Validation of the 2022 National Comprehensive Cancer Network Risk Stratification for Cutaneous Squamous Cell Carcinoma.

Importance: The 2022 National Comprehensive Cancer Network (NCCN) reclassified cutaneous squamous cell carcinoma (CSCC) into low-, high-, and very high-risk groups to better risk stratify tumors. Mohs micrographic surgery (Mohs) or peripheral and deep en face margin assessment (PDEMA) became preferred surgical modalities for high- and very high-risk tumors. This new risk stratification and the recommendation for Mohs or PDEMA in high- and very high-risk groups have not been validated. Objective: To compare outcomes in very high-, high-, and low-risk NCCN groups of CSCCs and in CSCCs treated with Mohs or PDEMA compared with wide local excision (WLE). Design, Setting, and Participants: This retrospective cohort study of CSCCs was performed in 2 tertiary care academic medical centers. Patients 18 years or older and diagnosed between January 1, 1996, and December 31, 2019, at Brigham and Women's Hospital and Cleveland Clinic Foundation were included. Data were analyzed from October 20, 2021, to March 29, 2023. Exposures: NCCN risk group, Mohs or PDEMA, and WLE. Main Outcomes and Measures: Local recurrence (LR), nodal metastasis (NM), distant metastasis (DM), and disease-specific death (DSD). Results: A total of 10 196 tumors from 8727 patients were stratified by NCCN guidelines into low-, high-, and very high-risk groups (6003 [59.0%] men; mean [SD] age, 72.4 [11.8] years). Compared with the low-risk group, the high- and very high-risk groups demonstrated a greater risk of LR (high-risk subhazard ratio [SHR], 1.99 [95% CI, 1.21-3.27; P = .007]; very high-risk SHR, 12.66 [95% CI, 7.86-20.39; P < .001]), NM (high-risk SHR, 4.26 [95% CI, 1.28-14.23; P = .02]; very high-risk SHR, 62.98 [95% CI, 19.24-206.17; P < .001]), DM (high-risk SHR, 2.2 × 107 [95% CI, 4.7 × 103-1.1 × 1011; P < .001]; very high-risk SHR, 6.3 × 108 [95% CI, 1.4 × 105-2.9 × 1012; P < .001]), and DSD (high-risk SHR, 4.02 [95% CI, 1.18-13.71; P = .03]; very high-risk SHR, 93.87 [95% CI, 29.19-301.85; P < .001]). Adjusted 5-year cumulative incidence was significantly higher in very high- vs high- and low-risk groups for LR (9.4% [95% CI, 9.2%-14.0%] vs 1.5% [95% CI, 1.4%-2.1%] and 0.8% [95% CI, 0.5%-1.2%], respectively), NM (7.3% [95% CI, 6.8%-10.9%] vs 0.5% [95% CI, 0.4%-0.8%] and 0.1% [95% CI, 0.03%-0.3%], respectively), DM (3.9% [95% CI, 2.6%-5.6%] vs 0.1% [95% CI, 0.04%-0.2%] and 0.01% [95% CI, not applicable], respectively), and DSD (10.5% [95% CI, 10.3%-15.4%] vs 0.5% [95% CI, 0.4%-0.8%] and 0.1% [95% CI, 0.04%-0.3%], respectively). Compared with CSCCs treated with WLE, those treated with Mohs or PDEMA had lower risk of LR (SHR, 0.65 [95% CI, 0.46-0.90]; P = .009), DM (SHR, 0.38 [95% CI, 0.18-0.83]; P = .02), and DSD (SHR, 0.55 [95% CI, 0.36-0.84]; P = .006). Conclusions and Relevance: The findings of this cohort study suggest that the NCCN high- and very high-risk groups identify CSCCs at greatest risk for developing poor outcomes. Further, Mohs or PDEMA resulted in lower LR, DM, and DSD compared with WLE.

Do Postoperative Antibiotics Affect Outcomes in Mohs Reconstructive Surgery?

OBJECTIVES/HYPOTHESIS: The prescribing of postoperative antibiotics for patients undergoing Mohs reconstructive surgery has increased in the last decade, while antibiotic resistance has been increasing. We hypothesized that routine prescribing of postoperative antibiotics after Mohs reconstruction does not decrease the risk of surgical site infection. STUDY DESIGN: Retrospective, single-institution cohort study. METHODS: This study assessed patients who underwent Mohs reconstructive surgery from January 1, 2012, to January 29, 2019. The main outcomes assessed included postoperative surgical site infections, partial or full flap/graft necrosis, hematoma, and dehiscence. RESULTS: A total of 900 defects in 800 patients (mean age [range] = 65.3 [21-96], 54.60% female) were identified over the 7-year period. Patient-specific variables reviewed included comorbidities, age, and smoking status. Surgery-specific variables analyzed included defect characteristics, time interval between Mohs micrographic surgery and reconstruction, reconstructive modalities, and use of postoperative antibiotics. All patients received peri-incisional antibiotics. On regression analysis, use of cartilage grafts (odds ratio [OR]: 6.53; 95% CI: 2.1-20.6; P = .001), current smoking status (OR: 6.67; 95% CI: 2.09-21.30; P = .001), full-thickness defects (OR: 1.2; 95% CI: 1.0-3.4; P = .045), and interpolated flap reconstruction (OR: 3.4; 95% CI: 1.0-11.5; P = .049) were associated with an increased risk of postoperative infections. Smoking and cartilage grafting remained significant on bivariable regression modeling. Use of perioperative antibiotics was not associated with a decreased risk of infection (OR: 1.82; 95% CI: 0.23-14.21; P = .568). CONCLUSIONS: We found no association between postoperative infections after Mohs reconstructive surgery and the use of postoperative antibiotics. These data support a more targeted approach to antibiotic prescribing in Mohs reconstructive surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E434-E439, 2021.

Histone deacetylase inhibition induces long-lasting changes in maternal behavior and gene expression in female mice.

In many species, including mice, maternal responsiveness is experience-dependent and permanent, lasting for long periods (months to years). We have shown that after brief exposures to pups, virgin female mice continue to respond maternally toward pups for at least one month. Administration of a histone deacetylase inhibitor (HDACi) reduces the amount of maternal experience required to affect maternal behavior and gene expression. In this set of studies, we examined the epigenetic mechanisms that underlie these motivated behaviors. We assessed whether the effects of HDACi persisted 1 month after the initial experience (in the absence of continued pup experience or HDACi treatment) and whether the maintenance of maternal memory was associated with stable changes in gene expression. Using chromatin immunoprecipitation, we examined whether Esr2 and Oxt gene expression might be mediated by recruitment of the histone acetyltransferase cAMP response element binding protein (CBP) to their promoter regions after maternal memory consolidation. We report that HDACi treatment induced long-lasting changes in maternal responsiveness. Maternal learning was associated with increased recruitment of CBP to the Esr2 and Oxt gene promoters during the consolidation of maternal memory as well as a persistent increase in estrogen receptor-ß (Esr2) mRNA and decreased expression of the de novo DNA methyltransferase Dnmt3a within the medial preoptic area. The consolidation of the maternal experience may involve the CBP recruitment and stable changes in gene expression, which maintain increased maternal responsiveness for long periods of time.

Experience-facilitated improvements in pup retrieval; evidence for an epigenetic effect.

The quality and quantity of maternal care received during infancy are highly predictive of successful infant development. It has been well established, primarily in rats, that the combination of hormonal and infant stimuli at birth modifies neural circuits that regulate maternal responsiveness. During subsequent interactions, infant stimuli are more likely to elicit rapid maternal responsiveness. Some species, such as humans, can display maternal care in the absence of the endocrine events of pregnancy and birth. Similarly, virgin C57BL/6J female mice, display maternal care toward infants, and experience with infants elicits long-lasting increases in maternal care. We hypothesized that these experience-induced changes in behavior may be mediated by chromatin modifications, which in turn change expression of genes that promote maternal care. One site of action is the medial preoptic area (MPOA). To test our hypothesis we treated virgin female mice with sodium butyrate, a histone deacetylase inhibitor. This treatment potentiated maternal responsiveness as well as the expression of several genes: estrogen receptor ß (Esr2), oxytocin (Oxt), and cyclicAMP response element binding protein (CREB) binding protein (Crebbp; a histone acetyltransferase) in the MPOA. These data suggest that experience induces high levels of maternal care via epigenetic modifications.