Detection of novel therapies using a multi-national, multi-institutional registry of cutaneous immune-related adverse events and management.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) remain a prevalent and common sequelae of immune checkpoint inhibitor (ICI) therapy, often necessitating treatment interruption and prolonged immune suppression. Treatment algorithms are still poorly defined, based on single-institution case reports without adequate safety assessments, and subject to publication bias. METHODS: Data in this registry were collected through a standardized REDCap form distributed to dermatologists via email listserv. RESULTS: Ninety-seven cirAEs were reported from 13 institutions in this registry. Topical and systemic steroids were the most common treatments used; however, targeted treatment matched to disease morphology was identified at numerous sites. Novel cirAE therapy uses that to our knowledge have not been previously described were captured including tacrolimus for the treatment of follicular, bullous, and eczematous eruptions and phototherapy for eczematous eruptions. Moreover, further evidence of cirAE treatment applications sparsely described in literature were also captured in this study including dupilumab and rituximab for bullous eruptions, phototherapy for lichenoid and psoriasiform eruptions, and acitretin for psoriasiform eruptions, among others. No serious adverse events were reported. Numerous targeted therapeutics including dupilumab, rituximab, and psoriasis biologics, among others, were associated with a cirAE grade improvement of ≥2 grades in every patient treated. CONCLUSION: This study suggests that a multi-institutional registry of cirAEs and management is not only feasible but that the information collected can be used to detect, evaluate, and rigorously assess targeted treatments for cirAEs. Further expansion and modification to include treatment progression may allow for sufficient data for specific treatment recommendations to be made.

Dysregulation of the TOX-RUNX3 pathway in cutaneous T-cell lymphoma.

Studies have examined gene expression changes in Sézary syndrome (SS), but disease pathogenesis remains largely unknown, and diagnosis and treatment are difficult. TOX is a transcription factor involved in CD4+ T-cell development with downstream effects on RUNX3, a known tumor suppressor gene. We sought to identify genes involved in SS disease pathogenesis with the potential to enable diagnosis and treatment. We utilized previously reported transcriptome sequencing data to construct a list of candidate genes, which was narrowed using pathway analysis. qRT-PCR confirmed TOX upregulation (>7 fold increase) in SS (n = 5), as well as two established markers, PLS3 and KIRD3DL2. We also evaluated expression of members of the TOX-RUNX3 pathway and confirmed downregulation of RUNX3 (0.59 fold decrease) and upregulation of GATA3 (2 fold increase). Moreover, TOX and RUNX3 expression were significantly inversely proportional. Using siRNA to suppress TOX, we demonstrated that TOX knockdown rescues RUNX3 expression and reduces cell viability. We evaluated TOX protein expression in paraffin-embedded skin biopsies with immunohistochemistry, showing nuclear staining of CTCL infiltrates, suggesting it is a candidate diagnostic biomarker. Further studies validating our findings and evaluating the TOX-RUNX3 pathway and the role of TOX as a disease marker and therapeutic target are warranted.

A Qualitative, Cross-Sectional Study of Positive and Negative Comments of Residency Programs Across 9 Medical and Surgical Specialties.

IMPORTANCE: Residency applicants often use social media to discuss the positive and negative features of prospective training programs. An examination of the content discussed by applicants could provide guidance for how a medical education faculty can better engage with prospective trainees and adapt to meet the educational expectations of a new generation of digital-native physicians. OBJECTIVE: The objective was to identify unstructured social media data submitted by residency applicants and categorize positive and negative statements to determine key themes. DESIGN: The study design was qualitative analysis of a retrospective cohort. SETTING: Publicly available datasets were used. PARTICIPANTS: The participants were anonymized medical trainees applying to residency training positions in 9 specialties-dermatology, general surgery, internal medicine, obstetrics/gynecology, plastic surgery, otolaryngology, physical medicine and rehabilitation, pediatrics, and radiology-from 2007 to 2017. MAIN OUTCOMES AND MEASURES: After we developed a standardized coding scheme that broke comments down into major features, themes, and subthemes, all unstructured comments were coded by two independent researchers. Positive and negative comments were coded separately. Frequency counts and percentages were recorded for each identified feature, theme, and subtheme. The percent positive and negative comments by specialty were also calculated. RESULTS: Of the 6314 comments identified, 4541 were positive and 1773 were negative. Institution was the most commonly cited major feature in both the positive (n = 767 [17%]) and negative (n = 827 [47%]) comments. Geography was the most cited theme, and City, Cost of Living, and Commute were commonly cited subthemes. Training was the next most cited major feature in both positive (n = 1005 [22%]) and negative (n = 291 [16%]) comments, with Clinical Training being more commonly cited compared to Research Opportunities. Overall, 72% of comments from all were positive; however, the percent of comments that were positive comments varied significantly across the 9 specialties. Pediatrics (65%), dermatology (66%), and internal medicine (68%) applicants were more likely to express negative comments compared with the global average, but physical medicine and rehabilitation (85%), radiology (82%), otolaryngology (81%), and plastic surgery (80%) applicants were more likely to express positive comments. CONCLUSIONS AND RELEVANCE: This qualitative analysis of positive and negative themes as posted by applicants in recent matching years is the first and provides new detailed insights into the motivations and desires of trainees.

Metastatic calcinosis cutis in a patient with Hodgkin's lymphoma.

Calcinosis cutis results from the deposition of insoluble calcium salts in the skin and subcutaneous tissue. Herein, we report a case of extensive metastatic calcinosis cutis in an 18-year-old woman with stage IV Hodgkin lymphoma with skeletal involvement. With combination therapy including radiation directed at her lymphoma and diltiazem, her lesions improved dramatically. This case demonstrates the previously unreported association between calcinosis cutis and Hodgkin lymphoma.

Underutilization of Mohs Micrographic Surgery for Less Common Cutaneous Malignancies in the United States.

BACKGROUND: Consensus guidelines have defined select less common skin cancers appropriate for Mohs micrographic surgery (MMS), as these tumors are characterized by asymmetric growth patterns that challenge conventional surgical extirpation of disease. OBJECTIVE: The authors aimed to define surgical patterns of care and to identify factors affecting treatment selection in the United States. MATERIALS AND METHODS: Retrospective cohort analysis of nonmetastatic nonmelanoma skin cancers deemed appropriate for MMS by American Academy of Dermatology/American College of Mohs Surgery/American Society for Dermatologic Surgery Association/American Society for Mohs Surgery appropriate use criteria from the National Cancer Data Base from 1998 to 2012. RESULTS: Of the included 15,121 patients, 8% received MMS, 30% primary excision, 12% narrow re-excision, and 50% wide re-excision. Utilization of MMS was negatively influenced by community cancer programs, Northeast region, lower education, uninsured status, and administration of radiotherapy. High-risk face areas, lower comorbidity score, and microcystic adnexal carcinoma were associated with higher likelihood of receiving MMS. After adjusting for tumor size, tumor location, and histology, MMS remained an independent predictor of achieving negative surgical margins (odds ratio 3.15, 95% CI 2.27-4.36, and p < .0001). CONCLUSION: There is considerable variation in surgical treatment patterns by both sociodemographic, treatment, and tumor characteristics. Despite low utilization, patients receiving MMS are more likely to achieve negative surgical margins and less likely to receive radiotherapy.

Tumor Stage Mycosis Fungoides in a Child.

Mycosis fungoides is uncommon in children and most often presents as stage IA/IB. We present a case of stage IIB mycosis fungoides in a 13-year-old boy and discuss diagnostic examination and treatment considerations.

Comparative proteomic analysis reveals unique tumor protein composition among the melanoma subtypes pure desmoplastic and superficial spreading.

The U.S. death rate for melanoma has not decreased, despite the use of depth at biopsy and sentinel lymph node status to determine the risk of metastasis. Additional prognostic indicators and therapeutic targets are required, and identification of candidate proteins was the goal of this study. We utilized comparative mass spectrometry to compare five samples of each of two forms of melanoma, pure desmoplastic, which by depth at diagnosis has a favorable prognosis, and superficial spreading. Ontological analysis was applied to identify proteins and networks that were increased in one of the two subtypes. Analysis revealed a protein signature increase in pure desmoplastic melanoma associated with cell-to-cell binding and a signature increase in superficial spreading melanoma responsible for the cellular stress response including a constellation of heat shock proteins. The two subtypes of melanoma compared in this study have two unique protein compositions that correlate with their phenotypes. Further validation studies are warranted to evaluate the utility of identified proteins as prognostic markers and therapeutic targets.