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In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities.

Importance Stereotactic ablative radiotherapy (SABR) is first-line treatment for patients with early-stage non–small cell lung cancer (NSCLC) who cannot undergo surgery. However, up to 1 in 6 such patients will develop isolated local recurrence (iLR) or isolated regional recurrence (iRR). Little is known about outcomes when disease recurs after SABR, or about optimal management strategies for such recurrences. Objective To characterize long-term outcomes for patients with iLR or iRR after SABR for early-stage NSCLC with the aim of informing treatment decision making for these patients with potentially curable disease. Design, Setting, and Participants In this cohort study, a retrospective review was conducted of 912 patients prospectively enrolled in an institutional database at a tertiary cancer center from January 1, 2004, through December 31, 2014. Main Outcomes and Measures Overall survival, progression-free survival, recurrence patterns, demographics, salvage techniques, patterns of salvage failure, and toxic effects. Results Of the 912 patients in the study (456 women and 456 men; median age, 72 years [range, 46-91 years]), 756 (82.9%) had T1 tumors at initial diagnosis; 502 tumors (55.0%) were adenocarcinomas and 309 tumors (33.9%) were squamous cell carcinomas. Of 912 patients with early-stage I to II NSCLC who received definitive SABR (50 Gy in 4 fractions or 70 Gy in 10 fractions), 102 developed isolated recurrence (49 with iLR and 53 with iRR), and 658 had no recurrence. Median times to recurrence after SABR were 14.5 months (range, 1.5-60.8 months) for iLR and 9.0 months (range, 1.9-70.7 months) for iRR; 39 of 49 patients (79.6%) with iLR and 48 of 53 patients (90.6%) with iRR underwent salvage with reirradiation, surgery, thermal ablation, or chemotherapy. Median follow-up times for patients with iLR or iRR were 57.2 months (interquartile range, 37.7-87.6 months) from initial SABR and 38.5 months (interquartile range, 19.9-69.3 months) from recurrence. Rates of overall survival at 5 years from initial SABR were no different between patients with iLR and salvage treatment (57.9%) and patients with no recurrence (54.9%; hazard ratio, 0.89; 95% CI, 0.56-1.43; P = .65) but were lower for patients with iRR and salvage treatment (31.1%; hazard ratio, 1.43; 95% CI, 1.00-2.34; P = .049). Patients receiving salvage treatment had longer overall survival than patients who did not (median, 37 vs 7 months after recurrence; hazard ratio, 0.40; 95% CI, 0.09-0.66; P = .006). Twenty-four of 87 patients (27.6%) who received salvage treatment for iLR or iRR subsequently developed distant metastases. No patient experienced grade 5 toxic effects after salvage treatment. Conclusions and Relevance Life expectancy after salvage treatment for iLR was similar to that for patients without recurrence, but survival after salvage treatment for iRR was similar to that of patients with stage III NSCLC. Patients who received salvage treatment had significantly improved survival. Because salvage treatment for iLR or iRR was based on a consistent multidisciplinary approach, this may help in clinical decision making., This cohort study examines long-term outcomes for patients with isolated local recurrence or isolated regional recurrence after stereotactic ablative radiotherapy for early-stage non–small cell lung cancer with the aim of informing treatment decision making., Key Points Question What are the outcomes for potentially curable local or regional recurrences after stereotactic ablative radiotherapy for early-stage non–small cell lung cancer? Findings In this cohort study of 912 patients who received stereotactic ablative radiotherapy for early-stage I to II non–small cell lung cancer, salvage treatment was significantly associated with improved survival. Survival for patients with local recurrence who received salvage treatment was no different than that for patients with no recurrence, and survival for patients with regionally recurrent disease was similar to that for patients with stage III disease. Meaning This study provides data on outcomes for patients with recurrence after stereotactic ablative radiotherapy, which may help in clinical decision making.

The MASER (Measuring, Analysing and Simulating Radio Emissions) project provides a comprehensive infrastructure dedicated to low frequency radio emissions (typically < 50 to 100 MHz). The four main...

Background & purpose We report disease control, survival, and toxicity in patients with advanced inoperable non-small cell lung cancer (NSCLC) receiving concurrent chemotherapy and intensity-modulated proton therapy (IMPT) at a single institution. Material and methods All patients were treated with IMPT with concurrent chemotherapy. Endpoints assessed were local, regional, and distant control, disease-free survival (DFS), and overall survival (OS). Results Fifty-one patients were enrolled with a median follow-up time of 23.0 months; 39 (76%) were treated with a simultaneous integrated boost to the gross tumor volume (GTV). The median GTV dose was 67.3 CGE and the median CTV dose was 60.0 CGE. Median OS and DFS times were 33.9 months and 12.6 months. The 3-year local control rate was 78.3%. Treatment was well tolerated, with a grade 3 toxicity rate of 18% (9 events: 4 esophagitis, 3 dermatitis, 1 esophageal stricture, and 1 fatigue) and no grade 4 or 5 toxicity. The most common grade 2 toxic effects were esophagitis (22 [43%]), dermatitis (16 [31%]), pain (15 [29%]), and fatigue (14 [27%]). Conclusions Treatment of inoperable NSCLC with IMPT and concurrent chemotherapy achieves excellent disease control with tolerable toxicity.

Purpose Hypofractionated radiotherapy delivers larger daily doses of radiation and may increase the biologically effective dose delivered to the prostate. We conducted a randomized trial testing the hypothesis that dose-escalated, moderately hypofractionated intensity-modulated radiation therapy (HIMRT) improves prostate cancer control compared with conventionally fractionated IMRT (CIMRT) for men with localized prostate cancer. Patients and Methods Men were randomly assigned to 75.6 Gy in 1.8-Gy fractions delivered over 8.4 weeks (CIMRT) or 72 Gy in 2.4 Gy fractions delivered over 6 weeks (HIMRT, biologically equivalent to 85 Gy in 1.8-Gy fractions assuming prostate cancer α-to-β ratio of 1.5). Failure was defined as prostate-specific antigen (PSA) failure (nadir plus 2 ng/mL) or initiation of salvage therapy. Modified Radiation Therapy Oncology Group criteria were used to grade late (≥ 90 days after completion of radiotherapy) GI and genitourinary toxicity. Results Most of the 206 men (72%) had cT1, Gleason score 6 or 7 (99%), and PSA level ≤ 10 ng/mL (90%) disease. Androgen deprivation therapy was received by 24%. With a median follow-up of 8.5 years, men treated with HIMRT experienced fewer treatment failures (n = 10) than men treated with CIMRT (n = 21; P = .036). The 8-year failure rate was 10.7% (95% CI, 5.8% to 19.1%) with HIMRT and 15.4% (95% CI, 9.1% to 25.4%) with CIMRT. There was no difference in overall survival ( P = .39). There was a nonsignificant increase in late grade 2 or 3 GI toxicity with HIMRT (8-year 5.0% v 12.6%; P = .08). However, GI toxicity was only 8.6% when rectal volume receiving 65 Gy of HIMRT was ≤ 15%. Late genitourinary toxicity was similar ( P = .84). There was no grade 4 toxicity. Conclusion The results of this randomized trial demonstrate superior cancer control for men with localized prostate cancer who receive dose-escalated moderately hypofractionation radiotherapy while shortening treatment duration.

Purpose: Radiation is used extensively to treat localized cancer, but improved understanding of its effects on the immune system has increased interest in its potential systemic (abscopal) effects, particularly in combination with checkpoint inhibitors such as anti-PD1. The majority of patients either do not respond or develop resistance to monotherapy over time. Here, we investigated the efficacy of OX40 (CD134) stimulation as an alternative immunotherapeutic approach in combination with radiotherapy (XRT) in a murine model of anti–PD1-resistant lung tumors. Experimental Design: We established a bilateral tumor model in 129Sv/Ev mice using an anti–PD1-resistant lung tumor cell line. Primary tumors were treated with intratumoral injection of an OX40 agonist antibody, given as adjuvant therapy after XRT (36 Gy in three 12-Gy fractions), whereas secondary tumors were left untreated to investigate abscopal outcomes. Results: The combination of XRT followed by OX40 stimulation effectively inhibited local and systemic antitumor growth, limited lung metastases, and improved survival rates. This treatment regimen augmented CD4+ and CD8+ T-cell expansion. XRT induced the expression of OX40 on T cells in tumors and spleens and increased the percentages of splenic CD103+ dendritic cells. Conclusions: Our data extend the benefits of radiation to systemic disease control, especially when combined with anti-OX40 agonist to promote immunologically mediated abscopal effects. Moreover, this study provides a rational treatment approach and sequence to overcome anti–PD1-resistant poorly immunogenic tumors. Clin Cancer Res; 24(22); 5735–43. ©2018 AACR.

Background mAbs targeting staphylococcal virulence factors could represent an interesting preventive strategy in PJI. We evaluate here MEDI6389 compared with isotype-matched control IgG (c-IgG) in a rabbit model of USA300 MRSA PJI. Methods Rabbits were randomized for prophylaxis with either c-IgG (n = 13; 30 mg/kg; controls) or MEDI6389 (n = 13; 30 mg/kg of each mAb) administered intravenously 12h before infection. A cemented screw and ultrahigh-molecular-weight polyethylene washer were placed intraarticularly in the external femoral condyle. After suturing the joint capsule and musculocutaneous layers, 300 µL of a standardized bacterial inoculum containing 5 × 105 CFU of a USA300 MRSA clinical isolate were injected intraarticularly. Animals were euthanized on day 8 and the knee joint was harvested for bacteriological analysis (synovial bacterial counts, and enumeration of screw-adherent bacteria after sonication) and histology (conventional pathology, and transmission electron microscopy [TEM] for neutrophils analysis). In vivo observations made on neutrophils were confirmed by TEM analysis of human neutrophils incubated in vitro with purified PVL, LukED, and gamma-hemolysin with or without the corresponding mAb. Results In comparison with the control group, the average amount of pus (1.7 ± 1.8 vs. 3.1 ± 1.2 g, P = 0.026) and the number of bacteria in the synovial pus (5.9±1.5 vs. 7.2±1.4 log10 CFU, P = 0.031) and on the screw (2.7 ± 1.5 vs. 4.1 ± 1.6 log10 CFU, P = 0.035) were decreased in animals pretreated by MEDI6389. Conventional pathological examination showed a marked reduction in synovitis of MEDI6389-pretreated animals. TEM of synovitis harvested from infected knee joints of control animals showed significant greater number of abnormal neutrophils that appeared rounded, with condensed nucleus and no granules, compared with those pretreated with MEDI6389 (P = 0.002). This classical leukocidin-induced neutrophilic killing phenotype could be neutralized with anti-leukocidin mAbs using ex vivo human neutrophils incubated with PVL, LukED, HlgAB, or HlgCB. Conclusion The preventive administration of MEDI6389 allows a reduction of local inflammation and bacterial burden in this USA300 MRSA rabbit PJI model. Disclosures All authors: No reported disclosures.

Background Severity and antimicrobial resistance of P. aeruginosa (PA) hospital-acquired pneumonia led the FDA to encourage the development of animal models for preclinical evaluation of new therapeutic strategies. We present here the validation of a rabbit model of PA acute pneumonia. Methods Rabbits were infected by endotracheal instillation of 1.8 mL of a standardized inoculum containing 9 × 107 CFU of PA clinical strain 6206 (predetermined 100% lethal dose). The natural history of the disease was described by the following parameters evaluated at 3, 4, 5, 6, 10 hours post-infection (hpi) and at the time of spontaneous death (6 rabbits/group): lung-to-body weight ratio (LW/BW), pulmonary, splenic and renal bacterial counts, pulmonary histology and blood markers (blood cell counts, blood gas and IL-8). Three groups of 12 rabbits were then treated with saline (controls), tobramycin or meropenem at doses determined by PK/PD analysis to confirm the efficacy of a human-equivalent dosing regimen. Results PA strain 6,206 caused fatal pneumonia in 13–23 hours by acute respiratory distress syndrome (pulmonary edema and necrosis with LW/BW > 10, pO2 Conclusion This rabbit model of PA acute pneumonia is a reliable evaluation tool for new therapeutic strategies. Our study also provides guidance for the development of animal models by describing the natural history of disease and therapeutic validation. Disclosures All authors: No reported disclosures.

Introduction L’utilisation d’anticorps monoclonaux (AcM) ciblant des facteurs de virulence de S. aureus pourrait representer une strategie preventive innovante des infections de prothese articulaire (IPA). Nous evaluons ici l’utilisation preventive de MEDI6389 dans un modele lapin d’IPA a SARM USA300. Materiels et methodes Des lapins blancs de Nouvelle-Zelande (2–2,8 kg) ont ete randomises pour recevoir une injection intraveineuse de 30 mg/kg d’immunoglobulines polyvalentes (IgIV, n = 13, controles) ou de 90 mg/kg de MEDI6389 (soit 30 mg/kg de chaque AcM, n = 13) 12 h avant infection. Une vis cimentee et une rondelle de polyethylene etaient placees en intra-articulaire dans le condyle femoral externe sous anesthesie generale apres arthrotomie. Apres suture de la capsule et des plans musculo-cutanes, 300 μL d’un inoculum standardise contenant 5 × 106 CFU d’une souche de SARM USA300 etaient injectes en intra-articulaire. Apres 8 jours, les lapins etaient euthanasies et l’articulation du genou recuperee pour analyses bacteriologiques (compte bacterien synovial, numeration des bacteries adherees au materiel apres sonication) et histologique (anatomopathologie conventionnelle et microscopie electronique a transmission [MET] pour analyse des polynucleaires neutrophiles [PNN]). Les observations faites sur les PNN in vivo ont ete confirmees in vitro par analyse en MET de PNN humains exposes aux toxines purifiees PVL, LukED, HlgAB ou HlgCB sans ou avec l’AcM correspondant. Le modele a ete approuve par le comite d’ethique veterinaire de notre institution. Resultats En comparaison au groupe controle, la quantite moyenne de pus (1,7 ± 1,8 vs 3,1 ± 1,2 g, p = 0,026) et le nombre de bacteries intrasynoviales (5,9 ± 1,5 vs 7,2 ± 1,4 log10 UFC, p = 0,031) et adherees a la vis (2,7 ± 1,5 vs 4,1 ± 1,6 log10 UFC, p = 0,035) etaient diminues chez les animaux ayant recu une prevention par MEDI6389. L’examen histologique conventionnel a montre une reduction marquee de l’aspect de synovite chez les animaux traites. En MET, le nombre de PNN alteres, arrondis, sans granules et avec noyau condense etait egalement significativement diminue (p = 0,002). Cet aspect pathologique des PNN classiquement associe aux leucocidines a ete confirme apres traitement ex vivo de PNN humains par PVL, LukED, HlgAB ou HlgCB purifiees, dont l’effet cytopathogene etait prevenu in vitro par incubation avec chacun des AcM. Conclusion Le ciblage specifique de l’AT, la PVL, LukED, Hlg ABC et le ClfA par administration preventive de MEDI6389 permet une reduction de l’inflammation locale et de la charge bacterienne dans ce modele lapin d’IPA a SARM USA300.

Purpose We report long-term disease control, survival, and toxicity for patients with locally advanced non-small cell lung cancer prospectively treated with concurrent proton therapy and chemotherapy on a nonrandomized case-only observational study. Methods All patients received passive-scatter proton therapy, planned with 4D-CT–based simulation; all received proton therapy concurrent with weekly chemotherapy. Endpoints were local and distant control, disease-free survival (DFS), and overall survival (OS). Results The 134 patients (21 stage II, 113 stage III; median age 69years) had a median gross tumor volume (GTV) of 70cm 3 (range, 5–753cm 3 ); 77 patients (57%) received 74Gy(RBE), and 57 (42%) received 60–72Gy(RBE) (range, 60–74.1Gy(RBE)). At a median follow-up time of 4.7years, median OS times were 40.4months (stage II) and 30.4months (stage III). Five-year DFS rates were 17.3% (stage II) and 18.0% (stage III). OS, DFS, and local and distant control rates at 5years did not differ by disease stage. Age and GTV were related to OS and DFS. Toxicity was tolerable, with 1 grade 4 esophagitis and 16 grade 3 events (2 pneumonitis, 6 esophagitis, 8 dermatitis). Conclusion This report of outcomes after proton therapy for 134 patients indicated that this regimen produced excellent OS with tolerable toxicity.

Introduction: Barrett’s esophagus (BE) may be present in patients with esophageal adenocarcinoma (EAC) after bimodality therapy (BMT). There is no specific guidance for follow-up of these patients with regard to the presence of BE or dysplasia. In this study, we assessed the outcomes of patients who, after BMT, had BE and those who did not. Method: Patients with EAC who had BMT were identified and analyzed retrospectively in two groups, with and without BE. We compared patient characteristics and outcome variables (local, distant, and no recurrence). Results: Of 228 patients with EAC, 68 (29.8%) had BE before BMT. Ninety-eight (42.9%) had BE after BMT, and endoscopic intervention was done in 11 (11.2%). With a median follow-up of 37 months, the presence of post-BMT BE was not significantly associated with overall survival (OS) and local recurrence-free survival (LRFS). Similarly, endoscopic intervention was not significantly associated with OS and LRFS. Fifty (73.5%) patients with BE before BMT had BE after BMT (p < 0.0001). Conclusion: The presence of BE after BMT was not associated with increased risk of local recurrence. The local recurrence rate was not influenced by endoscopic intervention. Prospective studies are warranted to generate guidance for intervention, if necessary, for this group of EAC patients.

Objective To provide comparative data on quality of life (QoL) after prostate cancer treatment to help patients make an informed decision regarding their choice of treatment. Methods Patients with pathologically proven, non-metastatic, T1–T3bN0 prostate cancer were included in this prospective non-randomized study if they were to receive treatment with curative intent. Sample size was at least 181 patients per cohort/treatment type. QoL was recorded at baseline and at each follow-up using the Expanded Prostate Cancer Index Composite (EPIC) instrument. The minimal clinically important difference was defined as half of the standard deviation of the baseline score for each domain. A mixed effects model was used to compare the different treatments. Data are presented on the brachytherapy and the bilateral nerve-sparing robot-assisted radical prostatectomy (RARP) cohorts. Hormonotherapy was not allowed. Results Between November 2007 and January 2013, 181 patients who received brachytherapy and 210 patients who underwent RARP were included. Of the patients who underwent RARP, 178 had bilateral nerve-sparing and were included in the present analysis. Response rate to EPIC questionnaires were higher in the brachytherapy than in the RARP arm: 82% vs 57% at 2 years after treatment and 55% vs 45% at 4 years after treatment. In the mixed effects model, patients in the RARP arm had better QoL with regard to urinary irritation/obstruction or bother and bowel function, and lower QoL regarding sexual function and urinary incontinence. Results were confirmed in a propensity score-matched model. Patient satisfaction was significantly higher in the brachytherapy group at 1, 2 and 3 years after treatment. Conclusion This prospective non-randomized study shows long-term differences in QoL domains after bilateral nerve-sparing RARP and brachytherapy. Differences in patient satisfaction should be further explored. These results could be used to counsel patients in the decision-making process.

Resectable esophageal adenocarcinoma (EAC) patients often receive chemoradiation followed by surgery. However, most patients experience recurrences. Overexpression of MTDH, an oncoprotein with multiple functions, has been found to be associated with poor prognosis in breast cancer, glioblastoma, melanoma and various gastrointestinal malignancies, but not in EAC. We sought to establish its role in resistant EAC (post-treatment residual EAC). MTDH was assessed by immunohistochemistry in resected EAC, and results were correlated with clinical outcomes. MTDH expression was detectable in 72.5% (50/69) of patients, while expression levels were high (positive) in 50.7% (35/69). Of 69 patients analyzed, 25 had no relapse and 44 patients had a relapse (8 with local-regional and 36 with distant). The median follow-up duration was 3 years (0.4-11.6). The median overall survival was not associated with MTDH status (2.79 years for MTDH-negative and 3.60 years for MTDH-positive patients, p = 0.121). In addition, MTDH was not associated with either the type of relapse (local or distant), baseline clinical stage, tumor grade, presence of signet ring cells, surgical (yp) stage, percentage of residual EAC or presence of lymphovascular invasion. Our data reveal that MTDH is not a prognostic biomarker in resistant EAC after trimodality therapy.

Importance Multiple randomized clinical trials have shown that definitive therapy improves overall survival among patients with high-risk prostate cancer. However, many patients do not receive definitive therapy because of sociodemographic and health-related factors. Objective To identify factors associated with receipt of nondefinitive therapy (NDT) among patients aged 70 years and younger with high-risk prostate cancer. Design, Setting, and Participants This cohort study identified 72 036 patients aged 70 years and younger with high-risk prostate cancer and Charlson Comorbidity Index scores of 2 or less who were entered in the National Cancer Database between January 2004 and December 2014. Data analysis was conducted from November 2018 to December 2019. Exposure Receipt of NDT as an initial treatment approach. Main Outcomes and Measures Survival rates were compared based on receipt of definitive therapy or NDT, and sociodemographic and health-related factors were associated with the type of therapy received. Residual life expectancy was estimated from the National Center for Health Statistics to calculate person-years of life lost. Results A total of 72 036 men with a median (range) age of 63 (30-70) years, Charlson Comorbidity Index scores of 2 or less, and high-risk prostate cancer without regional lymph node or distant metastatic disease were analyzed. Among eligible patients, 5252 (7.3%) received NDT as an initial therapeutic strategy. On univariate and multivariate analyses, NDT was associated with worse overall survival (univariate analysis hazard ratio, 2.54; 95% CI, 2.40-2.69;P Conclusions and Relevance In this study, receipt of NDT was associated with insurance status and race/ethnicity. While treatment decisions should be individualized for every patient, younger men with high-risk prostate cancer and minimal comorbidities should be encouraged to receive definitive local therapy regardless of other factors. These data suggest that significant barriers to life-extending treatment options for patients with prostate cancer remain.

Background: Preoperative chemoradiotherapy (CRT) is one standard option for localized esophageal or gastroesophageal junction (GEJ) cancer patients but an optimal concurrent chemotherapy combination is not established. Methods: 412 patients with resectable (cT1N1M0 or cT2-4N0-3M0) esophageal or GEJ cancer treated at the MDACC between October 2002 and June 2016 were analyzed. Exposures: CRT with DF or FOX followed by surgery (trimodality; TMT). Main outcomes and measures: Primary endpoints were overall survival (OS) and disease-free survival (DFS). Univariate and multivariate Cox analyses were performed. Results: Of the 412 patients analyzed, 264 (64%) received DF and 148 (36%) FOX. The median age was 60 years, and 95% had adenocarcinoma. The clinical complete response, positron-emission tomography response, and pathologic complete response rates were 73%, 73%, and 30%, respectively. Median follow-up was 60.4 months. Median OS for the entire cohort was 81.6 months (95% confidence interval [CI], 56.3–122.0); 81.6 months (95% CI, 55.9–not estimable) for the DF group and 67.7 months (95% CI, 41.6–not estimable) for the FOX group (P = .24). The median DFS was 45.6 months (95% CI, 33.1–61.7) for the entire cohort; 49.5 months (95% CI, 38.6–70.3) for DF and 33.0 months (95% CI, 18.1–70.4; P = .38) for FOX. Higher tumor location (unfavorable) and clinical complete response (favorable) were prognostic for both OS and DFS in the multivariate analysis. Conclusion: At our high-volume center, the outcome of 412 TMT esophageal cancer patients was excellent. Taxane-based chemotherapy produces nonsignificant favorable trend.

Importance Effective treatment options for locally advanced esophageal cancer are limited, and rates of local recurrence after standard chemoradiotherapy remain high. Objective To evaluate toxic effects, local control, and overall survival rates after chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose to the gross tumor and nodal disease for patients with unresectable locally advanced esophageal cancer. Design, Setting, and Participants A phase 1/2, single-arm trial was conducted in 46 patients from April 28, 2010, to April 9, 2015 (median follow-up, 52 months [range, 2-86 months]), at a tertiary academic cancer center. Outcomes of the study patients were compared with those of 97 similar patients treated at the same institution from January 10, 2010, to December 5, 2014, as part of the interim analysis. Statistical analysis was performed from December 15, 2018, to February 12, 2019. Interventions Chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose (50.4 Gy to subclinical areas at risk and 63.0 Gy to the gross tumor and involved nodes, all given in 28 fractions) with concurrent docetaxel and capecitabine or fluorouracil. Main Outcomes and Measures Toxic effects, local (in-field) control, and overall survival rates. Results All 46 patients (11 women and 35 men; median age, 65.5 years [range, 37.3-84.4 years]) received per-protocol therapy, as intensity-modulated photon therapy (39 [85%]) or intensity-modulated proton therapy (7 [15%]); 11 patients (24%) ultimately underwent resection. No patients experienced grade 4 or 5 toxic effects; the 10 acute grade 3 toxic events were esophagitis (4), dysphagia (3), and anorexia (3) and the 3 late grade 3 toxic events were all esophageal strictures. The actuarial local recurrence rates were 22% (95% CI, 11%-35%) at 6 months, 30% (95% CI, 18%-44%) at 1 year, and 33% (95% CI, 20%-46%) at 2 years. Overall, 15 patients (33%) experienced local failure, at a median interval of 5 months (range, 1-24 months). The median overall survival time was 21.5 months (range, 2.3-86.4 months). Exploratory comparison with a 97-patient contemporaneous institutional cohort receiving standard-dose (non–simultaneous integrated boost) chemoradiotherapy showed superior local control (hazard ratio, 0.49; 95% CI, 0.26-0.92;P = .03) and overall survival (hazard ratio, 0.66; 95% CI, 0.47-0.94;P = .02) in the group that received chemoradiotherapy with a simultaneous integrated boost. Conclusions and Relevance These findings suggest that chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose for locally advanced esophageal cancer is well tolerated, with encouraging local control, and thus warrants further study. Trial Registration ClinicalTrials.gov identifier:NCT01102088

Objective Several options are available for the local treatment of colorectal pulmonary metastases; however, the efficacy of each treatment has not been well characterized. We compared the risk of local recurrence after wedge resection or stereotactic body radiation therapy for pulmonary metastases of colorectal origin. Methods We retrospectively reviewed records of patients treated for pulmonary colorectal metastases with stereotactic body radiation therapy or wedge resection from 2006 to 2016 at a single institution. Local recurrence was defined as an enlarging nodule either adjacent to the staple line or within the radiation field on computed tomography. Matching weights using the propensity score with death as a competing event was used to estimate the risk of local recurrence for each metastatic nodule. Results A total of 381 patients underwent 762 wedge resections and 64 courses of stereotactic body radiation therapy for definitive treatment of 826 pulmonary nodules. The risk of local recurrence was increased with stereotactic body radiation therapy (hazard ratio, 3.28; 95% confidence interval, 1.53-7.04; P = .002) and larger tumor size (hazard ratio, 1.38 per additional centimeter; 95% confidence interval, 1.01-1.87; P = .042). After reweighting with matching weights, the marginal 2-year risk of local recurrence for each nodule was 14.1% (95% confidence interval, 9.8-18.5) after wedge resection and 29.4% (95% confidence interval, 13.8-45.0) after stereotactic body radiation therapy (P = .023). Conclusions Pulmonary colorectal metastases treated with stereotactic body radiation therapy have a higher risk of local recurrence than those treated with wedge resection. Stereotactic body radiation therapy should be reserved for patients with comorbidities precluding surgical resection.

79 Background: Since 2010 The University of Texas MD Anderson Cancer Center (UTMDACC) has been using Time Driven Activity Based Costing (TDABC) to assist in tracking and quantifying changes made to clinical processes to improve efficiency of patient care delivery. Radiation Oncology (RO) providers have recently utilized this method to assist in the growing clinical patient volumes and increasing enrollment in clinical trials. UTMDACC contains disease specific multi-disciplinary centers with separate clinics for different disciplines. Resources are limited which can affect clinical providers’ ability to meet the needs of increasing patient volumes. Implementing efficient clinic work flow models will allow clinicians to provide excellent quality of clinical care even with limited resources. Methods: Standard disease-site specific note templates were created and implemented throughout the entire RO department. Additionally, standardized roles for medical assistants, residents, physician assistants (PAs), attending physicians and nurses were implemented to minimize duplication of responsibilities. Using TDABC methodology, process maps for pre and post implementation pathways were created to illustrate areas of change and possible benefit. Results: Process maps were compared for new consult and follow up and on treatment patient visits. Process times for these patient care visits were compared pre- and post-implementation of templates and clinical roles. Time savings of 110, 18 and 34 minutes were observed for consult visits, follow up visits and on-treatment visits when comparing current to baseline process maps. Conclusions: Standardization of note templates and roles for all members of the care team has led to improvements in process flow and efficiency in the RO clinic setting. Our findings suggest that further implementation of TDABC methodology by having all providers work at the top of their license could can improve clinical efficiency and patient care. Further metrics with a larger sample size is recommended to validate our results. [Table: see text]

Importance Consensus is lacking as to the optimal radiotherapy dose and fractionation schedule for treating bone metastases. Objective To assess the relative efficacy of high-dose, single-fraction stereotactic body radiotherapy (SBRT) vs standard multifraction radiotherapy (MFRT) for alleviation of pain in patients with mostly nonspine bone metastases. Design, Setting, and Participants This prospective, randomized, single-institution phase 2 portion of a phase 2/3 noninferiority trial conducted at a tertiary cancer care center randomized 160 patients with radiologically confirmed painful bone metastases from September 19, 2014, through June 19, 2018. Patients were randomly assigned in a 1:1 ratio to receive either single-fraction SBRT (12 Gy for ≥4-cm lesions or 16 Gy for Main Outcomes and Measures The primary end point for this analysis was pain response, defined by international consensus criteria as a combination of pain score and analgesic use (daily morphine-equivalent dose) at 3 months. Pain failure was defined as worsening pain score (≥2 points on a 0-to-10 scale), an increase in morphine-equivalent opioid dose (MED) of 50% or more, reirradiation, or pathologic fracture. Failure, defined by worsening pain score, increase in MED, reirradiation, or radiographic disease progression was calculated with a subdistribution hazard ratio (SHR) using a competing risks model. We hypothesized that SBRT was noninferior to MFRT. Results In this phase 2 portion of a phase 2/3 noninferiority trial of 96 men and 64 women (mean [SD] age, 62.4 [10.4] years), 81 patients received SBRT and 79 received MFRT. Among evaluable patients who received treatment per protocol, the single-fraction group had more pain responders than the MFRT group (complete response + partial response) at 2 weeks (34 of 55 [62%] vs 19 of 52 [36%]) (P = .01), 3 months (32 of 44 [73%] vs 17 of 35 [49%]) (P = .04), and 9 months (17 of 22 [77%] vs 12 of 26 [46%]) (P = .04). An SHR of 0.71 (95% CI, 0.36-1.39) indicated that SBRT had 29% less risk of failure relative to the MFRT after considering death as a competing risk. The upper 95% CI for SHR was less than the noninferiority margin of 1.5, indicating that SBRT was noninferior to MFRT. No differences were found in treatment-related toxic effects or quality-of-life scores after SBRT vs MFRT. Conclusions and Relevance Delivering high-dose, single-fraction SBRT seems to be an effective treatment option for patients with painful bone metastases. Among evaluable patients, SBRT had higher rates of pain response (complete response + partial response) than did MFRT and thus should be considered for patients expected to have relatively long survival. Trial Registration ClinicalTrials.gov Identifier:NCT02163226

11578 Background: There lacks a consensus as to the optimal radiotherapy dose and fractionation schedule for treating bone metastases. We assessed the relative efficacy of single high-dose stereotactic radiation therapy (SBRT) versus standard multifraction radiation therapy (MFRT) for alleviation of pain in patients with mostly non-spine bone metastases. Methods: This prospective, randomized, single-institution phase II non-inferiority trial enrolled patients with radiologically confirmed painful bone metastases from September 2014 through June 2018. Patients were randomly assigned in a 1:1 ratio to receive either single-fraction SBRT (12 Gy for ≥4-cm lesions or 16 Gy for < 4-cm lesions) versus MFRT to 30 Gy in 10 fractions. Results: The primary endpoint was pain response, defined by international consensus criteria as a combination of pain score and analgesic use (daily morphine-equivalent dose [MED]). Failure of pain response was defined as worsening pain score (≥2 points on a 0-to-10 scale), an increase in morphine-equivalent opioid dose of ≥50%; re-irradiation; or pathologic fracture. Among evaluable patients who received treatment per protocol, the single-fraction SBRT group had more pain responders (CR+PR) at 2 weeks (62% vs. 36% MFRT, P= 0.01), at 1 month (62% vs 36%, P= 0.01), at 3 months (72% vs. 49% MFRT, P= 0.03), and at 9 months (77% vs. 12% MFRT, P= 0.03). No differences were found in treatment-related toxicity or quality of life scores after SBRT versus MFRT; local control rates at 1 year were higher in patients receiving single-fraction SBRT. Conclusions: Delivering high-dose single-fraction SBRT is an effective, convenient treatment option for patients with painful bone metastases. Among evaluable patients, SBRT led to higher rates of pain response (CR+PR) than did MFRT and thus should be considered for patients expected to have relatively long survival. Clinical trial information: ClinicalTrials.gov ID NCT02163226.

e15523 Background: Patients with gastrointestinal cancer are increasingly being diagnosed with oligometastatic disease due to the development of sensitive imaging. Oligometastases (OLM) represent a clinical and anatomical manifestation of resistant localized cancer and/or metastases. However, oligometastatic disease is complicated by the lack of uniformity due to the heterogeneity of cancer, therefore, differing prognoses. The aim of this study is to identify the factors associated with long-term survival in the patients with synchronous oligometastatic esophageal adenocarcinoma (EAC). Methods: Between 2002 and 2016, of 1400 patients with EAC (esophagus and Siewert types I and II) treated at our institute, 233 patients initially diagnosed with stage IVB were enrolled. OLM was defined as only metastasized to one organ and less than 5 metastases. We retrospectively analyzed the association between clinicopathological factors and prognosis, especially focused on the pattern of metastases. Results: Eighty-five patients (36.5%) had OLM, and 148 (63.5%) had non-oligometastais (Non-OLM). The patients in OLM had significantly better overall survival (OS) than the patients in Non-OLM (p = 0.0001). Univariate analysis showed pattern of metastases (lymphatic OLM) and treatment method (consolidative local radiotherapy: CLT) were significantly associated with prognosis (p = 0.04 and 0.01, respectively). Multivariate analysis revealed that lymph node metastases (cN0-N1), number of metastasis (solitary) and treatment (CLT) were independent predictors for OS of patients with OLM. (p = 0.03, 0.01 and 0.001, respectively). In OLM patients, the patients with lymphatic OLM who received CLT had more favorable prognosis (5-years survival rate 25%). Conclusions: This study suggests that CLT is one of the promising modalities for oligometastatic patients with EAC, especially the patients with lymphatic OLM.

e15526 Background: Paratracheal lymph node (LN) is considered regional for esophageal cancer, but its metastatic rate and influence to survival remain unclear. We aimed to evaluate the frequency of paratracheal LN metastasis and its prognostic influence. Methods: 1199 patients with localized esophageal or gastroesophageal junction adenocarcinoma (EAC) (January 2002 and December 2016) in our Gastrointestinal Medical Oncology Database were analyzed. 1R, 1L, 2R, 2L, 4R, and 4L according to 8th AJCC classification were defined as paratracheal LN. Results: Of 1199 patients, 73 (6.1%) had positive parataracheal LN at diagnosis. The median overall survival (OS) in 73 patients with initial paratracheal LN involvement was 2.10 years (range, xx). Of 1071 patients who were eligible for recurrence evaluation, 70 patients (6.5%) developed positive paratracheal LN recurrences as first recurrence. The median time to recurrence was 1.28 years (range; 0.28-5.96 years) and the median OS after recurrence was 0.95 years (range; 0.03-7.89). OS in 35 patients who had only patatracheal LN recurrence was significantly longer than in patients who had with other distant recurrences (median 2.26 vs 0.51 years; p < 0.0001). Higher T stage (T3/T4) was an independently risk factor for paratracheal LN recurrence (OR 5.10, 95% CI 1.46-17.89). We segregated patients in 3 groups based on the distance from esophagogastric junction to tumor proximal edge (lower; ≤2cm, middle; 2.0-7.0cm, higher; > 7.0cm), positive paratrachal LN metastases were more frequent in the proximal tumors (lower 4.2%, middle 12.0%, higher 30.3%; Cochran-Armitage Trend test, p < 0.001). Conclusions: Paratracheal LN metastases were associated with shorter survival in localized EAC patients. Careful investigation and surveillance for paratracheal LN are warranted.

9104 Background: We present findings of a randomized phase I/II trial studying PD-1 blockade with and without radiotherapy to lung lesions in patients with metastatic NSCLC. Methods: Patients with metastatic NSCLC were randomized to receive pembrolizumab with or without lung-directed radiotherapy (RT). RT referred to stereotactic body radiation therapy (SBRT, 50 Gy in 4 fractions or 70 Gy in 10 fractions) or traditional fractionation (45 Gy in 15 fractions). Pembrolizumab (200mg IV) was started on day 1 and given every 3 weeks for up to sixteen cycles. The primary endpoint was out-of-field response rate (RR), which refers to complete (CR) or partial response (PR) per irRC criteria. Results: Of 124 enrolled patients, 103 received treatment, 5 withdrew consent, 15 screen failures, and 1 was not financially cleared. Twenty-one patients completed 16 cycles of pembrolizumab; 16 patients received SBRT and 20 received traditional RT. Seven patients received salvage RT after progression on pembrolizumab alone and 15 patients received RT six months before starting the trial. In the combined-modality arm, there were 2 grade 4 toxicities and 9 grade 3 toxicities related to treatment. In the pembrolizumab arm, there were zero grade 4 toxicities and five grade 3 toxicities. At the present time, 72 patients were evaluable for response, 36 in both arms; median follow-up was 15.4 months (range: 1.4-125.2 months). RR for out-of-field lesions was 22% and 25% for the pembrolizumab + RT vs pembrolizumab respectively (p = 1.00); median PFS was 10.9 months (95% CI, 8.1-15.3 months) and 8.4 months (95% CI, 3.9-17.1 months) respectively (p = 0.83). When comparing the SBRT vs traditional fractionation sub-cohorts, non-irradiated RR was 38% and 10% respectively (p = 0.10); median PFS was 21.1 and 6.8 months respectively (p = 0.03). Within the pembrolizumab arm, comparing patients who received prior RT vs those that did not, RR was 33% and 19% respectively (p = 0.26). Conclusions: RT, while safe, did not increase the out-of-field response rate in NSCLC patients treated with pembrolizumab. Exploratory analysis suggests responses may be enhanced by SBRT, but not traditional fractionation, which warrants further investigation. Clinical trial information: NCT02444741.

Radiation pneumonitis (RP) is an inflammatory response to radiation therapy (RT). We assessed the association between RP and white blood cell (WBC) count, an established metric of systemic inflammation, after RT for non-small cell lung cancer.We retrospectively analyzed 366 patients with non-small cell lung cancer who received ≥60 Gy as definitive therapy. The primary endpoint was whether WBC count after RT (defined as 2 weeks through 3 months after RT completion) was associated with grade ≥3 or grade ≥2 RP. Median lung volume receiving ≥20 Gy (V20) was 31%, and post-RT WBC counts ranged from 1.7 to 21.2 × 10(3) WBCs/μL. Odds ratios (ORs) associating clinical variables and post-RT WBC counts with RP were calculated via logistic regression. A recursive-partitioning algorithm was used to define optimal post-RT WBC count cut points.Post-RT WBC counts were significantly higher in patients with grade ≥3 RP than without (P.05). Optimal cut points for post-RT WBC count were found to be 7.4 and 8.0 × 10(3)/μL for grade ≥3 and ≥2 RP, respectively. Univariate analysis revealed significant associations between post-RT WBC count and grade ≥3 (n=46, OR=2.6, 95% confidence interval [CI] 1.4‒4.9, P=.003) and grade ≥2 RP (n=164, OR=2.0, 95% CI 1.2‒3.4, P=.01). This association held in a stepwise multivariate regression. Of note, V20 was found to be significantly associated with grade ≥2 RP (OR=2.2, 95% CI 1.2‒3.4, P=.01) and trended toward significance for grade ≥3 RP (OR=1.9, 95% CI 1.0-3.5, P=.06).Post-RT WBC counts were significantly and independently associated with RP and have potential utility as a diagnostic or predictive marker for this toxicity.

Acute respiratory infections are the major cause of morbidity and mortality globally. Human bocavirus (HBoV), a novel virus, is recognized to increasingly associate with previously unknown etiology respiratory infections in young children. In this study, the epidemiological, clinical, and molecular characteristics of HBoV infections were described in hospitalized Vietnamese pediatric patients. From April 2010 to May 2011, 1,082 nasopharyngeal swab samples were obtained from patients with acute respiratory infections at the Children's Hospital 2, Ho Chi Minh City, Vietnam. Samples were screened for HBoV by PCR and further molecularly characterized by sequencing. HBoV was found in 78 (7.2%) children. Co-infection with other viruses was observed in 66.7% of patients infected with HBoV. Children 12-24 months old were the most affected age group. Infections with HBoV were found year-round, though most cases occurred in the dry season (December-April). HBoV was possible to cause severe diseases as determined by higher rates of hypoxia, pneumonia, and longer hospitalization duration in patients with HBoV infection than in those without (P-value

Background: Men with high-risk prostate cancer are often thought to have very poor outcomes in terms of disease control and survival even after definitive treatment. However, results after external beam radiotherapy have improved significantly through dose escalation and the use of androgen deprivation therapy (ADT). This report describes long-term findings after low-dose (< 75.6 Gy) or high-dose (≥ 75.6 Gy) external beam radiation, with or without ADT. Methods: This analysis included 741 men with high-risk prostate cancer (clinical classification ≥ T3, Gleason score ≥ 8, or prostate-specific antigen level ≥ 20 ng/mL) treated with external beam radiotherapy at a single tertiary institution from 1987 through 2004. The radiation dose ranged from 60 to 79.3 Gy (median, 70 Gy); 295 men had received ADT for ≥ 2 years, and the median follow-up time was 8.3 years. Results: The 5- and 10-year actuarial overall survival rates were significantly better for men treated with the higher radiation dose (no ADT plus ≥ 75.6 Gy, 87.3% and 72.0%, respectively; and ADT plus ≥ 75.6 Gy, 92.3% and 72%, respectively) (P = .0035). The corresponding 5- and 10-year biochemical failure-free survival rates were significantly better for patients treated with both ADT and higher radiation dose (82% and 77%, P < .0001). At 5 years, men who had not received ADT and had received radiation dose < 75.6 Gy had higher clinical local failure rates than those given ADT and radiation dose ≥ 75.6 Gy (24.2% versus 0%, P < .0001). The 10-year symptomatic local failure rate was only 2% for all patients. Conclusions: Contrary to lingering historical perceptions, treatment of high-risk prostate cancer with modern, high-dose, external beam radiotherapy and ADT can produce better biochemical, clinical, and survival outcomes over those from previous eras. Specifically, symptomatic local failure is uncommon, and few men die of prostate cancer even 10 or more years after treatment.

Purpose Reirradiation of thoracic malignancies is a treatment challenge, with concerns for toxicity and the inability to deliver definitive doses. Intensity modulated proton therapy (IMPT) may allow safe delivery of a higher dose of radiation to the tumor while minimizing toxicities. Methods and materials Between 2011 and 2016, 27 patients who received IMPT for reirradiation of thoracic malignancies with definitive intent were retrospectively analyzed. Patients were included if they received a prior thoracic radiation course. All doses were recalculated to an equivalent dose in 2-Gy fractions (EQD2). Patients received IMPT to a median dose of 66 EQD2 Gy (range, 43.2-84 Gy) for recurrence of thoracic cancer (93%) or sequentially after a course of thoracic stereotactic ablative radiation therapy (7%). Results Twenty-two patients (81%) were treated for non-small cell lung cancer. The median time to reirradiation was 29.5 months. At a median follow-up for all patients of 11.2 months (25.9 surviving patients), the median overall survival was 18.0 months, with a 1-year overall survival of 54%. Four patients (15%) experienced an in-field local failure (LF), with a 1-year freedom from LF rate of 78%. The 1-year freedom from locoregional failure and 1-year progression-free survival rates were 61% and 51%, respectively. Patients who received 66 EQD2 Gy or higher had improved 1-year freedom from LF (100% vs 49%; P = .013), 1-year freedom from locoregional failure (84% vs 23%; P = .035), and 1-year progression-free survival (76% vs 14%; P = .050). Reirradiation was well tolerated, with only 2 patients (7%) experiencing late grade 3 pulmonary toxicity, and none with grade 3 or higher esophagitis. There were no grade 4-5 toxicities. Conclusions These data represent the largest series of patients treated with IMPT for definitive reirradiation of thoracic cancers. They demonstrate that IMPT provided durable local control with minimal toxicity and suggest that higher doses may improve outcomes.

Purpose The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). Methods Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as ( 1 ) 326 intermediate-risk patients treated with RT alone, ( 2 ) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and ( 3 ) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. Results Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: ( 1 ) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; ( 2 ) 71 marginal patients: GS 3+4, T2a-b; and ( 3 ) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P =.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P =.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). Conclusions Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease. In patients with GS 4+3 or T2c disease, the addition of ADT to dose-escalated RT did improve FFF.

Peripartum cardiomyopathy (PPCM) is a life-threatening pregnancy-associated cardiomyopathy in previously healthy women. Although PPCM is driven in part by the 16-kDa N-terminal prolactin fragment (16K PRL), the underlying molecular mechanisms are poorly understood. We found that 16K PRL induced microRNA-146a (miR-146a) expression in ECs, which attenuated angiogenesis through downregulation of NRAS. 16K PRL stimulated the release of miR-146a-loaded exosomes from ECs. The exosomes were absorbed by cardiomyocytes, increasing miR-146a levels, which resulted in a subsequent decrease in metabolic activity and decreased expression of Erbb4, Notch1, and Irak1. Mice with cardiomyocyte-restricted Stat3 knockout (CKO mice) exhibited a PPCM-like phenotype and displayed increased cardiac miR-146a expression with coincident downregulation of Erbb4, Nras, Notch1, and Irak1. Blocking miR-146a with locked nucleic acids or antago-miRs attenuated PPCM in CKO mice without interrupting full-length prolactin signaling, as indicated by normal nursing activities. Finally, miR-146a was elevated in the plasma and hearts of PPCM patients, but not in patients with dilated cardiomyopathy. These results demonstrate that miR-146a is a downstream-mediator of 16K PRL that could potentially serve as a biomarker and therapeutic target for PPCM.

Sphingolipids serve not only as components of cellular membranes but also as bioactive mediators of numerous cellular functions. As the biological activities of these lipids are dependent on their structures, and due to the limitations of conventional ion activation methods employed during tandem mass spectrometry (MS/MS), there is a recognized need for the development of improved structure-specific methods for their comprehensive identification and characterization. Here, positive-ionization mode 193 nm ultraviolet photodissociation (UVPD)-MS/MS has been implemented for the detailed structural characterization of lipid species from a range of sphingolipid classes introduced to the mass spectrometer via electrospray ionization as their lithiated or protonated adducts. These include sphingosine d18:1(4E), dihydrosphingosine (sphinganine) d18:0, sphingadiene d18:2(4E,11Z), the isomeric sphingolipids ceramide d18:1(4E)/18:0 and dihydroceramide d18:0/18:1(9Z), ceramide-1-phosphate d18:1(4Z)/16:0, sphingomyelin d18:1(4E)/18:1(9Z) the glycosphingolipids galactosyl ceramide d18:1(4E)/24:1(15Z) and lactosyl ceramide d18:1(4E)/24:0, and several endogenous lipids present within a porcine brain total lipid extract. In addition to the product ions formed by higher energy collision dissociation (HCD), UVPD is shown to yield a series of novel structurally diagnostic product ions resulting from cleavage of both sphingosine carbon-carbon and acyl chain carbon-carbon double bonds for direct localization of site(s) of unsaturation, as well as via diagnostic cleavages of the sphingosine backbone and N-C amide bond linkages. With activation timescales and dissociation efficiencies similar to those found in conventional MS/MS strategies, this approach is therefore a promising new tool in the arsenal of ion activation techniques toward providing complete structural elucidation in automated, high-throughput lipid analysis workflows. Graphical Abstract ᅟ.

To develop and validate a set of atlases for auto-contouring cardiac substructures.Eight radiation oncologists manually and independently delineated 15 cardiac substructures from noncontrast CT images of 6 patients by referring to their respective fused contrast CT images. Individual contours were fused together for each structure, edited by 2 physicians, and became atlases to delineate other 6 patients. The auto-delineated contours of the 6 additional patients became templates for manual contouring. These 12 patients with well-defined contours composed the final atlases for multi-atlas segmentation.The average time for manually contouring the 15 cardiac substructures was about 40min. Inter-observer variability was small for the heart, the chambers, and the aorta compared with that for other structures that were not clearly distinguishable in CT images. The mean dice similarity coefficient and mean surface distance of auto-segmented contours were within one standard deviation of expert contouring variability. Good agreement between auto-segmented and manual contours was observed for the heart, the chambers, and the great vessels. Independent validation on other 19 patients showed reasonable agreement for the heart chambers.A set of cardiac atlases was created for auto-contouring from noncontrast CT images. The accuracy of auto-contouring for the heart, chambers, and great vessels was validated for potential clinical use.

Background: Statins are the primary class of medications used to lower cholesterol and reduce risks for coronary heart disease. However, statin muscular adverse effects are one of the main reasons for statin nonadherence and a barrier to cardiovascular risk reduction. Objectives: The primary objective of our study was to examine the effect of replenishing vitamin D on statin-induced myopathy in veteran patients who failed to maintain statin therapy in a pharmacist-run ambulatory care setting. Secondary objectives were to examine changes in patients’ vitamin D levels, fasting lipid profiles, and achievement of lipid goals after reinitiation of statin therapy. Methods: This was a retrospective cohort study of veteran patients conducted at a pharmacist-managed cholesterol-optimization clinic. Patients with low-serum vitamin D, history of statin-induced myopathy, and who received vitamin D replenishment prior to rechallenging statin therapy between December 1, 2008, and April 1, 2015, were identified. The primary outcome was the percentage of patients who maintained their statin therapy at 12 months after statin reinitiation. Results: Twenty-seven patients met the study criteria. All patients were able to maintain their statin therapy without myalgia after vitamin D supplementation. Eleven patients (40.7%) tolerated their previously failed statins. The most frequently restarted statins were atorvastatin, pravastatin, and rosuvastatin. A 22% to 30% increase in the number of patients who achieved cholesterol goals based on the national lipid guidelines was observed at 12-month follow-up. Conclusion: Replenishing low vitamin D in patients with statin-induced myopathy appears to be an effective strategy in improving medication adherence and subsequently preventing cardiovascular and mortality events.