Local Recurrence Rates After Excision of Desmoplastic Melanoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Few prospective studies have evaluated local recurrence rates (LRR) after excision of desmoplastic melanoma (DM); however, several retrospective studies have reported high LRR. OBJECTIVE: To determine LRR after excision of DM and evaluate factors affecting LRR. MATERIALS AND METHODS: Systematic review of the PubMed, Embase, and Web of Science databases was performed to identify studies reporting local recurrence after excision of DM with conventional wide local excision (WLE), Mohs micrographic surgery (MMS), or staged excision (SE). Meta-analysis was performed to calculate summary LRR and pooled risk ratios (RR). RESULTS: Literature search identified 4 studies evaluating MMS or SE (total n = 61 DM). 53 studies assessed WLE ( n = 3,080) and were analyzed quantitatively. The overall LRR after WLE of DM was 21% (95% CI, 0.16-0.28; n = 2,308). Local recurrence rate was higher with positive/unknown histologic excision margins (49%, 95% CI, 0.25-0.74; n = 91) versus negative histologic margins (11%, 95% CI, 0.07-0.17; n = 1,075; [ p < .01]). Neurotropism was also associated with increased LRR (RR, 1.79; 95% CI, 1.34-2.38, p < .01; n = 644). CONCLUSION: DM has high LRR after WLE. Local recurrence risk was greatest with positive excision margins, indicating the importance of achieving negative microscopic margins. Greater study of MMS and SE for DM is required.

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.

Rates of Opioid Prescriptions Obtained After Mohs Surgery: A Claims Database Analysis From 2009 to 2020.

IMPORTANCE: To curtail the opioid epidemic, physicians have been advised to limit opioid prescriptions. OBJECTIVE: To characterize the frequency and changes over time (2009-2020) of opioid prescriptions following Mohs micrographic surgery. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study using Optum Clinformatics DataMart (Optum CDM), a nationally representative insurance claims database, included patients aged 18 years and older who had Mohs micrographic surgery insurance claims in the Optum CDM database from 2009 to 2020. Data were analyzed from November 11, 2020, to March 30, 2021. EXPOSURES: Opioid prescription following Mohs surgery. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients who underwent Mohs surgery and obtained an opioid prescription within 2 days of surgery. Secondary outcomes included type and opioid quantity prescribed. RESULTS: Among 358 012 patients with Mohs micrographic surgery claims (mean [SD] age, 69 [13] years; 205 609 [57.4%] were men), the proportion of patients obtaining an opioid prescription after Mohs micrographic surgery increased from 2009 (34.6%) to 2011 (39.6%). This proportion then declined each year, reaching a low of 11.7% in 2020 (27.9% absolute decrease from 2011 to 2020). Hydrocodone, codeine, oxycodone, and tramadol were the 4 most commonly prescribed opioids. By 2020, hydrocodone was obtained less (2009: 47.5%; 2011: 67.1%; 2020: 45.4%; 21.7% absolute decrease from 2011 to 2020) and tramadol was obtained more (2009: 1.6%; 2020: 27.9%; 26.3% absolute increase from 2009 to 2020). CONCLUSIONS AND RELEVANCE: In this cross-sectional study of Mohs micrographic surgery claims, patients obtained fewer postsurgery opioid prescriptions over the study period, suggesting responsiveness of patients and dermatologic surgeons to public health concerns regarding the opioid epidemic. During this decline, prescriptions for hydrocodone decreased and tramadol increased.

Compliance with sentinel lymph node biopsy guidelines for invasive melanomas treated with Mohs micrographic surgery.

BACKGROUND: Sentinel lymph node biopsy (SLNB) has not been studied for invasive melanomas treated with Mohs micrographic surgery using frozen-section MART-1 immunohistochemical stains (MMS-IHC). The primary objective of this study was to assess the accuracy and compliance with National Comprehensive Cancer Network (NCCN) guidelines for SLNB in a cohort of patients who had invasive melanoma treated with MMS-IHC. METHODS: This retrospective cohort study included all patients who had primary, invasive, cutaneous melanomas treated with MMS-IHC at a single academic center between March 2006 and April 2018. The primary outcomes were the rates of documenting discussion and performing SLNB in patients who were eligible based on NCCN guidelines. Secondary outcomes were the rate of identifying the sentinel lymph node and the percentage of positive lymph nodes. RESULTS: In total, 667 primary, invasive, cutaneous melanomas (American Joint Committee on Cancer T1a-T4b) were treated with MMS-IHC. The median patient age was 69 years (range, 25-101 years). Ninety-two percent of tumors were located on specialty sites (head and/or neck, hands and/or feet, pretibial leg). Discussion of SLNB was documented for 162 of 176 (92%) SLNB-eligible patients, including 127 of 127 (100%) who had melanomas with a Breslow depth >1 mm. SLNB was performed in 109 of 176 (62%) SLNB-eligible patients, including 102 of 158 melanomas (65%) that met NCCN criteria to discuss and offer SLNB and 7 of 18 melanomas (39%) that met criteria to discuss and consider SLNB. The sentinel lymph node was successfully identified in 98 of 109 patients (90%) and was positive in 6 of those 98 patients (6%). CONCLUSIONS: Combining SLNB and MMS-IHC allows full pathologic staging and confirmation of clear microscopic margins before reconstruction of specialty site invasive melanomas. SLNB can be performed accurately and in compliance with consensus guidelines in patients with melanoma using MMS-IHC.

A Systematic Review of Primary, Adjuvant, and Salvage Radiation Therapy for Cutaneous Squamous Cell Carcinoma.

BACKGROUND: The gold standard of treatment for cutaneous squamous cell carcinoma (cSCC) is surgery radiation therapy (RT) is used selectively as definitive treatment for low-risk tumors or as adjuvant/salvage treatment for high-risk tumors. There is a lack of standardized studies evaluating the efficacy of RT in either clinical scenario. OBJECTIVE: To determine the efficacy of primary and adjuvant/salvage RT for the treatment of cSCC. MATERIALS AND METHODS: A systematic review of PubMed, Embase, Cochrane, and Web of Science was performed for studies that reported outcomes of cSCC treated with RT to the primary site alone. Outcomes included local control (LC), local recurrence (LR), nodal metastases (NM), distant metastases (DM), disease-specific death (DSD), and recurrence-free survival (RFS). RESULTS: Forty-six studies with 4,141 tumors were included. Pooled LC and LR rates were 87.3% and 8.6%, respectively. The rates of NM, DM, DSD, and RFS were 4.8%, 3.5%, 5.3%, and 73.5%, respectively. Local recurrence was significantly higher for T3 and T4 tumors, with rates above 25.9%. CONCLUSION: LR after RT to the primary site increased with increasing tumor stage, highlighting the importance of clear surgical margins for high-risk tumors. Prospective randomized studies characterizing outcomes by tumor stage for RT compared with surgery are needed to inform guidelines.

Mohs micrographic surgery for male genital tumors: Local recurrence rates and patient-reported outcomes.

BACKGROUND: Local recurrence rates (LRRs) after Mohs micrographic surgery (MMS) for male genital cancers have been reported in only a few small case series, and patient-reported outcomes (PROs) have not been studied. OBJECTIVE: To determine the LRR and PROs after MMS for male genital skin cancers. METHODS: Retrospective review of all male genital skin cancers removed with MMS between 2008 and 2019 at an academic center. LRR was determined by chart review and phone calls. PROs were assessed by survey. RESULTS: A total of 119 skin cancers in 108 patients were removed with MMS. Tumors were located on the penis (90/119) and scrotum (29/119). Diagnoses included squamous cell carcinoma in situ (n = 71), invasive squamous cell carcinoma (n = 32), extramammary Paget disease (n = 13), melanoma (n = 2), and basal cell carcinoma (n = 1). The LRR was 0.84% (1/119), with a mean follow-up time of 3.25 years (median, 2.36 years). The majority of survey respondents reported no changes in urinary (66%) or sexual functioning (57.5%) after surgery. LIMITATIONS: Retrospective single-center experience; short follow-up time; low survey response rate; no baseline functional data. CONCLUSION: MMS for male genital skin cancer has a low LRR and high patient-reported satisfaction with urinary and sexual function.

Navigating Barriers to Patient Access and Reimbursement in Mohs Micrographic Surgery.

BACKGROUND: Insurance companies have implemented new policies including excessive prior authorization (PA) requirements, high-deductible plans, and complicated billing structures in an effort to curb rising health care costs. Studies investigating the real-time impact on providers and patients are emerging, but few within the field of dermatology have been published. OBJECTIVE: To assess the impact of cost-cutting policies on patients and physicians. METHODS: A survey was electronically distributed to members of the American College of Mohs Surgery (ACMS). RESULTS: The majority of respondents (78.2%) practiced in a private setting, with no other demographic differences. The majority of respondents (70%) dedicated 1 to 2 employees to obtaining PAs. Fifty percent reported an average time of 30 minutes spent per PA. Fifty-six percent of respondents obtained PA from private insurance before Mohs surgery, whereas only 24.5% obtained PA from Medicare. Forty-nine percent of practitioners provided patients with a financial disclosure prior to Mohs surgery. Moreover, many practitioners reported screening patients for high-deductible policies and request an advanced deposit against the deductible. Sixty percent reported difficulty obtaining payment for service in the absence of an advanced deposit. CONCLUSION: The burden of restrictive health care policies will have long-term consequences for the patient-provider interaction and patient outcomes.

Cryptococcus-like changes in the setting of vasculitis.

Cutaneous vasculitis has many underlying causes, and the clinical and histological findings often overlap. Inflammatory vasculitis can mimic infection; however, distinction is critical for the timely institution of appropriate therapy. We present two patients who had generalized polymorphous eruptions whose cutaneous pathology showed vasculitis with unusual haloed yeast-like cells within the inflammatory infiltrate, mimicking Cryptococcus. The unusual cells stained negatively with Gomori methenamine silver and periodic acid-Schiff fungal stains, but positively for CD68 and had cytoplasmic reactivity with antibody to myeloperoxidase (MPO). Both patients had positive serum anti-MPO antibodies. The first patient experienced a rapidly fatal course, whereas the second patient improved with prompt initiation of systemic corticosteroids. Interestingly, the second case had prior biopsy showing Sweet syndrome with crypotoccoid-appearing cells. Cryptococcoid cells have been described previously in association with neutrophilic dermatoses, but not in the setting of vasculitis as was seen in our patients. Our cases add to the existing literature on crypotoccoid mimickers, and are the first to be reported in association with vasculitis.

Procedural management of rhinophyma: A comprehensive review.

BACKGROUND: Rhinophyma is a cosmetically deforming disease characterized by nodular overgrowth of the lower 2/3 of the nose and is considered the end stage of acne rosacea. AIMS: Review the spectrum of procedural techniques for treatment of rhinophyma with a focus on the advantages and disadvantages of each modality. METHODS: A comprehensive literature search was conducted using the search terms "rhinophyma," "treatment," and "surgery" in PubMed. Case reports, case series, and small retrospective trials using procedural techniques for management of rhinophyma were included for review. Animal studies, non-English articles, and reports of medical treatment of rhinophyma were excluded. RESULTS: There are currently no prospective, randomized controlled studies evaluating procedural management of rhinophyma. The most commonly employed treatments include scalpel excision, resection with heated knives, dermabrasion, electrosurgery and lasers, specifically carbon dioxide (CO2 ) and erbium:yttrium-aluminum-garnet (Er:YAG). The main complication associated with complete excision of rhinophymatous tissue is excessive scarring. To correct for this adverse effect, partial or tangential excision with preservation of underlying adnexal structures is now the accepted technique, irrespective of the chosen modality. CONCLUSION: There is no accepted gold standard for management of rhinophyma, and each modality succeeds in maintaining hemostasis, reducing scarring and achieving satisfactory cosmesis to different degrees. There is a conflicting data on the theoretical risk of recurrence with partial excision due to incomplete removal of tissue. Further studies evaluating this risk and alternate methods of prevention are required.

Nanoparticle-Encapsulated Doxorubicin Demonstrates Superior Tumor Cell Kill in Triple Negative Breast Cancer Subtypes Intrinsically Resistant to Doxorubicin.

The effect of size and release kinetics of doxorubicin-nanoparticles on anti-tumor efficacy was evaluated in a panel of human cancer cell lines, including triple-negative breast cancer (TNBC) cells that frequently demonstrate resistance to doxorubicin. Different nano-formulations of sol-gel-based Doxorubicin containing nanoparticles were synthesized. Increased cell kill in chemoreffactory triple-negative breast cancer cells was associated with the smallest size of nanoparticles and the slowest release of Dox. Modeling of dose-response parameters in Dox-sensitive versus Dox-resistant lines demonstrated increased EMax and area under the curve in Dox-resistant mesenchymal TNBC cells, implying potentially favorable activity in this molecular subtype of breast cancer. Mesenchymal TNBC cells demonstrated a high rate of fluorescent bead uptake suggestive of increased endocytosis, which may partially account for the enhanced efficacy of Dox-np in this subtype. Thus, manipulation of size and release kinetics of this nanoparticle platform is associated with enhanced dose-response metrics and tumor cell kill in therapeutically recalcitrant TNBC cell models. This platform is easily customizable and warrants further exploration.

Epidemiology and treatment of angiolymphoid hyperplasia with eosinophilia (ALHE): A systematic review.

BACKGROUND: Current knowledge of angiolymphoid hyperplasia with eosinophilia (ALHE) derives from retrospective reports and case series, leading to a nonevidence-based treatment approach. OBJECTIVE: We sought to systematically review the literature relating to cutaneous ALHE to estimate its epidemiology and treatment outcomes. METHODS: A literature search of PubMed, EMBASE, Web of Science, and Google Scholar was conducted. Articles detailing cases of histologically confirmed cutaneous ALHE were included. RESULTS: In all, 416 studies were included in the review, representing 908 patients. There was no sex predominance among patients with ALHE. Mean age at presentation was 37.6 years. There was a significant association between presence of multiple lesions and pruritus, along with bleeding. Surgical excision was the most commonly reported treatment for ALHE. Treatment failure was lowest for excision and pulsed dye laser. Mean disease-free survival after excision was 4.2 years. There were higher rates of recurrence postexcision with earlier age of onset, longer duration of disease, multiple lesions, bilateral lesions, pruritus, pain, and bleeding. LIMITATIONS: Potential for publication bias is a limitation. CONCLUSIONS: Surgical excision appears to be the most effective treatment for ALHE, albeit suboptimal. Pulsed dye and other lasers may be effective treatment options. More studies are needed to improve the treatment of ALHE.

Nitric Oxide-Releasing Nanoparticles Prevent Propionibacterium acnes-Induced Inflammation by Both Clearing the Organism and Inhibiting Microbial Stimulation of the Innate Immune Response.

Propionibacterium acnes induction of IL-1 cytokines through the NLRP3 (NLR, nucleotide oligomerization domain-like receptor) inflammasome was recently highlighted as a dominant etiological factor for acne vulgaris. Therefore, therapeutics targeting both the stimulus and the cascade would be ideal. Nitric oxide (NO), a potent biological messenger, has documented broad-spectrum antimicrobial and immunomodulatory properties. To harness these characteristics to target acne, we used an established nanotechnology capable of generating/releasing NO over time (NO-np). P. acnes was found to be highly sensitive to all concentrations of NO-np tested, although human keratinocyte, monocyte, and embryonic zebra fish assays revealed no cytotoxicity. NO-np significantly suppressed IL-1ß, tumor necrosis factor-α (TNF-α), IL-8, and IL-6 from human monocytes, and IL-8 and IL-6 from human keratinocytes, respectively. Importantly, silencing of NLRP3 expression by small interfering RNA did not limit NO-np inhibition of IL-1 ß secretion from monocytes, and neither TNF-α nor IL-6 secretion, nor inhibition by NO-np was found to be dependent on this pathway. The observed mechanism by which NO-np impacts IL-1ß secretion was through inhibition of caspase-1 and IL-1ß gene expression. Together, these data suggest that NO-np can effectively prevent P. acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response.

Trichophyton rubrum is inhibited by free and nanoparticle encapsulated curcumin by induction of nitrosative stress after photodynamic activation.

Antimicrobial photodynamic inhibition (aPI) utilizes radical stress generated from the excitation of a photosensitizer (PS) with light to destroy pathogens. Its use against Trichophyton rubrum, a dermatophytic fungus with increasing incidence and resistance, has not been well characterized. Our aim was to evaluate the mechanism of action of aPI against T. rubrum using curcumin as the PS in both free and nanoparticle (curc-np) form. Nanocarriers stabilize curcumin and allow for enhanced solubility and PS delivery. Curcumin aPI, at optimal conditions of 10 µg/mL of PS with 10 J/cm² of blue light (417 ± 5 nm), completely inhibited fungal growth (p<0.0001) via induction of reactive oxygen (ROS) and nitrogen species (RNS), which was associated with fungal death by apoptosis. Interestingly, only scavengers of RNS impeded aPI efficacy, suggesting that curcumin acts potently via a nitrosative pathway. The curc-np induced greater NO˙ expression and enhanced apoptosis of fungal cells, highlighting curc-np aPI as a potential treatment for T. rubrum skin infections.

Biafine topical emulsion accelerates excisional and burn wound healing in mice.

Macrophages play a fundamental role in wound healing; therefore, employing a strategy that enhances macrophage recruitment would be ideal. It was previously suggested that the mechanism by which Biafine topical emulsion improves wound healing is via enhanced macrophage infiltration into the wound bed. The purpose of this study was to confirm this observation through gross and histologic assessments of wound healing using murine full-thickness excisional and burn wound models, and compare to common standards, Vaseline and silver sulfadiazine (SSD). Full-thickness excisional and burn wounds were created on two groups of 60 mice. In the excisional arm, mice were divided into untreated control, Biafine, and Vaseline groups. In the burn arm, mice were divided into untreated control, Biafine, and SSD groups. Daily treatments were administered and healing was measured over time. Wound tissue was excised and stained to appropriately visualize morphology, collagen, macrophages, and neutrophils. Collagen deposition was measured and cell counts were performed. Biafine enhanced wound healing in murine full-thickness excisional and burn wounds compared to control, and surpassed Vaseline and SSD in respective wound types. Biafine treatment accelerated wound closure clinically, with greater epidermal/dermal maturity, granulation tissue formation, and collagen quality and arrangement compared to other groups histologically. Biafine application was associated with greater macrophage and lower neutrophil infiltration at earlier stages of healing when compared to other study groups. In conclusion, Biafine can be considered an alternative topical therapy for full-thickness excisional and burn wounds, owing to its advantageous biologically based wound healing properties.

Fidgetin-Like 2: A Microtubule-Based Regulator of Wound Healing.

Wound healing is a complex process driven largely by the migration of a variety of distinct cell types from the wound margin into the wound zone. In this study, we identify the previously uncharacterized microtubule-severing enzyme, Fidgetin-like 2 (FL2), as a fundamental regulator of cell migration that can be targeted in vivo using nanoparticle-encapsulated small interfering RNA (siRNA) to promote wound closure and regeneration. In vitro, depletion of FL2 from mammalian tissue culture cells results in a more than twofold increase in the rate of cell movement, in part due to a significant increase in directional motility. Immunofluorescence analyses indicate that FL2 normally localizes to the cell edge, importantly to the leading edge of polarized cells, where it regulates the organization and dynamics of the microtubule cytoskeleton. To clinically translate these findings, we utilized a nanoparticle-based siRNA delivery platform to locally deplete FL2 in both murine full-thickness excisional and burn wounds. Topical application of FL2 siRNA nanoparticles to either wound type results in a significant enhancement in the rate and quality of wound closure both clinically and histologically relative to controls. Taken together, these results identify FL2 as a promising therapeutic target to promote the regeneration and repair of cutaneous wounds.

Nitric oxide as a surgical adjuvant.

Advances in surgical technology have allowed for previously unconsidered therapeutic interventions. However, the complexity and invasiveness of surgical procedures are not without adverse consequences. Nitric oxide's fundamental role in a host of physiological processes, including angiogenesis, wound and bone healing, thromboresistance, smooth muscle relaxation and inflammation makes it a significant player in accelerating wound healing and mitigating the inflammation of ischemia reperfusion injury common to surgical procedures. In addition, the therapeutic properties of NO have been harnessed for the prophylactic treatment of implant infection and graft failure. In this article, we will discuss the mechanism by which NO mediates these processes, and its perioperative translational applications.

S-nitrosocaptopril nanoparticles as nitric oxide-liberating and transnitrosylating anti-infective technology.

Nitric oxide (NO), an essential agent of the innate immune system, exhibits multi-mechanistic antimicrobial activity. Previously, NO-releasing nanoparticles (NO-np) demonstrated increased antimicrobial activity when combined with glutathione (GSH) due to formation of S-nitrosoglutathione (GSNO), a transnitrosylating agent. To capitalize on this finding, we incorporated the thiol-containing ACE-inhibitor, captopril, with NO-np to form SNO-CAP-np, nanoparticles that both release NO and form S-nitrosocaptopril. In the presence of GSH, SNO-CAP-np demonstrated increased transnitrosylation activity compared to NO-np, as exhibited by increased GSNO formation. Escherichia coli and methicillin-resistant Staphylococcus aureus were highly susceptible to SNO-CAP-np in a dose-dependent fashion, with E. coli being most susceptible, and SNO-CAP-np were nontoxic in zebrafish embryos at translatable concentrations. Given SNO-CAP-np's increased transnitrosylation activity and increased E. coli susceptibility compared to NO-np, transnitrosylation rather than free NO is likely responsible for overcoming E. coli's resistance mechanisms and ultimately killing the pathogen. FROM THE CLINICAL EDITOR: This team of authors incorporated the thiol-containing ACE-inhibitor, captopril, into a nitric oxide releasing nanoparticle system, generating nanoparticles that both release NO and form S-nitrosocaptopril, with pronounced toxic effects on MRSA and E. coli in the presented model system.