Mendelian Randomization Analysis reveals Inverse Genetic Risks between Skin Cancers and Vitiligo.

Several observational studies have demonstrated a consistent pattern of decreased melanoma risk among patients with vitiligo. More recently, this finding has been supported by a suggested genetic relationship between the two entities, with certain variants significantly associated with an increased risk of melanoma, basal cell carcinoma, and squamous cell carcinoma but a decreased risk of vitiligo. We compared 48 associated variants from a recently published GWAS and identified three variants-located in the TYR, MC1R-DEF8, and RALY-EIF2S2-ASIP-AHCY-ITCH loci- that correlated with an increased risk for melanoma, basal cell carcinoma, and squamous cell carcinoma and a decreased risk for vitiligo. We then used results of skin cancers and vitiligo GWAS to compare the shared genetic properties between these two traits through an unbiased Mendelian randomization analysis. Our results suggest that the inverse genetic relationship between common skin cancers and vitiligo is broader than previously reported owing to the influence of shared genome-wide significant associations.

Antimalarials are not Effective as Pre-Exposure Prophylaxis for COVID-19: A Retrospective Matched Control Study.

The early phase of the COVID-19 pandemic prompted a repurposing of antiviral and immunomodulatory drugs as investigational therapeutics, including hydroxychloroquine and chloroquine. While antimalarials have been well-refuted as a treatment for COVID-19, data on these drugs' role in preventing SARS-CoV-2 infection as pre-exposure prophylaxis is more limited. We investigated the efficacy of antimalarial drugs as pre-exposure SARS-CoV-2 prophylaxis in a US tertiary-care center. We identified all adult patients exposed to antimalarials with active prescriptions from July 1, 2019 to February 29, 2020 and exact-matched antimalarial-treated study patients with controls on age, sex, race, and Charleston Comorbidity Index. We used multivariable logistic regression to calculate the odds ratio (OR) of COVID-19 diagnosis by antimalarial exposure, adjusting for demographics, comorbidities, local infection rates, and specific conditions identified in early studies as risk factors for COVID-19. There were 3,074 patients with antimalarial prescriptions and 58,955 matched controls. Hydroxychloroquine represented 98.8% of antimalarial prescriptions. There were 51 (1.7%) infections among antimalarial-exposed and 973 (1.6%) among controls. No protective effect for SARS-CoV-2 infection was demonstrated among antimalarial-exposed patients in the multivariate model (OR=1.06, 95% CI 0.80-1.40, P=0.70). These findings corroborate prior work demonstrating that hydroxychloroquine and related antimalarials do not have a role in protection against SARS-CoV-2.Klebanov N, Pahalyants V, Said JT, et al. Antimalarials are not effective as pre-exposure prophylaxis for COVID-19: a retrospective matched control study. J Drugs Dermatol. 2023;22(8):840-843. doi:10.36849/JDD.6593.

Unsupervised Phenotype-Based Clustering of Clinicopathologic Features in Cutaneous Melanoma.

Pathogenic phenotypes in cutaneous melanoma have been vastly cataloged, although these classifications lack concordance and are confined to either morphological or molecular contexts. In this study, we perform unsupervised k-medoids clustering as a machine learning technique of 2,978 primary cutaneous melanomas at Mass General Brigham and apply this information to elucidate computer-defined subsets within the clinicopathologic domain. We identified five optimally separated clusters of melanoma that occupied two distinct clinicopathologic subspaces: a lower-grade partition associated with common or dysplastic nevi (i.e., nevus-associated melanomas) and a higher-grade partition lacking precursor lesions (i.e., de novo melanomas). Our model found de novo melanomas to be more mitogenic, more ulcerative, and thicker than nevus-associated melanomas, in addition to harboring previously unreported differences in radial and vertical growth phase status. The utilization of mixed clinicopathologic variables, reflective of actual clinical data contained in surgical pathology reports, has the potential to increase the biological relevance of existing melanoma classification schemes and facilitate the discovery of new genomic subtypes.

Risk of COVID-19 in Patients with Cancer Receiving Immune Checkpoint Inhibitors.

OBJECTIVE: The aim of this study was to determine the rate of coronavirus disease-19 (COVID-19) among patients with cancer treated with immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: This was a retrospective study of 1,545 patients with cancer treated with ICIs between July 1, 2019, and February 29, 2020, and 20,418 age-, sex-, and cancer category-matched controls in a large referral hospital system. Confirmed COVID-19 case and mortality data were obtained with Massachusetts Department of Public Health from March 1 through June 19, 2020. RESULTS: The mean age was 66.6 years, and 41.9% were female. There were 22 (1.4%) and 213 (1.0%) COVID-19 cases in the ICI and control groups, respectively. When adjusting for demographics, medical comorbidities, and local infection rates, ICIs did not increase COVID-19 susceptibility. CONCLUSION: ICIs did not increase the rate of COVID-19. This information may assist patients and their oncologists in decision-making surrounding cancer treatment during this pandemic.

Air Duster Inhalant Abuse Causing Non-ST Elevation Myocardial Infarction.

Inhalant abuse, also known as huffing, is common among teenagers and adolescents in the United States and worldwide. Inhaled aerosols are dangerous due to both the presence of volatile hydrocarbons causing direct organ damage and the risk of the compressed air causing physical trauma (e.g. expansion, barotrauma) or skin trauma from chemical or temperature burn. Here, we present the case of a 35-year-old man who was inhaling multiple canisters of Dust-Off (Falcon Safety Products Inc., Branchburg, NJ) keyboard air duster daily for approximately one month. He presented with intermittent burning chest pains, and was found to have elevated troponin (peak 17 ng/mL, normal range 0-0.5 ng/mL) without ST-segment elevations, concerning for non-ST elevation myocardial infarction (NSTEMI) as well as elevated aminotransferases and elevated serum creatinine. He was treated conservatively with supportive measures, with successful resolution of his laboratory abnormalities as well as his chest pain. Clinicians should be aware of the possible medical complications of inhalant abuse, and the expected clinical course. In this case, we aim to demonstrate the acute onset and self-resolution of significant cardiomyocyte damage in a young male patient abusing duster.

Selective uveal melanoma inhibition with calcium channel blockade.

Uveal malignant melanoma (UMM), the most common primary adult intraocular tumor with a marked metastatic potential, is genetically unique and has unfortunately had few treatment breakthroughs. In this study, we subjected a UMM cell line to high­throughput library screening with 1,018 FDA­approved compounds to identify potential UMM­selective cytotoxic agents. Amlodipine, a dihydropyridine calcium channel blocker (CCB), ranked no. 2 and no. 8 of the most cytotoxic compounds. Thus, we further characterized the differential effects of calcium blockade on UMM and cutaneous malignant melanoma (CMM) lines in vitro using growth inhibition, cell cycle progression, apoptosis and senescence assays. Amlodipine had a significantly higher growth inhibitory potency in UMM (IC50=13.1 µM) than CMM (IC50=15.9 µM, P<0.05) lines. In 3D spherical cell culture, amlodipine treatment significantly impaired tissue volume growth in two UMM lines, but exerted no significant effects among all 3 CMM lines tested. Treatment with 10 and 20 µM amlodipine induced a significant impairment of cell cycle progression and the apoptosis of UMM lines, implicating both of these processes as mediators of the observed growth inhibition in UMM compared to CMM. On the whole, the findings of this study suggest that calcium channel blockade is a potentially effective strategy for selective uveal melanoma targeting.

Burden of unique and low prevalence somatic mutations correlates with cancer survival.

Tumor mutational burden correlates with improved survival and immunotherapy response in some malignancies, and with tumor aggressiveness in others. To study the link between mutational burden and survival, we analyzed survival effects of tumor exonic missense mutation burden (TEMMB) across 6947 specimens spanning 31 cancers which have undergone whole exome sequencing as part of TCGA. We adjusted TEMMB for age, sex, stage, and recruitment center, and computed Cox-proportional models of TEMMB survival effects. We assigned a recurrence score (RS) to each cohort, defining RS as the burden of recurrent mutations exceeding 1% population prevalence. High TEMMB was associated with improved survival in cutaneous melanoma: hazard ratio (HR) = 0.71 [0.60-0.85], p = 0.0002, urothelial bladder carcinoma: HR = 0.74 [0.59-0.93], p = 0.01, and ovarian carcinoma: HR = 0.80 [0.70-0.93], p = 0.003. High TEMMB was associated with decreased survival in colorectal adenocarcinoma: HR = 1.32 [1.00-1.74], p < 0.05. We identified that TEMMB survival effects were governed by the balance of recurrent and non-recurrent mutations. In cancers with a low RS, high TEMMB was correlated with better survival outcomes (r = 0.49, p = 0.02). In conclusion, TEMMB effects on survival depend on recurrent mutation enrichment; tumor types that are highly enriched in passenger mutations show a survival benefit in the setting of high tumor mutational burden.

Use of Targeted Next-Generation Sequencing to Identify Activating Hot Spot Mutations in Cherry Angiomas.

Importance: Shared gene variants in benign-malignant process pairs, such as BRAF mutations common to benign nevi and melanoma, are associated with differing phenotypic manifestations. Study of gene mechanisms underlying cherry angioma may uncover previously unknown disease relationships. Objective: To identify somatic mutations present in cherry angioma specimens by using targeted next-generation sequencing. Design, Setting, and Participants: In a single-center case series, 10 formalin-fixed, paraffin-embedded cherry angioma specimens from biopsies performed at Massachusetts General Hospital in Boston from July 10, 2016, to January 23, 2018, were obtained and underwent sequencing across a panel of 323 genes most relevant to cancer. Somatic mutations were curated by excluding variants that were presumed to be germline or of low mapping quality. Main Outcomes and Measures: Identification of somatic mutations associated with cherry angiomas. Results: In 10 cherry angioma tissue samples originating from 6 female and 4 male patients with a median (range) age of 54 (26-79) years, 5 samples (50%) revealed somatic missense mutations in GNAQ (Q209H, Q209R, and R183G) and GNA11 (Q209H). Individually, these mutational hot spots are known to be involved in entities that include congenital and anastomosing hemangiomas, hepatic small-vessel neoplasms (Q209), port-wine stains, and Sturge-Weber syndrome (R183). Both hot spots are associated with blue nevi, melanoma associated with blue nevus, and uveal melanoma. Conclusions and Relevance: In this case series study, the high prevalence of 5 known genetic drivers within the benign cherry angioma entity appears to support the context-dependent role of gene alterations in both benign and malignant proliferations from various cellular origins.

Growth suppression by dual BRAF(V600E) and NRAS(Q61) oncogene expression is mediated by SPRY4 in melanoma.

The underlying forces that shape mutational patterns within any type of cancer have been poorly characterized. One of the best preserved exclusionary relationships is that between BRAF(V600E) and NRAS(Q61) in melanomas. To explore possible mechanisms which could explain this phenomenon, we overexpressed NRAS(Q61) in a set of BRAF(V600E) melanoma lines and vice versa. Controlled expression of a second activating oncogene led to growth arrest ("synthetic suppression") in a subset of cells, which was accompanied by cell cycle arrest and senescence in several melanoma cell lines along with apoptosis. Through differential gene expression analysis, we identified SPRY4 as the potential mediator of this synthetic response to dual oncogene suppression. Ectopic introduction of SPRY4 recapitulated the growth arrest phenotype of dual BRAF(V600E)/NRAS(Q61) expression while SPRY4 depletion led to a partial rescue from oncogenic antagonism. This study thus defined SPRY4 as a potential mediator of synthetic suppression, which is likely to contribute to the observed exclusivity between BRAF(V600E) and NRAS(Q61R) mutations in melanoma. Further leverage of the SPRY4 pathway may also hold therapeutic promise for NRAS(Q61) melanomas.

A Case of Nivolumab-Induced Cutaneous Toxicity with Multiple Morphologies.

Cutaneous reactions are among the most prevalent immune-related adverse events in patients treated with immunotherapy. Given that immunotherapies often act through blocking inhibitory signals on T cells, these treatments also have the potential to generate a host of immune toxicities. We report the case of a 73-year-old woman with a history of non-small cell lung cancer treated with nivolumab 10 months prior to presentation who developed painful nodules, bullae, and a scaly rash on her extremities. Four months after discontinuation of nivolumab, she noted an acute eruption of painful nodules on her extremities, followed by pink papules and tense bullae on her palms and soles. Biopsies were performed of three lesions in sites of varying morphologies. These findings were felt to be consistent with a nivolumab-induced lichenoid reaction. She was initially treated with intralesional steroid injections, topical steroid ointment, and liquid nitrogen cryotherapy with minimal improvement. As the lesions continued to progress, the patient was admitted to the hospital and started on intravenous methylprednisolone. She eventually transitioned to daily oral prednisone with a slow taper with good effect and no recurrence of lesions.

Clinical spectrum of cutaneous melanoma morphology.

BACKGROUND: Melanoma can mimic other cutaneous lesions, but the full spectrum and prevalence of these morphologic variants remain largely unknown. OBJECTIVE: To classify nonacral cutaneous melanomas into distinct morphologic clusters and characterize clusters' clinicopathologic features. METHODS: All pathologic melanoma diagnoses (occurring during 2011-2016) were reviewed for routine prebiopsy digital photographs (n = 400). Six dermatologists independently assigned lesions into 1 of 14 diagnostic classes on the basis of morphology. Image consensus clusters were generated by K-means; clinicopathologic features were compared with analysis of variance and χ2. RESULTS: Five morphologic clusters were identified: typical (n = 136), nevus-like (n = 81), amelanotic/nonmelanoma skin cancer (NMSC)-like (n = 70), seborrheic keratosis (SK)-like (n = 68), and lentigo/lentigo maligna (LM)-like (n = 45) melanomas. Nevus-like melanomas were found in younger patients. Nevus-like and lentigo/LM-like melanomas tended to be thinner and more likely identified on routine dermatologic examinations. NMSC-like melanomas were tender, thicker, more mitotically active, and associated with prior NMSC. Typical and SK-like melanomas had similar clinicopathologic features. LIMITATIONS: Cluster subdivision yielded diminished sample sizes. Visual assignment was performed without clinical context. CONCLUSION: When primary cutaneous melanomas were assigned into diagnostic groups and subjected to novel consensus clustering, recurrent morphologic patterns emerged. The spectrum of these morphologies was unexpectedly diverse, which might have implications for visual training and possibly clinical diagnosis.

Genetic Predisposition to Infectious Disease.

In contemporary medical practice, approaches to infectious disease management have been primarily rooted in a pathogen-centered model. However, host genetics also contribute significantly to infectious disease burden. The fast expansion of bioinformatics techniques and the popularization of the genome-wide association study (GWAS) in recent decades have allowed for rapid and affordable high-throughput genomic analyses. This review focuses on the host model of infectious disease with particular emphasis placed on the genetic variations underlying observed infectious disease predisposition. First, we introduce observational twin-twin concordance studies of diseases such as poliomyelitis, tuberculosis, and hepatitis which suggest the important role of host genetics. We review the well-established links between specific genetic alterations and predisposition to malaria (P. falciparum and P. vivax), Creutzfeldt-Jacob disease (CJD), human immunodeficiency virus (HIV), and Norwalk virus. Finally, we discuss the novel findings yielded by modern GWAS studies, which suggest the strong contribution of immunologic variation in the major histocompatibility complex (MHC) to host genetic infectious disease susceptibility. Future large-scale genomic studies hold promise in providing insights into immunology-pathogen links and may allow for the development of personalized genomic approaches to infectious disease prevention and treatment.

Optimization of Anterior Incision Placement for Distal Biceps Repair.

Introduction Damage to the posterior interosseous nerve (PIN) is a known complication when using a cortical button during distal biceps tendon repair. Prior studies show that the trajectory of the drill through the biceps tuberosity can affect the distance from the PIN. We develop a mathematical model to predict the location of the tuberosity based on a palpable bony landmark and patient demographic factors. Methods The medical charts and elbow radiographs of (n = 82) adult patients were retrospectively reviewed. Using standard radiographic software, two observers measured the distance from the olecranon tip to the center of the biceps tuberosity. Multivariate regression analysis was used to build a linear model. The model was cross-validated with five arms from three distinct cadavers. A surgical wire was guided into the volar aspect of each forearm using the model, and a dissection was then performed to assess the proximity of the surgical wire to the insertion of the biceps tendon on the radial tuberosity. Results Olecranon-tuberosity distance (OTD) ranged from 52.3 mm to 77.2 mm (mean 66.5 mm). Univariate analyses revealed males had significantly longer OTD (mean 69.3 mm) compared to females (mean 61.2 mm, t-test, p < 0.001). Increased body mass index (BMI) weakly correlated with increased distance (Pearson's r = 0.22, p = 0.048). Height showed strong positive correlation with increased distance (r = 0.77, p < 0.001). Multivariate regression revealed that significant predictive factors for olecranon-tuberosity distance were height (coefficient = 35.8, p < 0.001), BMI (coefficient = 0.14, p = 0.032), and male sex (coefficient = 3.17, p = 0.0039). The average error in the cadaveric validation, measured as distance from the surgical wire to the distal biceps insertion was 1.8 mm. Conclusion A highly accurate mathematical model can be used to predict the location of the biceps tuberosity in relation to the palpable tip of the olecranon, based only on height, BMI, and sex of the patient. Knowledge of this distance can guide accurate placement of the skin incision when a transverse single-incision approach is utilized for repair of the distal biceps tendon using a cortical button. Diagnostics showed the model to be less accurate near the extremes of the measurement. Since patients with a target incision point far removed from average would most benefit from such a model, we will continue by identifying and enrolling patients at the low and high ends of the range. We further hypothesize that the technique described above could be similarly applied to benefit other procedures.

Pleomorphic Dermal Sarcoma of the Scalp.

Pleomorphic dermal sarcoma (PDS) is a rare mesenchymal tissue tumor. Distinguishing PDS from similar conditions, such as atypical fibroxanthoma (AFX), its less aggressive tumor counterpart, is difficult, as they are clinically and histologically similar. We present a case of a 77-year-old man presenting with a large nodular scalp lesion of three weeks duration. Pathology revealed a 3.3 cm invasive pleomorphic dermal sarcoma. Surgical excision with 2 cm margins was performed with successful healing of the graft. This case highlights a rare case of a large pleomorphic dermal sarcoma and discusses the histological features and management of PDS.