Lipopolysaccharide impairs amyloid ß efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier.

BACKGROUND: Defects in the low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein (Pgp) clearance of amyloid beta (Aß) from brain are thought to contribute to Alzheimer's disease (AD). We have recently shown that induction of systemic inflammation by lipopolysaccharide (LPS) results in impaired efflux of Aß from the brain. The same treatment also impairs Pgp function. Here, our aim is to determine which physiological routes of Aß clearance are affected following systemic inflammation, including those relying on LRP-1 and Pgp function at the blood-brain barrier. METHODS: CD-1 mice aged between 6 and 8 weeks were treated with 3 intraperitoneal injections of 3 mg/kg LPS at 0, 6, and 24 hours and studied at 28 hours. 125I-Aß1-42 or 125I-alpha-2-macroglobulin injected into the lateral ventricle of the brain (intracerebroventricular (ICV)) or into the jugular vein (intravenous (IV)) was used to quantify LRP-1-dependent partitioning between the brain vasculature and parenchyma and peripheral clearance, respectively. Disappearance of ICV-injected 14 C-inulin from brain was measured to quantify bulk flow of cerebrospinal fluid (CSF). Brain microvascular protein expression of LRP-1 and Pgp was measured by immunoblotting. Endothelial cell localization of LRP-1 was measured by immunofluorescence microscopy. Oxidative modifications to LRP-1 at the brain microvasculature were measured by immunoprecipitation of LRP-1 followed by immunoblotting for 4-hydroxynonenal and 3-nitrotyrosine. RESULTS: We found that LPS: caused an LRP-1-dependent redistribution of ICV-injected Aß from brain parenchyma to brain vasculature and decreased entry into blood; impaired peripheral clearance of IV-injected Aß; inhibited reabsorption of CSF; did not significantly alter brain microvascular protein levels of LRP-1 or Pgp, or oxidative modifications to LRP-1; and downregulated LRP-1 protein levels and caused LRP-1 mislocalization in cultured brain endothelial cells. CONCLUSIONS: These results suggest that LRP-1 undergoes complex functional regulation following systemic inflammation which may depend on cell type, subcellular location, and post-translational modifications. Our findings that systemic inflammation causes deficits in both Aß transport and bulk flow like those observed in AD indicate that inflammation could induce and promote the disease.

"Was It Worth It?": A Pilot Study in Patient Perspectives on the Worthwhileness of Radiation Therapy.

OBJECTIVES: Radiation therapy is a core oncologic treatment, but literature detailing patient satisfaction post-treatment is sparse. The authors conducted a pilot study to determine whether a simple survey would be feasible to administer and could elucidate factors predictive of satisfaction with radiotherapy. MATERIALS AND METHODS: Patients with cancer receiving radiotherapy in an academic radiation oncology department from 2014 to 2015 received a 4-item radiotherapy-focused version of the "Was It Worth It?" questionnaire (r-WIWI) on the last day of treatment and at the first follow-up. Univariate analysis and logistic regression modeling were performed on collected patient and treatment characteristics to explore predictors of satisfaction. RESULTS: Two hundred patients completed an r-WIWI questionnaire at treatment completion and 60 at the time of the first follow-up. Seventy-one percent and 90% of patients found radiotherapy worthwhile on the last day of treatment and at first follow-up, respectively. Patients treated during the morning and for a longer duration as measured in elapsed days were more likely to report treatment being worthwhile. Age, sex, race, marital status, employment status, treatment intent or modalities, daily radiation treatment delays, distance traveled, insurance type, site of treatment, and cancer stage were not predictive of patient satisfaction. CONCLUSIONS: The r-WIWI survey was feasible to administer and most patients reported treatment being worthwhile on the last day of treatment and at first follow-up. Morning treatment times and longer treatment duration as measured in elapsed days were predictive of higher satisfaction in this pilot study. A broader study of factors associated with patient satisfaction with radiotherapy using the r-WIWI is indicated.

A Radiation Oncology-Specific Automated Trigger Indicator Tool for High-Risk, Near-Miss Safety Events.

PURPOSE: Error detection in radiation oncology relies heavily on voluntary reporting, and many adverse events and near misses likely go undetected. Trigger tools use existing data in patient charts to identify otherwise-unaccounted-for events and have been successfully employed in other areas of medicine. We developed an automated radiation oncology-specific trigger tool and validated it against near-miss data from a high-volume incident learning system (ILS). METHODS AND MATERIALS: Twenty triggers were derived from an electronic radiation oncology information system. Data from the systems over an approximately 3.5-year period were split randomly into training and test sets. The probability of a high-grade (grade 3-4) near miss for each treatment course in the training set was estimated using a regularized logistic regression model. The predictive model was applied to the test set. Records for 25 flagged treatment courses with an ILS entry were reviewed to explore the association between triggers and near misses, and 25 flagged courses without an ILS entry were reviewed to detect unreported near misses. RESULTS: Of the 3159 treatment courses analyzed, 357 had a grade 3 to 4 ILS entry; 2210 courses composed the training set, and the test set had 949 courses. Areas under the curve on the training and test sets were 0.650 and 0.652, respectively. Of 20 triggers, 9 reached statistical significance on univariate analysis. Fifty percent of the 25 treatment courses in the test set with the highest predicted likelihood of a high-grade near miss with an ILS entry had a direct relationship between the triggers and the near miss. Review of the 25 treatment courses with the highest predicted likelihood of high-grade near miss without an ILS entry found 2 unreported near-miss events. CONCLUSIONS: The radiation oncology-specific automated trigger tool performed modestly and identified additional treatment courses with near-miss events. Radiation oncology trigger tools deserve further exploration.

A Blinded, Prospective Study of Error Detection During Physician Chart Rounds in Radiation Oncology.

PURPOSE: Peer review during physician chart rounds is a major quality assurance and patient safety step in radiation oncology. However, the effectiveness of chart rounds in detecting problematic treatment plans is unknown. We performed a prospective blinded study of error detection at chart rounds to clarify the effectiveness of this quality assurance step. METHODS AND MATERIALS: Radiation Oncology Incident Learning System publications were queried for problematic plans approved for treatment that would be detectable at chart rounds. A resident physician, physicist, and dosimetrist collaboratively generated 20 treatment plans with simulated errors identical in nature to those reported to the Radiation Oncology Incident Learning System. These were inserted randomly into weekly chart rounds over 9 weeks, with a median of 2 problematic plans presented per chart rounds (range, 1-4). Data were collected on detection, attendance, length, and number of cases presented at chart rounds. Data were analyzed using descriptive statistics and univariable logistic regression with odds ratios. RESULTS: The median length of chart rounds over the study period was 60 minutes (range, 42-79); median number of cases presented per chart rounds was 45 (range, 38-50). The overall detection rate was 55% (11 of 20). Detection rates were higher for cases presented earlier in chart rounds: 75% versus 25% of problematic plans were detected within 30 minutes of start of chart rounds versus after 30 minutes (odds ratio, 0.11; 95% confidence interval, 0.01-0.88; P = .037). Detection rates showed a trend toward increase during the study period but this was not significant: 33% in weeks 1 to 5 and 73% during weeks 6 to 9 (5.3; 95% confidence interval, 0.78-36; P = .08). CONCLUSIONS: The detection of clinically significant problematic plans during chart rounds could be significantly improved. Problematic plans are more frequently detected earlier in chart rounds and inserting such plans into chart rounds may enhance detection; however, larger studies are needed to confirm these findings. A multi-institutional study is planned.

Cardiac Angiosarcoma from a Saphenous Vein Coronary Artery Bypass Graft.

Primary cardiac sarcomas (PCS) are rare and the prognosis is generally poor. Angiosarcomas are the most common cardiac sarcoma histology. The best management of PCS is poorly defined. Chronic lymphedema, foreign bodies, including Dacron grafts, and arteriovenous fistulas have been associated with angiosarcoma, and angiosarcomas arising from saphenous vein femoropopliteal bypass grafts have been reported. We present the first known case of a cardiac angiosarcoma originating from an autologous saphenous vein graft used in a coronary artery bypass. The patient's course and the literature on primary cardiac angiosarcomas are reviewed.

Radiation Therapy Dose Escalation to Clinically Involved Pelvic Sidewall Lymph Nodes in Locally Advanced Rectal Cancer.

PURPOSE: Lateral pelvic sidewall lymph nodes (PSW LN) may be involved in up to 24% of locoregionally advanced rectal cancers. PSW LN are not resected in total mesorectal excision (TME), and no standard of care regarding the management of PSW LN exists in the United States. We assessed our institutional experience of preoperative radiation therapy (RT) boost to clinically involved PSW LN that were not planned for resection. METHODS AND MATERIALS: Data from all patients with rectal adenocarcinoma treated between 2006 and 2018 were reviewed to identify those who received a cumulative dose of >50.4 Gy to suspicious PSW LN during neoadjuvant chemoradiation therapy (nCRT). Demographic, cancer characteristic, treatment, and toxicity data were derived from the chart. RESULTS: Of a total of 261 patients, 12 patients met the inclusion criteria. The median age was 47.5 years, and 83% of patients were men. All patients had T3/4 disease, 17% of patients had N1b disease and the remainder had N2 disease, and 33% had M1 disease (all ≤2 metastases). Seventy-five percent of patients had moderately or poorly differentiated histology. The mean distance from the anal verge was 4.85 cm (range, 2-8.9 cm), and 58% had ≥2 PSW LN with an average short axis diameter of 1.11 cm (range, 0.4-3.2 cm). Boost doses ranged from 53.48 Gy to 60.2 Gy in 27 to 30 fractions (1.8-2.15 Gy/fraction). The median follow-up time was 18 months. One patient who received concurrent capecitabine and irinotecan had grade 3 perineal dermatitis and anemia during nCRT. The median hospitalization time for TME was 6.5 days. Within 90 days of TME, 1 patient required surgical exploration for perineal wound breakdown, and another required a blood transfusion for anemia. At the time of the last follow up, 75% of patients were alive. Local control at 12 months was 90%. CONCLUSIONS: RT dose escalation to nonresected PSW LN during nCRT was well tolerated with a low risk of acute toxicity and perioperative complications and has a high rate of local control at 12 months. RT boost warrants further study in patients with clinically involved nonresected PSW LN.

Durable Improvement in Patient Safety Culture Over 5 Years With Use of High-volume Incident Learning System.

PURPOSE: Incident learning systems (ILSs) require substantial time and effort to maintain, risking staff burnout and ILS disuse. Herein, we assess the durability of ILS-associated safety culture improvements and ILS engagement at 5 years. METHODS AND MATERIALS: A validated survey assessing safety culture was administered to all staff of an academic radiation oncology department before starting ILS and annually thereafter for 5 years. The survey consists of 70 questions assessing key cultural domains, overall patient safety grade, and barriers to incident reporting. A χ2 test was used to compare baseline scores before starting the ILS (pre-ILS) with the aggregate 5 years during which ILS was in use (with ILS). ILS engagement was measured by the self-reported number of ILS entries submitted in the previous 12 months. RESULTS: The survey response rate was ≥68% each year (range, 68%-80%). High-volume event reporting was sustained (4673 reports; average of 0.9 ILS entries per treatment course). ILS engagement increased, with 43% of respondents submitting reports during the 12 months pre-ILS compared with 64% with ILS in use (P < .001). Significant improvements (pre- vs. with-ILS) were observed in the cultural domains of patient safety perceptions (25% vs 39%; P < .03), and responsibility and self-efficacy (43% vs 60%; P < .01). The overall patient safety grade of very good or excellent significantly increased (69% vs 85%; P < .01). Significant reductions were seen in the following barriers to error reporting: embarrassment in front of colleagues, getting colleagues into trouble, and effect on department reputation. CONCLUSIONS: Comprehensive incident learning was sustained over 5 years and is associated with significant durable improvements in metrics of patient safety culture.

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Current Trends and Controversies.

Hepatocellular carcinoma is the fourth leading cause of cancer-related death worldwide. Depending on the extent of disease and competing comorbidities for mortality, multiple liver-directed therapy options exist for the treatment of hepatocellular carcinoma. Advancements in radiation oncology have led to the emergence of stereotactic body radiation therapy as a promising liver-directed therapy, which delivers high doses of radiation with a steep dose gradient to maximize local tumor control and minimize radiation-induced treatment toxicity. In this study, we review the current clinical data as well as the unresolved issues and controversies regarding stereotactic body radiation therapy for hepatocellular carcinoma: (1) Is there a radiation dose-response relationship with hepatocellular carcinoma? (2) What are the optimal dosimetric predictors of radiation-induced liver disease, and do they differ for patients with varying liver function? (3) How do we assess treatment response on imaging? (4) How does stereotactic body radiation therapy compare to other liver-directed therapy modalities, including proton beam therapy? Based on the current literature discussed, this review highlights future possible research and clinical directions.