Rarely Seen Compartment Syndrome of the Shoulder and Back: Diagnosis and Management.

Compartment syndrome (CS) is a well-known surgical emergency with high morbidity including potential long-term disability and limb loss. The most important factor determining the degree of morbidity with CS is time to treatment; therefore, early diagnosis and surgery are vital. We present a patient who fell off his bicycle and sustained cervical spine fractures causing near complete quadriplegia. He was found by the road over 12 hours later, so his creatine phosphokinase (CPK) was trended and serial examinations were performed. We identified tight deltoid, trapezius, and latissimus compartments and brought him to the operating room for fasciotomies. Although lab values and compartment pressures can be helpful, they should not guide treatment. It is important to consider atypical sites for CS and complete a head to toe physical examination. Patients should proceed to the operating room if clinical suspicion exists for CS because of the morbidity associated with a missed diagnosis.

Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages.

Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2-/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity.

Techniques in Nipple Areolar Reconstruction: A Retrospective Analysis of Surgical Interventions and Patient-reported Satisfaction Scores.

Background: Nipple areolar complex (NAC) reconstruction often signifies completion of the breast reconstruction process for some patients and has been shown to improve both psychosocial and sexual well-being. Several techniques have been described; however, there currently exists little evidence in the literature describing outcomes or patient satisfaction. Methods: A retrospective analysis of NAC reconstructions over the last decade was queried for patient demographics, operative technique, and postoperative outcomes. A standardized, validated survey was also utilized to evaluate overall satisfaction, with a focus on aesthetic outcome, shape, color, and projection. Results: Eighty-three patients were identified, with 49 (59.0%) completing the survey. The modalities used for reconstruction include the C-V flap (45.7%), the modified skate flap technique (42.2%), and free nipple grafting (FNG, 12.0%). No significant differences in age, BMI, or comorbidities were found among the three types. The most utilized donor site for skate flap reconstruction was the suprapubic area (37.1%). There were also no significant differences in complication rate (C-V 10.5%, FNG 10%, skate 5.7%, P = 0.630) or revision surgery (C-V 2.6%, FNG 0%, skate 5.7%, P = 0.732). The most common complication was nipple necrosis. Adjusting for time to follow-up using multivariate analysis, there was a significant difference in overall patient satisfaction when compared across all three techniques, with the modified skate flap having the highest mean overall satisfaction scores. Conclusions: NAC reconstruction can be completed safely and effectively with a variety of techniques. The modified skate flap technique was associated with high levels of patient satisfaction and a low complication rate.

Lifetime Exposure to Cigarette Smoke, B Cell Tumor Immune Infiltration, and Immunoglobulin Abundance in Ovarian Tumors.

BACKGROUND: Cigarette smoke exposure has been linked to systemic immune dysfunction, including for B cell and immunoglobulin (Ig) production, and poor outcomes in ovarian cancer patients. No study has evaluated the impact of smoke exposure across the lifecourse on B cell infiltration and Ig abundance in ovarian tumors. METHODS: We measured markers of B and plasma cells and Ig isotypes using multiplex immunofluorescence on 395 ovarian cancer tumors in the Nurses' Health Study (NHS)/NHSII. We conducted beta-binomial analyses evaluating odds ratios (OR) and 95% confidence intervals (CI) for positivity of immune markers by cigarette exposure among cases and Cox proportional hazards models to evaluate hazard ratios (HR) and 95%CI for developing tumors with low (

Sternal fixation for traumatic sternal fractures demonstrates better long-term quality of life outcomes than nonoperative management: A survey analysis.

INTRODUCTION: Sternal fractures are rare, causing significant pain, respiratory compromise, and decreased upper extremity range of motion. Sternal fixation (SF) is a viable treatment option; however, there remains a paucity of literature demonstrating long-term benefits. This study examined long-term outcomes of SF, hypothesizing they have better long-term quality of life (QoL) than patients managed nonoperatively (NOM). METHODS: This was a survey study at our level 1 academic hospital. All patients diagnosed with a sternal fracture were included from January 2016 to July 2021. Patients were grouped whether they received SF or NOM. Basic demographics were obtained. Three survey phone call attempts were conducted. The time from injury to survey was recorded. Outcomes included responses to the QoL survey, which included mobility, self-care, usual activities, chest pain/discomfort, and anxiety/depression. The survey scale is 1-5 (1 = worst condition possible; 5 = best possible condition). Patients were asked to rate their current health on a scale of 0-100 (100 being the best possible health imaginable). Chi square and t-tests were used. Significance was set at p < 0.05. RESULTS: Three hundred eighty four patients were surveyed. Sixty nine underwent SF and 315 were NOM. Thirty-eight (55.1%) SF patients and 126 (40%) NOM patients participated in the survey. Basic demographics were similar. Average days from sternal fracture to survey was 1198 (±492) for the SF group and 1454 (±567) for the NOM group. The SF cohort demonstrated statistically significant better QoL than the NOM cohort for all categories except anxiety/depression. CONCLUSION: SF provides better long-term QoL and better overall health scores compared to NOM.

Patient Experience of Women With Dense Breasts Undergoing Screening Contrast-Enhanced Mammography.

OBJECTIVE: We investigated patient experience with screening contrast-enhanced mammography (CEM) to determine whether a general population of women with dense breasts would accept CEM in a screening setting. METHODS: In this institutional review board-approved prospective study, patients with heterogeneous and extremely dense breasts on their mammogram were invited to undergo screening CEM and complete pre-CEM and post-CEM surveys. On the pre-CEM survey, patients were asked about their attitudes regarding supplemental screening in general. On the post-CEM survey, patients were asked about their experience undergoing screening CEM, including causes and severity of any discomfort and whether they would consider undergoing screening CEM again in the future or recommend it to a friend. RESULTS: One hundred sixty-three women were surveyed before and after screening CEM. Most patients, 97.5% (159/163), reported minimal or no unpleasantness associated with undergoing screening CEM. In addition, 91.4% (149/163) said they would probably or very likely undergo screening CEM in the future if it cost the same as a traditional screening mammogram, and 95.1% (155/163) said they would probably or very likely recommend screening CEM to a friend. Patients in this study, who were all willing to undergo CEM, more frequently reported a family history of breast cancer than a comparison cohort of women with dense breasts (58.2% vs 47.1%, P = .027). CONCLUSION: Patients from a general population of women with dense breasts reported a positive experience undergoing screening CEM, suggesting screening CEM might be well received by this patient population, particularly if the cost was comparable with traditional screening mammography.

Pneumopericardium following severe thoracic trauma.

BACKGROUND: Traumatic pneumopericardium (PPC) is a rare clinical entity associated with chest trauma, resulting from a pleuropericardial connection in the presence of a pneumothorax, interstitial air tracking along the pulmonary perivascular sheaths from ruptured alveoli to the pericardium, or direct trachea-bronchial-pericardial communication.  Our objectives were to describe the modern management approach to PPC and to identify variables that could improve survival with severe thoracic injury. METHODS: We conducted a retrospective study of the trauma registry between 2015 and 2022 at a Level I verified adult trauma center for all patients with PPC. Demographics, injury patterns, and treatment characteristics were compared between blunt and penetrating trauma. This study focused on the management strategies and the physiologic status regarding PPC and the development of tension physiology. The main outcome measure was operative versus nonoperative management. RESULTS: Over a seven-year period, there were 46,389 trauma admissions, of which 488 patients had pneumomediastinum. Eighteen patients were identified with PPC at admission. Median age was 39.5 years (range, 18-77 years), predominantly male (n = 16, 89 %), Black (n = 12, 67 %), and the majority from blunt trauma (78 %). Half had subcutaneous emphysema on presentation while 39 % had recognizable pneumomediastinum on chest x-ray. Tube thoracostomy was the most common intervention in this cohort (89 %). Despite tube thoracostomy, tension PPC was observed in three patients, two mandating emergent pericardial windows for progression to tension physiology, and the remaining requiring reconstruction of a blunt tracheal disruption. The majority of PPC patients recovered with expectant management (83 %), and no deaths were directly related to PPC. CONCLUSIONS: Traumatic PPC is a rare radiographic finding with the majority successfully managed conservatively in a monitored ICU setting. These patients often have severe thoracic injury with concomitant injuries requiring thoracostomy alone; however, emergent surgical intervention may be required when PPC progresses to tension physiology to improve overall survival.

WITHDRAWN: Impact of spatial clustering of cytotoxic and tumor infiltrating lymphocytes on overall survival in women with high grade serous ovarian cancer.

The authors have withdrawn their manuscript owing to incorrect handling of multiple measures in the survival analyses. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Partial Resuscitative Endovascular Balloon Occlusion of the Aorta Aids in the Successful Non-Operative Management of a Life-Threatening Penetrating Liver Injury.

In recent years, isolated non-operative management of penetrating liver injuries has become the standard of care for the hemodynamically stable patient. However, when the patient becomes hemodynamically unstable, adjuncts such as resuscitative endovascular balloon occlusion of the aorta (REBOA) deployed in Zone 1 can be used to achieve complete aortic occlusion from the celiac axis down. Unfortunately, hemorrhage control through REBOA comes at the risk of deadly intra-abdominal ischemia. Partial REBOA (pREBOA) introduces the opportunity to make targeted changes in volume and thus titrate the amount of aortic occlusion in real-time to adequately manage hemorrhage while allowing some distal blood flow. This is a novel approach and one which may give providers more time to gain definitive hemorrhage control while minimizing the morbidity of ischemia. Here, we present a case of life-threatening penetrating liver injury that was successfully managed non-operatively with the assistance of p-REBOA.

Multiplex Immunofluorescence Captures Progressive Immune Exhaustion with Advancing Penile Squamous Cell Cancer Stage.

Penile squamous cell carcinoma (PSCC) is a rare and deadly malignancy. Therapeutic advances have been stifled by a poor understanding of disease biology. Specifically, the immune microenvironment is an underexplored component in PSCC and the activity of immune checkpoint inhibitors observed in a subset of patients suggests immune escape may play an important role in tumorigenesis. Herein, we explored for the first time the immune microenvironment of 57 men with PSCC and how it varies with the presence of human papillomavirus (HPV) infection and across tumor stages using multiplex immunofluorescence of key immune cell markers. We observed an increase in the density of immune effector cells in node-negative tumors and a progressive rise in inhibitory immune players such as type 2 macrophages and upregulation of the PD-L1 checkpoint in men with N1 and N2-3 disease. There were no differences in immune cell densities with HPV status.

Breast Imaging Fellowship Virtual Interviews: The Program Director's Perspective.

OBJECTIVE: To evaluate breast imaging fellowship program directors' perspectives on the virtual interview process. METHODS: A 20-question survey constructed by members of the Fellowship Match Committee of the Society of Breast Imaging was distributed to all 99 breast imaging program directors registered with the Society. An initial e-mail with a link to the survey was distributed on September 9, 2022, and the survey was closed on October 1, 2022. Results were compiled and a descriptive statistical analysis was performed utilizing Microsoft Excel. RESULTS: There were 63 total responses (63/99, 64% response rate). There was a wide distribution in both the number of applications received and the number of interviews each program offered. Just under a fifth (12/63, 19%) of programs received 1 to 5 applications, whereas a quarter (16/63, 25%) received over 40 applications. In contrast, over a quarter (17/63, 27%) of programs interviewed 1 to 5 applicants, and only a small number (3/63, 5%) interviewed over 40 applicants. When reporting what worked best with the virtual interview process, the responses fell into the following 4 categories: efficiency, flexibility, virtual format, or other. When reporting what did not work well, the most common response (14/37, 38%) was conveying the atmosphere of the program in the virtual setting. CONCLUSION: This study provides an assessment of the virtual interview experience from the perspective of breast imaging fellowship programs, which may be useful in optimizing future interview experiences for programs and applicants.

Lower Extremity Vascular Injury in the Pediatric Trauma Patient: Management and Outcomes at an Adult Level I Trauma Center.

BACKGROUND: Traumatic vascular injuries of the lower extremity in the pediatric population are uncommon but can result in significant morbidity. The objective of this study is to demonstrate our experience with these injuries by describing patterns of traumatic vascular injury, the initial management, and data regarding early outcomes. METHODS: In total, 506 patients presented with lower extremity vascular injury between January 1, 2009 and January 1, 2021 to Grady Memorial Hospital, an urban, adult Level I trauma center in Atlanta, Georgia. Thirty-two of the 506 patients were aged less than 18 years and were evaluated for a total of 47 lower extremity vascular injuries. To fully elucidate the injury patterns and clinical course in this population, we examined patient demographics, mechanism of injury, type of vessel injured, surgical repair performed, and early outcomes and complications. RESULTS: The median (interquartile range) age was 16 (2) years (range, 3-17 years), and the majority were male (n = 29, 90.6%). Of the vascular injuries identified, 28 were arterial and 19 were venous. Of these injuries, 14 patients had combined arterial-venous injuries. The majority of injuries were the result of a penetrating injury (n = 28, 87.5%), and of these, all but 2 were attributed to gunshot wounds. Twenty-seven vascular interventions were performed by nonpediatric surgeons: 11 by trauma surgeons, 13 by vascular surgeons, 2 by orthopedic surgeons, and 1 by an interventional radiologist. Two patients required amputation: 1 during the index admission and 1 delayed at 3 months. Overall survival was 96.9%. CONCLUSIONS: Vascular injuries as the result of trauma at any age often require early intervention, and we believe that these injuries in the pediatric population can be safely managed in adult trauma centers with a multidisciplinary team composed of trauma, vascular, and orthopedic surgeons with the potential to decrease associated morbidity and mortality from these injuries.

TiME OUT: Time-specific machine-learning evaluation to optimize ultramassive transfusion.

BACKGROUND: Ultramassive transfusion (UMT) is a resource-demanding intervention for trauma patients in hemorrhagic shock, and associated mortality rates remains high. Current research has been unable to identify a transfusion ceiling or point where UMT transitions from lifesaving to futility. Furthermore, little consideration has been given to how time-specific patient data points impact decisions with ongoing high-volume resuscitation. Therefore, this study sought to use time-specific machine learning modeling to predict mortality and identify parameters associated with survivability in trauma patients undergoing UMT. METHODS: A retrospective review was conducted at a Level I trauma (2018-2021) and included trauma patients meeting criteria for UMT, defined as ≥20 red blood cell products within 24 hours of admission. Cross-sectional data were obtained from the blood bank and trauma registries, and time-specific data were obtained from the electronic medical record. Time-specific decision-tree models predicating mortality were generated and evaluated using area under the curve. RESULTS: In the 180 patients included, mortality rate was 40.5% at 48 hours and 52.2% overall. The deceased received significantly more blood products with a median of 71.5 total units compared with 55.5 in the survivors ( p < 0.001) and significantly greater rates of packed red blood cells and fresh frozen plasma at each time interval. Time-specific decision-tree models predicted mortality with an accuracy as high as 81%. In the early time intervals, hemodynamic stability, undergoing an emergency department thoracotomy, and injury severity were most predictive of survival, while, in the later intervals, markers of adequate resuscitation such as arterial pH and lactate level became more prominent. CONCLUSION: This study supports that the decision of "when to stop" in UMT resuscitation is not based exclusively on the number of units transfused but rather the complex integration of patient and time-specific data. Machine learning is an effective tool to investigate this concept, and further research is needed to refine and validate these time-specific decision-tree models. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Is Traumatic Anterior Stove-In Chest Truly so Rare? A Single Institution Experience.

INTRODUCTION: The anterior stove-in chest (ASIC) is a rare form of flail chest involving bilateral rib or sternal fractures resulting in an unstable chest wall that caves into the thoracic cavity. Given ASIC has only been described in a handful of case reports, this study sought to review our institution's experience in the surgical management of ASIC injuries. METHODS: A retrospective review of patients with ASIC was conducted at our level I trauma center from 1//2021 to 3//2023. Information pertaining to patient demographics, fracture pattern, operative management, and outcomes was obtained and compared across patients in the case series. RESULTS: 6 patients met inclusion criteria, all males aged 37-78 years. 5 suffered motor vehicle collisions, and 1 was a pedestrian struck by an automobile. The median injury severity score was 28. All received ORIF within 5 days of admission, most commonly for ongoing respiratory distress. Patients 2 and 4 underwent bilateral ORIF of the ribs and sternum while patients 1, 5, and 6 underwent left-sided repair. Patient 3 required ORIF of left ribs and the sternum to stabilize their injuries. 5 of 6 patients were liberated from the ventilator and survived to discharge. CONCLUSIONS: This study demonstrates successful operative management of 6 patients with ASIC and suggests that early operative intervention with ORIF for affected segments may improve respiratory mechanics, ability to wean from the ventilator, and overall survival. Further research is needed to generate standardized guidelines for the management of this uncommon and complex thoracic injury.

Rigid Plate Fixation for Closure of Emergent Sternotomies for Trauma.

BACKGROUND: No studies to date have evaluated the use of rigid plate fixation for emergent sternotomy in trauma patients. We evaluated our use of rigid plate fixation vs wire cerclage in patients requiring emergent sternotomy. We hypothesized there would be no difference in complications related to sternal closure between the two groups. METHODS: We performed a retrospective cohort study to include all patients who underwent emergent sternotomy from 1/1/2018 to 1/31/2021 and survived to have their sternum closed. Outcomes in patients closed with wire cerclage group (WC) were compared to patients who underwent rigid plate fixation (RPF). RESULTS: Twenty-two patients underwent emergent sternotomy. There were 11 patients in each group. There was no significant difference in admission demographics, ISS, or admission characteristics between the two groups. Complication rates related to closure (wound infection and hardware removal) were not significantly different (WC 27% vs RPF 9%, P = .58). Neither hospital length of stay (WC: 29 days vs RPF: 13 days, P = .13), ICU length of stay (WC: 6 days vs RPF: 7 days, P = .62), nor the number of ventilator days (WC: 3 days vs RPF: 1 day, P .11) were statistically different. All patients survived to discharge. DISCUSSION: This is the first study comparing RPF and WC for sternotomy closure in the setting of trauma. We found no difference in the rate of wound related complications. This study demonstrates the feasibility of rigid plate fixation for trauma sternotomy closure and lays the foundation for future prospective studies.

Application of the Microbiology Concept Inventory to improve programmatic curriculum.

The Microbiology Concept Inventory is an assessment tool derived from the fundamental statements created by the American Society for Microbiology. This two-tier, multiple-choice question inventory requires students to choose the most correct answer for each question and provide a brief justification of their reasoning. Educators can utilize this tool to identify common misconceptions held by students and adjust curriculum to address and prevent the persistence of student misconceptions. Over the course of 5 years, the Microbiology Concept Inventory was annually administered to undergraduate students enrolled in entry-level, mid-level, and senior capstone microbiology courses at a mid-western rural university. Analysis was completed to compare course, year, majors and minors, gender, ethnicity, and cumulative GPA. Results of this study showed a significant difference in Microbiology Concept Inventory scores between students with high cumulative GPAs (3.5-4.0) and students with comparatively lower cumulative GPAs (2.5-2.99, 3.0-3.49). Results between the other demographic categories revealed statistically different scores in favor of white students, but no differences in scores between genders. The results suggest evidence of ethnic bias, but no gender bias as measured by the Microbiology Concept Inventory. Additionally, significant differences in scores across cohorts are indicative of improvements in the curricula due to prior targeted changes. Analysis of concept inventory results can guide curriculum changes for course instructors. Implementation of curriculum changes can enrich students' academic success.

Increased spatial coupling of integrin and collagen IV in the immunoresistant clear cell renal cell carcinoma tumor microenvironment.

Background: Immunotherapy (IO) has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with IO naïve and IO exposed primary ccRCC tumors to better understand IO resistance. Spatial molecular imaging (SMI) was obtained for tumor and adjacent stroma samples. Spatial gene set enrichment analysis (GSEA) and autocorrelation (coupling with high expression) of ligand-receptor transcript pairs were assessed. Multiplex immunofluorescence (mIF) validation was used for significant autocorrelative findings and the cancer genome atlas (TCGA) and the clinical proteomic tumor analysis consortium (CPTAC) databases were queried to assess bulk RNA expression and proteomic correlates. Results: 21 patient samples underwent SMI. Viable tumors following IO harbored more stromal CD8+ T cells and neutrophils than IO naïve tumors. YES1 was significantly upregulated in IO exposed tumor cells. The epithelial-mesenchymal transition pathway was enriched on spatial GSEA and the associated transcript pair COL4A1-ITGAV had significantly higher autocorrelation in the stroma. Fibroblasts, tumor cells, and endothelium had the relative highest expression. More integrin αV+ cells were seen in IO exposed stroma on mIF validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV. In CPTAC, collagen IV protein was more abundant in advanced stages of disease. Conclusions: On spatial transcriptomics, COL4A1 and ITGAV were more autocorrelated in IO-exposed stroma compared to IO-naïve tumors, with high expression amongst fibroblasts, tumor cells, and endothelium. Integrin represents a potential therapeutic target in IO treated ccRCC.

Use of Kaolin-Impregnated Gauze Aids in Hemostasis and Blood Loss Mitigation in a Penetrating Injury to the Bladder and Small Bowel.

Hemorrhage control can be technically challenging in penetrating injuries to the pelvis. In an era of decreased availability of blood, rapid hemostasis is critical to minimize blood loss, limit transfusions, and control contamination from hollow viscus injuries. QuikClot Control+® 12x12 Hemostatic Device(C+) (Teleflex Medical OEM, Plymouth, MN), a form of kaolin-impregnated gauze, maybe a helpful adjunct to ebb the flow of hemorrhage from large surface area wounds. We present a case in which C+ was utilized in the preperitoneal packing of a gunshot wound to the pelvis and aided in obtaining hemostasis while simultaneously allowing the team time to complete the remainder of the case. Though further large randomized control trials are required to identify the role of C+ in trauma laparotomy, it remains a tool in the surgeon's armamentarium when dealing with hemorrhage.

Throwing Shoulder Range of Motion and Hamstring Flexibility in Adolescent Baseball Players: A Pilot Study.

Overhead throwing athletes with limited hamstring flexibility should be counseled appropriately regarding their risk for shoulder injury. Baseball players should stretch and prepare their bodies to throw to reduce the compensatory mechanisms that may occur from hamstring stiffness. We aim to identify the association between the contralateral hamstring-popliteal angle and throwing shoulder total range of motion (ROM) in high school baseball players. Fifteen high school varsity baseball players (ages 14-18 years old) volunteered for this observational study. All the athletes played five times a week and played different positions. Bilateral hamstring and throwing shoulder total ROMs were measured using a goniometer by the same examiner. Three examiners determined the maximum ROM by joint end feel for each measurement to ensure quality control. Contralateral hamstring flexibility was measured using the popliteal angle test. These measurements were compared to the throwing shoulder total ROM to determine the presence of an association. The relationship between the contralateral hamstring flexibility and throwing shoulder total ROM was determined using a linear regression analysis. The correlation coefficient (r) was +0.3928, indicating a positive linear relationship. We conclude that higher contralateral hamstring-popliteal angles may cause a compensatory increase in throwing shoulder total ROM. We highlight the role hamstring stiffness may play in shoulder injury development in adolescent baseball players.

Development of a MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although cSCC contributes to substantial morbidity and mortality in high-risk individuals, deployment of otherwise effective chemoprevention of cSCC is limited by toxicities. Our systematic computational drug repurposing screen predicted that selumetinib, a MAPK (mitogen-activated protein kinase) kinase inhibitor (MEKi), would reverse transcriptional signatures associated with cSCC development, consistent with our genomic analysis implicating MEK as a chemoprevention target. Although systemic MEKi suppresses the formation of cSCC in mice, systemic MEKi can cause severe adverse effects. Here, we report the development of a metabolically labile MEKi, NFX-179, designed to potently and selectively suppress the MAPK pathway in the skin before rapid metabolism in the systemic circulation. NFX-179 was identified on the basis of its biochemical and cellular potency, selectivity, and rapid metabolism upon systemic absorption. In our ultraviolet-induced cSCC mouse model, topical application of NFX-179 gel reduced the formation of new cSCCs by an average of 60% at doses of 0.1% and greater at 28 days. We further confirmed the localized nature of these effects in an additional split-mouse randomized controlled study where suppression of cSCC was observed only in drug-treated areas. No toxicities were observed. NFX-179 inhibits the growth of human SCC cell lines in a dose-dependent manner, and topical NFX-179 application penetrates human skin and inhibits MAPK signaling in human cSCC explants. Together, our data provide a compelling rationale for using topical MEK inhibition through the application of NFX-179 gel as an effective strategy for cSCC chemoprevention.