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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

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.

Purpose of Review Liver-directed SABR (stereotactic ablative body radiotherapy) is emerging as an effective local therapy option for HCC (hepatocellular carcinoma). This review summarizes recent clinical progresses and proposes future directions. Recent Findings SABR is an effective and safe, non-invasive local therapy option for HCC in the primary and salvage treatment settings, as well as a bridge to liver transplantation in selected patients. Randomized trials comparing SABR with other locoregional modalities are currently ongoing. Summary Research efforts are being made toward better predicting normal tissue toxicity and tumor radiosensitivity for a tailored maximal safe treatment in HCC SABR. More recently, potential synergy with immunotherapies is of increasing interest in HCC.

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.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 χDuring 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).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.

The article Stereotactic Ablative Radiotherapy (SABR/SBRT) for Hepatocellular Carcinoma, written by Byung-Han Rhieu, Amol K. Narang and Jeffrey Meyer, was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 16 October 2018 without open access.

Iron overload is associated with increased severity of nonalcoholic fatty liver disease (NAFLD) including progression to nonalcoholic steatohepatitis and hepatocellular carcinoma.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.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.Iron increased ROS (p0.001) and oxidative stress (p0.001) and decreased insulin signaling by 33 % (p0.001). 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 (p0.05) and further decreased insulin response 59 % (p0.05) versus iron alone. In contrast, cells treated with oleic acid were protected against iron-mediated injury; ROS levels were decreased by half (p0.01) 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 (p0.01). Curcumin was similarly effective in cells treated with both stearic acid and iron.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.

AIM: We investigated whether homologous recombinant deletion of the endothelial cell-specific protein Von Willebrand factor (vWF) affected hematopoiesis in longterm 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.

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.

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 P0.0012) and suppressed levels of Nfkb and Tgfb, (all P0.0020) 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.

Fanconi Anemia (FA) patients are at risk for head and neck squamous cell carcinomas. Their normal tissue radiosensitivity often presents a challenge to deliver radiotherapy. Locally applied GS-nitroxide JP4-039 radioprotects the oral mucosa of Fancd2-/-(129/Sv) mice from single fraction or fractionated irradiation (Berhane et al, Radiation Research 182:35-49, 2014). We sought to prove that JP4-039 targets the mitochondria of the oral mucosal cells, and protects normal tissue in vivo, but does not prevent radiocontrolability of tumors. Fancd2+/+, Fancd2+/- and Fancd2-/- mice of a different background strain (C57BL/6), received intraoral flurochrome labelled bodipy-JP4-039 in F15 liposomes, were sacrificed 2 hr later and the oral mucosa removed sectioned, and stained with an antibody to mitochondrial protein TOM-20 and examined microscopically for co-localization of bodipy-JP4-039. Mitochondria were isolated from explanted oral mucosal cells and uptake of JP4-039 compared to non-mitochondrial targeted Tempo, measured using EPR. Fancd2+/+, Fancd2+/- and Fancd2-/- mice with orthotopic TC-1 murine squamous cell tumors were treated with JP-4-039/F15, then irradiated. Mitochondrial uptake in normal tissue but not tumors was demonstrated by co-localization of Bodipy-JP4-039 and mitochondrial protein TOM-20. EPR analysis of purified mitochondria from explanted oral cavity cells of Fancd2+/+ and Fancd2-/- mice treated with F15-JP4-039 showed a 15.6 and 19.1 fold increased uptake of nitroxide signal in JP4-039 treated mice, respectively, compared to Tempo uptake in mitochondria . There was no significant difference in tumor control between the JP4-039/F15 treated then irradiated compared to control irradiated mice, in any of the 3 genotypes: Fancd2+/+ group, p = 0.6851; Fancd2+/− group p = 0.7174 and p = 0.7559 in the Fancd2−/− group. JP4-039/F15 administration prior to either single fraction 28 Gy or prior to each fraction of fractionated head and neck irradiation (8 Gy x 4) showed significant normal tissue protection (decreased ulceration) but not tumor radioprotection. Irradiation reduced tumor volume in mice of all genotypes with no detectable effect of JP4-039/F15. Specifically, with wild type Fancd2+/+ mice after 28 Gy, there was no radioprotective effect of JP4-039/F15 on tumor regrowth (p = 0.7520). Tumor bearing Fancd2−/− (p = 0.1843) and Fancd2+/− mice also showed normal tissue but not tumor protection (p = 0.4106 and p = 0.1843, respectively). The data support use of normal mucosal radioprotective JP4-039/F15 during radiotherapy of FA patients with head and neck cancer. Citation Format: Michael W. Epperly, Ashwin Shinde, Hebist Berhane, Byung Han Rhieu, Ronny Kalash, Karen Xu, Darcy Franicola, Xichen Zhang, Tracy Dixon, Donna Shields, Hong Wang, Peter Wipf, Kalindi Parmar, Eva Guinan, Valerian Kagan, Yulia Tyurina, Robert L. Ferris, Song Li, Joel S. Greenberger. Intraoral administration of mitochondrial targeted GS-nitroxide (JP4-039) radioprotects the oral mucosa but not orthotopic tumors in Fancd2-/- mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3340. doi:10.1158/1538-7445.AM2015-3340

Fanconi anemia (FA) patients suffer from bone marrow failure, hematologic malignancies and late onset of squamous cell carcinoma. Some FA patients are highly sensitive to irradiation due to cellular DNA repair defect. Very severe radiation-induced mucositis can be dose limiting for these FA patients. We tested intraoral delivery of the mitochondrial-targeted antioxidant, JP4-039, in a novel F15 emulsion, to reduce mucositis in irradiated FA mice, namely FancD2-deficient mice, with orthotopic TC-1 squamous cell carcinoma cell line derived tumors. TC-1 cells (1 x 106) were injected into the left cheek of Fancd2+/+, Fancd2+/-, and Fancd2-/- mice. Once tumors were palpable, mice were treated with fractionated irradiation of 8 Gy x 4 days to the oral cavity. Subgroups of mice (N=4/group) received intraoral JP4-039/F15 (100 ul containing 4 mg/ml of JP4-039 via a feeding tube placed in the oral cavity) 10 minutes prior to irradiation, F15 alone or irradiation alone. Tumor size was measured daily. Five days after the last radiation dose, mice were sacrificed, tumors and tongue tissue removed for histopathology, and gene transcripts quantitated by real time polymerase chain reaction (RT-PCR). Intraoral JP4-039/F15 prior to 8 Gy x 4 significantly decreased oral cavity ulceration (p < 0.001). Following 8 Gy x 4, F15-JP4-039 treated Fancd2-/- knockout mice had 47.8 ± 11.1% of the tongue ulcerated compared to 81.7 ± 11.6% ulceration in irradiated control mice (p < 0.001). Results in F15-JP4-039 treated irradiated heterozygotes and wild-type Fancd2+/+ mice (34.1 ± 21.2 or 16.9 ± 12.6% ulceration, respectively) were also improved compared to control-irradiated mice (88.3 ± 8.0 or 76.3 ± 17.2% ulceration, respectively) (p < 0.001 for all groups). In contrast, F15 alone did not reduce ulceration. Fancd2-/- F15-JP4-039 treated mice still displayed increased ulceration compared to Fancd2+/+ mice (47.8 ± 11.1% and 16.9 ± 12.6%, respectively, p < 0.0001), Both single fraction and fractionated irradiation controlled tumors at 5 days in Fancd2+/+, Fancd2+/-, and Fancd2-/- mice (0.4 ± 0.3, 0.05 ± 0.05, or 0.1 ± 0.1 mm3, respectively) compared to nonirradiated controls (2.1 ± 0.4, 1.9 ± 0.5, or 3.1 ± 0.1 mm3, respectively, p ≤ 0.027). Tumor bearing Fancd2-/- mice had reduction in irradiation induced normal oral tissue NFKB, MnSOD, p21, and IL1a transcripts, while tumor bearing Fancd2+/+ and Fancd2+/- mice showed elevated transcripts for irradiation induced TGFB, Nrf2, Gadd45, IL1a, and p-21 (p Disclosures No relevant conflicts of interest to declare.

2571 Background: The DNA repair defect in Fanconi anemia (FA) patients makes radiotherapy of head and neck cancers a challenge due to mucositis as a dose limiting toxicity. We tested intraoral deli...