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.

Pathologic Upstaging of Cutaneous Melanoma After Mohs Micrographic Surgery.

BACKGROUND: Mohs micrographic surgery (MMS) is used for melanoma in situ (MIS) and thin invasive melanomas, particularly on the head and neck, during which a debulk section is typically prepared. Tumor upstaging occurs if the debulking specimen meets criteria for an increased tumor (T) stage per the American Joint Committee on Cancer 8th edition compared with the initial biopsy. Upstaging can alter survival and recurrence outcomes, resulting in increased patient morbidity and mortality. OBJECTIVE: To determine the rate of cutaneous melanoma upstaging during MMS. MATERIALS AND METHODS: A multicenter study was performed. Information from electronic medical records from 3 dermatologic surgeons performing MMS for cutaneous melanoma were logged from January 1, 2017 to December 31, 2021. Deidentified information regarding patient demographics and tumor characteristics was recorded. RESULTS: Three-hundred and ten cases of cutaneous melanoma treated with MMS were identified. 2.3% of cases were upstaged, ranging from T1a to T3a. No significant risk factors for upstaging were identified. CONCLUSION: Our data demonstrate a lower rate of cutaneous melanoma upstaging during MMS than the current literature. Differences may be accounted for because of differing patient populations, cutaneous melanoma detection at an earlier clinical stage, and evolving melanoma histologic criteria.

An Update and Review of Clinical Outcomes Using Immunohistochemical Stains in Mohs Micrographic Surgery for Melanoma.

BACKGROUND: Mohs micrographic surgery (MMS) provides optimal margin control through complete peripheral and deep margin assessment. The treatment of melanoma using MMS has historically been limited by difficulty in interpreting melanocytes using frozen sections. Immunohistochemical (IHC) staining, a technique whereby chromogen-tagged antibodies are used to detect antigens of interest, has revolutionized the surgical treatment of melanoma. OBJECTIVES: This article provides an update and literature review of current IHC stains used in MMS for melanoma, their sensitivities and specificities, and clinical outcomes. MATERIALS AND METHODS: A PubMed search was performed using keywords including "immunohistochemistry," "staining," and "Mohs surgery." Articles related to the use of IHC staining for the treatment of melanoma with MMS were included. RESULTS: Six IHC stains met the criteria for the review including melanoma antigen recognized by T cells (MART-1), SRY-related HMG-box (SOX10), microphthalmia-associated transcription factor, HMB-45, MEL-5, S-100, and preferentially expressed antigen in melanoma. CONCLUSION: The adaptation of IHC methods to frozen sections has enabled MMS to become a preferred treatment option for melanoma in special-site areas. Future studies are needed to standardize IHC techniques and to define best practices when using frozen section in the treatment of melanoma.

CAPABLE: A Scoring System Utilizing Patient-Reported Measures to Evaluate Patient Experience After Mohs Surgery.

BACKGROUND: Patient experience metrics are gaining prominence in health care. We introduce the CAPABLE survey to assess postoperative experiences of Mohs surgery patients. OBJECTIVE: We sought to determine whether CAPABLE scores aligned with overall patient satisfaction in Mohs surgery. METHODS: This was a cross-sectional, survey-based study of patients presenting for their first postoperative visit after Mohs surgery. The CAPABLE survey included questions on postoperative instructions, activity limitations, pain control, provider accessibility, and bleeding, followed by 2 overall satisfaction questions taken from the Outpatient and Ambulatory Surgery Consumer Assessment of Healthcare Providers and Systems survey. The pilot study took place at the University of Texas Dell Medical School (DMS), followed by a validation study ( n = 206) at DMS and Oregon Health and Science University (OHSU). We assessed for correlations between CAPABLE scores and overall satisfaction. RESULTS: In the pilot study ( n = 137), overall CAPABLE scores and scores of individual CAPABLE components correlated positively with overall satisfaction.In the multisite validation study ( n = 206) spanning DMS and OHSU, CAPABLE scores correlated positively with overall satisfaction. CONCLUSION: The CAPABLE survey is a concise tool for assessing specific, actionable components of the postoperative patient experience in Mohs surgery, while correlating with overall patient satisfaction.

NCX1 represents an ionic Na+ sensing mechanism in macrophages.

Inflammation and infection can trigger local tissue Na+ accumulation. This Na+-rich environment boosts proinflammatory activation of monocyte/macrophage-like cells (MΦs) and their antimicrobial activity. Enhanced Na+-driven MΦ function requires the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5), which augments nitric oxide (NO) production and contributes to increased autophagy. However, the mechanism of Na+ sensing in MΦs remained unclear. High extracellular Na+ levels (high salt [HS]) trigger a substantial Na+ influx and Ca2+ loss. Here, we show that the Na+/Ca2+ exchanger 1 (NCX1, also known as solute carrier family 8 member A1 [SLC8A1]) plays a critical role in HS-triggered Na+ influx, concomitant Ca2+ efflux, and subsequent augmented NFAT5 accumulation. Moreover, interfering with NCX1 activity impairs HS-boosted inflammatory signaling, infection-triggered autolysosome formation, and subsequent antibacterial activity. Taken together, this demonstrates that NCX1 is able to sense Na+ and is required for amplifying inflammatory and antimicrobial MΦ responses upon HS exposure. Manipulating NCX1 offers a new strategy to regulate MΦ function.

Permanent section margin concordance after Mohs micrographic surgery with immunohistochemistry for invasive melanoma and melanoma in situ: A retrospective dual-center analysis.

BACKGROUND: Mohs micrographic surgery (MMS) for melanoma practices vary among dermatologic surgeons. The implementation of immunohistochemical staining in MMS for melanoma mitigates challenges associated with slide interpretation; however, the reliability of melanoma antigen recognized by T cells 1 (MART-1), the preferred immunostain for melanoma, has yet to be compared with permanent section pathology. OBJECTIVE: To assess concordance rates of MART-1 frozen sections and permanent section pathologic interpretation of melanoma treated with MMS. METHODS: A dual-center retrospective analysis was conducted to collect concordance and demographic data. Chi-square tests were performed for group comparisons of categorical variables. RESULTS: Of the 379 permanent sections sent, 367 were concordant with frozen section pathology for an overall concordance rate of 96.8%. Cases were stratified into indeterminately concordant and indisputably concordant. Twenty-two (6%) of cases were indeterminately concordant, whereas 345 (94.0%) of cases were indisputably concordant. LIMITATIONS: The concordance rate is derived from a comparison of adjacent tissue margins, an inevitable consequence of utilizing 2 techniques. CONCLUSION: To the author's knowledge, this study represents the largest investigation examining concordance rates of MART-1 frozen sections in Mohs for melanoma. High concordance disputes the ongoing need for additional permanent margins when using MART-1 in routine cases.

Rapid shear stress-dependent ENaC membrane insertion is mediated by the endothelial glycocalyx and the mineralocorticoid receptor.

The contribution of the shear stress-sensitive epithelial Na+ channel (ENaC) to the mechanical properties of the endothelial cell surface under (patho)physiological conditions is unclear. This issue was addressed in in vivo and in vitro models for endothelial dysfunction. Cultured human umbilical vein endothelial cells (HUVEC) were exposed to laminar (LSS) or non-laminar shear stress (NLSS). ENaC membrane insertion was quantified using Quantum-dot-based immunofluorescence staining and the mechanical properties of the cell surface were probed with the Atomic Force Microscope (AFM) in vitro and ex vivo in isolated aortae of C57BL/6 and ApoE/LDLR-/- mice. Flow- and acetylcholine-mediated vasodilation was measured in vivo using magnetic resonance imaging. Acute LSS led to a rapid mineralocorticoid receptor (MR)-dependent membrane insertion of ENaC and subsequent stiffening of the endothelial cortex caused by actin polymerization. Of note, NLSS stress further augmented the cortical stiffness of the cells. These effects strongly depend on the presence of the endothelial glycocalyx (eGC) and could be prevented by functional inhibition of ENaC and MR in vitro endothelial cells and ex vivo endothelial cells derived from C57BL/6, but not ApoE/LDLR-/- vessel. In vivo In C57BL/6 vessels, ENaC- and MR inhibition blunted flow- and acetylcholine-mediated vasodilation, while in the dysfunctional ApoE/LDLR-/- vessels, this effect was absent. In conclusion, under physiological conditions, endothelial ENaC, together with the glycocalyx, was identified as an important shear stress sensor and mediator of endothelium-dependent vasodilation. In contrast, in pathophysiological conditions, ENaC-mediated mechanotransduction and endothelium-dependent vasodilation were lost, contributing to sustained endothelial stiffening and dysfunction.

Factors Influencing General Dermatologists When Referring Patients With Head and Neck Melanoma for Mohs Micrographic Surgery: A Nationwide Cross-Sectional Survey.

BACKGROUND: Mohs micrographic surgery (MMS) for cutaneous melanoma has demonstrated higher cure rates, lower local recurrence rates, and improved survival compared with wide local excision (WLE). However, factors affecting referrals by general dermatologists for MMS of head and neck melanoma (HNM) are unknown. OBJECTIVE: To elucidate referral factors and treatment perspectives of general dermatologists regarding MMS for melanoma in situ (MIS)/lentigo maligna (LM) and early-stage melanoma on the head and neck. MATERIALS AND METHODS: A cross-sectional analysis was performed using survey responses of general dermatologists with membership in the American Academy of Dermatology . RESULTS: A total of 231 and 132 of the 402 responding general dermatologists routinely referred melanoma in situ MIS/LM and early invasive melanoma for MMS, respectively. Lack of local access to a Mohs surgeon was the most common deterring reason for MIS/LM referral to MMS, whereas the preference for WLE was the most common deterring reason for early invasive melanoma. CONCLUSION: Lack of local access to a Mohs surgeon treating HNM with MMS is the primary barrier in referrals to Mohs surgeons for MIS and LM. Among general dermatologists, WLE is preferred for early invasive HNM.

Tranexamic Acid Prevention of Hemorrhagic Complications Following Interpolated Flap Repair: A Single-Center, Retrospective, Cohort Study.

BACKGROUND: Tranexamic acid (TXA) is increasingly being used to prevent hemorrhagic complications after dermatologic surgery. Interpolated flap repairs following Mohs micrographic surgery are at risk for increased bleeding events and unplanned health care utilization, particularly among patients on antithrombotic medication. OBJECTIVE: To assess bleeding events after interpolated flap repair in patients receiving TXA compared with those who did not. MATERIALS AND METHODS: A retrospective review identified interpolated flap repairs in a 5-year period. Hemorrhagic complications were analyzed, defined as major bleeding events, which included all unplanned medical visits, and minor bleeding events, which included any unplanned patient phone calls or messages through electronic medical record. RESULTS: One hundred fifteen patients had interpolated flap repair during the 5-year period, of which 21 (18.3%) received TXA postprocedure. Twenty-seven bleeding events were identified in the non-TXA group compared with 1 event in the TXA-treated group. Patients who received TXA were less likely to have had a bleeding event (28.7% vs 4.8%, p < .01). CONCLUSION: Patients undergoing interpolation flap repair were less likely to experience a bleeding event after subcutaneous injection of TXA.

Postoperative Complications After Interpolated Flap Repair for Mohs Defects of the Nose: A Multicenter Prospective Cohort Study.

BACKGROUND: Dermatologists perform most interpolated flaps after skin cancer resection. Prospective, multicenter data on complications after interpolated flap repair in this setting are limited. OBJECTIVE: To determine the rate of physician-reported complications after interpolated flap repair of the nose. METHODS: Multicenter, prospective cohort study of 169 patients undergoing 2-stage interpolated flap repair of post-Mohs nasal defects. Frequency of bleeding, infection, dehiscence, necrosis, hospitalization, and death in the 30 days after flap placement and flap takedown are reported. RESULTS: Patients experienced 23 complications after flap placement (13.61%) and 6 complications after flap takedown (3.55%) that were related to the surgical procedure. The most frequent complication after flap placement was bleeding (9, 5.33%, 95% confidence interval [CI]: 2.83%-9.82%). The most frequent complication after flap takedown was infection (5, 2.96%, 95% CI: 1.27%-6.74%). There was one hospitalization related to an adverse reaction to antibiotics. There were no deaths. CONCLUSION: Most complications after interpolated flap repair for post-Mohs defects of the nose are minor and are associated with flap placement. Interpolated flap repair for post-Mohs defects can be performed safely in the outpatient setting under local anesthesia.

Refractory focal epithelial hyperplasia successfully treated with novel use of nano-pulse stimulation technology.

Focal epithelial hyperplasia (FEH), or Heck's disease, is an uncommon HPV-related dermatosis that presents with multiple discrete papules or nodules on the lips, tongue, and gingival or oral mucosa. Treatment is often sought due to cosmesis, social stigma, and functional impairment. Treatment is challenging and a variety of treatment modalities have been attempted with varying degrees of success. This report describes the novel use of nano-pulse stimulation in the successful treatment of recalcitrant FEH of the upper and lower vermillion lip.

Systematic review and meta-analysis of local recurrence rates of head and neck cutaneous melanomas after wide local excision, Mohs micrographic surgery, or staged excision.

BACKGROUND: Prospective trials have not compared the local recurrence rates of different excision techniques for cutaneous melanomas on the head and neck. OBJECTIVE: To determine local recurrence rates of cutaneous head and neck melanoma after wide local excision (WLE), Mohs micrographic surgery (MMS), or staged excision. METHODS: A systematic review of PubMed, EMBASE, and Web of Science identified all English case series, cohort studies, and randomized controlled trials that reported local recurrence rates after surgery for cutaneous head and neck melanoma. A meta-analysis utilizing a random effects model calculated weighted local recurrence rates and confidence intervals (CI) for each surgical technique and for subgroups of MMS and staged excision. RESULTS: Among 100 manuscripts with 13,998 head and neck cutaneous melanomas, 51.0% (7138) of melanomas were treated by WLE, 34.5% (4826) by MMS, and 14.5% (2034) by staged excision. Local recurrence rates were lowest for MMS (0.61%; 95% CI, 0.1%-1.4%), followed by staged excision (1.8%; 95% CI, 1.0%-2.9%) and WLE (7.8%; 95% CI, 6.4%-9.3%). LIMITATIONS: Definitions of local recurrence varied. Surgical techniques included varying proportions of invasive melanomas. Studies had heterogeneity. CONCLUSION: Systematic review and meta-analysis show lower local recurrence rates for cutaneous head and neck melanoma after treatment with MMS or staged excision compared to WLE.

Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma.

BACKGROUND: Current staging systems for cutaneous squamous cell carcinoma (cSCC) have limited positive predictive value for identifying patients who will experience metastasis. OBJECTIVE: To develop and validate a gene expression profile (GEP) test for predicting risk for metastasis in localized, high-risk cSCC with the goal of improving risk-directed patient management. METHODS: Archival formalin-fixed paraffin-embedded primary cSCC tissue and clinicopathologic data (n = 586) were collected from 23 independent centers in a prospectively designed study. A GEP signature was developed using a discovery cohort (n = 202) and validated in a separate, nonoverlapping, independent cohort (n = 324). RESULTS: A prognostic 40-GEP test was developed and validated, stratifying patients with high-risk cSCC into classes based on metastasis risk: class 1 (low risk), class 2A (high risk), and class 2B (highest risk). For the validation cohort, 3-year metastasis-free survival rates were 91.4%, 80.6%, and 44.0%, respectively. A positive predictive value of 60% was achieved for the highest-risk group (class 2B), an improvement over staging systems, and negative predictive value, sensitivity, and specificity were comparable to staging systems. LIMITATIONS: Potential understaging of cases could affect metastasis rate accuracy. CONCLUSION: The 40-GEP test is an independent predictor of metastatic risk that can complement current staging systems for patients with high-risk cSCC.

Opioid Prescribing Recommendations After Mohs Micrographic Surgery and Reconstruction: A Delphi Consensus.

BACKGROUND: Prescription opioids play a large role in the opioid epidemic. Even short-term prescriptions provided postoperatively can lead to dependence. OBJECTIVE: To provide opioid prescription recommendations after Mohs micrographic surgery (MMS) and reconstruction. METHODS: This was a multi-institutional Delphi consensus study consisting of a panel of members of the American College of Mohs Surgery from various practice settings. Participants were first asked to describe scenarios in which they prescribe opioids at various frequencies. These scenarios then underwent 2 Delphi ratings rounds that aimed to identify situations in which opioid prescriptions should, or should not, be routinely prescribed. Consensus was set at ≥80% agreement. Prescription recommendations were then distributed to the panelists for feedback and approval. RESULTS: Twenty-three Mohs surgeons participated in the study. There was no scenario in which consensus was met to routinely provide an opioid prescription. However, there were several scenarios in which consensus were met to not routinely prescribe an opioid. CONCLUSION: Opioids should not be routinely prescribed to every patient undergoing MMS. Prescription recommendations for opioids after MMS and reconstruction may decrease the exposure to these drugs and help combat the opioid epidemic.

Systematic Review of Technical Variations for Mohs Micrographic Surgery for Melanoma.

BACKGROUND: Mohs micrographic surgery (MMS) for cutaneous melanoma is becoming more prevalent, but surgical technique varies. OBJECTIVE: To define variations in published techniques for MMS for melanoma. METHODS AND MATERIALS: A systematic review was performed of PubMed, EMBASE, and Scopus databases to identify all articles describing surgical techniques for MMS for melanoma. Technical details were recorded for the preoperative, intraoperative, and postoperative phases of MMS. RESULTS: Twenty-four articles were included. Mohs surgeons vary in how they assess clinical margins, how wide a margin they excise on the first MMS layer, and how they process tissue to determine tumor stage and margin clearance during MMS for melanoma. CONCLUSION: Mohs micrographic surgery for melanoma is performed with varied surgical techniques. To establish best practices, additional research is necessary to determine how different techniques affect outcomes.

Thrombin Inhibition Prevents Endothelial Dysfunction and Reverses 20-HETE Overproduction without Affecting Blood Pressure in Angiotensin II-Induced Hypertension in Mice.

Angiotensin II (Ang II) induces hypertension and endothelial dysfunction, but the involvement of thrombin in these responses is not clear. Here, we assessed the effects of the inhibition of thrombin activity by dabigatran on Ang II-induced hypertension and endothelial dysfunction in mice with a particular focus on NO- and 20-HETE-dependent pathways. As expected, dabigatran administration significantly delayed thrombin generation (CAT assay) in Ang II-treated hypertensive mice, and interestingly, it prevented endothelial dysfunction development, but it did not affect elevated blood pressure nor excessive aortic wall thickening. Dabigatran's effects on endothelial function in Ang II-treated mice were evidenced by improved NO-dependent relaxation in the aorta in response to acetylcholine in vivo (MRI measurements) and increased systemic NO bioavailability (NO2- quantification) with a concomitant increased ex vivo production of endothelium-derived NO (EPR analysis). Dabigatran treatment also contributed to the reduction in the endothelial expression of pro-inflammatory vWF and ICAM-1. Interestingly, the fall in systemic NO bioavailability in Ang II-treated mice was associated with increased 20-HETE concentration in plasma (UPLC-MS/MS analysis), which was normalised by dabigatran treatment. Taking together, the inhibition of thrombin activity in Ang II-induced hypertension in mice improves the NO-dependent function of vascular endothelium and normalises the 20-HETE-depedent pathway without affecting the blood pressure and vascular remodelling.

Invasive Melanoma and Melanoma in Situ Treated With Modified Mohs Micrographic Surgery With En Face Permanent Sectioning: A 10-Year Retrospective Review.

BACKGROUND: Successful surgical treatment of cutaneous melanoma is dependent on margin control. OBJECTIVE: To determine efficacy of modified Mohs micrographic surgery (mMMS) with en face permanent margins in management of invasive melanoma (IM) and melanoma in situ (MIS). METHODS: A retrospective cohort study evaluating local recurrence, 5-year recurrence-free survival, and 5-year melanoma-specific survival. Overall, 657 melanomas (128 IM and 529 MIS) from 631 patients were treated using mMMS during a 10-year period. Follow-up information was obtained from medical records and telephone encounters. RESULTS: The median follow-up time was 5.18 years. Most melanomas were located on the head and neck 93.6% (615/657). Margins required for clearance were 0.77 ± 0.44 cm (mean ± SD). Local recurrence was identified in 1.98% (13/657) of melanomas with no local recurrences in IM. Five-year local recurrence-free and melanoma-specific survival rates were estimated to be 96.9% (95% confidence interval [CI]: 94.6%-98.2%) and 99.0% (95% CI: 97.7%-99.6%). There were 5 melanoma-related deaths. CONCLUSION: Modified Mohs micrographic surgery is an effective treatment of melanoma as evidenced by low local recurrence rates and high melanoma-specific survival.

Using a Multimedia Tool for Informed Consent in Mohs Surgery: A Randomized Trial Measuring Effects on Patient Anxiety, Knowledge, and Satisfaction.

BACKGROUND: Multimedia educational materials have been found to improve aspects of informed consent, although data in the context of Mohs micrographic surgery (MMS) is limited. OBJECTIVE: To assess whether a preoperative educational video decreases anxiety, increases comprehension, and improves overall satisfaction for patients undergoing same-day office consultation and MMS. MATERIALS AND METHODS: This single-center randomized controlled trial included patients above the age of 18 years undergoing MMS for skin cancer between October 2015 and December 2015. Patients were randomized to view a short preoperative video on MMS in addition to traditional informed consent versus informed consent without video viewing. Questionnaires were used to assess preoperative anxiety, knowledge, and satisfaction. RESULTS: From 231 consecutively enrolled subjects, there were no significant differences in anxiety (p = .626) or satisfaction (p = .065) between groups. Subjects receiving the intervention were able to more accurately recognize risks of MMS (88% vs 69% of controls, p < .001) and had improved subject-reported confidence in understanding procedural risks and benefits (89% vs 71% of controls, p = .049). Composite comprehension scores were similar between groups (p = .131). CONCLUSION: A preoperative MMS educational video increased recognition of procedural risks, but did not improve patient anxiety or satisfaction.