Influenza activity and regional mortality for non-small cell lung cancer.

Lung cancer is the leading cause of cancer deaths in the United States and worldwide. While influenza illness is known to be particularly dangerous for frail and elderly patients, the relationship between influenza illness and outcomes in patients with cancer remains largely unknown. The Surveillance, Epidemiology, and End Results (SEER) database was queried to identify patients with non-small cell lung cancer (NSCLC) diagnosed between 2009 and 2015. Influenza-like illness (ILI) activity, provided by the Outpatient Influenza-like Illness Surveillance Network of the Center of Disease for Control and Prevention, was merged with the SEER dataset on the state-month level. Regional monthly mortality rates were compared during low versus high flu months in this ecological cohort study. 202,485 patients with NSCLC from 13 SEER-reporting states were included in the analysis. 53 of 1049 state-months (5.1%) had high flu activity. Monthly mortality rates during low and high flu months were 0.041 (95% CI 0.041-0.042) and 0.051 (95% CI 0.050-0.053), respectively (RR 1.24 [95% CI 1.21-1.27]). The association between ILI activity and mortality was observed at the individual state level and in all clinical and regional subgroups. Increased regional influenza activity is associated with higher mortality rates for patients with NSCLC. Vaccine-directed initiatives and increased awareness amongst providers will be necessary to address the growing but potentially preventable burden of influenza-related lung cancer deaths in the U.S.

Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism.

Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.

Prevalence of Estrogen Receptor Alpha (ESR1) Somatic Mutations in Breast Cancer.

Estrogen receptor-positive breast tumors, which initially respond effectively to endocrine therapy, progress due to acquired endocrine therapy resistance, including genomic alterations in estrogen receptor alpha (ESR1). A recent study has suggested that there is a sufficient number of preexisting ESR1 mutations acting as an intrinsic resistance mechanism to warrant primary screening. We determined the incidence of de novo ESR1 mutations in hormone-positive treatment-naïve primary breast tumors using 12 publicly available international datasets in the cBioPortal. The prevalence of mutation was statistically significantly lower in treatment-naïve primary tumors (n = 6 of 3682, 0.16%) than in metastatic (n = 156 of 1089, 14.3%, 2-sided P < .001) or previously treated primary tumors (n = 11 of 92, 12.0%, 2-sided P < .001). Pathogenic ESR1 mutations are a common mechanism of acquired but not intrinsic resistance to endocrine therapy and may not warrant universal testing of primary breast cancer populations.

Smurf2 inhibition enhances chemotherapy and radiation sensitivity in non-small-cell lung cancer.

Lung cancer has been the most common cancer worldwide for several decades. The outcomes of patients with locally advanced lung cancer remain dismal, and only a minority of patients survive more than 5 years. However, tumor therapeutic resistance mechanisms are poorly studied. Identification of therapeutic resistance pathways in lung cancer in order to increase the sensitivity of lung tumor cells to therapeutic agents is a crucial but challenging need. To identify novel genes that modulate the response to platinum-based therapy, we performed a genome-wide high-throughput ribonucleic acid interference (RNAi) screen via transfection of human lung cancer (PC9) cells with a viral short hairpin RNA (shRNA) library. We further validated a potential target via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenic survival assays on PC9 and A549 lung tumor cells transfected with small interfering RNAs (siRNAs) to successfully downregulate protein expression and then treated with increasing doses of cisplatin or X-ray radiation. We determined protein expression by immunohistochemistry (IHC) after chemoradiotherapy and analyzed gene expression-based survival outcomes in two cohorts of human non-small-cell lung cancer (NSCLC) patients. The screen identified several targets involved in epithelial-to-mesenchymal transition (EMT), including Smurf1, Smurf2, YAP1, and CEBPZ, and glycolytic pathway proteins, including PFKFB3. Furthermore, we found that the small molecule proteasome inhibitor bortezomib significantly downregulated Smurf2 in lung cancer cells. The addition of bortezomib in combination with cisplatin and radiation therapy in PC9 and A549 cells led to an increase in deoxyribonucleic acid (DNA) double-strand breaks with increased numbers of γ-H2AX-positive cells and upregulation of apoptosis. Finally, we found that Smurf2 protein expression was upregulated in situ after treatment with cisplatin and radiation therapy in a relevant cohort of patients with stage III NSCLC. Additionally, Smurf2 gene expression was the strongest predictor of survival in patients with squamous NSCLC after chemotherapy or chemoradiotherapy. We successfully identified and validated Smurf2 as both a common modulator of resistance and an actionable target in lung cancer. These results suggest the urgent need to investigate clinical Smurf2 inhibition via bortezomib in combination with cisplatin and radiation for patients with locally advanced NSCLC.

Outcomes for localized treatment of large cell neuroendocrine carcinoma of the lung in the United States.

BACKGROUND: Treatment paradigms for large cell neuroendocrine carcinoma (LCNEC) of the lung are based largely upon small retrospective studies and smaller prospective trials. It is unclear if these tumors behave like non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). Data are lacking with regard to the role of radiotherapy (RT). U. S. guidelines recommend that LCNEC be treated as a NSCLC. We sought to perform a cross-sectional study of LCNEC cases to understand treatment paradigms and outcomes in this disease. METHODS: The Surveillance, Epidemiology and End Results database was queried for cases of stage I-III pulmonary LCNEC diagnosed 2004-2013. Treatment groups were defined as no surgery, RT alone, surgery alone, and surgery + RT. The Cox-proportional hazards regression model was used to compare overall survival and cause-specific survival (OS/CSS), stratified by AJCC 6th Staging. Factors that were significant on univariable analysis were included in multivariable analysis. RESULTS: We identified 1,523 cases of LCNEC, with 748, 177, and 598 cases of stage I, II, and III disease, respectively. In stage I and II disease, RT was associated with improved survival for non-surgical patients, but not for those who underwent surgery. In stage I disease, the adjusted hazard ratios for OS for RT alone, surgery, and surgery + RT were 0.39, 0.21, and 0.22, respectively (P<0.001). In stage II disease, the adjusted hazard ratios for RT alone, surgery, and surgery + RT were 0.51 (P=0.15), 0.39 (P=0.004), and 0.38 (P=0.01), respectively. For patients with stage III disease, RT was associated with improved survival in surgical and non-surgical patients. The adjusted hazard ratios for RT alone, surgery, and surgery + RT were 0.49, 0.43, and 0.36, respectively (P<0.001). CONCLUSIONS: Our findings indicate that non-metastatic LCNEC may be treated as a NSCLC with respect to RT. Prospective studies are necessary to increase our understanding of optimal treatment regimens.

Creation of a Rat Lower Limb Lymphedema Model.

BACKGROUND: Lymphedema is a frequent complication after surgical treatments of cancer involving lymph node resection. However, research of lymphedema treatments, such as vascularized lymph node transfer, is limited by the absence of an adequate lymphedema animal model. The purpose of this study was to determine if we could create sustainable lower limb lymphedema in the rat with a combination of inguinal lymphadenectomy, circumferential skin and subcutaneous tissue excision, and radiotherapy. METHODS: Inguinal lymphadenectomies were completed in 15 Sprague-Dawley rats. In cohort A, 5 rats received a 0.5- to 1.0-cm wide excision of proximal thigh skin and subcutaneous tissue. This step was omitted for the 10 rats in cohort B. Cohort A then received a single radiation dose of 22.7 Gy, whereas cohort B received a cumulative dose of 40.5 Gy. Bioimpedance measurements were obtained monthly to assess lymphedema progression, and lymphatic drainage at 6 months postradiation was visualized via indocyanine green (ICG) lymphangiography. RESULTS: Two rats in cohort A developed visually appreciable lymphedema in the lower limb, with bioimpedance ratios of 0.684 and 0.542 and ankle circumference ratios of 1.294 and 1.061, respectively, consistent with lymphedema. Furthermore, ICG lymphangiography in these cohort A rats revealed impaired lower limb lymphatic drainage. In cohort B, however, bioimpedance and circumference ratios, and ICG lymphangiography, did not reveal abnormal lymphatic drainage. CONCLUSIONS: The combination of inguinal lymphadenectomy, circumferential skin and subcutaneous tissue excision, and radiotherapy can successfully create lower limb lymphedema in the rat. When soft tissue excision is omitted, lymphedema does not develop.

Targeting MEK5 impairs nonhomologous end-joining repair and sensitizes prostate cancer to DNA damaging agents.

Radiotherapy is commonly used to treat a variety of solid human tumors, including localized prostate cancer. However, treatment failure often ensues due to tumor intrinsic or acquired radioresistance. Here we find that the MEK5/ERK5 signaling pathway is associated with resistance to genotoxic stress in aggressive prostate cancer cells. MEK5 knockdown by RNA interference sensitizes prostate cancer cells to ionizing radiation (IR) and etoposide treatment, as assessed by clonogenic survival and short-term proliferation assays. Mechanistically, MEK5 downregulation impairs phosphorylation of the catalytic subunit of DNA-PK at serine 2056 in response to IR or etoposide treatment. Although MEK5 knockdown does not influence the initial appearance of radiation- and etoposide-induced γH2AX and 53BP1 foci, it markedly delays their resolution, indicating a DNA repair defect. A cell-based assay shows that nonhomologous end joining (NHEJ) is compromised in cells with ablated MEK5 protein expression. Finally, MEK5 silencing combined with focal irradiation causes strong inhibition of tumor growth in mouse xenografts, compared with MEK5 depletion or radiation alone. These findings reveal a convergence between MEK5 signaling and DNA repair by NHEJ in conferring resistance to genotoxic stress in advanced prostate cancer and suggest targeting MEK5 as an effective therapeutic intervention in the management of this disease.

Radiation-Induced Lipid Peroxidation Triggers Ferroptosis and Synergizes with Ferroptosis Inducers.

Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of DNA repair and inhibition of apoptosis. Therefore, compounds that sensitize cancer cells to radiation via alternative cell death pathways are valuable. We report here that ferroptosis, a form of nonapoptotic cell death driven by lipid peroxidation, is partly responsible for radiation-induced cancer cell death. Moreover, we found that small molecules activating ferroptosis through system xc- inhibition or GPX4 inhibition synergize with radiation to induce ferroptosis in several cancer types by enhancing cytoplasmic lipid peroxidation but not increasing DNA damage or caspase activation. Ferroptosis inducers synergized with cytoplasmic irradiation, but not nuclear irradiation. Finally, administration of ferroptosis inducers enhanced the antitumor effect of radiation in a murine xenograft model and in human patient-derived models of lung adenocarcinoma and glioma. These results suggest that ferroptosis inducers may be effective radiosensitizers that can expand the efficacy and range of indications for radiation therapy.

Focused ultrasound induced-blood-brain barrier opening in mouse brain receiving radiosurgery dose of radiation enhances local delivery of systemic therapy.

OBJECTIVE: Investigate the temporal effects of focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening in post-radiotherapy mouse brains. METHODS AND MATERIALS: C57B6 mice without tumors were used to simulate the scenario after gross total resection (GTR) of brain tumor. Radiation dose of 6 Gy x 5 was delivered to one-hemisphere of the mouse brain. FUS-induced BBB-opening was delivered to the irradiated and non-irradiated brain and was confirmed with MRI. Dynamic MRI was performed to evaluate blood vessel permeability. Two time points were selected: acute (2 days after radiation) and chronic (31 days after radiation). RESULTS: BBB opening was achieved after FUS in the irradiated field as compared to the contralateral non-irradiated brain without any decrease in permeability. In the acute group, a trend for higher gadolinium concentration was observed in radiated field. CONCLUSION: Localized BBB-opening can be successfully achieved without loss of efficacy by FUS as early as 2 days after radiotherapy. ADVANCES IN KNOWLEDGE: Adjuvant radiation after GTR is commonly used for brain tumors. Focused ultrasound facilitated BBB-opening can be achieved without loss of efficacy in the post-irradiated brain as early as 2 days after radiation therapy. This allows for further studies on early application of FUS-mediated BBB-opening.

Large-Cell Neuroendocrine Carcinoma of the Lung: A Population-Based Study.

INTRODUCTION: Large-cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung malignancies. There are limited data on the epidemiology and best treatment practices for this malignancy. This study aimed to be the largest cohort with the most up-to-date analysis of the epidemiology of LCNEC. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried to identify cases of LCNEC diagnosed from 2010 through 2015, reflecting years the American Joint Committee on Cancer 7th edition staging system was in use. Using these data, we compared the epidemiology, demographics, clinical characteristics, and survival times of LCNEC with small-cell lung carcinoma (SCLC) and non-SCLC (NSCLC). Trends in incidence and mortality were recorded from 2004 to 2015. RESULTS: A total of 195,148 cases of lung cancer, including 1681 (0.9%) cases of LCNEC, were analyzed. LCNEC was more common among male subjects, and disease usually presented at stage IV (55%). Brain metastasis occurred more frequently in LCNEC (19.2%) than SCLC (16.7%, P < .001) or NSCLC (13%, P < .001). Incidence increased by 0.011 people per 100,000 per year, primarily of stage IV disease. Annual mortality from LCNEC doubled over the time period studied. Survival in patients with stage I-III LCNEC mirrored survival trends of patients with NSCLC, whereas stage IV LCNEC behaved similarly to SCLC. CONCLUSION: LCNEC generally presents at more advanced stages than NSCLC but earlier than SCLC. Stage I-III LCNEC behaves similarly to NSCLC, whereas stage IV is more akin to SCLC. LCNEC incidence is increasing. Despite this, it remains poorly studied and did not demonstrate an improved prognosis in our cohort.

Effects of ß-Adrenergic Antagonists on Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Locally advanced non-small cell lung cancer (NSCLC) is highly resistant to chemoradiotherapy, and many cancer patients experience chronic stress. Studies that suggest stimulation of ß-adrenergic receptors (ß-AR) promotes tumor invasion and therapy resistance. We investigated whether ß-AR inhibition with beta-blockers acts as a chemotherapy and radiation sensitizer in vitro and in patients treated with chemoradiation for locally advanced NSCLC. METHODS: We investigated the effects of the non-selective beta-blocker propranolol on two human lung adenocarcinoma cell lines (PC9, A549) treated with radiation or cisplatin. We retrospectively evaluated 77 patients with Stage IIIA NSCLC who received induction chemoradiation followed by surgery. Pathological and imaging response, metastatic rate, and survival were analyzed using SPSS v22.0 and PrismGraphpad6. RESULTS: Propranolol combined with radiation or cisplatin decreased clonogenic survival of PC9 and A549 cells in vitro (p < 0.05). Furthermore, propranolol decreased expression of phospho-protein kinase A (p-PKA), a ß-adrenergic pathway downstream activation target, in both cell lines compared to irradiation or cisplatin alone (p < 0.05). In patients treated for Stage IIIA NSCLC, 16 took beta-blockers, and 61 did not. Beta-blockade is associated with a trend to improved overall survival (OS) at 1 year (81.3% vs 57.4%, p = 0.08) and distant metastasis-free survival (DMFS) (2.6 years vs. 1.3 years, p = 0.16). Although beta-blocker use was associated with decreased distant metastases (risk ratio (RR) 0.19; p = 0.03), it did not affect primary tumor pathological response (p = 0.40) or imaging response (p = 0.36). CONCLUSIONS: ß-AR blockade enhanced radiation and cisplatin sensitivity of human lung cancer cells in vitro. Use of beta-blockers is associated with decreased distant metastases and potentially improved OS and DMFS. Additional studies are warranted to evaluate the role of beta-blockers as a chemoradiation sensitizer in locally advanced NSCLC.

Velocity-based Adaptive Registration and Fusion for Fractionated Stereotactic Radiosurgery Using the Small Animal Radiation Research Platform.

PURPOSE: To implement Velocity-based image fusion and adaptive deformable registration to enable treatment planning for preclinical murine models of fractionated stereotactic radiosurgery (fSRS) using the small animal radiation research platform (SARRP). METHODS AND MATERIALS: C57BL6 mice underwent 3 unique cone beam computed tomography (CBCT) scans: 2 in the prone position and a third supine. A single T1-weighted post-contrast magnetic resonance imaging (MRI) series of a murine metastatic brain tumor model was selected for MRI-to-CBCT registration and gross tumor volume (GTV) identification. Two arms were compared: Arm 1, where we performed 3 individual MRI-to-CBCT fusions using rigid registration, contouring GTVs on each, and Arm 2, where the authors performed MRI-to-CBCT fusion and contoured GTV on the first CBCT followed by Velocity-based adaptive registration. The first CBCT and associated GTV were exported from MuriPlan (Xstrahl Life Sciences) into Velocity (Varian Medical Systems, Inc, Palo Alto, CA). In Arm 1, the second and third CBCTs were exported similarly along with associated GTVs (Arm 1), while in Arm 2, the first (prone) CBCT was fused separately to the second (prone) and third (supine) CBCTs, performing deformable registrations on initial CBCTs and applying resulting matrices to the contoured GTV. Resulting GTVs were compared between Arms 1 and 2. RESULTS: Comparing GTV overlays using repeated MRI fusion and GTV delineation (Arm 1) versus those of Velocity-based CBCT and GTV adaptive fusion (Arm 2), mean deviations ± standard deviation in the axial, sagittal, and coronal planes were 0.46 ± 0.16, 0.46 ± 0.22, and 0.37 ± 0.22 mm for prone-to-prone and 0.52 ± 0.27, 0.52 ± 0.36, and 0.68 ± 0.31 mm for prone-to-supine adaptive fusions, respectively. CONCLUSIONS: Velocity-based adaptive fusion of CBCTs and contoured volumes allows for efficient fSRS planning using a single MRI-to-CBCT fusion. This technique is immediately implementable on current SARRP systems, facilitating advanced preclinical treatment paradigms using existing clinical treatment planning software.

Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy.

Purpose: In the proper context, radiotherapy can promote antitumor immunity. It is unknown if elective nodal irradiation (ENI), a strategy that irradiates tumor-associated draining lymph nodes (DLN), affects adaptive immune responses and combinatorial efficacy of radiotherapy with immune checkpoint blockade (ICB).Experimental Design: We developed a preclinical model to compare stereotactic radiotherapy (Tumor RT) with or without ENI to examine immunologic differences between radiotherapy techniques that spare or irradiate the DLN.Results: Tumor RT was associated with upregulation of an intratumoral T-cell chemoattractant chemokine signature (CXCR3, CCR5-related) that resulted in robust infiltration of antigen-specific CD8+ effector T cells as well as FoxP3+ regulatory T cells (Tregs). The addition of ENI attenuated chemokine expression, restrained immune infiltration, and adversely affected survival when combined with ICB, especially with anti-CLTA4 therapy. The combination of stereotactic radiotherapy and ICB led to long-term survival in a subset of mice and was associated with favorable CD8 effector-to-Treg ratios and increased intratumoral density of antigen-specific CD8+ T cells. Although radiotherapy technique (Tumor RT vs. ENI) affected initial tumor control and survival, the ability to reject tumor upon rechallenge was partially dependent upon the mechanism of action of ICB; as radiotherapy/anti-CTLA4 was superior to radiotherapy/anti-PD-1.Conclusions: Our results highlight that irradiation of the DLN restrains adaptive immune responses through altered chemokine expression and CD8+ T-cell trafficking. These data have implications for combining radiotherapy and ICB, long-term survival, and induction of immunologic memory. Clinically, the immunomodulatory effect of the radiotherapy strategy should be considered when combining stereotactic radiotherapy with immunotherapy. Clin Cancer Res; 24(20); 5058-71. ©2018 AACR.

Lupus Nephritis: A Treatment Update.

BACKGROUND: Lupus nephritis (LN) is a common complication in many patients with systemic lupus erythematosus, although renal-limited lupus nephritis has been reported as well. Early diagnosis of lupus nephritis is critical as early detection and effective treatment can improve renal outcomes in such patients. OBJECTIVE: The treatment of lupus nephritis is largely determined based on the histological class present on the renal biopsy specimen. In most cases, Class I and II of lupus nephritis do not require any specific treatment, but class III and IV lupus nephritis require immunosuppressive therapy. Treatment of Class V and VI remains controversial. In 2012, six guidelines were introduced for the management of lupus nephritis. These guidelines offer comprehensive treatment plans for each class of Lupus nephritis but differ from each other in many aspects. The purpose of this article is to review the current literature of the available pharmacological treatments used in the six classes of lupus nephritis as well as resistant lupus nephritis, strategies to address the problems of inadequate therapeutic response, medication related side effects, relapses of lupus nephritis, and some future treatment options. METHODS: We reviewed the available literature and treatment guidelines on lupus nephritis in detail to present a comprehensive review of the available treatment options for different classes of lupus nephritis. CONCLUSION: Lupus nephritis which does not respond to initial treatment is associated with worse renal outcomes. Several therapeutic approaches are available for the induction and maintenance immunosuppression of the different classes of LN. Management of LN should be individualized for each patient based on their risk-benefit profile.

Proteinuria: A presenting manifestation of mirror syndrome in pregnancy
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Hypertension and proteinuria in pregnant women are most commonly signs of preeclampsia which develops after 20 weeks of gestation. There are rare incidences of uncontrolled hypertension and nephrotic range proteinuria even in the first trimester of pregnancy which can be indicators of severe underlying fetal and placental abnormalities rather than preeclampsia. A G2P0 30-year-old Caucasian woman was admitted to University Hospital for the incidental finding of severe hypertension and proteinuria during her regular prenatal checkup at 14 weeks. She had complaints of mild bifrontal headache, facial and lower extremity edema. Her admission blood pressure was 193/108 mmHg, she had 8 g proteinuria, normal creatinine, and negative immunological and infectious workup. Further evaluation with dedicated obstetric ultrasonography showed hydropic placenta and fetus with aneuploidy. These findings strengthened the suspicion for a rare disease process called mirror syndrome, and emergent delivery was done to treat maternal disease process. Mirror syndrome is a rare disease that occurs basically due to fetal/placental pathology. It can present at any gestational period, and the clinical features include edema, proteinuria, and hypertension, mimicking preeclampsia. Prompt diagnosis and treatment is very crucial to prevent maternal complications.
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Treatment of Diabetic Kidney Disease With Hypertension Control and Renin Angiotensin System Inhibition.

The global incidence and prevalence of diabetes continues to expand due primarily to the influences of obesity and the contribution of obesity to the progression of type 2 diabetes mellitus. The rising prevalence of type 2 diabetes has driven an increase in rates of CKD in the past 3 decades in the United States. In turn, so have the rates for complications related to type 2 diabetes including CKD, eg, diabetic kidney disease (DKD). Although incident rates for DKD have stabilized in the recent years, diabetes continues to be the leading cause of ESRD in the United States. The United Kingdom Prospective Diabetes Study data and other population-level studies support that lowering blood pressure reduces kidney disease and cardiovascular disease in patients with type 2 diabetes. Furthermore, strategies targeting renin-angiotensin-aldosterone system interruption have shown to improve DKD outcomes to a greater extent than other classes of antihypertensive regimens.

Quality Assessment of Stereotactic Radiosurgery of a Melanoma Brain Metastases Model Using a Mouselike Phantom and the Small Animal Radiation Research Platform.

PURPOSE: To establish a novel preclinical model for stereotactic radiosurgery (SRS) with combined mouselike phantom quality assurance in the setting of brain metastases. METHODS AND MATERIALS: C57B6 mice underwent intracranial injection of B16-F10 melanoma cells. T1-weighted postcontrast magnetic resonance imaging (MRI) was performed on day 11 after injection. The MRI images were fused with cone beam computed tomography (CBCT) images using the Small Animal Radiation Research Platform (SARRP). The gross tumor volume (GTV) was contoured using the MRI. A single sagittal arc using the 3 × 3 mm2 collimator was used to deliver 18 Gy prescribed to the isocenter. MRI was performed 7 days after radiation treatment, and the dose delivered to the mice was confirmed using 2 mouselike anthropomorphic phantoms: 1 in the axial orientation and the other in the sagittal orientation. The SARRP output was measured using a PTW Farmer type ionization chamber as per the American Association of Physicists in Medicine Task Group report 61, and the H-D curve was generated up to a maximum dose of 30 Gy. Irradiated films were analyzed based on optical density distribution and H-D curve. RESULTS: The tumor volume on day 11, before intervention, was 2.48 ± 1.37 mm3 in the no-SRS arm versus 3.75 ± 1.19 mm3 in the SRS arm (NS). In the SRS arm, GTV maximum dose (Dmax) and mean dose were 2048 ± 207 and 1785 ± 14 cGy. Using the mouselike phantoms, the radiochromic film showed close precision in comparison with projected isodose lines, with a Dmax of 1903.4 and 1972.7 cGy, the axial and sagittal phantoms, respectively. Tumor volume 7 days after treatment was 7.34 ± 8.24 mm3 in the SRS arm and 60.20 ± 40.4 mm3 in the no-SRS arm (P=.009). No mice in the control group survived more than 22 days after implantation, with a median overall survival (mOS) of 19 days; mOS was not reached in the SRS group, with 1 death noted. CONCLUSIONS: Single-fraction SRS of 18 Gy delivered in a single arc can be delivered accurately with MRI T1-weighted postcontrast-based treatment planning. The mouse like phantom allows for verification of dose delivery and accuracy.