A hands-on introduction to medical physics and radiation therapy for middle school students.

Lesson plans were developed to present concepts of medical physics and radiation therapy to a middle school audience. These workshop learning units relied on hands-on participation and collaboration within student groups to acquaint students with computed tomography simulation and treatment planning processes. These lesson plans were delivered at two different educational outreach programs targeted at student groups that have traditionally been underrepresented in science, technology, engineering, and mathematics (STEM) fields. The lesson plans are scheduled to be delivered at a third program in the future. The activities were used to introduce occupations in medical physics and radiation therapy as possible career opportunities for students, and to generate enthusiasm for continuing STEM education. Lesson plans are available upon request for educators interested in exploring medical physics educational outreach activities in their communities.

ACCLAIM: A randomized trial of abatacept (CTLA4-Ig) for relapsing-remitting multiple sclerosis.

BACKGROUND: Costimulatory blockade of T lymphocytes with the CTLA4-Ig fusion protein abatacept could be an effective treatment for the immune-mediated neuroinflammatory disease relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To evaluate efficacy and safety of abatacept in RRMS. METHODS: ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) was a Phase II, randomized, double-blind, placebo-controlled, multi-center trial. In all, 65 of 123 planned participants with RRMS were randomized to monthly intravenous infusions of abatacept or placebo for 24 weeks in a 2:1 ratio, switched to the opposite treatment at 28 weeks, and received their final dose of study medication at 52 weeks. Enrollment was closed early due to slow accrual. The primary endpoint was the mean number of new gadolinium-enhancing (Gd+) lesions obtained on magnetic resonance imaging (MRI) scans performed every 4 weeks. RESULTS: No statistically significant differences were observed in mean number of new Gd+ MRI lesions between the abatacept and placebo groups. No statistically significant differences were observed in other MRI and clinical parameters of RRMS disease activity. Abatacept was well tolerated. CONCLUSION: The ACCLAIM study did not demonstrate efficacy of abatacept in reducing the number of new Gd+ MRI lesions, or clinical measures of disease activity in RRMS.

American Radium Society Appropriate Use Criteria Postmastectomy Radiation Therapy: Executive Summary of Clinical Topics.

PURPOSE: To conduct an appropriate use criteria expert panel update on clinical topics relevant to current clinical practice regarding postmastectomy radiation therapy (PMRT). METHODS AND MATERIALS: An analysis of the medical literature from peer-reviewed journals was conducted from May 4, 2010 to May 4, 2022 using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to search the PubMed database to retrieve a comprehensive set of relevant articles. A well-established methodology (modified Delphi) was used by the expert panel to rate the appropriate use of procedures. RESULTS: Evidence for key questions in PMRT regarding benefit in special populations and technical considerations for delivery was examined and described. Risk factors for local-regional recurrence in patients with intermediate-risk disease that indicate benefit of PMRT include molecular subtype, age, clinical stage, and pathologic response to neoadjuvant chemotherapy. Use of hypofractionated radiation in PMRT has been examined in several recent randomized trials and is under investigation for patients with breast reconstruction. The use of bolus varies significantly by practice region and has limited evidence for routine use. Adverse effects occurred with both PMRT preimplant and postimplant exchange in 2-staged breast reconstruction. CONCLUSIONS: Most patients with even limited nodal involvement will likely benefit from PMRT with significant reduction in local-regional recurrence and potential survival. Patients with initial clinical stage III disease and/or any residual disease after neoadjuvant chemotherapy should be strongly considered for PMRT. Growing evidence supports the use of hypofractionated radiation for PMRT with equivalent efficacy and decreased acute side effects, but additional evidence is needed for special populations. There is limited evidence to support routine use of bolus in all patients. Timing of PMRT regarding completion of 2-staged breast reconstruction requires a discussion of increased risks with radiation postimplant exchange compared with increased risk of failure of reconstruction or surgical complications with radiation preimplant exchange.

Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis.

OBJECTIVE: To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN). METHODS: In a multicenter, randomized, open-label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group), or treated with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients' peripheral blood were analyzed by flow cytometry. RESULTS: Treatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab (P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/µl in the RCB group versus 11 cells/µl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group (P = 0.0349), a finding that is consistent with the observed impaired maturation of naive B cells and enhanced censoring of autoreactive B cells. CONCLUSION: The addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN.

A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy.

PURPOSE: Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points. EXPERIMENTAL DESIGN: Three patients with colon cancer, four with non-Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles. RESULTS: Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specific T-cell responses was observed after therapy. Tregs as detected by expression of CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion. CONCLUSIONS: Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.

Patients affected by endemic pemphigus foliaceus in Colombia, South America exhibit autoantibodies to optic nerve sheath envelope cell junctions.

BACKGROUND: The majority of the patients affected by a new variant of endemic pemphigus foliaceus in El Bagre, Colombia (El Bagre EPF or pemphigus Abreu-Manu), have experienced vision problems; we have previously reported several ocular abnormalities. METHODS: Here, we aimed to investigate reactivity to optic nerves in these patients. We utilized bovine, rat and mouse optic nerves, and performed immunofluorescence and confocal microscopy to test for optical nerve autoreactivity. We tested 45 patients affected by this disease and 45 controls from the endemic area matched by age, sex and work activity. RESULTS: Overall, 37 of the 45 patient sera reacted to the optic nerve envelope that is composed of leptomeninges; the reactivity was polyclonal and present mostly at the cell junctions (P < 0.001). The immune response was directed against optic nerve sheath cell junctions and the vessels inside it, as well as other molecules inside the nerve. No control cases were positive. Of interest, all the patient autoantibodies co-localized with commercial antibodies to desmoplakins I-II, myocardium-enriched zonula occludens-1- associated protein (MYZAP), armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF), and plakophilin-4 (p0071) from Progen Biotechnik (P < 0.001). CONCLUSION: We conclude that the majority of the patients affected by pemphigus Abreu-Manu have autoantibodies to optic nerve sheath envelope cell junctions. These antibodies also co-localize with armadillo repeat gene deleted in velo-cardio-facial syndrome, p0071 and desmoplakins I-II. The clinical significance of our findings remains unknown.

Mentorship Programs in Radiation Oncology Residency Training Programs: A Critical Unmet Need.

PURPOSE: To conduct a nationwide survey to evaluate the current status of resident mentorship in radiation oncology. METHODS AND MATERIALS: An anonymous electronic questionnaire was sent to all residents and recent graduates at US Accreditation Council for Graduate Medical Education-accredited radiation oncology residency programs, identified in the member directory of the Association of Residents in Radiation Oncology. Factors predictive of having a mentor and satisfaction with the mentorship experience were identified using univariate and multivariate analyses. RESULTS: The survey response rate was 25%, with 85% of respondents reporting that mentorship plays a critical role in residency training, whereas only 53% had a current mentor. Larger programs (≥ 10 faculty, P=.004; and ≥ 10 residents, P<.001) were more likely to offer a formal mentorship program, which makes it more likely for residents to have an active mentor (88% vs 44%). Residents in a formal mentoring program reported being more satisfied with the overall mentorship experience (univariate odds ratio 8.77, P<.001; multivariate odds ratio 5, P<.001). On multivariate analysis, women were less likely to be satisfied with the mentorship experience. CONCLUSIONS: This is the first survey focusing on the status of residency mentorship in radiation oncology. Our survey highlights the unmet need for mentorship in residency programs.

Can emergent treatments result in more severe errors?: An analysis of a large institutional near-miss incident reporting database.

PURPOSE: Emergent radiation treatments may be subject to more errors because of the compressed time frame. Few data exist on the magnitude of this problem or how to guide safety improvement interventions. The purpose of this study is to examine patterns of near-miss events in emergent treatments using a large institutional incident reporting system. METHODS AND MATERIALS: Events in the incident reporting database from February 2012 to October 2013 were reviewed prospectively by a multidisciplinary team to identify emergent treatments. Reports were scored for potential near-miss risk index (NMRI) on a 0 to 4 scale. Workflow steps of where events originated and were detected were analyzed. Events were categorized by use of the causal factor system from the Radiation Oncology Incident Learning System. Mann-Whitney U tests were used to compare mean NMRI score, and Fisher exact tests were performed to compare the proportion of high-risk events between emergent and nonemergent treatments and between emergent treatments on weekdays and weekends or holidays. RESULTS: Over the study period, approximately 1600 patients were treated, 190 of them emergently. Seventy-one incident reports were submitted for 55 unique patients. Fewer events were reported for emergent treatments than for nonemergent treatments (0.37 events per new treatment vs 0.86; P < .01). Mean risk index for emergent reports was 1.90 versus 1.48 for nonemergent reports (P < .01). Rate of NMRI 4 was 10% for emergent treatments versus 4% for nonemergent treatments (P < .01). Emergent treatments started on a weekend or holiday had a higher proportion of critical near-miss events than emergent treatments started during the week (37% vs 7.9%, P = .034). CONCLUSIONS: In this study, fewer near-miss incidents were reported per treatment course for emergent treatments. This may be attributable to reporting bias. More importantly, when emergent near misses occur, they are of greater severity.

Metrics of success: Measuring impact of a departmental near-miss incident learning system.

PURPOSE: There is a growing interest in the application of incident learning systems (ILS) to radiation oncology. The purpose of the present study is to define statistical metrics that may serve as benchmarks for successful operation of an incident learning system. METHODS AND MATERIALS: A departmental safety and quality ILS was developed to monitor errors, near-miss events, and process improvement suggestions. Event reports were reviewed by a multiprofessional quality improvement committee. Events were scored by a near-miss risk index (NMRI) and categorized by event point of origination and discovery. Reporting trends were analyzed over a 2-year period, including total number and rates of events reported, users reporting, NMRI, and event origination and discovery. RESULTS: A total of 1897 reports were evaluated (1.0 reports/patient, 0.9 reports/unique treatment course). Participation in the ILS increased as demonstrated by total events (2.1 additional reports/month) and unique users (0.5 new users/month). Sixteen percent of reports had an NMRI of 0 (none), 42% had an NMRI of 1 (mild), 25% had an NMRI of 2 (moderate), 12% had an NMRI of 3 (severe), and 5% had an NMRI of 4 (critical). Event NMRI showed a significant decrease in the first 6 months (1.68-1.42, P < .001). Trends in origination and discovery of reports were broadly distributed between radiation therapy process steps and staff groups. The highest risk events originated in imaging for treatment planning (NMRI = 2.0 ± 1.1; P < .0001) and were detected in on-treatment quality management (NMRI = 1.7 ± 1.1; P = .003). CONCLUSIONS: Over the initial 2-year period of ILS operation, rates of reporting increased, staff participation increased, and NMRI of reported events declined. These data mirror previously reported findings of improvement in safety culture endpoints. These metrics may be useful for other institutions seeking to create or evaluate their own ILS.

Preclinical and phase I clinical trial of blockade of IL-15 using Mikbeta1 monoclonal antibody in T cell large granular lymphocyte leukemia.

Twelve patients with T cell large granular lymphocyte leukemia and associated hematocytopenia were treated in a phase I dose-escalation trial with the murine monoclonal antibody Mikbeta1. Mikbeta1 identifies CD122, the beta-subunit shared by the IL-2 and IL-15 receptors. At the doses administered in this study the antibody inhibited the actions of IL-15 on both natural killer and T cells and that of IL-2 when the intermediate-affinity IL-2 receptor was expressed. Mikbeta1 treatment was not associated with significant toxicity or with the development of an immune response to the infused monoclonal antibody. At these doses of Mikbeta1, >95% saturation of the IL-2/IL-15beta receptor (CD122) on the surfaces of the leukemic cells was achieved. Furthermore, in seven patients this led to the down-modulation of the receptor from the surfaces of the leukemic cells. Nevertheless, no patients manifested a reduction in peripheral leukemic cell count or an amelioration of their hematocytopenia. This latter observation may reflect the fact that the monoclonal T cell large granular lymphocyte leukemia leukemic cells of the patients did not produce IL-2 or IL-15 or require their actions for cell survival. In light of the lack of toxicity and lack of immunogenicity of the antibody observed in the present study and the role for IL-15 in the pathogenesis of autoimmune diseases, clinical trials should be performed using the humanized version of Mikbeta1 in groups of patients with human T cell lymphotropic virus I-associated myelopathy/tropical spastic paraparesis, rheumatoid arthritis, multiple sclerosis and refractory celiac disease.