Implementation of a patient safety training program in radiation oncology residency: A pilot study.

PURPOSE: An educational program using Radiation Oncology-Incident Learning System (RO-ILS) was developed to improve safety culture and training for radiation oncology (RO) residents. METHODS: The program included a pre-training assessment, interactive training, integration of residents into quality assurance meetings, and a post-training assessment over a 3 month rotation. RESULTS: Twelve residents completed the safety training program. Pre-training assessment mean scores (five-point scale) of experience with Incident Learning Systems (ILS), root-cause analysis (RCA), failure-mode and effect analysis (FMEA), safety training, and culture were 2.3, 2.8, 2.0, 4.0, and 4.4, respectively. Post-training assessment showed a significant increase in ILS 4.0 (p < 0.001), RCA 3.8 (p = 0.008), and FMEA 3.3 (p = 0.006) and safety culture (4.8, p = 0.043). Additionally, residents were anonymously surveyed ≥ 10 months after graduation to determine the long-term value of the program. The overall assessment from the graduated residents indicates that this education is valued by RO in many institutions. The majority of the residents are either currently utilizing or plan to utilize the information gained in this program in their new institutions. CONCLUSIONS: We report a successful implementation of a safety training program in a RO residency with significant improvements in self-reported confidence with the concepts of ILS, RCA, and FMEA and an improved perception of safety culture. This program can be implemented across all residency programs.

Unsealed Source: Scope of Practice for Radiopharmaceuticals Among United States Radiation Oncologists.

Purpose: Our purpose was to determine the utilization of and barriers to implementation of radiopharmaceutical therapy (RPT) among U.S. radiation oncologists. Methods and Materials: An anonymous, voluntary 21-item survey directed toward attending radiation oncologists was distributed via social media platforms (Twitter, LinkedIn, Facebook, Student Doctor Network). Questions assessed practice characteristics, specific RPT prescribing patterns, RPT prescribing interest, and perceived barriers to RPT implementation. Nonparametric χ2 test was used for correlation statistics. Results: Of the 142 respondents, 131 (92.3%) practiced in the United States and were included for this analysis. Respondents were well balanced in terms of practicing region, population size served, practice setting, and years in practice. Forty-eight percent (n = 63) reported prescribing at least 1 RPT. An additional 7% (n = 8) participate in RPT administration without billing themselves. Among those that actively prescribed RPT, the mean cumulative cases per month was 4.2 (range, 1-5). The most commonly prescribed radionuclides were radium-223 (40%; mean 2.8 cases/mo), iodine-131 (18%; mean 2.3 cases/mo), yttrium-90 (13%; mean 3.4 cases/mo), "other" (8%), samarium-153 (6%; mean 1.0 cases/mo), and strontrium-89 and phosphorous-32 (2% each; mean 1.8 and 0.4 cases/mo, respectively). Of those who answered "other," lutetium-177 dotatate was most commonly prescribed (8%). No significant (P < .05) association was noted between practice type, practice location, years of practice, or practice volume with utilization of any RPTs. Most radiation oncologists (56%, n = 74) responded they would like to actively prescribe more RPT, although 27% (n = 35) were indifferent, and 17% (n = 22) said they would not like to prescribe more RPT. Perceived barriers to implementation were varied but broadly categorized into treatment infrastructure (44%, n = 57), interspecialty relations (41%, n = 53), lack of training (23%, n = 30), and financial considerations (16%, n = 21). Conclusions: Among surveyed U.S. radiation oncologists, a significant number reported prescribing at least 1 RPT. The majority expressed interest in prescribing additional RPT. Wide-ranging barriers to implementation exist, most commonly interspecialty relations, treatment infrastructure, lack of training, and financial considerations.

Integrated Functional Analysis of the Nuclear Proteome of Classically and Alternatively Activated Macrophages.

Macrophages (Mφ) play a central role in coordinating host response to pathogens, cellular injury, and environmental stimuli. Herein, we report multidimensional, nuclear proteomic analyses of protein expression and posttranslational modifications (PTMs) that control biological processes during Mφ activation. For this, Mφ were incubated with IFN-γ/LPS and IL-4, and their differentiation to proinflammatory (M1) and anti-inflammatory (M2a, referred as M2 for simplicity throughtout the manuscript) phenotypes was confirmed by detection of CD64 and CD206 surface markers and TNF-α, arginase I, and iNOS-dependent nitrite levels. We used a sequential method of organellar enrichment and labeling of nuclear fractions with BODIPY FL-maleimide fluorescence dye followed by two-dimensional electrophoresis (2DE) to capture quantitative changes in abundance and S-nitrosylated (SNO) proteome signatures. Exact same gels were then labeled with Pro-Q Diamond to detect protein phosphorylation. MALDI-TOF/TOF MS analysis of the protein spots with fold change of ≥|1.5| in any of the groups yielded 229 identifications. We found that 145, 78, and 173 protein spots in M1 Mφ and 105, 81, and 164 protein spots in M2 Mφ were changed in abundance, S-nitrosylation, and phosphorylation, respectively, with respect to M0 controls (fold change: ≥|1.5|, p ≤ 0.05). Targeted analysis by immunoprecipitation and Western blotting was performed to verify the differential abundance and phosphorylation levels of two of the proteins in M1 and M2 (vs. M0) Mφ. Ingenuity Pathway Analysis of the nuclear proteome datasets showed that the abundance and posttranslational (SNO and Phosphor) modifications of the proteins predicted to be involved in cytoskeletal organization/cell movement, phagocytosis/endocytosis, and cell proliferation/cell death were differentially regulated with proinflammatory and anti-inflammatory activation of Mφ.

Comparison of Local Control of Brain Metastases With Stereotactic Radiosurgery vs Surgical Resection: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Brain metastases are a common source of morbidity for patients with cancer, and limited data exist to support the local therapeutic choice between surgical resection and stereotactic radiosurgery (SRS). Objective: To evaluate local control of brain metastases among patients treated with SRS vs surgical resection within the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial. Design, Setting, and Participants: This unplanned, exploratory analysis of the international, multi-institutional randomized clinical trial EORTC 22952-26001 (conducted from 1996-2007) was performed from February 9, 2017, through July 25, 2018. The EORTC 22952-26001 trial randomized patients with 1 to 3 brain metastases to whole-brain radiotherapy vs observation after complete surgical resection or before SRS. Patients in the present analysis were stratified but not randomized according to local modality (SRS or surgical resection) and treated per protocol with 1 to 2 brain metastases and tumors with a diameter of no greater than 4 cm. Interventions: Surgical resection or SRS. Main Outcomes and Measures: The primary end point was local recurrence of treated lesions. Cumulative incidence of local recurrence was calculated according to modality (surgical resection vs SRS) with competing risk regression to adjust for prognostic factors and competing risk of death. Results: A total of 268 patients were included in the analysis (66.4% men; median age, 60.7 years [range, 26.9-81.1 years]); 154 (57.5%) underwent SRS and 114 (42.5%) underwent surgical resection. Median follow-up time was 39.9 months (range, 26.0-1982.0 months). Compared with the SRS group, patients undergoing surgical resection had larger metastases (median 28 mm [range, 10-40 mm] vs 20 mm [range, 4-40 mm]; P < .001), more frequently had 1 brain metastasis (112 [98.2%] vs 114 [74.0%]; P < .001), and differed in location (parietal, 21 [18.4%] vs 61 [39.6%]; posterior fossa, 30 [26.3%] vs 12 [7.8%]; P < .001). In adjusted models, local recurrence was similar between the SRS and surgical resection groups (hazard ratio [HR], 1.15; 95% CI, 0.72-1.83). However, when stratified by interval, patients with surgical resection had a much higher risk of early (0-3 months) local recurrence compared with those undergoing SRS (HR, 5.94; 95% CI, 1.72-20.45), but their risk decreased with time (HR for 3-6 months, 1.37 [95% CI, 0.64-2.90]; HR for 6-9 months, 0.75 [95% CI, 0.28-2.00]). At 9 months or longer, the surgical resection group had a lower risk of local recurrence (HR, 0.36; 95% CI, 0.14-0.93). Conclusions and Relevance: In this exploratory analysis, local control of brain metastases was similar between SRS and surgical resection groups. Stereotactic radiosurgery was associated with improved early local control of treated lesions compared with surgical resection, although the relative benefit decreased with time. Trial Registration: ClinicalTrials.gov Identifier: NCT00002899.

Gene Expression Profiling and Functional Characterization of Macrophages in Response to Circulatory Microparticles Produced during Trypanosoma cruzi Infection and Chagas Disease.

BACKGROUND: Chronic inflammation and oxidative stress are hallmarks of chagasic cardiomyopathy (CCM). In this study, we determined if microparticles (MPs) generated during Trypanosoma cruzi (Tc) infection carry the host's signature of the inflammatory/oxidative state and provide information regarding the progression of clinical disease. METHODS: MPs were harvested from supernatants of human peripheral blood mononuclear cells in vitro incubated with Tc (control: LPS treated), plasma of seropositive humans with a clinically asymptomatic (CA) or symptomatic (CS) disease state (vs. normal/healthy [NH] controls), and plasma of mice immunized with a protective vaccine before challenge infection (control: unvaccinated/infected). Macrophages (mφs) were incubated with MPs, and we probed the gene expression profile using the inflammatory signaling cascade and cytokine/chemokine arrays, phenotypic markers of mφ activation by flow cytometry, cytokine profile by means of an ELISA and Bioplex assay, and oxidative/nitrosative stress and mitotoxicity by means of colorimetric and fluorometric assays. RESULTS: Tc- and LPS-induced MPs stimulated proliferation, inflammatory gene expression profile, and nitric oxide (∙NO) release in human THP-1 mφs. LPS-MPs were more immunostimulatory than Tc-MPs. Endothelial cells, T lymphocytes, and mφs were the major source of MPs shed in the plasma of chagasic humans and experimentally infected mice. The CS and CA (vs. NH) MPs elicited >2-fold increase in NO and mitochondrial oxidative stress in THP-1 mφs; however, CS (vs. CA) MPs elicited a more pronounced and disease-state-specific inflammatory gene expression profile (IKBKB, NR3C1, and TIRAP vs. CCR4, EGR2, and CCL3), cytokine release (IL-2 + IFN-γ > GCSF), and surface markers of mφ activation (CD14 and CD16). The circulatory MPs of nonvaccinated/infected mice induced 7.5-fold and 40% increases in ∙NO and IFN-γ production, respectively, while these responses were abolished when RAW264.7 mφs were incubated with circulatory MPs of vaccinated/infected mice. CONCLUSION: Circulating MPs reflect in vivo levels of an oxidative, nitrosative, and inflammatory state, and have potential utility in evaluating disease severity and the efficacy of vaccines and drug therapies against CCM.

Macrophages Promote Oxidative Metabolism To Drive Nitric Oxide Generation in Response to Trypanosoma cruzi.

Trypanosoma cruzi is the causative agent of chronic chagasic cardiomyopathy. Why macrophages (mφs), the early responders to infection, fail to achieve parasite clearance is not known. Mouse (RAW 264.7) and human (THP-1 and primary) mφs were infected for 3 h and 18 h with T. cruzi TcI isolates, SylvioX10/4 (SYL, virulent) and TCC (nonpathogenic), which represent mφ stimulation and infection states, respectively. Mφs incubated with lipopolysaccharide and gamma interferon (LPS/IFN-γ) and with interleukin-4 (IL-4) were used as controls. We monitored the cytokine profile (using enzyme-linked immunosorbent assay [ELISA]), reactive oxygen species (ROS; fluorescent probes), nitric oxide (·NO; Griess assay), and metabolic state using a custom-designed mitoxosome array and Seahorse XF24 Analyzer. LPS/IFN-γ treatment of mφs elicited a potent increase in production of tumor necrosis alpha (TNF-α) at 3 h and of ROS and ·NO by 18 h. Upon SYL infection, murine mφs elicited an inflammatory cytokine profile (TNF-α ≫ TGF-ß + IL-10) and low levels of ·NO and ROS production. LPS/IFN-γ treatment resulted in the inhibition of oxidative metabolism at the gene expression and functional levels and a switch to the glycolytic pathway in mφs, while IL-4-treated mφs utilized oxidative metabolism to meet energy demands. SYL infection resulted in an intermediate functional metabolic state with increased mitoxosome gene expression and glycolysis, and IFN-γ addition shut down the oxidative metabolism in SYL-infected mφs. Further, TCC- and SYL-stimulated mφs exhibited similar levels of cell proliferation and production of TNF-α and ROS, while TCC-stimulated mφs exhibited up to 2-fold-higher levels of oxidative metabolism and ·NO production than SYL-infected mφs. Inhibiting ATP-coupled O2 consumption suppressed the ·NO generation in SYL-infected mφs. Mitochondrial oxygen consumption constitutes a mechanism for stimulating ·NO production in mφs during T. cruzi infection. Enhancing the oxidative metabolism provides an opportunity for increased ·NO production and pathogen clearance by mφs to limit disease progression.

Novel risk scores for survival and intracranial failure in patients treated with radiosurgery alone to melanoma brain metastases.

PURPOSE: Stereotactic radiosurgery (SRS) alone is an increasingly common treatment strategy for brain metastases. However, existing prognostic tools for overall survival (OS) were developed using cohorts of patients treated predominantly with approaches other than SRS alone. Therefore, we devised novel risk scores for OS and distant brain failure (DF) for melanoma brain metastases (MBM) treated with SRS alone. METHODS AND MATERIALS: We retrospectively reviewed 86 patients treated with SRS alone for MBM from 2009-2014. OS and DF were estimated using the Kaplan-Meier method. Cox proportional hazards modeling identified clinical risk factors. Risk scores were created based on weighted regression coefficients. OS scores range from 0-10 (0 representing best OS), and DF risk scores range from 0-5 (0 representing lowest risk of DF). Predictive power was evaluated using c-index statistics. Bootstrapping with 200 resamples tested model stability. RESULTS: The median OS was 8.1 months from SRS, and 54 (70.1 %) patients had DF at a median of 3.3 months. Risk scores for OS were predicated on performance status, extracranial disease (ED) status, number of lesions, and gender. Median OS for the low-risk group (0-3 points) was not reached. For the moderate-risk (4-6 points) and high-risk (6.5-10) groups, median OS was 7.6 months and 2.4 months, respectively (p < .0001). Scores for DF were predicated on performance status, ED status, and number of lesions. Median time to DF for the low-risk group (0 points) was not reached. For the moderate-risk (1-2 points) and high-risk (3-5 points) groups, time to DF was 4.8 and 2.0 months, respectively (p < .0001). The novel scores were more predictive (c-index = 0.72) than melanoma-specific graded prognostic assessment or RTOG recursive partitioning analysis tools (c-index = 0.66 and 0.57, respectively). CONCLUSIONS: We devised novel risk scores for MBM treated with SRS alone. These scores have implications for prognosis and treatment strategy selection (SRS versus whole-brain radiotherapy).

Role of NF-κB activation and VEGF gene polymorphisms in VEGF up regulation in non-proliferative and proliferative diabetic retinopathy.

The present study was aimed to investigate the relation between nuclear factor kappa beta (NFκB) activation and downstream up-regulation of vascular endothelial growth factor (VEGF) in diabetic retinopathy (DR). Moreover the study was intended to evaluate the role of VEGF gene single nucleotide polymorphisms (SNPs) in DR occurrence and to investigate the functional relevance of VEGF gene SNPs in terms of VEGF expression in DR. Serum level of VEGF, VEGF R1 (receptor 1), VEGF R 2 (receptor 2) and NFκB (p50/65) activity was measured by enzyme linked immune sorbent assay. Genotyping and allelic composition of different SNPs i.e., rs2010963, rs3025039, rs1570360 and rs 2071559 were investigated by Taqman SNP genotyping assay. VEGF, NFκB p50/p65, and VEGF R1 & R2 gene expressions were quantified by real time quantitative polymerase chain reaction. Increased NFκB p50/p65 activity and expressions were observed in non proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) subjects compared to type 2 diabetes mellitus without retinopathy (DNR) group. Significantly elevated levels of serum VEGF and highest VEGF expression were found among PDR subjects compared to DNR or NPDR subjects. CC genotype and C allele of rs2010963 and TT genotype and T allele of rs3025039 were significantly over represented among PDR subjects compared to DNR group. Increased activation of NFκß in NPDR and PDR subjects might involve increased up regulation of VEGF. VEGF SNPs i.e., rs2010963 C allele and rs3025039 T allele might be associated with PDR occurrence and in turn regulates VEGF expression among PDR subjects.

Role of hyperglycemia-mediated erythrocyte redox state alteration in the development of diabetic retinopathy.

PURPOSE: To evaluate erythrocyte redox state and its surrogates in patients with different stages of diabetic retinopathy and their association with cellular metabolic derangement developed in retinal microvascular cells. METHODS: Sixty type 2 diabetic patients with nonproliferative diabetic retinopathy (NPDR), 85 patients with proliferative diabetic retinopathy (PDR), and 70 patients with diabetes but without retinopathy were considered as diabetic control (DC) for the study. In addition, 65 normal individuals without diabetes were enrolled as healthy control in this study. Erythrocyte oxidized nicotinamide adenine dinucleotide phosphate / reduced nicotinamide adenine dinucleotide phosphate (NADP / NADPH), oxidized nicotinamide adenine dinucleotide / reduced nicotinamide adenine dinucleotide (NAD / NADH) glutathione, plasma and vitreous lactate, and pyruvate levels were determined by enzymatic reaction-based spectrophotometric assay for the patients and individuals. RESULT: Erythrocyte NADP+ to NADPH ratio to NADPH ratio was found to be significantly higher among NPDR and PDR patients compared with DC subjects (P < 0.0001). Erythrocyte-reduced glutathione was significantly decreased in patients of NPDR (P = 0.0004) and patients of PDR (P = 0.0157) compared to DC. Erythrocyte NAD to NADH ratio was also significantly decreased in patients of NPDR (P < 0.0001) and PDR (P < 0.0001) compared to DC subjects. Lactate to pyruvate ratio of plasma was elevated significantly in patients with NPDR compared with DC (P < 0.0001) and those having PDR (P = 0.0046). In the vitreous fluid, the lactate to pyruvate ratios were found to be significantly lower in normal individuals without diabetes compared with patients having PDR (P < 0.0001). CONCLUSION: Hyperglycemia-mediated erythrocyte redox state alterations might be a potential risk factor for the development of NPDR in poorly controlled diabetic subjects.

Association of tumor necrosis factor α, interleukin 6, and interleukin 10 promoter polymorphism with proliferative diabetic retinopathy in type 2 diabetic subjects.

PURPOSE: New blood vessel formation in the retina because of prolonged hypoxia is believed to be directly associated with increased expression of several growth factors and angiogenic cytokines. In the present study, we made an attempt to investigate the possible association of the promoter polymorphisms of interleukin 6, tumor necrosis factor α, and interleukin 10 for the pathogenesis of proliferative diabetic retinopathy (PDR). METHODS: This case-control study comprised 493 volunteers (253 PDR cases and 240 diabetic controls). Cases and controls were ascertained such that age, sex, nutrition, and glycemic status were matched. Genotypes were determined by polymerase chain reaction-based methods. RESULTS: Interleukin 10-1082GG (P = 0.0037; odds ratio [OR] = 2.232), tumor necrosis factor α-238AA (P = 0.0001; OR = 5.791), and GA (P = 0.0015; OR = 1.909) genotypes were significantly associated with PDR occurrence. The interleukin 10-1082G allele (P = 0.0048, OR = 1.4442) and the tumor necrosis factor α-238A allele (P = 0.0001; OR = 2.2897) were significantly increased among PDR cases. CONCLUSION: From our study, it may be concluded that the genetic variation, that is, tumor necrosis factor α-238A and interleukin 10-1082G alleles are the potent risk factors for the pathogenesis of PDR.

Assessment of gelatinase and tumor necrosis factor-α level in the vitreous and serum of patients with Eales disease: role of inflammation-mediated angiogenesis in the pathogenesis of Eales disease.

BACKGROUND: Eales disease (ED) is an idiopathic, inflammatory, venoocclusive disorder of peripheral retina resulting in retinal angiogenesis and vitreous hemorrhage. The objective of the present study is to investigate the expression and activation of gelatinase associated with the retinal neovascularization in ED and the relation between the levels of gelatinase and the cytokine tumor necrosis factor-α, known to upregulate matrix metalloproteinase (MMP) expression on various cells. METHODS: Vitreous and serum samples from 19 patients with ED who underwent retinal surgery were estimated for levels of MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, and tumor necrosis factor-α by enzyme-linked immunosorbent assay method. Matrix metalloproteinase-2 and MMP-9 activities in serum and vitreous samples were evaluated by gelatin zymography method. Vitreous samples from 16 patients with macular hole undergoing vitrectomy were used as controls. RESULTS: Among the 2 gelatinase examined in vitreous and serum samples, only level and activity of MMP-9 were significantly higher in serum (P = 0.0001) and vitreous (P = 0.0002) samples of patients with ED than those of control subjects. Simultaneously, a positive correlation was found between intraocular tumor necrosis factor-α and MMP-9 concentration (Spearman correlation coefficient, r = 0.7040, P = 0.0023) in patients with ED. CONCLUSION: Increase in MMP-9 activity and its concentration in serum and vitreous of patients with ED compared with that of control subjects and correlation between intraocular levels of MMP-9 and tumor necrosis factor-α in patients with ED seem to provide a plausible explanation for inflammation-mediated angiogenesis during the development of this condition.