Radioresistant Pulmonary Oligometastatic and Oligoprogressive Lesions From Nonlung Primaries: Impact of Histology and Dose-Fractionation on Local Control After Radiation Therapy.

Purpose: We investigated whether pulmonary metastases from historically considered radioresistant primaries would have inferior local control after radiation therapy than those from nonradioresistant nonlung primaries, and whether higher biologically effective dose assuming alpha/beta=10 (BED10) would be associated with superior local control. Methods and Materials: We identified patients treated with radiation therapy for oligometastatic or oligoprogressive pulmonary disease to 1 to 5 lung metastases from nonlung primaries in 2013 to 2020 at a single health care system. Radioresistant primary cancers included colorectal carcinoma, endometrial carcinoma, renal cell carcinoma, melanoma, and sarcoma. Nonradioresistant primary cancers included breast, bladder, esophageal, pancreas, and head and neck carcinomas. The Kaplan-Meier estimator, log-rank test, and multivariable Cox proportional hazards regression were used to compare local recurrence-free survival (LRFS), new metastasis-free survival, progression-free survival, and overall survival. Results: Among 114 patients, 73 had radioresistant primary cancers. The median total dose was 50 Gy (IQR, 50-54 Gy) and the median number of fractions was 5 (IQR, 3-5). Median follow-up time was 59.6 months. One of 41 (2.4%) patients with a nonradioresistant metastasis experienced local failure compared with 18 of 73 (24.7%) patients with radioresistant metastasis (log-rank P = .004). Among radioresistant metastases, 12 of 41 (29.2%) patients with colorectal carcinoma experienced local failure compared with 6 of 32 (18.8%) with other primaries (log-rank P = .018). BED10 ≥100 Gy was associated with decreased risk of local recurrence. On univariable analysis, BED10 ≥100 Gy (hazard ratio [HR], 0.263; 95% CI, 0.105-0.656; P = .004) was associated with higher LRFS, and colorectal primary (HR, 3.060; 95% CI, 1.204-7.777; P = .019) was associated with lower LRFS, though these were not statistically significant on multivariable analysis. Among colorectal primary patients, BED10 ≥100 Gy was associated with higher LRFS (HR, 0.266; 95% CI, 0.072-0.985; P = .047) on multivariable analysis. Conclusions: Local control after radiation therapy was encouraging for pulmonary metastases from most nonlung primaries, even for many of those classically considered to be radioresistant. Those from colorectal primaries may benefit from testing additional strategies, such as resection or systemic treatment concurrent with radiation.

Dose-Volume Predictors of Radiation Pneumonitis After Thoracic Hypofractionated Radiation Therapy.

PURPOSE: Hypofractionated radiation therapy (HFRT) is a common treatment for thoracic tumors, typically delivered as 60 Gy in 15 fractions. We aimed to identify dosimetric risk factors associated with radiation pneumonitis in patients receiving HFRT at 4 Gy per fraction, focusing on lung V20, mean lung dose (MLD), and lung V5 as potential predictors of grade ≥2 pneumonitis. METHODS AND MATERIALS: All patients were treated with thoracic HFRT to 60 Gy in 15 fractions or 72 Gy in 18 fractions at a single health care system from 2013 to 2020. Tumors near critical structures (trachea, proximal tracheobronchial tree, esophagus, spinal cord, or heart) were considered central (within 2 cm), and those closer were classified as ultracentral (within 1 cm). The primary endpoint was grade ≥2 pneumonitis. Logistic regression analyses, adjusting for target size and dosimetric variables, were used to establish a dose threshold associated with <20% risk of grade ≥2 pneumonitis. RESULTS: During a median 24.3-month follow-up, 18 patients (16.8%) developed grade ≥2 radiation pneumonitis, with no significant difference between the 2 dose regimens (17.3% vs 16.3%, P = .88). Four patients (3.7%) experienced grade ≥3 pneumonitis, including 2 grade 5 cases. Patients with grade ≥2 pneumonitis had significantly higher lung V20 (mean 23.4% vs 14.5%, P < .001), MLD (mean 13.0 Gy vs 9.5 Gy, P < .001), and lung V5 (mean 49.6% vs 40.6%, P = .01). Dose thresholds for a 20% risk of grade ≥2 pneumonitis were lung V20 <17.7%, MLD <10.6 Gy, and V5 <41.3%. Multivariable analysis revealed a significant association between lung V20 and grade ≥2 pneumonitis (adjusted odds ratio, 1.48, P = .03). CONCLUSIONS: To minimize the risk of grade ≥2 radiation pneumonitis when delivering 4 Gy per fraction at either 60 Gy or 72 Gy, it is advisable to maintain lung V20<17.7%. MLD <10.6 Gy and V5<41.3% can also be considered as lower-priority constraints. However, additional validation is necessary before incorporating these constraints into clinical practice or trial planning guidelines.

Effects of detraining on left ventricular mass in endurance-trained individuals: a systematic review and meta-analysis.

AIMS: Detraining refers to a loss of training adaptations resulting from reductions in training stimulus due to illness, injury, or active recovery breaks in a training cycle and is associated with a reduction in left ventricular mass (LVM). The purpose of this study was to conduct a systematic review and meta-analysis to determine the influence of detraining on LVM in endurance-trained, healthy individuals. METHODS AND RESULTS: Using electronic databases (e.g. EMBASE and MEDLINE), a literature search was performed looking for prospective detraining studies in humans. Inclusion criteria were adults, endurance-trained individuals with no known chronic disease, detraining intervention >1 week, and pre- and post-detraining LVM reported. A pooled statistic for random effects was used to assess changes in LVM with detraining. Fifteen investigations (19 analyses) with a total of 196 participants (ages 18-55 years, 15% female) met inclusion criteria, with detraining ranging between 1.4 and 15 weeks. The meta-analysis revealed a significant reduction in LVM with detraining (standardized mean difference = -0.586; 95% confidence interval = -0.817, -0.355; P < 0.001). Independently, length of detraining was not correlated with the change in LVM. However, a meta-regression model revealed length of the detraining, when training status was accounted for, was associated with the reduction of LVM (Q = 15.20, df = 3, P = 0.0017). Highly trained/elite athletes had greater reductions in LVM compared with recreational and newly trained individuals (P < 0.01). Limitations included relatively few female participants and inconsistent reporting of intervention details. CONCLUSION: In summary, LVM is reduced following detraining of one week or more. Further research may provide a greater understanding of the effects of sex, age, and type of detraining on changes in LVM in endurance-trained individuals.

In healthy, endurance-trained individuals, detraining results in significant reductions in left ventricular mass. When accounting for training status, the length of the detraining period is positively associated with reductions in left ventricular mass. Limited research on this topic hinders the ability to assess sex differences or the impact of the type of detraining (i.e. only activities of daily living vs. reduced training load) on the response to detraining.

Three-Dimensional-Derived Echocardiographic Left Ventricular Structure and Function and Indices from the 12-Lead Electrocardiogram across the Menstrual Cycle in Healthy Physically Active Females: An Exploratory Study.

Background: The impact of the menstrual phases on left ventricular (LV) structure and function using 3D echocardiography and resting electrocardiogram (ECG) in healthy, eumenorrheic, and physically active females has not been investigated. Methods: sixteen females (20 y ± 2) underwent 3D echocardiography and an ECG at three time points in the menstrual cycle phases (follicular, ovulation, luteal). LV end-diastolic volume (LVEDVi), LV ejection fraction (LVEF), LV mass allometrically indexed to height2.7 (LVMi), torsion, and global longitudinal, circumferential, and radial strain (GLS, GCS, and GRS) were evaluated. ECG data of the P and QRS waves were presented as well as axis deviation, chamber enlargement, and any rhythm abnormalities. Results: LVMi was significantly higher in the luteal phase (36.4 g/m2.7 ± 3.3) compared to the follicular (35.0 g/m2.7 ± 3.7) and ovulation (34.7 g/m2.7 ± 4.3) phases (p = 0.026). There were no differences in other indices of LV structure and function or ECG variables across all phases of the menstrual cycle or evidence of arrhythmia. Conclusions: In physically active females, there is a small but significantly higher LVMi associated with the luteal phase of the menstrual cycle with no concomitant change in LV function or ECG parameters. These findings are important to consider when conducting clinical or research serial assessments.

Nightmares: an independent risk factor for cardiovascular disease?

STUDY OBJECTIVES: Prior work has established associations between post-traumatic stress disorder (PTSD), disrupted sleep, and cardiovascular disease (CVD), but few studies have examined health correlates of nightmares beyond risks conferred by PTSD. This study examined associations between nightmares and CVD in military veterans. METHODS: Participants were veterans (N = 3468; 77% male) serving since September 11, 2001, aged 38 years (SD = 10.4); approximately 30% were diagnosed with PTSD. Nightmare frequency and severity were assessed using the Davidson Trauma Scale (DTS). Self-reported medical issues were assessed using the National Vietnam Veterans Readjustment Study Self-report Medical Questionnaire. Mental health disorders were established using the Structured Clinical Interview for DSM-IV. The sample was stratified by the presence or absence of PTSD. Within-group associations between nightmare frequency and severity and self-reported CVD conditions, adjusting for age, sex, race, current smoking, depression, and sleep duration. RESULTS: Frequent and severe nightmares during the past week were endorsed by 32% and 35% of participants, respectively. Those endorsing nightmares that were frequent, severe, and the combination thereof were more likely to also evidence high blood pressure (ORs 1.42, OR 1.56, and OR 1.47, respectively) and heart problems (OR 1.43, OR 1.48, and OR 1.59, respectively) after adjusting for PTSD diagnosis and other covariates. CONCLUSIONS: Nightmare frequency and severity among veterans are associated with cardiovascular conditions, even after controlling for PTSD diagnosis. Study findings suggest that nightmares may be an independent risk factor for CVD. Additional research is needed to validate these findings using confirmed diagnoses and explore potential mechanisms.

Effects of trauma-focused rumination among trauma-exposed individuals with and without posttraumatic stress disorder: An experiment.

Rumination, or thinking repetitively about one's distress, is a risk factor for posttraumatic stress disorder (PTSD). Current theories suggest that rumination contributes to PTSD symptoms directly, by increasing negative reactions to trauma cues (i.e., symptom exacerbation), or represents a form of cognitive avoidance, if verbal ruminations are less distressing than trauma imagery. The goal of this study was to test the symptom exacerbation and cognitive avoidance accounts of trauma-focused rumination. We recruited 135 trauma-exposed participants (n = 60 diagnosed with PTSD) and randomly assigned them to ruminate about their trauma, distract themselves, or engage in trauma imagery. For individuals with and without PTSD, rumination led to larger increases in subjective distress (i.e., negative affect, fear, sadness, subjective arousal, valence) than distraction, ηp 2 s = .04-.13, but there were no differences between rumination and imagery ηp 2 s = .001-.02. We found no evidence that rumination or imagery elicited physiological arousal, ds = 0.01-0.19, but did find that distraction reduced general physiological arousal, as measured by heart rate, relative to baseline, d = 0.84, which may be due to increases in parasympathetic nervous system activity (i.e., respiratory sinus arrhythmia), d = 0.33. These findings offer no support for the avoidant function of rumination in PTSD. Instead, the findings were consistent with symptom exacerbation, indicating that rumination leads directly to emotional reactivity to trauma reminders and may be a fruitful target in PTSD intervention.

Rubicon promotes rather than restricts murine lupus and is not required for LC3-associated phagocytosis.

NADPH oxidase deficiency exacerbates lupus in murine models and patients, but the mechanisms remain unknown. It is hypothesized that NADPH oxidase suppresses autoimmunity by facilitating dead cell clearance via LC3-associated phagocytosis (LAP). The absence of LAP reportedly causes an autoinflammatory syndrome in aged, nonautoimmune mice. Prior work implicated cytochrome b-245, ß polypeptide (CYBB), a component of the NADPH oxidase complex, and the RUN and cysteine-rich domain-containing Beclin 1-interacting protein (RUBICON) as requisite for LAP. To test the hypothesis that NADPH oxidase deficiency exacerbates lupus via a defect in LAP, we deleted Rubicon in the B6.Sle1.Yaa and MRL.Faslpr lupus mouse models. Under this hypothesis, RUBICON deficiency should phenocopy NADPH oxidase deficiency, as both work in the same pathway. However, we observed the opposite - RUBICON deficiency resulted in reduced mortality, renal disease, and autoantibody titers to RNA-associated autoantigens. Given that our data contradict the published role for LAP in autoimmunity, we assessed whether CYBB and RUBICON are requisite for LAP. We found that LAP is not dependent on either of these 2 pathways. To our knowledge, our data reveal RUBICON as a novel regulator of SLE, possibly by a B cell-intrinsic mechanism, but do not support a role for LAP in lupus.

Respiratory sinus arrhythmia reactivity in anxiety and posttraumatic stress disorder: A review of literature.

Respiratory sinus arrhythmia (RSA) reactivity is thought to indicate how adaptively one responds to stress. RSA reactivity has been examined across anxiety disorders and posttraumatic stress disorder (PTSD), to better understand the psychophysiological stress response of these disorders. The current state of the literature is mixed, and the association between RSA reactivity and PTSD/anxiety is unclear. This review examines RSA reactivity in response to laboratory stressor tasks across samples with anxiety and PTSD. Results indicated a complex literature that may suggest an association between anxiety/PTSD and RSA reactivity. There is evidence to suggest a pattern of heightened RSA withdrawal in PTSD and trait anxious samples. There was little evidence to suggest a heightened RSA withdrawal pattern in other anxiety disorders. This review also highlights methodological considerations which may allow for clearer interpretations of RSA reactivity. The current literature includes heterogeneity across stressor tasks, RSA measures, and comorbidities that complicates interpretation of results. Studies using samples with comorbid depression produce more consistent evidence of heightened RSA withdrawal in anxiety/PTSD. Future directions for understanding the contribution of these variables (i.e., stressor tasks, RSA measures, comorbid depression) and mechanisms contributing to the possible association between RSA reactivity and anxiety/PTSD are considered.

Challenges in the abortion supply chain: a call to action for evaluation research.

BACKGROUND: Reducing the burden of unsafe abortion rests considerably on women's ability to access appropriate and timely treatment or services. A critical component of that care relies on a functional supply chain to ensure availability of abortion drugs and supplies within the health system. Disruptions in the supply of medical abortion drugs delay provision of abortion services and can increase the risks to a woman's health. We examine the ways in which supply chain management (SCM) affects women's ability to access safe and timely abortion to meet their reproductive health needs and highlight the gap in evaluation research on which SCM interventions best improve access to safe abortion care. SCM comprises a critical component of efficient and sustainable abortion service provision and is a requisite for expansion of services. Furthermore, governments are responsible for safeguarding links in the abortion supply chain, from registration to distribution of abortion drugs and supplies. Strategic public-private partnerships and use of innovative local or community-based distribution mechanisms can strengthen supply chain systems. Finally, alternatives to the pull-based models of distribution could alleviate bottlenecks in the final steps of abortion supply chains. Programs aimed at increasing access to safe and comprehensive abortion care must include SCM as a foundational component of service provision. Without access to a sustainable and affordable supply of abortion drugs and equipment, any attempt at providing abortion services will be critically limited. More implementation research is needed to identify the most effective interventions for improving SCM.

Parallels Between the Antiviral State and the Irradiated State.

Improved understanding of host antiviral defense and antitumor immunity have elucidated molecular pathways important to both processes. During viral infection, RNA or DNA in the host cell serves as a danger signal that initiates the antiviral response. Recent studies have elucidated similarities in the signaling pathways activated by viruses and the signaling pathways induced by tumor DNA that is released into the cytoplasm of irradiated tumor cells. Both the host defense to viral infection and the sterile inflammation provoked by radiotherapy induce a type I interferon response that is necessary for pathogen control and immune-mediated tumor control, respectively. These findings have led to the hypothesis that radiotherapy employs a form of viral mimicry.

Proceedings of the ASTRO-RSNA Oligometastatic Disease Research Workshop.

PURPOSE: On June 13 to 14, 2019, the American Society for Radiation Oncology and the Radiological Society of North America convened a workshop on the treatment of oligometastatic disease in Washington, DC. The workshop was initiated for several reasons. First, oligometastatic disease is of increasing academic and community interest and has been identified by the American Society for Radiation Oncology membership as a top research priority. Second, emerging imaging and diagnostic technologies are more readily defining and detecting oligometastatic disease, making contemporary discussion of oligometastatic disease especially relevant. Third, radiosurgery and radiation in general are theorized to be ideal noninvasive therapy for the treatment of oligometastatic disease. Finally, innovations in targeted therapy and immune therapy have the potential to reverse widely disseminating disease into an oligometastatic state. METHODS AND MATERIALS: The workshop was organized into 2 keynote addresses, 6 scientific sessions, and 3 group discussions during an end-of-workshop breakout session. New scientific work was presented in the form of 4 oral presentations and a poster session. Workshop participants were charged with attempting to answer 3 critical questions: (1) Can we refine the clinical and biological definitions of oligometastatic disease; (2) how can we better treat oligometastatic disease; and (3) what clinical trials are needed? RESULTS: Here, we present the proceedings of the workshop. CONCLUSIONS: The clinical implications of improved treatment of oligometastatic disease are enormous and immediate. Radiation oncology and diagnostic radiology should rightly be at the forefront of the characterization and treatment of oligometastatic disease. Focused effort is required so that we can translate current efforts of large numbers of studies with few patients to larger studies of larger impact.

Emotion regulation in posttraumatic stress disorder (PTSD): Rumination accounts for the association between emotion regulation difficulties and PTSD severity.

OBJECTIVE: The current study investigated whether rumination accounts for the relationship between multiple aspects of emotion regulation (ER) difficulties and posttraumatic stress disorder (PTSD) severity. METHOD: Participants were 90 community members (43% diagnosed with PTSD; Mage = 26.7, 86% female) who were interviewed using the Clinician-Administered PTSD Scale-5 and completed self-reported measures of ER and rumination. RESULTS: The indirect effect of rumination completely accounted for the relationship between overall ER difficulties and PTSD severity. This finding was replicated for three unique aspects of ER (i.e., nonacceptance of negative emotions, impulse control difficulties under emotional distress, and the ability to maintain goal-oriented behavior under emotional distress). Reverse models testing the indirect effect of ER on the link between rumination and PTSD were nonsignificant. CONCLUSIONS: Rumination is an important cognitive process linking specific aspects of ER difficulties to PTSD. Clinical interventions focused on improving ER abilities among those with PTSD may benefit from targeting rumination.

Exploring single-cell data with deep multitasking neural networks.

It is currently challenging to analyze single-cell data consisting of many cells and samples, and to address variations arising from batch effects and different sample preparations. For this purpose, we present SAUCIE, a deep neural network that combines parallelization and scalability offered by neural networks, with the deep representation of data that can be learned by them to perform many single-cell data analysis tasks. Our regularizations (penalties) render features learned in hidden layers of the neural network interpretable. On large, multi-patient datasets, SAUCIE's various hidden layers contain denoised and batch-corrected data, a low-dimensional visualization and unsupervised clustering, as well as other information that can be used to explore the data. We analyze a 180-sample dataset consisting of 11 million T cells from dengue patients in India, measured with mass cytometry. SAUCIE can batch correct and identify cluster-based signatures of acute dengue infection and create a patient manifold, stratifying immune response to dengue.

Resting respiratory sinus arrhythmia and posttraumatic stress disorder: A meta-analysis.

Respiratory sinus arrhythmia (RSA) has been examined as a psychophysiological marker of stress vulnerability. Research indicates that low resting RSA is associated with physical and mental health problems, including posttraumatic stress disorder (PTSD). Some research suggests that people diagnosed with PTSD have lower RSA than people without PTSD, but findings have been mixed and the overall magnitude of this effect is unknown, indicating the need for a comprehensive meta-analysis. This meta-analysis examined the association between PTSD and baseline RSA in 55 studies, including 12 unpublished studies, with a total sample size of 6689. Studies were included if they used a PTSD measure, a baseline measure of RSA, and involved humans. Studies were excluded if they were not available in English, did not present quantitative data, presented duplicate data, were a case series, or did not provide results required for computing an effect size. The meta-analysis indicated there is a small but significant association between PTSD and RSA (g = -0.26; 95% CI = -0.35, -0.16) with moderate heterogeneity. Moderator analyses suggested that effects are larger for adults than for children and for DSM-5 PTSD measures than for non-DSM referenced measures. We found some evidence for publication bias among the meta-analysis findings. Overall, there is a small but reliable association between PTSD and lower resting RSA, providing support for further research examining the complex relationship between parasympathetic activity and PTSD.

Periodic, moderate water flow reversibly increases hair bundle density and size in Nematostella vectensis.

Animals employ hair bundles on hair cells to detect flow, vibrations and gravity. Hair bundles on sea anemone tentacles detect nearby vibrations in the water column produced by prey movements and then regulate discharge of cnidae to capture prey. This study investigated: (1) the progressive effects of periodic water flow on hair bundle morphology and density of hair bundles and cnidae in sea anemones, (2) the reversibility of the flow response and (3) the ability of the response to be expedited with increased flow duration. Linear density of hair bundles along tentacles and each hair bundle's dimensions was measured in anemones exposed to flow and in the absence of flow. With increasing numbers of days of flow, hair bundles in anemones exposed to flow for 1 h every weekday for 20 days increased in density and grew longer and wider at bases and middles, whereas controls did not. Time courses fit to a linear function exhibited significantly larger positive slopes from animals exposed to flow compared with controls. Hair bundles in anemones exposed to flow for 3 h each day increased in linear density, length, base width and middle width after 10 days of flow and returned to control levels after 10 days following cessation of flow. In addition, there was a trend for an increase in density of cnidae with flow. Therefore, anemone hair bundles are dynamically and reversibly modified by periodic, moderate flow to become more abundant and robust. These findings may have relevance to hair cells in acoustico-lateralis systems of higher animals.

Harnessing the Immunomodulatory Effects of Radiation Therapy.

In this article, we discuss the immunogenicity of radiation-induced cell death and describe the innate immune signaling pathways that precede adaptive antitumoral immunity. The innate and adaptive immune systems work in concert to generate systemic immune responses. In the setting of cancer, DNA damage caused by radiotherapy activates the innate immune system while tumor cell death liberates antigen that serves as a target for adaptive immunity. The immunomodulatory effects of radiation have been investigated in preclinical models; here we summarize the available data, with particular attention to the effects of radiotherapy timing, location, dose, and fractionation strategy on the antitumoral immune response. We synthesize preclinical and clinical information regarding the potential superiority of hypofractionated radiation for induction of proinflammatory responses. Although many questions remain, early successes with combining immunotherapy and radiotherapy merit further inquiry into the dose and fractionation strategies best able to activate and sustain an antitumoral response.

Association between perceptions of military service and mental health problems in a nationally representative sample of United States military veterans.

OBJECTIVE: In this study, we examined the prevalence of positive and negative perceptions of military service, associations between these perceptions and other demographic and military-related factors, and the extent to which endorsement of positive and negative perceptions of military service are associated with current mental health problems among United States veterans. METHOD: We analyzed data from the National Health and Resilience in Veterans Study (NHRVS), a nationally representative survey of 1,484 United States military veterans, 564 of which reported combat exposure. We assessed perceptions of the effects of military service using a scale developed by Elder and Clipp (1989). RESULTS: Results showed that desirable effects of service (53.6-86.5%) were more frequently endorsed than undesirable effects (9.5%-48.1%), and that combat-exposed veterans (11.5%-59.7%) were more likely to endorse undesirable effects of service than veterans without combat exposure (4.0%-40.7%). We also found that undesirable effects of service predicted significantly higher odds of probable current mental health disorders (OR = 1.08, 95% CI [1.04, 1.12]), and current suicidal ideation (OR = 1.09, 95% CI [1.05, 1.13]), even after conservative adjustment for possible confounding variables. Desirable effects of service predicted significantly lower odds of current suicidal ideation (OR = 0.96, 95% CI [0.93, 0.99]). CONCLUSION: Taken together, results of this study suggest that perceptions of military service are associated with suicidal ideation and other mental health conditions. In addition, assessing veterans' perceptions of their service could be used as a method to identify possible at-risk veterans who may benefit from mental health services and resources. (PsycINFO Database Record

Mini-review of conventional and hypofractionated radiation therapy combined with immunotherapy for non-small cell lung cancer.

A successful antitumoral response requires immunological activation as well as an antigenic pool capable of stimulating both the innate and the adaptive immune system. Recent advances in immunotherapy have been aimed at boosting the activation status of the innate and adaptive immune system, including cytokine administration, monoclonal antibodies engineered to target high yield elements in oncogenic signaling pathways, cancer vaccines, and checkpoint inhibitors. Herein, we examine the ways that radiation therapy induced cell death provides a pool of stimulus antigen, and draw parallels from the immunobiology of autoimmunity to explore how the immunogenicity of antigen derived from radiation-induced cell death might augment the antitumoral response. We also review basic research into the ability of different radiation dose fractionation schedules to induce an antitumoral response. After a discussion of basic immunotherapeutic principles, we review the published literature in the field of non-small cell lung cancer (NSCLC) and examine the ways that combining radiation and immunotherapy have begun to change the therapeutic terrain. We provide a summary of ongoing clinical trials aimed at combining immunotherapy and radiation therapy in NSCLC while emphasizing the need for identification of biomarkers with predictive power and the assessment of efficacy as a function of fractionation strategy.