Evaluation of a Combinatorial Immunotherapy Regimen That Can Cure Mice Bearing MYCN-Driven High-Risk Neuroblastoma That Resists Current Clinical Therapy.

Background: Incorporating GD2-targeting monoclonal antibody into post-consolidation maintenance therapy has improved survival for children with high-risk neuroblastoma. However, ~50% of patients do not respond to, or relapse following, initial treatment. Here, we evaluated additional anti-GD2-based immunotherapy to better treat high-risk neuroblastoma in mice to develop a regimen for patients with therapy-resistant neuroblastoma. Methods: We determined the components of a combined regimen needed to cure mice of established MYCN-amplified, GD2-expressing, murine 9464D-GD2 neuroblastomas. Results: First, we demonstrate that 9464D-GD2 is nonresponsive to a preferred salvage regimen: anti-GD2 with temozolomide and irinotecan. Second, we have previously shown that adding agonist anti-CD40 mAb and CpG to a regimen of radiotherapy, anti-GD2/IL2 immunocytokine and anti-CTLA-4, cured a substantial fraction of mice bearing small 9464D-GD2 tumors; here, we further characterize this regimen by showing that radiotherapy and hu14.18-IL2 are necessary components, while anti-CTLA-4, anti-CD40, or CpG can individually be removed, and CpG and anti-CTLA-4 can be removed together, while maintaining efficacy. Conclusions: We have developed and characterized a regimen that can cure mice of a high-risk neuroblastoma that is refractory to the current clinical regimen for relapsed/refractory disease. Ongoing preclinical work is directed towards ways to potentially translate these findings to a regimen appropriate for clinical testing.

Bringing a Structural Competency Framework to the (Simulated) Bedside: The Premature Discharge Objective Structured Clinical Exam.

PROBLEM: Structural competency is increasingly valued as a framework to address health equity within undergraduate medical education. As of academic year 2023-2024, the Liaison Committee on Medical Education (LCME) requires that medical schools have content regarding basic principles of structurally competent health care. Despite encouraging data about the effectiveness of structural competency curricula, most occur within the walls of a classroom and do not enter the authentic or simulated clinical space. APPROACH: From 2022 to 2023, an objective structured clinical exam (OSCE) focused on premature discharge, previously known as discharge against medical advice, was integrated into the required fourth-year Health Policy course at Weill Cornell Medical College, which uses the framework of structural competency. After a simulated clinical encounter, students completed a reflection assignment and participated in group debriefing to reflect on how policy coursework affected their simulated clinical experience. Students completed an evaluation about their OSCE experience, and OSCE checklist performance was analyzed. OUTCOMES: Of 82 students who participated in the curriculum, 68 completed a curricular evaluation, and 62 consented to have their OSCE performance evaluated for research. Mean overall OSCE checklist performance evaluating students' patient-centered communication skills, harm reduction skills, and discharge planning and counseling was 14.3/16 (89.6%; standard deviation 9.8%). Students reported it was valuable to focus on structural factors affecting care within the simulated clinical encounter by using the structural competency framework. NEXT STEPS: To the authors' knowledge, this is the first OSCE for medical students designed to deepen their understanding of structural competency by embedding the experience into an existing course using the framework. Future work should explore how this curriculum affects students' attitudes toward structurally vulnerable patients. With structural competency as an LCME requirement, the use of OSCEs may give educators a means to teach and assess fundamental concepts.

Lipopolysaccharide-induced changes in effort-related motivational function: Interactions with 2-deoxyglucose.

Inflammation is linked to motivational deficits seen in depression and other disorders. Lipopolysaccharide (LPS) induces an inflammatory response and impairs motivated behavior in humans and rodents. It has been suggested that inflammation can shift metabolic needs to functions that warrant more response to the perceived threat (e.g., fighting infection), therefore altering aspects of motivation. Animal models have been developed to assess alterations in motivated behavior by giving the animal the option to work (i.e., lever press) for a highly palatable food reward vs. approaching and consuming a freely available, albeit less preferred, food. This model was used to determine if administration of 2-deoxy-D-glucose (2DG), a substance that inhibits glucose uptake and glycolysis, could reverse the motivational deficits induced by LPS in rats. A food preference/intake task was also conducted to see if LPS affected intake of the highly palatable vs. less palatable foods when both are freely available. It was hypothesized that 2-DG would reverse the motivational deficits caused by LPS and there would be no effect on food preference/intake of the highly palatable food. Results showed that 2-DG significantly reversed LPS effects at the lowest dose, while methylphenidate did not. The food intake/preference tests showed that LPS significantly decreased food intake of both foods but did not alter preference for the highly palatable food compared to vehicle. These results suggest that in addition to having effects on exertion of effort during instrumental behavior, LPS also has direct effects on primary food motivation.

Wegener's granulomatosis of the penis: diagnosis and management.

A 24 year old uncircumcised man presented with a 1 month history of a painful, fungating lesion on his glans penis. Following biopsy, and further clinical developments, a diagnosis of Wegener's Granulomatosis (WG) was made. The penile lesion was treated with surgical debridement, and a penile stump was salvageable. This is only the fourth case of WG initially presenting with a penile lesion to be reported in the literature.