Entering Medicine as a Physician and a Patient.

This essay describes the author's experience with the line between life and death and what the fragility of life means for patients and their medical teams.

Skin cancer in renal transplant recipients: outcomes from a safety net hospital in Boston.

BACKGROUND: Renal transplant recipients (RTRs) are prone to skin cancer due to the immunosuppression required to maintain graft function. Existing studies of skin cancer in RTRs focus on patients with Fitzpatrick skin types I-II, with limited documentation of incidence in skin types III-VI. This study seeks to better characterize skin cancers in RTRs with skin types III-VI. PRIMARY AIMS: Compare the incidence of skin cancer in RTRs of skin types I-II with skin types III-VI. SECONDARY AIMS: Explore the association between the development of skin cancer and other contributing factors in RTRs of skin types I-VI. METHODS: Retrospective chart review of RTRs at a single institution between January 1, 2000 and December 31, 2022. Patients were followed from the date of transplant to the last clinical follow-up or death. 777 RTRs were included in the study, including 245 patients with Fitzpatrick skin types I-II and 532 with skin types III-VI. A total of 48 patients developed NMSCs, 2 patients developed melanoma, and 3 patients developed Kaposi sarcoma. RESULTS AND CONCLUSIONS: There is a higher incidence of skin cancer in RTRs with Fitzpatrick skin types III-VI compared to the reported incidence among non-transplant recipients of the same skin types, but the incidence remains considerably lower compared to RTR of skin types I-II.

The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma.

Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated. Here, we evaluated the corepressor for element 1-silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition-associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor-resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was recapitulated by the p38 MAPK inhibitor BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial for patients with BRAFi-resistant melanoma.

Epigenetics and cutaneous neoplasms: from mechanism to therapy.

Epigenetics encompasses heritable, reversible gene expression patterns that do not arise from mutations in genomic DNA but, rather, are regulated by DNA methylation, histone modifications, RNA modifications and ncRNAs; and epigenetic dysregulation is increasingly recognized as a mechanism of neoplastic disease progression as well as resistance to cancer therapy. This review article focuses on epigenetic modifications implicated in the progression and therapeutic resistance of common cutaneous malignancies, including basal cell carcinoma, squamous cell carcinoma, T-cell lymphoma and malignant melanoma, with an emphasis on therapeutic strategies that may be used to target such disease-associated alterations.

Epigenetics involves the study of how genes can be turned on or off by factors that affect how these genes are packaged and regulated. In cancer, there are often epigenetic changes that contribute to the formation of tumors. Many of these epigenetic changes, some of which can be passed down through generations, increase the risk of skin cancers such as basal cell carcinoma, squamous cell carcinoma, T-cell lymphoma and malignant melanoma. Emerging therapies designed to target these epigenetic changes may be effective treatments for these types of skin cancers. Researchers are currently investigating how to best use these therapies to help the ever-increasing number of people with skin cancer.

Epigenetic Dysregulation in Autoimmune and Inflammatory Skin Diseases.

Epigenetics is the study of heritable, reversible gene expression patterns that do not originate from alterations in the DNA sequence. Epigenetic modifications influence gene expression patterns and include DNA methylation, histone modifications, and gene regulation via non-coding RNAs. While the study of epigenetics has been most broadly applied to neoplastic diseases, the role of the epigenome in a wide range of disease processes including autoimmune, allergic, and inflammatory processes is increasingly being recognized. Recent advances in the study of the epigenome have led to novel insights into the pathogenesis and potential therapeutic targets of various pathologic entities including inflammatory diseases. In this review, we examine the nature of epigenetic modifications in several well-studied autoimmune, allergic, and/or inflammatory disorders of the skin including systemic lupus erythematosus, vitiligo, systemic sclerosis, alopecia areata, pemphigus, psoriasis, atopic dermatitis, keloidal scarring, and hidradenitis suppurativa with the aim to determine how such epigenetic changes may be targeted for therapeutic benefit.

Drugging the Epigenome: Overcoming Resistance to Targeted and Immunotherapies in Melanoma.

This past decade has seen tremendous advances in understanding the molecular pathogenesis of melanoma and the development of novel effective therapies for melanoma. Targeted therapies and immunotherapies that extend survival of patients with advanced disease have been developed; however, the vast majority of patients experience relapse and therapeutic resistance over time. Moreover, cellular plasticity has been demonstrated to be a driver of therapeutic resistance mechanisms in melanoma and other cancers, largely functioning through epigenetic mechanisms, suggesting that targeting of the cancer epigenetic landscape may prove a worthwhile endeavor to ensure durable treatment responses and cures. Here, we review the epigenetic alterations that characterize melanoma development, progression, and resistance to targeted therapies as well as epigenetic therapies currently in use and under development for melanoma and other cancers. We further assess the landscape of epigenetic therapies in clinical trials for melanoma and provide a framework for future advances in epigenetic therapies to circumvent the development of therapeutic resistance in melanoma.

Follicular occlusion triad: an isotopic response or adverse effect of rituximab?

Follicular occlusion triad is a symptom complex of three conditions with a similar pathophysiology including hidradenitis suppurativa (HS), dissecting cellulitis of the scalp, and acne conglobata. Although the exact pathogenesis of the triad is unknown, it appears to be related to follicular occlusion in areas with apocrine glands. Wolf isotopic response refers to the occurrence of a new dermatosis at the site of another, unrelated, previously healed dermatosis. We present a 26-year-old man with a history of pemphigus foliaceus (PF) who developed large draining nodules with scarring and sinus tracts, compatible with follicular occlusion triad, preferentially at areas previously affected by PF thirteen months after treatment with rituximab. To the authors' knowledge there are no reported cases of follicular occlusion triad or HS manifesting as an isotopic response. However, one member of the triad, HS, has been reported to occur infrequently following the use of biologic agents such as adalimumab, infliximab, tocilizumab, and rituximab for chronic immune-mediated inflammatory diseases (psoriasis, Crohn disease, rheumatoid arthritis, and ankylosing spondylitis).

The Role of Collagen XVII in Cancer: Squamous Cell Carcinoma and Beyond.

Alterations in the extracellular matrix (ECM) likely facilitate the first steps of cancer cell metastasis and supports tumor progression. Recent data has demonstrated that alterations in collagen XVII (BP180), a transmembrane protein and structural component of the ECM, can have profound effects on cancer invasiveness. Collagen XVII is a homotrimer of three α1 (XVII) chains. Its intracellular domain contains binding sites for plectin, integrin ß4, and BP230, while the extracellular domain facilitates interactions between the cell and the ECM. Collagen XVII and its shed ectodomain have been implicated in cell motility and adhesion and are believed to promote tumor development and invasion. A strong association of collagen XVII ectodomain shedding and tumor invasiveness occurs in squamous cell carcinoma (SCC). Aberrant expression of collagen XVII has been reported in many epithelial cancers, ranging from squamous cell carcinoma to colon, pancreatic, mammary, and ovarian carcinoma. Thus, in this review, we focus on collagen XVII's role in neoplasia and tumorigenesis. Lastly, we discuss the importance of targeting collagen XVII and its ectodomain shedding as a novel strategy to curb tumor growth and reduce metastatic potential.

Hidradenitis suppurativa and pemphigus: a cross-sectional study.

A recent study of comorbidities in hospitalized pemphigus patients in the United States has demonstrated a significant association of hidradenitis suppurativa (HS) and pemphigus, but this association has not been firmly established in other populations. A retrospective, cross-sectional study was undertaken to determine the prevalence of HS in patients with pemphigus and compare with control subjects. Regression analysis was performed to obtain ORs, and 95% CIs, to evaluate the prevalence between pemphigus patients and controls matched by age, sex, and ethnicity. Among the patients included in the study, 1985 patients had pemphigus and 9874 were control subjects. The average age of presentation of pemphigus was 72.1 ± 18.5 and the group was comprised of 59.8% females. Overall, the pemphigus group had lower rates of smoking (25.7% vs. 27.9%; P = 0.045). The prevalence of HS was greater in patients with pemphigus than in control subjects (OR 4.98; 95% CI 1.01-24.69; P < 0.001), with an even more prominent association among patients who have been prescribed "pemphigus-related treatments" (OR 6.30; 95% CI 1.27-31.22; P < 0.001). The study detected a significant association between HS and pemphigus in an Israeli population. Future prospective studies are needed to establish a temporal order of appearance and the mechanistic relationship between these entities.

Autoimmune blistering diseases provoked during the treatment of chronic inflammatory disease with biologic agents: a systematic review.

BACKGROUND: To investigate the clinical course of autoimmune blistering diseases (AIBDs) following treatment with biologic agents (BAs) for chronic inflammatory diseases. METHODS: A comprehensive review of available, published literature was performed using PubMed and CINAHL search engines. Diagnostic criteria of AIBD included positive direct immunofluorescence studies and/or positive serology with clinically suggestive features. RESULTS: A total of 22 cases of AIBDs provoked by the use of BAs were found. The most commonly implicated agents were tumor necrosis factor-alpha inhibitors (n = 14). The mean age of onset of AIBD was 59.4 years (median 61.5 years, range 31-82). Average time to onset of AIBD following initiation of the suspected BA was 33.7 ± 43.8 weeks (range 3 days to 152 weeks). Psoriasis was the most common associated condition for which the BA was prescribed (n = 11), followed by rheumatoid arthritis (n = 6) and ulcerative colitis (n = 5). Of the 21 cases reporting AIBD outcome, 17 reported remission or complete resolution upon stopping treatment with the involved BA. Four cases reported continued bullae formation without worsening of disease following cessation of the BA or systemic corticosteroids used to treat the AIBD. Five cases rechallenged the patient with the involved BA and four of the five reported recurrence, often with quicker onset and more severe symptoms. CONCLUSIONS: BAs may be suspected in patients developing AIBD while being treated for chronic inflammatory diseases. A majority of cases resolve upon cessation of the offending agent.