Decreasing Stigma Toward People Who Inject Drugs: Harm Reduction Training for First-Year Medical Students.

PROBLEM: Stigma in health care toward people who inject drugs (PWID) is a well-described, significant barrier to quality care, resulting in poor health outcomes. Harm reduction offers a person-centered counter-framework for minimizing harm for people who use drugs. Despite the evidence in support of harm reduction, medical students typically receive minimal training on harm reduction and the care of PWID. APPROACH: To fill this gap, medical students at the University of California, Los Angeles organized around the principles of harm reduction to improve the medical school curriculum related to PWID. Students screened lectures for stigmatizing language and collaborated with faculty to improve lecture materials. They partnered with a community organizer and hosted a mandatory 1-hour lecture and 30-minute discussion introducing the principles of harm reduction within an overdose prevention, recognition, and response training for first-year medical students during medical school orientation in August 2022. An anonymous online pretest and posttest survey, assessing student attitudes toward PWID, was used to evaluate the effects of the training. OUTCOMES: A total of 156 students completed the pretest survey, and 107 students completed the pretest and posttest survey (68.5% response rate). The overall posttest mean stigma score was 1.8 (standard deviation [SD] = 0.5) and was significantly lower than the pretest mean of 2.1 (SD = 0.7; P < .0001), indicating a reduction in stigma among medical student attitudes after the course. There was statistically significant improvement in attitudes for 7 of 13 component measures. NEXT STEPS: This analysis demonstrated that the mandatory class has the capacity to improve medical student attitudes toward PWID. The authors plan to further evaluate the program's effectiveness through measuring and reporting outcomes for future student cohorts. The authors are working with curriculum directors to further incorporate harm reduction principles into other lectures and problem-based learning exercises.

Intratumoral drug-releasing microdevices allow in situ high-throughput pharmaco phenotyping in patients with gliomas.

The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle to the advancement of therapy for high-grade gliomas, particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial (number NCT04135807), we provide first-in-human evidence that drug-releasing intratumoral microdevices (IMDs) can be safely and effectively used to obtain patient-specific, high-throughput molecular and histopathological drug response profiling. These data can complement other strategies to inform the selection of drugs based on their observed antitumor effect in situ. IMDs are integrated into surgical practice during tumor resection and remain in situ only for the duration of the otherwise standard operation (2 to 3 hours). None of the six enrolled patients experienced adverse events related to the IMD, and the exposed tissue was usable for downstream analysis for 11 out of 12 retrieved specimens. Analysis of the specimens provided preliminary evidence of the robustness of the readout, compatibility with a wide array of techniques for molecular tissue interrogation, and promising similarities with the available observed clinical-radiological responses to temozolomide. From an investigational aspect, the amount of information obtained with IMDs allows characterization of tissue effects of any drugs of interest, within the physiological context of the intact tumor, and without affecting the standard surgical workflow.

Decreased Incidence of CSF Leaks after Skull Base Fractures in the 21st Century: An Institutional Report.

Objectives Cerebrospinal fluid (CSF) leaks are a possible complication in patients with skull base fractures (SBFs). The widely cited incidence of CSF leaks is 10 to 30% in SBF patients; however, this estimate is based only on a few outdated studies. A recent report found CSF leaks in <2% SBF patients, suggesting the incidence may be lower now. To investigate this, we report here our institutional series. Design This study is a retrospective chart review. Setting The study was conducted at two major academic medical centers (2000-2018). Participants Adult patients with SBF were included in this study. Main Outcome Measures Variables included age, gender, CSF leak within 90 days, management regimen, meningitis within 90 days, and 1-year mortality. Results Among 4,944 patients with SBF, 199 (4%) developed a CSF leak. SBF incidence was positively correlated with year of clinical presentation ( r -squared 0.78, p < 0.001). Among CSF leaks, 42% were conservatively managed, 52% were treated with lumbar drain, and 7% required surgical repair. Meningitis developed in 28% CSF leak patients. The 1-year mortality for all SBF patients was 11%, for patients with CSF leaks was 12%, and for patients with meningitis was 16%. Conclusion In the largest institutional review of SBF patients in the 21st century, we found CSF leak incidence to be 4%. This is lower than the widely cited range of 10 to 30%. Nevertheless, morbidity and mortality associated with this complication remains clinically significant, and SBF patients should continue to be monitored for CSF leaks. We provide here our institutional treatment algorithm for these patients that may help to inform the treatment strategy at other institutions.

Combined immunotherapy with controlled interleukin-12 gene therapy and immune checkpoint blockade in recurrent glioblastoma: An open-label, multi-institutional phase I trial.

BACKGROUND: Veledimex (VDX)-regulatable interleukin-12 (IL-12) gene therapy in recurrent glioblastoma (rGBM) was reported to show tumor infiltration of CD8+ T cells, encouraging survival, but also up-regulation of immune checkpoint signaling, providing the rationale for a combination trial with immune checkpoint inhibition. METHODS: An open-label, multi-institutional, dose-escalation phase I trial in rGBM subjects (NCT03636477) accrued 21 subjects in 3 dose-escalating cohorts: (1) neoadjuvant then ongoing nivolumab (1mg/kg) and VDX (10 mg) (n = 3); (2) neoadjuvant then ongoing nivolumab (3 mg/kg) and VDX (10 mg) (n = 3); and (3) neoadjuvant then ongoing nivolumab (3 mg/kg) and VDX (20 mg) (n = 15). Nivolumab was administered 7 (±3) days before resection of the rGBM followed by peritumoral injection of IL-12 gene therapy. VDX was administered 3 hours before and then for 14 days after surgery. Nivolumab was administered every two weeks after surgery. RESULTS: Toxicities of the combination were comparable to IL-12 gene monotherapy and were predictable, dose-related, and reversible upon withholding doses of VDX and/or nivolumab. VDX plasma pharmacokinetics demonstrate a dose-response relationship with effective brain tumor tissue VDX penetration and production of IL-12. IL-12 levels in serum peaked in all subjects at about Day 3 after surgery. Tumor IFNγ increased in post-treatment biopsies. Median overall survival (mOS) for VDX 10 mg with nivolumab was 16.9 months and for all subjects was 9.8 months. CONCLUSION: The safety of this combination immunotherapy was established and has led to an ongoing phase II clinical trial of immune checkpoint blockade with controlled IL-12 gene therapy (NCT04006119).