Adoption of an incident learning system in a regionally expanding academic radiation oncology department.

AIM AND BACKGROUND: We describe a successful implementation of a departmental incident learning system (ILS) across a regionally expanding academic radiation oncology department, dovetailing with a structured integration of the safety and quality program across clinical sites. MATERIALS AND METHODS M: Over 6 years between 2011 and 2017, a long-standing departmental ILS was deployed to 4 clinical locations beyond the primary clinical location where it had been established. We queried all events reported to the ILS during this period and analyzed trends in reporting by clinical site. The chi-square test was used to determine whether differences over time in the rate of reporting were statistically significant. We describe a synchronous development of a common safety and quality program over the same period. RESULTS: There was an overall increase in the number of event reports from each location over the time period from 2011 to 2017. The percentage increase in reported events from the first year of implementation to 2017 was 457% in site 1, 166.7% in site 2, 194.3% in site 3, 1025% in site 4, and 633.3% in site 5, with an overall increase of 677.7%. A statistically significant increase in the rate of reporting was seen from the first year of implementation to 2017 (p < 0.001 for all sites). CONCLUSIONS: We observed significant increases in event reporting over a 6-year period across 5 regional sites within a large academic radiation oncology department, during which time we expanded and enhanced our safety and quality program, including regional integration. Implementing an ILS and structuring a safety and quality program together result in the successful integration of the ILS into existing departmental infrastructure.

Iron overload causes oxidative stress and impaired insulin signaling in AML-12 hepatocytes.

BACKGROUND: Iron overload is associated with increased severity of nonalcoholic fatty liver disease (NAFLD) including progression to nonalcoholic steatohepatitis and hepatocellular carcinoma. AIMS: To identify potential role(s) of iron in NAFLD, we measured its effects on pathways of oxidative stress and insulin signaling in AML-12 mouse hepatocytes. METHODS: Rapid iron overload was induced with 50 µM ferric ammonium citrate and 8-hydroxyquinoline. Insulin response was measured by Western blot of phospho-protein kinase B. Lipid content was determined by staining with Oil Red O. Reactive oxygen species (ROS) were measured by flow cytometry using 5-(and 6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. Oxidative stress was measured by Western blots for phospho-jnk and phospho-p38. RESULTS: Iron increased ROS (p < 0.001) and oxidative stress (p < 0.001) and decreased insulin signaling by 33 % (p < 0.001). Treatment with stearic or oleic acids (200 µM) increased cellular lipid content and differentially modulated effects of iron. Stearic acid potentiated iron-induced ROS levels by two-fold (p < 0.05) and further decreased insulin response 59 % (p < 0.05) versus iron alone. In contrast, cells treated with oleic acid were protected against iron-mediated injury; ROS levels were decreased by half (p < 0.01) versus iron alone while insulin response was restored to control (untreated) levels. The anti-oxidant curcumin reduced effects of iron on insulin signaling, ROS, and oxidative stress (p < 0.01). Curcumin was similarly effective in cells treated with both stearic acid and iron. CONCLUSIONS: An in vitro model of NAFLD progression is described in which iron-induced oxidative stress inhibits insulin signaling. Pathophysiological effects of iron were increased by saturated fat and decreased by curcumin.

Patterns of Incident Reporting Across Clinical Sites in a Regionally Expanding Academic Radiation Oncology Department.

PURPOSE: We evaluated patterns of event reporting across five clinical locations within an academic radiation oncology department, with the goal of better understanding variability across sites. METHODS AND MATERIALS: We analyzed 1,351 events reported to a departmental incident learning system over 1 calendar year across the five locations with respect to volume of events, event type, process map location of origin and detection, and event reporter. RESULTS: We found marked variability in reporting patterns, including reporting rate, event type, event severity, event location of origin and detection within the departmental process map, and discipline of event reporters. These differences relate both to variability in process and workflow (reflected by frequency of specific workflow events at each site) and in reporting culture (reflected by volume or rate of event reporting, and discipline of event reporter). CONCLUSIONS: These data highlight the variability in reporting culture even within a single department, and therefore the need to tailor and individualize safety and quality programs to the unique clinical site, with the long-term goal of achieving a common culture of safety while supporting unique processes at individual locations. This work also raises concern about extrapolating single-institution incident learning system results without understanding the unique workflow and culture of clinical sites.

Real-time management of incident learning reports in a radiation oncology department.

PURPOSE: The optimal approach to managing incident learning system (ILS) reports remains unclear. Here, we describe our experience with prospective coding of events reported to the ILS with comparisons of risk scores on the basis of event type and process map location. METHODS AND MATERIALS: Reported events were coded by type, origin, and method of discovery. Events were given a risk priority number (RPN) and near-miss risk index (NMRI) score. We compared workflow versus near-miss events with respect to origin and detection in the process map and by risk scores. A χ2 test was used to compare the differences between workflow and near-miss events. A comparison of RPN scores was done by independent t test. RESULTS: During 2016, 1351 events were reported. Of these events, 1300 (96.2%) were workflow and 51 (3.8%) near-miss events. Workflow events were more likely to both originate (1041 of 1300 events; 81.2%) compared with near-miss events (31 of 51 events; 62.7%; P = .005) and be detected in pre-treatment (997 of 1300 events; 76.7%) compared with near-miss events (24 of 51 events; 47%; P < .001). Average occurrence (scale: 1-10) was 6.14 for workflow versus 3.33 for near-miss events (P < .001), average severity was 2.94 versus 7.35 (P < .001), and average detectability was 1.33 versus 4.67 (P < .001). Mean overall RPN was 22.4 for workflow versus 108.4 for near-miss events (P = .07) and mean NMRI was 1.16 versus 3.19, respectively. Events that originated and were detected in treatment delivery had the greatest mean overall RPN (38.2 and 32.1, respectively) and NMRI scores (1.62 and 1.6, respectively). CONCLUSIONS: Our experience demonstrates that workflow event reports are far more common than near-misses and that near-miss events are more likely to both originate and be discovered in later treatment phases. The frequency of workflow reports highlights the imperative need for safety and operational teams to work collaboratively to maximize the benefit of ILS. We suggest a potential utility of the RPN system to guide mitigation strategies for future near-miss events.

Induction of TGF-ß by Irradiation or Chemotherapy in Fanconi Anemia (FA) Mouse Bone Marrow Is Modulated by Small Molecule Radiation Mitigators JP4-039 and MMS350.

BACKGROUND/AIM: Total-body irradiation and/or administration of chemotherapy drugs in bone marrow transplantation induce cytokines that can suppress engraftment. Fanconi Anemia (FA) patients have a hyperactive responsiveness to the inhibitory cytokine, transforming growth factor-beta (TGF-ß). Small molecule radiation mitigator drugs, JP4-039 and MMS350, were evaluated for suppression of irradiation or drug-induced TGF-ß. MATERIALS AND METHODS: In vivo induction of TGF-ß by total-body ionizing irradiation (TBI), L-phenylalanine mustard (L-PAM), busulfan or fludarabine, was quantified. In parallel, mitigator drug amelioration of TGF-ß induction in FA D2-/- (FANCD2-/-) mouse bone marrow, was studied in vitro. Tissue culture medium, cell lysates, and mouse plasma were analyzed for TGF-ß levels. RESULTS: Induction of TGF-ß levels in FANCD2-/- and FANCD2+/+ mice and in mouse bone marrow were modulated by both JP4-039 and MMS350. CONCLUSION: Bone marrow transplantation in FA recipients may benefit from administration of small molecule agents that suppress TGF-ß induction.

Intraoral Mitochondrial-Targeted GS-Nitroxide, JP4-039, Radioprotects Normal Tissue in Tumor-Bearing Radiosensitive Fancd2(-/-) (C57BL/6) Mice.

We evaluated normal tissue specific radioprotection of the oral cavity in radiosensitive Fanconi Anemia (FA) Fancd2(-/-) mice with orally established tumors using mitochondrial-targeted GS-nitroxide (JP4-039). Adult (10-12 weeks old) Fancd2(+/+), Fancd2(+/-) and Fancd2(-/-) mice (C57BL/6 background) and subgroups with orally established TC-1 epithelial cell tumors received a single fraction of 28 Gy or four daily fractions of 8 Gy to the head and neck. Subgroups received JP4-039 in F15 emulsion (F15/JP4-039; 0.4 mg/mouse), 4-amino-Tempo in F15 emulsion (F15/4-amino-Tempo; 0.2 mg/mouse) or F15 emulsion alone prior to each irradiation. Oral mucosa of Fancd2(-/-) mice showed baseline elevated RNA transcripts for Sod2, p53, p21 and Rad51 (all P < 0.0012) and suppressed levels of Nfkb and Tgfb, (all P < 0.0020) compared with Fancd2(+/+) mice. The oral mucosa in tumor-bearing mice of all genotypes showed decreased levels of p53 and elevated Tgfb and Gadd45a (P ≤ 0.0001 for all three genotypes). Intraoral F15/JP4-039, but not F15/4-amino-Tempo, modulated radiation-induced normal tissue transcript elevation, ameliorated mucosal ulceration and reduced the depletion of antioxidant stores in oral cavity tissue of all genotypes, but did not radioprotect tumors. Mitochondrial targeting makes F15/JP4-039 an effective normal tissue radioprotector for Fancd2(-/-) mice, as well as wild-type mice.

Patterns of care for omission of radiation therapy for elderly women with early-stage breast cancer receiving hormonal therapy.

PURPOSE: For well-selected elderly women who undergo segmental mastectomy for early-stage, estrogen receptor-positive breast cancer, hormonal therapy alone is emerging as an acceptable adjuvant therapy option since the initial publication of Cancer and Leukemia Group B 9343 study in 2004 and update in 2013. The rate of adoption of adjuvant hormonal therapy alone in lieu of radiation therapy (RT) and its associated patterns of care is not known in the United States and was the subject of this study. METHODS AND MATERIALS: We used the National Cancer Data Base to identify women aged ≥70 diagnosed with T1N0/T1Nx invasive breast cancer who underwent segmental mastectomy between 1998 and 2011. Because hormone receptor status was not specifically and reliably coded, only those who received hormonal therapy were included in this analysis. Univariate and multivariable exploratory analyses of factors associated with the use of RT were performed using SPSS, version 17.0. RESULTS: Of the 182,115 patients who met inclusion criteria, 97,530 (53.6%) patients underwent hormonal therapy and were included in the analysis. The RT utilization rate in this subset decreased with time from 84.9% in 1998 to 75.1% in 2011 (P< .001). Multivariable analysis revealed that the factors associated with decreased use of RT include (in order of association): older age, later year of diagnosis, greater comorbidity score, low grade, lack of insurance, treatment at academic facility, race, rural location, lower median income, and distance from facility. CONCLUSIONS: This study assesses the patterns of care associated with the omission of RT in elderly women with early-stage breast cancer who received adjuvant hormonal therapy. Since the publication of major clinical trials, this strategy has been increasingly adopted. The strongest predictors of using this strategy included advanced patient age, high comorbidity score, and low-grade disease.

Organ-specific responses of total body irradiated doxycycline-inducible manganese superoxide dismutase Tet/Tet mice.

BACKGROUND/AIM: We evaluated doxycycline-inducible manganese superoxide dismutase (MnSOD(tet/tet)) mice after 9.25 Gy total-body irradiation (TBI) or 20 Gy thoracic irradiation. MATERIALS AND METHODS: Six-week-old MnSOD(tet/tet) or control C57BL/6NHsd mice on or off doxycycline (doxy) in food received 9.25 Gy TBI, were sacrificed at day 19 and bone marrow, brain, esophagus, heart, intestine, kidney, liver, lung, spleen and tongue harvested, total RNAs extracted and transcripts for irradiation response genes quantitated by real time-polymerase chain reaction (RT-PCR). RESULTS: MnSOD(tet/tet) mice only survived with daily injections of doxy beginning 5 days after birth until weaning, at which time they were placed on food containing doxy. Manganese superoxide dismutase (MnSOD) transcript levels were reduced in all tissues except the lung. Adult mice survived with low MnSOD levels, but induced by doxy or TBI. Thoracic-irradiated MnSOD(tet/tet) mice survived past day 120. CONCLUSION: MnSOD(tet/tet) mice should be valuable for elucidating the role of MnSOD in growth and irradiation response.

Can Radiosensitivity Associated with Defects in DNA Repair be Overcome by Mitochondrial-Targeted Antioxidant Radioprotectors.

Radiation oncologists have observed variation in normal tissue responses between patients in many instances with no apparent explanation. The association of clinical tissue radiosensitivity with specific genetic repair defects (Wegner's syndrome, Ataxia telangiectasia, Bloom's syndrome, and Fanconi anemia) has been well established, but there are unexplained differences between patients in the general population with respect to the intensity and rapidity of appearance of normal tissue toxicity including radiation dermatitis, oral cavity mucositis, esophagitis, as well as differences in response of normal tissues to standard analgesic or other palliative measures. Strategies for the use of clinical radioprotectors have included modalities designed to either prevent and/or palliate the consequences of radiosensitivity. Most prominently, modification of total dose, fraction size, or total time of treatment delivery has been necessary in many patients, but such modifications may reduce the likelihood of local control and/or radiocurability. As a model system in which to study potential radioprotection by mitochondrial-targeted antioxidant small molecules, we have studied cell lines and tissues from Fanconi anemia (Fancd2(-/-)) mice of two background strains (C57BL/6NHsd and FVB/N). Both were shown to be radiosensitive with respect to clonogenic survival curves of bone marrow stromal cells in culture and severity of oral cavity mucositis during single fraction or fractionated radiotherapy. Oral administration of the antioxidant GS-nitroxide, JP4-039, provided significant radioprotection, and also ameliorated distant bone marrow suppression (abscopal effect of irradiation) in Fancd2 (-/-) mice. These data suggest that radiation protection by targeting the mitochondria may be of therapeutic benefit even in the setting of defects in the DNA repair process for irradiation-induced DNA double strand breaks.

Improved longevity of hematopoiesis in long-term bone marrow cultures and reduced irradiation-induced pulmonary fibrosis in Toll-like receptor-4 deletion recombinant-negative mice.

AIM: We measured long-term hematopoiesis in continuous bone marrow cultures derived from Toll-like receptor-4 (Tlr4(-/-))(C57BL/6J) mice. MATERIALS AND METHODS: We measured hematopoiesis in vitro over 27 weeks in long-term bone marrow cultures from Tlr4(-/-) and control mice, and irradiation-induced pulmonary fibrosis in mice irradiated to 20 Gy to the thorax. RESULTS: There was a significant increase in the duration of hematopoiesis in long-term bone marrow cultures from Tlr4(-/-) mice in production of total non-adherent cells and day 7 and day 14 multi-lineage colony-forming cells. The histology of bone marrow hematopoietic and stromal cell lines was indistinguishable between different mouse strains. There was no detectable late irradiation pulmonary fibrosis in Tlr4(-/-) mice. CONCLUSION: Homozygous deletion of both alleles of Tlr4, encoding for an inflammatory mediator receptor, improves the duration of hematopoiesis in vitro and reduces irradiation-induced lung fibrosis.

Increased hematopoiesis in long-term bone marrow cultures and reduced irradiation-induced pulmonary fibrosis in Von Willebrand factor homologous deletion recombinant mice.

AIM: We investigated whether homologous recombinant deletion of the endothelial cell-specific protein Von Willebrand factor (vWF) affected hematopoiesis in long-term bone marrow cultures, and irradiation induction of pulmonary fibrosis/organizing alveolitis. MATERIALS AND METHODS: We established long-term bone marrow cultures from vWF(-/-) (C57BL/6 background) and vWF(+/+) littermate mice. Non-adherent cells removed weekly were tested for formation of multi-lineage hematopoietic stem cells forming colonies at 7 and 14 days in secondary semi-solid medium cultures. Irradiation fibrosis in the lungs of 20-Gy thoracic irradiated mice was quantitated and scored. RESULTS: Hematopoiesis was increased over 20 weeks in vWF(-/-) compared to vWF(+/+) cultures in production of non-adherent cells, and cells forming colonies at 7 or 14 days in secondary semi-solid medium culture. The irradiated lungs showed no increased fibrosis. CONCLUSION: Absence of vWF increases hematopoiesis in long-term bone marrow cultures and has a protective effect in irradiated lungs.

Differences in irradiated lung gene transcription between fibrosis-prone C57BL/6NHsd and fibrosis-resistant C3H/HeNHsd mice.

BACKGROUND/AIM: We compared pulmonary irradiation-induced whole-lung, gene transcripts over 200 days after 20 Gy thoracic irradiation in female fibrosis-prone C57BL/6NHsd mice with fibrosis-resistant C3H/HeNHsd mice. MATERIALS AND METHODS: Lung specimens were analyzed by real time polymerase chain reaction (rt-PCR) and changes over time in representative gene transcript levels were correlated with protein levels using western blot. RESULTS: C3H/HeNHsd mice showed a significantly longer duration of elevation of gene transcripts for stress-response genes nuclear factor kappa-light-chain-enhancer of activated B cells (Nfkb), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), transcription factor SP1 (SP1), activator protein 1 (AP1), radioprotection gene manganese superoxide dismutase (Sod2), and endothelial cell-associated genes von Willebrand factor (Vwf) and vascular endothelial growth factor (Vegf). C57BL/6NHsd mice showed acute elevation then down-regulation and a second elevation in gene transcripts for Nfkb, connective tissue growth factor (Ctgf), insulin-like growth factor-binding protein 7 (Igfbp7), tumor necrosis factor-alpha (Tnfa) Ctgf, Igfbp7, Tnfa, collagen 1a, and toll like receptor 4 (Tlr4). There were reciprocal patterns of elevation and decrease in levels of transcripts for epigenetic reader proteins bromodomain coding protein 1 (Brd1)Brd2,-3, and -4 between mouse strains. CONCLUSION: Regulatory pathways linked to radiation pulmonary fibrosis may identify new targets for mitigators of radiation-induced fibrosis.

ß-Catenin loss in hepatocytes promotes hepatocellular cancer after diethylnitrosamine and phenobarbital administration to mice.

Hepatocellular Carcinoma (HCC) is the fifth most common cancer worldwide. ß-Catenin, the central orchestrator of the canonical Wnt pathway and a known oncogene is paramount in HCC pathogenesis. Administration of phenobarbital (PB) containing water (0.05% w/v) as tumor promoter following initial injected intraperitoneal (IP) diethylnitrosamine (DEN) injection (5 µg/gm body weight) as a tumor inducer is commonly used model to study HCC in mice. Herein, nine fifteen-day male ß-catenin knockout mice (KO) and fifteen wild-type littermate controls (WT) underwent DEN/PB treatment and were examined for hepatic tumorigenesis at eight months. Paradoxically, a significantly higher tumor burden was observed in KO (p<0.05). Tumors in KO were ß-catenin and glutamine synthetase negative and HGF/Met, EGFR & IGFR signaling was unremarkable. A significant increase in PDGFRα and its ligand PDGF-CC leading to increased phosphotyrosine-720-PDGFRα was observed in tumor-bearing KO mice (p<0.05). Simultaneously, these livers displayed increased cell death, stellate cell activation, hepatic fibrosis and cell proliferation. Further, PDGF-CC significantly induced hepatoma cell proliferation especially following ß-catenin suppression. Our studies also demonstrate that the utilized DEN/PB protocol in the WT C57BL/6 mice did not select for ß-catenin gene mutations during hepatocarcinogenesis. Thus, DEN/PB enhanced HCC in mice lacking ß-catenin in the liver may be due to their ineptness at regulating cell survival, leading to enhanced fibrosis and regeneration through PDGFRα activation. ß-Catenin downregulation also made hepatoma cells more sensitive to receptor tyrosine kinases and thus may be exploited for therapeutics.