Efficacy of Cemiplimab as Adjuvant or Neoadjuvant Therapy in the Treatment of Cutaneous Squamous Cell Carcinoma.

INTRODUCTION: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer in the White population. Unfortunately, the prognosis of advanced cSCC is poor, and management can be challenging. Until recently, the choice of systemic medications was limited, and those that were available had modest efficacy. Cemiplimab is an anti-programmed cell-death protein 1 inhibitor and the first immunotherapeutic agent approved for the treatment of metastatic or locally advanced cSCC. The purpose of this study was to evaluate the efficacy of cemiplimab when used as adjuvant or neoadjuvant therapy in patients treated at our institution. METHODS: A retrospective review of patients with locally advanced or metastatic cSCC who were treated with cemiplimab as adjuvant or neoadjuvant therapy at a single institution between February 2019 and November 2022 was performed. Response to treatment was objectively assessed based on Response Evaluation Criteria in Solid Tumors, version 1.1, criteria. The primary end point was objective response rate. Secondary endpoints included time to observed response, disease-control rate, progression-free survival, overall survival, and adverse effects of therapy. RESULTS: A total of 6 patients were identified with a median age of 79 years (range, 51-90 years). Four patients had locally advanced cSCC, and 2 had distant metastasis. Cemiplimab was used as adjuvant therapy in 3 patients and neoadjuvant therapy in 2 patients. There was 1 patient in which it was used for limb salvage, who would have otherwise required an amputation. Objective response rate, complete response, and partial response were 66% (4 of 6), 33% (2 of 6), and 33% (2 pf 6), respectively. Average time to observed response was 2.9 months. Disease-control rate was 83% (5 of 6), and average progression-free survival was 10 months. Toxicity was reported in 2 patients, both of which were grade 1 severity. CONCLUSIONS: Cemiplimab has established its utility in the treatment of advanced cSCC, demonstrating clinical efficacy while generally having a tolerable adverse effect profile. Our preliminary results suggest that cemiplimab has potential as an adjuvant or neoadjuvant therapy in combination with surgery for treatment of cSCC.

Replacing the Scalpel With a Computer Mouse: An Evaluation of Time Spent on Electronic Health Record for Plastic Surgery Residents and Its Impact on Resident Training.

BACKGROUND: Following the integration of the electronic health record (EHR) into the healthcare system, concern has grown regarding EHR use on physician well-being. For surgical residents, time spent on the EHR increases the burden of a demanding, hourly restricted schedule and detracts from time spent honing surgical skills. To better characterize these burdens, we sought to describe EHR utilization patterns for plastic surgery residents. METHODS: Integrated plastic surgery resident EHR utilization from March 2019 to March 2020 was extracted via Cerner Analytics at a tertiary academic medical center. Time spent in the EHR on-duty (0600-1759) and off-duty (1800-0559) in the form of chart review, orders, documentation, and patient discovery was analyzed. Statistical analysis was performed in the form of independent t tests and Analysis of Variance (ANOVA). RESULTS: Twelve plastic surgery residents spent a daily average of 94 ± 84 minutes on the EHR, one-third of which was spent off-duty. Juniors (postgraduate years 1-3) spent 123 ± 99 minutes versus seniors (postgraduate years 4-6) who spent 61 ± 49 minutes (P < 0.01). Seniors spent 19% of time on the EHR off-duty, compared with 37% for juniors (P < 0.01). Chart review comprised the majority (42%) of EHR usage, followed by patient discovery (22%), orders (14%), documentation (12%), other (6%), and messaging (1%). Seniors spent more time on patient discovery (25% vs 21%, P < 0.001), while juniors spent more time performing chart review (48% vs 36%, P = 0.19). CONCLUSION: Integrated plastic surgery residents average 1.5 hours on the EHR daily. Junior residents spend 1 hour more per day on the EHR, including more time off-duty and more time performing chart review. These added hours may play a role in duty hour violations and detract from obtaining operative skill sets.

Utility of Antibiotic Use in Pediatric Facial Fractures: A Systematic Review.

Background: In regard to antibiotic stewardship, it is important to understand the appropriate time to prescribe antibiotics in pediatric facial fracture management. Objective: To evaluate the utility of antibiotics in pediatric facial fractures and determine situational variables influencing appropriate antibiotic prescription. Methods: A comprehensive literature search was conducted in PubMed, Cochrane, and Web of Science databases for articles published from 2000 to 2022. Inclusion criteria consisted of all studies assessing pediatric facial fractures that mentioned antibiotic use. Results: A total of 13 studies were included in the full review. The reviewed studies comprised 31 pediatric patients ranging from 6 months to 18 years old. Most studies were case reports and case series (N = 9). Antibiotics were prescribed for the majority (96.7%) of patients. Antibiotic regimens varied by timing of administration, antibiotic used, and dosage. Fracture locations also varied widely, including orbital, zygomatic, nasal, mandibular, and maxillary fractures. Conclusions: Additional studies with more substantial evidence are needed to fully understand the situational appropriateness of antibiotic use in pediatric facial fractures.

Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma.

PURPOSE: Glioblastoma (GBM) is the most common and most lethal primary malignant brain tumor. The receptor tyrosine kinase MET is frequently upregulated or overactivated in GBM. Although clinically applicable MET inhibitors have been developed, resistance to single modality anti-MET drugs frequently occurs, rendering these agents ineffective. We aimed to determine the mechanisms of MET inhibitor resistance in GBM and use the acquired information to develop novel therapeutic approaches to overcome resistance.Experimental Design: We investigated two clinically applicable MET inhibitors: crizotinib, an ATP-competitive small molecule inhibitor of MET, and onartuzumab, a monovalent monoclonal antibody that binds to the extracellular domain of the MET receptor. We developed new MET inhibitor-resistant cells lines and animal models and used reverse phase protein arrays (RPPA) and functional assays to uncover the compensatory pathways in MET inhibitor-resistant GBM. RESULTS: We identified critical proteins that were altered in MET inhibitor-resistant GBM including mTOR, FGFR1, EGFR, STAT3, and COX-2. Simultaneous inhibition of MET and one of these upregulated proteins led to increased cell death and inhibition of cell proliferation in resistant cells compared with either agent alone. In addition, in vivo treatment of mice bearing MET-resistant orthotopic xenografts with COX-2 or FGFR pharmacological inhibitors in combination with MET inhibitor restored sensitivity to MET inhibition and significantly inhibited tumor growth. CONCLUSIONS: These data uncover the molecular basis of adaptive resistance to MET inhibitors and identify new FDA-approved multidrug therapeutic combinations that can overcome resistance.

The p53 Pathway in Glioblastoma.

The tumor suppressor and transcription factor p53 plays critical roles in tumor prevention by orchestrating a wide variety of cellular responses, including damaged cell apoptosis, maintenance of genomic stability, inhibition of angiogenesis, and regulation of cell metabolism and tumor microenvironment. TP53 is one of the most commonly deregulated genes in cancer. The p53-ARF-MDM2 pathway is deregulated in 84% of glioblastoma (GBM) patients and 94% of GBM cell lines. Deregulated p53 pathway components have been implicated in GBM cell invasion, migration, proliferation, evasion of apoptosis, and cancer cell stemness. These pathway components are also regulated by various microRNAs and long non-coding RNAs. TP53 mutations in GBM are mostly point mutations that lead to a high expression of a gain of function (GOF) oncogenic variants of the p53 protein. These relatively understudied GOF p53 mutants promote GBM malignancy, possibly by acting as transcription factors on a set of genes other than those regulated by wild type p53. Their expression correlates with worse prognosis, highlighting their potential importance as markers and targets for GBM therapy. Understanding mutant p53 functions led to the development of novel approaches to restore p53 activity or promote mutant p53 degradation for future GBM therapies.