Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma.

We performed multi-omic profiling of epidermal keratinocytes, precancerous actinic keratoses, and squamous cell carcinomas to understand the molecular transitions during skin carcinogenesis. Single-cell mutational analyses showed that most keratinocytes in normal skin had lower mutation burdens than melanocytes and fibroblasts, however keratinocytes with TP53 or NOTCH1 mutations had substantially higher mutation burdens, suggesting that these mutations prime keratinocytes for transformation by increasing their mutation rate. Mutational profiling and spatial transcriptomics on squamous cell carcinomas adjacent to actinic keratoses revealed TERT promoter and CDKN2A mutations emerging in actinic keratoses, whereas additional mutations inactivating ARID2 and activating the MAPK-pathway delineated the transition to squamous cell carcinomas. Spatial variation in gene expression patterns was common in both tumor and immune cells, with high expression of checkpoint molecules at the invasive front of tumors. In conclusion, this study documents key events during the evolution of cutaneous squamous cell carcinoma.

Establishing Consensus for Mohs Micrographic Surgical Techniques in the Treatment of Melanoma in Situ for Future Clinical Trials: A Modified Delphi Study.

BACKGROUND: Mohs micrographic surgery (MMS) is a promising treatment modality for melanoma in situ (MIS). However, variations in surgical technique limit the generalizability of existing data and may impede future study of MMS in clinical trials. METHODS: A modified Delphi method was selected to establish consensus on optimal MMS techniques for treating MIS in future clinical trials. The Delphi method was selected due to the limited current data, the wide range of techniques used in the field, and the intention to establish a standardized technique for future clinical trials. A literature review and interviews with experienced MMS surgeons were performed to identify dimensions of the MMS technique for MIS that (1) likely impacted costs or outcomes of the procedure, and (2) showed significant variability between surgeons. A total of 8 dimensions of technical variation were selected. The Delphi process consisted of 2 rounds of voting and commentary, during which 44 expert Mohs surgeons across the United States rated their agreement with specific recommendations using a Likert scale. RESULTS: Five of eight recommendations achieved consensus in Round 1. All 3 of the remaining recommendations achieved consensus in Round 2. Techniques achieving consensus in Round 1 included the use of a starting peripheral margin of ≤5 mm, application of immunohistochemistry, frozen tissue processing, and resecting to the depth of subcutaneous fat. Consensus on the use of Wood's lamp, dermatoscope, and negative tissue controls was established in Round 2. CONCLUSIONS: This study generated 8 consensus recommendations intended to offer guidance for Mohs surgeons treating MIS. The adoption of these recommendations will promote standardization to facilitate comparisons of aggregate data in multicenter clinical trials.

Surgical Procedural Definitions for Hidradenitis Suppurativa Developed by Expert Delphi Consensus.

Importance: Various surgical approaches for hidradenitis suppurativa (HS) have been described in the literature, but the nomenclature is inconsistent. Excisions have been described as wide, local, radical, and regional with variable descriptions of margins. Deroofing procedures have been described with various approaches though descriptions of the approach are generally more uniform. No international consensus has been formed to globally standardize terminology for HS surgical procedures. Lack of such agreement may contribute to misunderstanding or misclassification in HS procedural research studies and impair clear communication among clinicians or between clinicians and patients. Objective: To create a set of standard definitions for HS surgical procedures. Design, Setting, and Participants: This consensus agreement study was conducted from January to May 2021 using the modified Delphi consensus method to reach agreement among a group of international HS experts regarding standardized definitions for an initial set of HS surgical terms, including "incision and drainage," "deroofing/unroofing," "excision," "lesional excision," and "regional excision," ultimately expanded to 10 terms. Provisional definitions were drafted based on existing literature and discussion among an expert 8-member steering committee. Online surveys were disseminated to members of the HS Foundation, direct contacts of the expert panel, and the HSPlace listserv to reach physicians with considerable experience with HS surgery. Consensus was defined as greater than 70% agreement to accept a definition. Results: In the first and second modified Delphi round, 50 and 33 experts participated, respectively. Ten surgical procedural terms and definitions reached consensus with greater than 80% agreement. Overall, the term "local" excision was abandoned and replaced with the descriptors "lesional" or "regional" excision. Of note, "regional" replaced the terms "wide" and "radical" excision. Furthermore, modifiers such as "partial" vs "complete" should also be included when describing surgical procedures. A combination of these terms helped formulate the final glossary of HS surgical procedural definitions. Conclusion and Relevance: An international group of HS experts agreed on a set of definitions describing surgical procedures frequently used by clinicians and in the literature. The standardization and application of such definitions are vital to allow for accurate communication, reporting consistency, and uniform data collection and study design in the future.

Long-Term Appearance-Related Outcomes of Facial Reconstruction After Skin Cancer Resection.

Background: Aesthetic outcomes of facial reconstruction after skin cancer resection (RSCR) may affect long-term quality of life. Objective: To evaluate postoperative patient perceptions of skin cancer defect reconstruction using patient-reported outcome measures. Methods: Patients who underwent RSCR from 2016 to 2021 completed validated FACE-Q scales, including Satisfaction with Facial Appearance (SFA), Scar Appearance, and Appearance-Related Distress (ARD). Scores were scaled 0-100 and compared. Results: Sixty-one respondents completed the survey at a median of 3.0 (interquartile range: 1.6-4.1) years post-treatment. The majority had basal cell carcinomas (n = 41, 67%) and nasal defects (n = 40, 66%). Patients who received either revision surgery or office-based procedures to improve scarring reported lower satisfaction with scar appearance (65.8 ± 31.8 vs. 80.1 ± 20.8, p = 0.048). Dissatisfaction with scar appearance was correlated with decreased SFA (mean score: 76.6 ± 24.5; r = 0.44, p = 0.0004) and greater ARD (mean score: 23.8 ± 24.3; r = -0.66, p < 0.0001). Younger patients were also more likely to experience ARD (ß = -0.54, 95% confidence interval: [-0.96, -0.12, p = 0.014). SFA and ARD did not differ by operative factors, including reconstruction type, or single- versus multistage reconstruction. Conclusion: Although overall SFA after RSCR is high, regardless of reconstruction type, decreased satisfaction is correlated to poorer psychosocial function. Younger patients and those requiring revision procedures may be at greatest risk.

Skin Color Match in Head and Neck Reconstructive Surgery.

OBJECTIVES/HYPOTHESIS: To quantify the degree of color match achieved during microvascular facial reconstruction, and to describe a novel technique for improving reconstructive skin color match. We hypothesize that split-thickness skin grafts (STSG) placed atop de-epithelialized free tissue produces better facial skin color match than free tissue with intact epithelium. STUDY DESIGN: Cross sectional photographic study of reconstructed facial skin color match. METHODS: Sixty-eight adults, who underwent head and neck reconstructive surgery, were divided into six categories based on cutaneous reconstructive technique: cervicofacial flap, radial forearm free flap (RFFF), fibula free flap, anterolateral thigh free flap (ALT), STSG over adiopofascial flap (STAFF), and STSG over myogenous flap (STMF). Averaged color samplings of the reconstructed defect and adjacent normal skin were taken from digital photographs. The color difference was calculated using the delta-E calculation. Blinded expert observers also rated the degree of color match. Nonparametric cohort contrast and correlation statistical analyses were performed. RESULTS: The mean delta-E's and 10-point Likert ratings for the ALT, fibula, RFFF, STAFF, STMF, and cervicofacial flaps were 11.6, 10.0, 7.7, 6.3, 8.8, and 4.7, and 5.1, 6.4, 2.4, 3.2, 2.7, and 1.1, respectively. Likert scale inter-rater correlation was strong, with coefficient = 0.80. CONCLUSIONS: On average, STSG over de-epithelialized myogenous and adipofascial free tissue transfers produced a better color match than the skin paddles of donor sites, with the exception of the radial forearm donor site. Delta-E values obtained from photos correlated well with expert ratings of color match. This reliable technique for quantifying color match may be used in future studies. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1753-1759, 2022.

Office-Based Surgical Intervention for Hidradenitis Suppurativa (HS): A Focused Review for Dermatologists.

Easily accessible office-based procedures that require minimal resources may facilitate timely surgical management of hidradenitis suppurativa (HS). This review focuses on excision and unroofing as two surgical HS treatments that can be tailored to the outpatient setting. Fifty-five articles were included in our review, representing 3914 patients. The majority were retrospective studies (58%, n = 32), and the studies reported data both across patients and by number of treated lesions. Recurrence rates for unroofing (14.5%) were found to be half that of excision (30%) across patients (p = 0.015) and slightly lower across lesions [20% recurrence vs 26% for excision (p = 0.023)]. Complication rates at the lesion level were also significantly associated with procedure, with rates after excision more than double those after roofing (26% vs. 12%, p < 0.001). The complication rate after combined medical and surgical therapy did not differ between procedures. Studies also suggest that continuing medical therapy in the perioperative period may be associated with improved recurrence rates, although delayed wound healing with biologic therapy has been reported. The existing data are limited by low-quality uncontrolled studies with small sample sizes, variable reporting of outcomes, and lack of uniform definitions for recurrence and remission. Further systematic prospective studies are needed to better compare complication and recurrence rates across these procedures in HS, especially in the context of concomitant medical therapy.

An expert panel consensus on opioid-prescribing guidelines for dermatologic procedures.

BACKGROUND: Opioid overprescribing is a major contributor to the opioid crisis. The lack of procedure-specific guidelines contributes to the vast differences in prescribing practices. OBJECTIVE: To create opioid-prescribing consensus guidelines for common dermatologic procedures. METHODS: We used a 4-step modified Delphi method to conduct a systematic discussion among a panel of dermatologists in the fields of general dermatology, dermatologic surgery, and cosmetics/phlebology to develop opioid prescribing guidelines for some of the most common dermatologic procedural scenarios. Guidelines were developed for opioid-naive patients undergoing routine procedures. Opioid tablets were defined as oxycodone 5-mg oral equivalents. RESULTS: Postoperative pain after most uncomplicated procedures (76%) can be adequately managed with acetaminophen and/or ibuprofen. Group consensus identified no specific dermatologic scenario that routinely requires more than 15 oxycodone 5-mg oral equivalents to manage postoperative pain. Group consensus found that 23% of the procedural scenarios routinely require 1 to 10 opioid tablets, and only 1 routinely requires 1 to 15 opioid tablets. LIMITATIONS: These recommendations are based on expert consensus in lieu of quality evidence-based outcomes research. These recommendations must be individualized to accommodate patients' comorbidities. CONCLUSIONS: Procedure-specific opioid prescribing guidelines may serve as a foundation to produce effective and responsible postoperative pain management strategies after dermatologic interventions.

Cutaneous fibrolipomatous hamartoma: Report of 2 cases with retrocalcaneal location.

Precalcaneal congenital fibrolipomatous hamartoma is an underreported benign entity that has been described in the literature under different names. We present two cases of unilateral fibrolipomatous hamartoma (FLH) appearing in a unique location: on the posterior aspect of the foot overlying the heel. We propose the term "FLH of the skin" as a more inclusive and less confusing term for this condition, thus allowing distinction with FLH arising from neural tissue. High-frequency ultrasonography appears to be a useful diagnostic tool that may avoid unnecessary biopsies for this condition.

p16, Cyclin D1, and HIF-1α Predict Outcomes of Patients with Oropharyngeal Squamous Cell Carcinoma Treated with Definitive Intensity-Modulated Radiation Therapy.

We evaluated a panel of 8 immunohistochemical biomarkers as predictors of clinical response to definitive intensity-modulated radiotherapy in patients with oropharyngeal squamous cell carcinoma (OPSCC). 106 patients with OPSCC were treated to a total dose of 66-70 Gy and retrospectively analyzed for locoregional control (LRC), disease-free survival (DFS), and overall survival (OS). All tumors had p16 immunohistochemical staining, and 101 tumors also had epidermal growth factor receptor (EGFR) staining. 53% of the patients had sufficient archived pathologic specimens for incorporation into a tissue microarray for immunohistochemical analysis for cyclophilin B, cyclin D1, p21, hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase, and major vault protein. Median followup was 27.2 months. 66% of the tumors were p16 positive, and 34% were p16 negative. On univariate analysis, the following correlations were statistically significant: p16 positive staining with higher LRC (P = 0.005) and longer DFS (P < 0.001); cyclin D1 positive staining with lower LRC (P = 0.033) and shorter DFS (P = 0.002); HIF-1α positive staining with shorter DFS (P = 0.039). On multivariate analysis, p16 was the only significant independent predictor of DFS (P = 0.023). After immunohistochemical examination of a panel of 8 biomarkers, our study could only verify p16 as an independent prognostic factor in OPSCC.

p16 not a prognostic marker for hypopharyngeal squamous cell carcinoma.

OBJECTIVE: To investigate the prognostic significance of p16 in patients with hypopharyngeal squamous cell carcinoma (HPSCC) and to evaluate the relationship between p16 and human papillomavirus (HPV). Unlike in oropharyngeal SCC (OPSCC), the prognostic significance of p16 in HPSCC and its association with HPV is unclear. DESIGN: Retrospective medical chart review. SETTING: University tertiary referral center. PATIENTS: A total of 27 patients with HPSCC treated with definitive radiation therapy between 2002 and 2011 whose tissue was available for immunohistochemical analysis. INTERVENTIONS: Twenty-two patients were treated with chemoradiation, and 5 with radiation alone. All tumor biopsy specimens were analyzed for p16 and, when sufficient tissue was available, for HPV DNA. MAIN OUTCOME MEASURES: Overall survival (OS), locoregional control (LRC), disease-free survival (DFS), and laryngoesophageal dysfunction-free survival (LEDFS) were analyzed according to p16 status. RESULTS: Findings for p16 were positive in 9 tumors and negative in 18 tumors. Median follow-up was 29.3 months. There was no significant difference in OS, LRC, DFS, or LEDFS for patients with p16-positive vs p16-negative tumors. Only 1 of the 19 tumors tested for HPV was found to be HPV positive. When used as a test for HPV, p16 had a positive predictive value of 17%. CONCLUSIONS: In contrast to OPSCC, p16 expression in patients with HPSCC had a low positive predictive value for HPV and did not predict improved OS, LRC, DFS, or LEDFS. Thus, for HPSCC, p16 is not a prognostic biomarker. Caution must be taken when extrapolating the prognostic significance of p16 in patients with OPSCC to patients with head and neck SCC of other subsites.

Validation of the insomnia severity index as a web-based measure.

Although the Insomnia Severity Index (ISI) is already administered online, this frequently used instrument has not been validated for Web delivery. This study compares online and paper-and-pencil ISI versions completed by participants in a randomized controlled trial testing an Internet-delivered intervention for insomnia. Forty-three adults with insomnia completed both ISI versions during pre- (Assessment 1) and post-intervention (Assessment 2). Correlations between total scores of both versions were significant (rs ≥ .98, ps < .001). For both ISI versions, internal consistency was acceptable (Assessment 1, α = .61; Assessment 2, α ≥ .88). Among participants not receiving the parent study intervention, correlations between 1 format at Assessment 1 and the alternative format at Assessment 2 were generally significant (rs = .26-.82). Together, findings suggest the ISI can be delivered online.

Outcomes of patients with head-and-neck cancer of unknown primary origin treated with intensity-modulated radiotherapy.

PURPOSE: To analyze survival, failure patterns, and toxicity in patients with head-and-neck carcinoma of unknown primary origin (HNCUP) treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Records from 27 patients with HNCUP treated during the period 2002-2008 with IMRT were reviewed retrospectively. Nodal staging ranged from N1 to N3. The mean preoperative dose to gross or suspected disease, Waldeyer's ring, and uninvolved bilateral cervical nodes was 59.4, 53.5, and 51.0 Gy, respectively. Sixteen patients underwent neck dissection after radiation and 4 patients before radiation. Eight patients with advanced nodal disease (N2b-c, N3) or extracapsular extension received chemotherapy. RESULTS: With a median follow-up of 41.9 months (range, 25.3-93.9 months) for non deceased patients, the 5-year actuarial overall survival, disease-free survival, and nodal control rates were 70.9%, 85.2%, and 88.5%, respectively. Actuarial disease-free survival rates for N1, N2, and N3 disease were 100%, 94.1%, and 50.0%, respectively, at 5 years. When stratified by non advanced (N1, N2a nodal disease without extracapsular spread) vs. advanced nodal disease (N2b, N2c, N3), the 5-year actuarial disease-free survival rate for the non advanced nodal disease group was 100%, whereas for the advanced nodal disease group it was significantly lower at 66.7% (p = 0.017). Three nodal recurrences were observed: in 1 patient with bulky N2b disease and 2 in patients with N3 disease. No nodal failures occurred in patients with N1 or N2a disease who received only radiation and surgery. CONCLUSION: Definitive IMRT to 50-56 Gy followed by neck dissection results in excellent nodal control and overall and disease-free survival, with acceptable toxicity for patients with T0N1 or non bulky T0N2a disease without extracapsular spread. Patients with extracapsular spread, advanced N2 disease, or N3 disease may benefit from concurrent chemotherapy, targeted therapeutic agents, or accelerated radiation regimens in addition to surgery.

Heavy drinking on college campuses: no reason to change minimum legal drinking age of 21.

The recent Amethyst Initiative argues that a minimum legal drinking age (MLDA) of 21 has created a culture of heavy alcohol use on college campuses by making drinking clandestine and extreme. This group and others argue that lowering the MLDA will reduce the problem of "binge drinking" on college campuses. However, such a policy change would remove one of the most researched and supported policies in the nation's alcohol control arsenal. There is little evidence that other interventions or policies are capable of working on the same broad level as MLDA 21, and there could also be a deleterious ripple effect in related legislation because MLDA 21 works in conjunction with other drinking laws. In addition, historic and international experiences with a lowered MLDA indicate there are serious social and public health consequences. Instead of removing efficacious interventions, we must remain committed to implementing and enforcing evidence-based practices and legislation.