Adapting with the Pandemic: Modified Mohs Micrographic Surgery Using Rim and Deep Margin Technique.

The COVID-19 pandemic has changed many facets of medical care and has resulted in a rise in delayed treatments across all specialties, including cosmetic dermatology. Delayed care for squamous cell carcinomas (SCC) and basal cell carcinoma (BCC) is not only a burden for medical providers, but also confers a risk to patients, as delayed surgeries are associated with increased metastatic risk and tumor size. Mohs micrographic surgery (MMS) delayed by more than one year leads to increased risk of complications, including bleeding and impaired wound healing, especially in the elderly population. To decrease bleeding risks, we have developed a modified MMS technique known as the "rim and deep margin" technique. Here, we present additional cases using this technique to minimize bleeding and operative time for patients with an increased risk of morbidity. This technique has been used successfully in the past for large tumors and can now be used for patients who have faced delay of care, as evidenced by its success during the COVID-19 pandemic.

Molecular and Structural Basis for Cγ-C Bond Formation by PLP-Dependent Enzyme Fub7.

Pyridoxal 5'-phosphate (PLP)-dependent enzymes that catalyze γ-replacement reactions are prevalent, yet their utilization of carbon nucleophile substrates is rare. The recent discovery of two PLP-dependent enzymes, CndF and Fub7, has unveiled unique C-C bond forming capabilities, enabling the biocatalytic synthesis of alkyl- substituted pipecolic acids from O-acetyl-L-homoserine and ß-keto acid or aldehyde derived enolates. This breakthrough presents fresh avenues for the biosynthesis of pipecolic acid derivatives. However, the catalytic mechanisms of these enzymes remain elusive, and a dearth of structural information hampers their extensive application. Here, we have broadened the catalytic scope of Fub7 by employing ketone-derived enolates as carbon nucleophiles, revealing Fub7's capacity for substrate-dependent regioselective α-alkylation of unsymmetrical ketones. Through an integrated approach combining X-ray crystallography, spectroscopy, mutagenesis, and computational docking studies, we offer a detailed mechanistic insight into Fub7 catalysis. Our findings elucidate the structural basis for its substrate specificity, stereoselectivity, and regioselectivity. Our work sets the stage ready for subsequent protein engineering effort aimed at expanding the synthetic utility of Fub7, potentially unlocking novel methods to access a broader array of noncanonical amino acids.

Home Is Where the Match Is: Mentorship and Dermatology Residency Match Trends Before and During the COVID-19 Pandemic.

Dermatology is one of the most competitive residencies for matching among medical school applicants. A strong connection with a residency program through research or clinical rotations may distinguish between similarly qualified applicants. Our previous study of research-mentor relationships among matched dermatology applicants corroborated the importance of program connections.1 However, the 2020-2021 residency match cycle was uniquely affected by the COVID-19 pandemic, which prevented applicants from fostering connections with faculty at outside institutions. Our study objectives were to evaluate research-mentor relationships among matched dermatology applicants in the 2020-2021 pandemic match cycle with comparisons to pre-pandemic match cycles.

An analysis of lactate dehydrogenase (LDH) levels in advanced stage IV melanoma of the skin: prognostic capabilities and demographic variability.

Despite its limitations, in part due to decreased specificity in advanced disease, serum lactate dehydrogenase (LDH) is one of few serum factors used in cancer staging. This study quantifies the predictive capabilities of LDH in stage IV melanoma of the skin and explores the validity of suggested demographic discrepancies which may exist in its use. The 1975-2017 Surveillance Epidemiology and End Results (SEER) database was queried for stage IV cutaneous melanoma cases. Demographic characteristics were compared between LDH groups using chi-square and t tests. Subsequent Cox multivariable regression was performed to assess survival differences. 334 cases of stage IV cutaneous melanoma (average age: 63.0 years) with measured serum LDH levels were identified. Of these patients, 150 (44.9%) had normal LDH, 112 (33.5%) had LDH < 1.5 × upper limit of normal (ULN), 57 (17.1%) had LDH 1.5-10 × ULN, and 15 (4.5%) had LDH > 10 × ULN. Lower incomes were associated with higher LDH; individuals with incomes < $50,000 had the greatest proportion of LDH 10 × ULN (19.2%; p = 0.0031). LDH > 10 × ULN also had the lowest proportion of White patients (p = 0.04). On Cox multivariable survival analysis, increasing LDH levels showed increased risk of death (LDH < 1.5 × ULN: HR = 2.05, p = 0.01; LDH 1.5-10 × ULN: HR = 1.46, p < 0.001; LDH > 10 × ULN: HR = 5.91, p < 0.001). This study reaffirms the utility of LDH as a significant predictor of mortality with incremental severity, suggesting possible use for mortality projections. We note that Black patients and those with lower incomes may be more likely to have an elevated LDH. Older age groups and presence of ulceration among patients with stage IV melanoma were also associated with a greater risk of mortality.

Bone Densities Assessed by Hounsfield Units at L5 in Computed Tomography Image Independently Predict Hepatocellular Carcinoma Development in Cirrhotic Patients.

A previous study identified that bone density (BD) assessed by Hounsfield unit (HU) at T12 in computed tomography (CT) image was a predictor for hepatocellular carcinoma (HCC) development in cirrhotic patients. Here, we conducted a verification study, where clinical variables together with BDs (assessed from three different bone areas: T12, L5, and femur trochanter) were assessed for their predictive values for time-to-HCC development in cirrhotic patients. Univariate Cox proportional hazard analysis showed that age (p = 0.017), T12 BD (p = 0.013) and L5 BD (p = 0.005), but not femur BD, were significant predictors. Multivariate analysis revealed that L5 BD was the only independent factor associated with time-to-HCC development (adjusted p = 0.007). Kaplan-Meier analysis confirmed that BD which was lower than median HU was associated with a shorter time-to-HCC development for both T12 BD and L5 BD (p = 0.001 each). Longitudinal follow-ups for BDs in HCC patients having received serial CT imaging studies unveiled a significantly rapid reduction in BD, right before HCC was diagnosed (p = 0.025 when compared with the average BD reduction rate). In conclusion, BD assessed by HU at L5 was an independent predictor for HCC development in cirrhotic patients. Rapid BD reduction during CT scan follow-ups could serve as a warning sign for HCC development.

Molecular Mechanisms of Cutaneous Squamous Cell Carcinoma.

Non-melanoma skin cancers are cutaneous malignancies representing the most common form of cancer in the United States. They are comprised predominantly of basal cell carcinomas and squamous cell carcinomas (cSCC). The incidence of cSCC is increasing, resulting in substantial morbidity and ever higher treatment costs; currently in excess of one billion dollars, per annum. Here, we review research defining the molecular basis and development of cSCC that aims to provide new insights into pathogenesis and drive the development of novel, cost and morbidity saving therapies.

Favre-Racouchot disease: protective effect of solar elastosis.

Favre-Racouchot disease (FRD) is an occupational disorder characterized by solar elastosis with open and cystically dilated comedones that tend to appear on the periorbital and temporal face of elderly light-complexioned men. It is a benign condition caused by chronic excessive ultraviolet exposure, as well as ionizing radiation and/or smoking. However, malignant skin neoplasms are uncommonly observed arising in FRD, which suggests a protective role of some element of FRD against carcinogenesis. We explore elastosis as a possibly beneficial tissue response. The clinical manifestations, pathogenesis, and recommended treatment options of this disorder are reviewed.

Assessment of skin of color and diversity and inclusion content of dermatologic published literature: An analysis and call to action.

BACKGROUND: Previous reports have revealed inadequate resident education and textbook representation of dermatological conditions in patients with skin of color (SoC). This suggests that the literature and continuing medical education are important alternative dermatology educational resources to aid in diagnosing and treating patients of color. OBJECTIVE: This study develops criteria to assess and examine the prevalence of SoC-related publications among top dermatology journals. METHODS: We developed the first-ever prespecified criteria that allow for the assessment of diversity in the dermatologic literature. The archives of 52 dermatology journals from January 2018 to October 2020, selected based on Scopus ranking, were analyzed for journal characteristics and content regarding skin and hair of color, diversity and inclusion, and socioeconomic/health care disparities that affect underrepresented populations with SoC. RESULTS: Our study reveals that the average percentage of overall publications relevant to SoC is quite low. The percent of SoC articles ranged from 2.04% to 16.8% with a mean of 16.3%. The top-performing dermatology journals in SoC were, not surprisingly, from countries with populations with SoC; however, the Journal of Cosmetic and Laser Therapy, Australasian Journal of Dermatology, and Journal of the American Academy of Dermatol Case Reports were among the top 10. Research and higher-impact journals were among the lowest in SoC rankings, including the Journal of Investigative Dermatology, Experimental Dermatology, and Journal of the American Academy of Dermatology, and had <5% of articles on SoC. CONCLUSION: We believe that the criteria we established could be used by journal editors to include at least 16.8% of SoC-relevant articles in each issue. Increasing SoC content in the dermatological literature, and particularly in high-impact journals, will serve as an invaluable educational resource and aid in promoting excellence in the care of patients with SoC.

A rare case of a periorbital respiratory (choristomatous) cyst.

Respiratory cysts are benign lesions lined by normal respiratory epithelium. There are few reported cases localized to the orbit, while those of the eyelid are exceedingly rare. Respiratory cysts usually arise either from a non-hereditary congenital malformation, where they are distinguished as choristomatous, or from trauma. Here, we report a case of a 53-year-old man who presented with a large right lower eyelid cyst that was histopathologically diagnosed as a respiratory cyst.

Whole-Exome and Transcriptome Analysis of UV-Exposed Epidermis and Carcinoma In Situ Reveals Early Drivers of Carcinogenesis.

Squamous cell carcinoma in situ (SCCIS) is a prevalent precancerous lesion that can progress to cutaneous squamous cell carcinoma. Although SCCIS is common, its pathogenesis remains poorly understood. To better understand SCCIS development, we performed laser captured microdissection of human SCCIS and the adjacent epidermis to isolate genomic DNA and RNA for next-generation sequencing. Whole-exome sequencing identified UV-signature mutations in multiple genes, including NOTCH1-3 in the epidermis and SCCIS and oncogenic TP53 mutations in SCCIS. Gene families, including SLFN genes, contained UV/oxidative-signature disruptive epidermal mutations that manifested positive selection in SCCIS. The frequency and distribution of NOTCH and TP53 mutations indicate that NOTCH mutations may precede TP53 mutations. RNA sequencing identified 1,166 differentially expressed genes; the top five enriched gene ontology biological processes included (i) immune response, (ii) epidermal development, (iii) protein phosphorylation, (iv) regulation of catalytic activity, and (v) cytoskeletal regulation. The NEURL1 ubiquitin ligase, which targets Notch ligands for degradation, was upregulated in SCCIS. NEURL1 protein was found to be elevated in SCCIS suggesting that increased levels could represent a mechanism for downregulating Notch during UV-induced carcinogenesis. The data from DNA and RNA sequencing of epidermis and SCCIS provide insights regarding SCCIS formation.

Microcystic adnexal carcinoma of the head and neck: Characteristics, treatment, and survival statistics.

Studies on microcystic adnexal carcinoma (MAC) survival rates have been limited. This effort examines the association of patient demographics, treatment modalities, and tumor stage with overall survival (OS) in patients with MAC of the head and neck. All cases of MAC with primary sites of the skin of the head and neck, confirmed histologically, and diagnosed from 2004 to 2016 in the National Cancer Database, were analyzed. We utilized Kaplan-Meier and Cox proportional-hazard models to analyze the characteristics and survival outcomes of the 415 cases that met the criteria. The mean age of diagnosis was 63.8 years (SD ±15.8). Mean OS was 10.8 years with 5- and 10-year OS being 81.0% and 68.0%, respectively. Women were more frequently affected (59.0%; P < .001). Stand-alone primary site surgery was the most common treatment (81.4%): 15.9% of patients were treated with postexcision radiation therapy (RT). 18.3% were treated with RT with or without surgery and/or chemotherapy. RT was independently associated with a decreased hazard of death (HR = 0.23; P = .044). MAC of the head and neck disproportionately affects whites, is more common in women, and has the potential to metastasize. Surgical excision is the commonest treatment; our study shows benefit from judicious RT.

Glutathione Supplementation as an Adjunctive Therapy in COVID-19.

Morbidity and mortality of coronavirus disease 2019 (COVID-19) are due in large part to severe cytokine storm and hypercoagulable state brought on by dysregulated host-inflammatory immune response, ultimately leading to multi-organ failure. Exacerbated oxidative stress caused by increased levels of interleukin (IL)-6 and tumor necrosis factor α (TNF-α) along with decreased levels of interferon α and interferon ß (IFN-α, IFN-ß) are mainly believed to drive the disease process. Based on the evidence attesting to the ability of glutathione (GSH) to inhibit viral replication and decrease levels of IL-6 in human immunodeficiency virus (HIV) and tuberculosis (TB) patients, as well as beneficial effects of GSH on other pulmonary diseases processes, we believe the use of liposomal GSH could be beneficial in COVID-19 patients. This review discusses the epidemiology, transmission, and clinical presentation of COVID-19 with a focus on its pathogenesis and the possible use of liposomal GSH as an adjunctive treatment to the current treatment modalities in COVID-19 patients.

Understanding the Relationship between Glutathione, TGF-ß, and Vitamin D in Combating Mycobacterium tuberculosis Infections.

Tuberculosis (TB) remains a pervasive global health threat. A significant proportion of the world's population that is affected by latent tuberculosis infection (LTBI) is at risk for reactivation and subsequent transmission to close contacts. Despite sustained efforts in eradication, the rise of multidrug-resistant strains of Mycobacteriumtuberculosis (M. tb) has rendered traditional antibiotic therapy less effective at mitigating the morbidity and mortality of the disease. Management of TB is further complicated by medications with various off-target effects and poor compliance. Immunocompromised patients are the most at-risk in reactivation of a LTBI, due to impairment in effector immune responses. Our laboratory has previously reported that individuals suffering from Type 2 Diabetes Mellitus (T2DM) and HIV exhibited compromised levels of the antioxidant glutathione (GSH). Restoring the levels of GSH resulted in improved control of M. tb infection. The goal of this review is to provide insights on the diverse roles of TGF- ß and vitamin D in altering the levels of GSH, granuloma formation, and clearance of M. tb infection. We propose that these pathways represent a potential avenue for future investigation and development of new TB treatment modalities.