Citations

509 Background: Bladder cancer is a leading cause of cancer death in the United States. The histology in > 90% of cases is urothelial carcinoma (UC). Tumors may present either as non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Current standard of care for patients with high risk NMIBC includes transurethral resection of bladder tumor (TURBT) followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG). Meanwhile, patients with BCG unresponsive NMIBC or MIBC are recommended to undergo radical cystectomy (RC), which adversely impacts quality of life and is associated with significant morbidity. MV-NIS is an investigational oncolytic measles virus with an excellent clinical safety profile. This ongoing phase I clinical study is designed to test the safety, efficacy and identify the recommended phase 2 dose (RP2D) of intravesical MV-NIS in patients with NMIBC or MIBC who are scheduled for RC and not eligible for neoadjuvant chemotherapy. Methods: Bladder UC patients were evaluated for eligibility and provided informed consent prior to enrolling. To date 8 patients have been enrolled: 4 to the single dose safety cohort, and 4 to the multi-dose expansion cohort. Patients were administered intravesical ̃1x109 TCID50 MV-NIS once at least 1 week prior to RC (safety cohort), or twice at 4 and 2 weeks prior to RC (expansion cohort). Patients were closely monitored during the 2-hour instillation period. Tumor specimens from the pre-treatment TURBT and post-treatment RC were analyzed to determine pre- and post-treatment pathological stage and evaluate tumor killing and immune cell infiltrate. Results: Intravesical MV-NIS treatment was well tolerated in all patients. Only a single Adverse Event (AE) attributable to MV-NIS treatment (Grade 1 hematuria). AEs Grade > 2 were related to post-surgical complications. Tumor downstaging was observed in 4 of 8 patients. Among 4 patients in the expansion cohort, 2 had no residual disease (pT0). Central assessment of RC tissues showed significant inflammatory infiltrate in all treated bladder specimens. Detailed analyses are ongoing to characterize MV infection and immune infiltrate in bladder tissue. Conclusions: The higher-than-expected rate of tumor downstaging and pT0 pathology, paired with the significant immune infiltrate observed in post-treatment bladder tissue, provide compelling evidence that intravesical MV-NIS has clinical activity against UC. These results support the use of two doses of ̃1x109 TCID50 as the RP2D in future clinical studies for BCG unresponsive NMIBC or MIBC patients. MV-NIS induced inflammation may act synergistically with checkpoint blockade therapies. Clinical trial information: NCT03171493.

BACKGROUND In total, 2.7 million injectable filler treatments were performed in 2019 in the United States. Although generally considered to be a safe treatment modality, adverse events may occur in rare situations. OBJECTIVE Analyze serious adverse events from injectable filler treatments, including infections, cutaneous necrosis, blindness, or delayed-onset nodule formation, spanning 11 years for 3 board-certified dermatologists and review their incidence, management, and outcomes. MATERIALS AND METHODS A retrospective analysis was performed of injectable filler treatments spanning 11 years at a multipractitioner outpatient clinic. Serious adverse events were identified, and treatment measures were documented. A literature search was performed to determine recent trends and outcomes for comparison. RESULTS Between January 2009 and August 2020, 18,013 mL of injectable filler was administered to 7,659 patients. Of the 18,013 mL administered, 74.1% comprised hyaluronic acid derivatives, 19.19% poly-l-lactic acid, and 6.71% calcium hydroxylapatite. Four serious adverse events were identified. Three events were delayed-onset skin nodule formation. One adverse event was related to vascular compromise and subsequent cutaneous necrosis. After appropriate treatment, all adverse events resolved without significant long-term sequelae. CONCLUSION Serious adverse events associated with injectable fillers, when performed by board-certified dermatologists, are extremely rare and can be successfully managed with appropriate treatment.

Large group lectures, which are widely used in continuing medical education, are susceptible to pitfalls that can negatively impact their effectiveness. In this article, we describe evidence-based best practices from the educational literature that can revive the medical lecture as an effective educational tool. We provide practical tips for both developing and delivering lectures, emphasizing the key role that learning objectives can and should have in the development of lectures, the importance of organization, effective use of visuals and application of restraint in slide design. Pause techniques to authentically engage the audience are described. We also provide practical tips for promoting attention in virtual presentations.

BACKGROUND: Although there has been a considerable increase in the representation of women in medicine, a gender gap still exists with regard to leadership positions. This gender discrepancy has been identified in the field of anesthesiology, in terms of first and senior authorship, as well as in general composition of editorial boards in Anesthesiology and Anesthesia & Analgesia . The goal of this study is to examine the current representation of women in editorial boards of anesthesia journals with respect to the hierarchy of different editorial positions and to assess whether there has been improvement toward equity in recent years. METHODS: A comprehensive search was performed for anesthesiology journals indexed in the Scimago Journal and Country Rank in May 2020. The editorial boards of the top 20 journals by impact factor were analyzed. Editorial board members were categorized based on their title. Gender was assigned using images or pronouns on research databases or hospital-affiliated websites. The percentage of women within each category was calculated. When available, the year the editors obtained their medical degree was collected. A binomial proportion test was used to analyze the distribution of women overall and among editorial roles, compared to the proportion of women anesthesiologists (26%). A Wilcoxon rank-sum test was used to compare time since medical degree between genders. Additionally, women representation in anesthesiology editorial boards in 2020 was compared to 2010. RESULTS: A total of 19 journals were included in this study, as 1 journal did not disclose editorial board membership. Overall, women occupied 18% of all editorial board positions. All editors-in-chief and assistant/associate/deputy editors-in-chief were men. Women consisted of 17.1% of executive/section/senior editors, 17.9% of editors, and 20.6% of associate/assistant editors. There were significantly fewer women editorial board members than the percentage of women anesthesiologists (18% vs 26%; P < .001). Editorial boards from 2010 were available for 14 journals, and of these journals, women comprised 12% of editorial board members in 2010 compared to 19% in 2020 ( P = .001). CONCLUSIONS: These findings suggest that in anesthesiology journals, women are underrepresented at all editorial levels, especially at higher levels. As editorial boards have a significant impact on which articles are published by a journal and thereby significant influence on the specialty as a whole, the lack of gender equity in editorial boards should be addressed.

297 Background: MT-5111 is a 55 kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction and does not rely on inhibition of kinase signaling or cytoskeletal or DNA damage. Methods: This is a phase 1 study in adult pts with advanced HER2+ solid tumors. The dose-escalation portion (modified 3+3 design) enrolls pts into sequential cohorts followed by expansion cohorts for HER2+ breast cancer (BC), gastric or gastroesophageal junction adenocarcinoma (GEA), and other HER2+ tumors. MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death, or withdrawn consent. Results: As of Sep 2021 (contains preliminary data), 24 pts (mean age 64 yrs) were treated, 13 (54%) of whom had gastrointestinal (GI) tumors (6 biliary, 3 GEA, 2 pancreatic, 2 colo/rectal) (Table). Pts with GI tumors had a median of 3 prior systemic tx and 1 prior HER2-targeting tx. No Grade (G) 4/5 tx-emergent adverse events (AEs) occurred. Tx-related AEs occurred in 13 (54%) pts, most commonly fatigue (n=7, 29%). One pt with biliary cancer and concurrent lymphangitic carcinomatosis and H. influenzae infection (4.5 µg/kg) had a possibly related G3 serious AE (SAE) of dyspnea, which resolved 9 days later. Another related SAE occurred in a pt with GEA (6.75 µg/kg) who had a G1 transient troponin increase that resolved during hospitalization, with no clinical symptoms or ECG/ECHO changes; the pt withdrew from study before further dosing. All other related AEs were ≤G2. No other clinically significant changes in cardiac biomarkers (troponin, ECG, LVEF) or cases of capillary leak syndrome occurred. Two pts (3 and 4.5 µg/kg) had reversible G2 infusion-related reactions. Best response to date has been stable disease. AUClast data matched PK simulations based on non-human primate studies. Cmax data at 10 µg/kg indicate that current in-pt exposure was between IC50 values of high and medium HER2-expressing cell lines (approx 10-89 ng/mL). Thus, at least 10 µg/kg may be required to achieve effective exposure. No dose-limiting toxicities have been observed. The 10 µg/kg cohort is now accruing. Following this cohort, an expansion cohort for pts with BC will open. Conclusions: MT-5111 was well tolerated with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing and is nearing levels expected to be required for efficacious exposure. Clinical trial information: NCT04029922. [Table: see text]

Abstract Background: Somatic EGFR mutations define a subset of non–small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74–0.77) in the training and 0.77 (95% CI, 0.74–0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

Abstract Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two‐sample Mendelian randomization (MR). Methods We genotyped a well‐established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage‐PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P ‐difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society