, and DE-CT yielded no evidence of decreased myocardial perfusion and cardiac dysfunction related to RT. However, invasive hemodynamic assessment with PV loop analysis indicated subtle, but significant, changes in cardiac function of irradiated ApoE−/− mice. PV loop analysis may be useful for future preclinical studies of radiation-induced heart disease, especially if subtle changes in cardiac function are expected.

Carbon ion therapy (CIT) offers several potential advantages for treating cancers compared with X-ray and proton radiotherapy, including increased biological efficacy and more conformal dosimetry. However, CIT potency has not been characterized in primary tumor animal models. Here, we calculate the relative biological effectiveness (RBE) of carbon ions compared with X-rays in an autochthonous mouse model of soft tissue sarcoma. We used Cre/loxP technology to generate primary sarcomas in KrasLSL-G12D/+; p53fl/fl mice. Primary tumors were irradiated with a single fraction of carbon ions (10 Gy), X-rays (20 Gy, 25 Gy, or 30 Gy), or observed as controls. The RBE was calculated by determining the dose of X-rays that resulted in similar time to posttreatment tumor volume quintupling and exponential growth rate as 10 Gy carbon ions. The median tumor volume quintupling time and exponential growth rate of sarcomas treated with 10 Gy carbon ions and 30 Gy X-rays were similar: 27.3 and 28.1 days and 0.060 and 0.059 mm3/day, respectively. Tumors treated with lower doses of X-rays had faster regrowth. Thus, the RBE of carbon ions in this primary tumor model is 3. When isoeffective treatments of carbon ions and X-rays were compared, we observed significant differences in tumor growth kinetics, proliferative indices, and immune infiltrates. We found that carbon ions were three times as potent as X-rays in this aggressive tumor model and identified unanticipated differences in radiation response that may have clinical implications. Mol Cancer Ther; 17(4); 858–68. ©2018 AACR.

Locally advanced pancreatic tumours are highly resistant to conventional radiochemotherapy. Here we show that such resistance can be surmounted by an injectable depot of thermally responsive elastin-like polypeptide (ELP) conjugated with iodine-131 radionuclides (sup131/supI-ELP) when combined with systemically delivered nanoparticle albumin-bound paclitaxel. This combination therapy induced complete tumour regressions in diverse subcutaneous and orthotopic mouse models of locoregional pancreatic tumours.sup131/supI-ELP brachytherapy was effective independently of the paclitaxel formulation and dose, but external beam radiotherapy (EBRT) only achieved tumour-growth inhibition when co-administered with nanoparticle paclitaxel. Histological analyses revealed thatsup131/supI-ELP brachytherapy led to changes in the expression of intercellular collagen and junctional proteins within the tumour microenvironment. These changes, which differed from those of EBRT-treated tumours, correlated with the improved delivery and accumulation of paclitaxel nanoparticles within the tumour. Our findings support the further translational development ofsup131/supI-ELP depots for the synergistic treatment of localized pancreatic cancer.

Exposure of the gastrointestinal (GI) tract to ionizing radiation can cause acute and delayed injury. However, critical cellular targets that regulate the development of radiation-induced GI injury remain incompletely understood. Here, we investigated the role of vascular endothelial cells in controlling acute and delayed GI injury after total-abdominal irradiation (TAI). To address this, we used genetically engineered mice in which endothelial cells are sensitized to radiation due to the deletion of the tumor suppressor p53. Remarkably, we found that VE-cadherin-Cre; p53(FL/FL) mice, in which both alleles of p53 are deleted in endothelial cells, were not sensitized to the acute GI radiation syndrome, but these mice were highly susceptible to delayed radiation enteropathy. Histological examination indicated that VE-cadherin-Cre; p53(FL/FL) mice that developed delayed radiation enteropathy had severe vascular injury in the small intestine, which was manifested by hemorrhage, loss of microvessels and tissue hypoxia. In addition, using dual-energy CT imaging, we showed that VE-cadherin-Cre; p53(FL/FL) mice had a significant increase in vascular permeability of the small intestine in vivo 28 days after TAI. Together, these findings demonstrate that while sensitization of endothelial cells to radiation does not exacerbate the acute GI radiation syndrome, it is sufficient to promote the development of late radiation enteropathy.

Pancreatic tumors remain one of the deadliest manifestations of cancer in clinical oncology. Even when tumors are diagnosed early, remain loco-regionalized, and receive cutting-edge cancer treatment, the 5-year survival rate remains less than 27%. This high mortality rate arises from the significant biologic barriers that inhibit drug delivery effectiveness in pancreatic tumors, as well as their underlying genetic mutations that confer resistance to traditional radiation and chemotherapeutic standards of care. In this work, we hypothesized that a new form of radiation brachytherapy might prove highly synergistic for overcoming the resistance native to pancreatic tumors. Utilizing the thermally stabilized biopolymer ELP, 131iodine radionuclides can be delivered intratumorally to provide continuous, focalized, high-dose β-radiation to treat pancreatic cancer from the inside out. Dose-escalation studies revealed that the two important variables for improving outcomes were the 131I-ELP radioactivity dose and the duration of concurrent paclitaxel therapy. 100% tumor regression was achieved across multiple genotypic models of pancreatic cancer models: MIA PaCa-2, AsPc-1, and BxPc3 (both subcutaneous and orthotopic). The potent synergistic results of 131I-ELP brachytherapy were replicated using both a novel micelle formulation of paclitaxel and the clinical standard Abraxane. Multigroup analysis revealed true molecular synergy as assessed by the Bliss Independence framework (p < 0.01). External beam irradiation, when similarly employed as comparison, merely induced growth inhibition when combined with paclitaxel utilizing a 5Gy hypofractionation regimen. Immunohistochemical analysis of treated tumors revealed differential modulation of biomolecular components that regulate the effectiveness of drug delivery and radiotoxicity. Levels of PECAM, VE-cadherin, claudin-4, HIF-1α, and stromal collagen were all specifically investigated, while macroscopic analysis revealed significantly enhanced accumulation and retention of fluorescently tagged paclitaxel when tumors were treated with biopolymer brachytherapy. Standard x-ray therapy indicated little to no improvement. No signs of any toxic side effects were observed in serologic enzyme analysis and multiorgan biodistribution studies. Citation Format: Jeffrey L. Schaal, Jayanta Bhattacharyya, Xinghai Li, Samagya Banskota, Jeremy Brownstein, David Kirsch, Michael Zalutsky, Ashutosh Chilkoti. Biopolymer β-brachytherapy delivered concomitantly with systemic paclitaxel outperforms traditional x-ray radiation to induce complete regression in multiple pancreatic tumor xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5831.