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Supplemental Methods

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Gating strategy to identify macrophage and MDSC populations.

Absence of CD90+ populations in F4/80+ CD11b+ macrophages.

We sought to define cellular immune mechanisms of synergy between tumor-antigen–targeted monoclonal antibodies and chemotherapy. Established B16 melanoma in mice was treated with cytotoxic doses of cyclophosphamide in combination with an antibody targeting tyrosinase-related protein 1 (αTRP1), a native melanoma differentiation antigen. We find that Fcγ receptors are required for efficacy, showing that antitumor activity of combination therapy is immune mediated. Rag1−/− mice deficient in adaptive immunity are able to clear tumors, and thus innate immunity is sufficient for efficacy. Furthermore, previously treated wild-type mice are not significantly protected against tumor reinduction, as compared with mice inoculated with irradiated B16 alone, consistent with a primarily innate immune mechanism of action of chemo-immunotherapy. In contrast, mice deficient in both classical natural killer (NK) lymphocytes and nonclassical innate lymphocytes (ILC) due to deletion of the IL2 receptor common gamma chain IL2γc−/−) are refractory to chemo-immunotherapy. Classical NK lymphocytes are not critical for treatment, as depletion of NK1.1+ cells does not impair antitumor effect. Depletion of CD90+NK1.1− lymphocytes, however, both diminishes therapeutic benefit and decreases accumulation of macrophages within the tumor. Tumor clearance during combination chemo-immunotherapy with monoclonal antibodies against native antigen is mediated by the innate immune system. We highlight a novel potential role for CD90+NK1.1− ILCs in chemo-immunotherapy. Cancer Immunol Res; 3(3); 296–304. ©2015 AACR.

Therapy with αTRP1+CY can activate T cells against melanoma.

Depletion of NKp46+ (A), CD90+ (B), and CD8+ (C) cells.Gating strategy to identify macrophage and MDSC populations.

Therapeutic efficacy of αTRP1 combined with two doses of cyclophosphamide (CY) in established melanoma.

A 23-year-old man with Bruton's X-linked agammaglobulinemia (XLA), who required intravenous immunoglobulin G (IgG) every 3 weeks, presented with an erythematous scaly eruption adjacent to the chest port for antibiotic therapy (Figures 1A,B). His past medical history included

Granulomatous mycosis fungoides (GMF) harbors a worse prognosis compared with classic MF and remains a significant diagnostic dilemma. We analyzed clinicopathologic, immunophenotypic, and molecular characteristics of GMF to develop a diagnostic algorithm. Our methodology involved a retrospective case series study of patients with GMF from our database between 2014 and 2020. A total of 8 patients with 9 biopsies of GMF were identified. Skin manifestations had variable clinical phenotype. Histologically, all cases demonstrated atypical CD4 + T-cell infiltrate with scant in 50% (n = 4), focal 37.5% (n = 3), and absent 25% (n = 2) epidermotropism. Granuloma formation was seen in 77.8% biopsies (n = 7) with sarcoid-type granulomas in 57.1% (n = 4) and granuloma annulare-like type in 42.9% (n = 3). In 66.7% of biopsies (n = 6), the CD4:CD8 ratio was4:1 and 66.6% (n = 6) of biopsies showed ≥50% loss of CD7 expression. T-cell receptor gene rearrangement studies performed on biopsy sections were positive in all biopsies (n = 6), whereas peripheral blood T-cell receptor gene rearrangement studies did not identify clonality. In conclusion, GMF has subtle or absent epidermotropism and variable granulomatous reaction; thus, the diagnosis requires a multimodal approach, and our proposed algorithm provides a framework to approach this diagnostic challenge.

Lip edema with non-caseating granulomas or lymphangiectasia pose a clinical and pathological challenge. These findings can be attributed to cheilitis granulomatosa (CG), Melkersson-Rosenthal syndrome (MRS), or Crohn disease (CD) depending on the appropriate clinical context. Lymphangiectasis, in particular, is a common pathological finding in CD due to lymphatic obstruction by granulomas and intralymphatic granulomas. Because oral symptoms can precede gastrointestinal symptoms of CD or be seen in patients with asymptomatic gastrointestinal disease, the identification of lymphangiectasia should raise the possibility of underlying CD. We present a case of a young woman with several years of lip swelling, with notable lymphangiectasia and subtle granulomas on pathological evaluation. The patient was diagnosed with MRS at an outside institution and treated with systemic steroids, without further systemic evaluation. We believe that early recognition of lymphangiectasia and consideration of CD early in the work-up are critical for early diagnosis and appropriate management. Neither clinical nor histopathological findings should be used in isolation to diagnose GC, MRS, or CD as there is significant debate as to the etiology and overlapping findings of these conditions. We highlight the importance of lymphangiectasia in diagnosing underlying CD in the appropriate clinical context.

Mucoceles are one of the most common benign mucosal growth in the oral cavity. They may be under-recognized in children. Mucoceles infrequently present in groups. We present an unusual case of eruptive superficial mucoceles in a 6-day old male that served as a diagnostic dilemma.

Background Tumor necrosis factor (TNF) inhibitors are widely used in pediatric patients with inflammatory bowel disease, as well as psoriasis. However, there is growing evidence that these medications can also paradoxically induce a psoriasiform skin reaction in a subset of patients. Goals We seek to share our experience in treating severe TNF inhibitor-induced psoriasis in a pediatric patient with Crohnrs disease. Study We report a case of a 10-year-old female with Crohnrs disease, who developed psoriasis after twelve months of infliximab therapy. Her skin disease was recalcitrant to topical therapies, methotrexate, and phototherapy. Results The patient was transitioned to ustekinumab with significant improvement in her symptoms and maintenance of remission of her bowel disease. Conclusion This is the first reported case of a school-age pediatric patient with TNF inhibitor-induced psoriasis treated with ustekinumab. Controlled trials are warranted to fully assess the safety and efficacy of ustekinumab for treating TNF inhibitor-induced psoriasis in the pediatric population.J Drugs Dermatol. 2020;19(3): doi:10.36849/JDD.2020.2106.

We present a 53-year-old woman with severe lichenoid dermatitis secondary to pembrolizumab therapy that was refractory to both topical and oral steroids. After almost three months without improvement, the rash was effectively combated with a single 15mg dose of methotrexate. We hope this case will help guide the management of the cutaneous adverse effects of anti-PD1 immunotherapy.

The preliminary year before dermatology training can be the source of much anxiety. However, there are aspects of it that can be rewarding and even fun. Herein, I present some of my own experiences as well as those of colleagues to help relieve stress and hopefully focus on the positive aspects of this busy year and the transition into dermatology training.

Physician burnout is a hot topic today, but what is burnout and who is at risk? In the field of dermatology-one with relatively few emergencies and often modest work hours-does burnout even apply to us? Herein, I provide a working definition of physician burnout and discuss who it affects as well as potential causes in dermatology.

Tattoos have a long history in the United States and the world. As dermatologists, we often treat patients who regret their tattoos and are seeking to have them removed. Laser technology allows for more effective tattoo removal. There are many unique risks to tattoo removal compared to general laser procedures, including paradoxical tattoo ink darkening and even allergic reactions to tattoo ink. Given the persistence of tattoos throughout history, this treatment challenge will likely persist for many years to come.

Melkersson-Rosenthal syndrome (MRS) is a rare syndrome of facial nerve palsy, facial edema, and lingua plicata that can be difficult to treat. We observed a patient with MRS of 4 years' duration that was unsuccessfully treated with multiple therapies. After a variety of diagnoses were considered at outside institutions, including Bell palsy, we diagnosed the patient with MRS based on clinical presentation of the classic triad. Treatment with adalimumab, a tumor necrosis factor α (TNF-α) antibody, showed improvement and relapse-free progress. Further research is needed regarding the role of TNF-α inhibitors in managing this rare condition.

Dermatology is an exciting and rewarding specialty. Looking for jobs after training can be a daunting task. From deciding to pursue a fellowship or a job in private practice, the opportunities are extensive. I have collected advice from recent dermatology graduates to help jump-start the planning process.

Ulcerated melanomas may have a unique biology and microenvironment. We test whether markers of immune infiltration correlate with clinical outcome in ulcerated compared to non-ulcerated primary melanoma tumors.Sixty-two stage II-III cutaneous melanomas, 32 ulcerated and 30 non-ulcerated, were analyzed for tumor-infiltrating lymphocytes (TILs). Immunohistochemistry (IHC) was performed for CD2, a marker previously shown to correlate with overall survival (OS) and recurrence-free survival (RFS) in this patient population. IHC using antibody, VE1, to BRAF V600E was also performed on a subset of 41 tumors to assess the relationship of BRAF mutation to immune markers.We found, using Cox regression models, that the presence of TILs was associated with improved OS (p = 0.034) and RFS (p = 0.002) in ulcerated melanoma tumors, but not in non-ulcerated melanoma (p = 0.632, 0.416). CD2 expression also was correlated with improved OS (p = 0.021) and RFS (p = 0.001) in ulcerated melanoma, but no relationship was seen in non-ulcerated melanoma (p = 0.427, 0.682). In this small population, BRAF status did not correlate with TILs or CD2+ count.Our data show that immune markers including TILs and CD2 count correlate more closely with survival in ulcerated melanomas than that in non-ulcerated melanomas. We propose that immune biomarkers may be particularly relevant to ulcerated, as compared to non-ulcerated, melanomas and that this merits study in larger populations.

Instructional methods for the simple suture technique vary widely and are seldom based on educational research. Published data indicate that video primers and structured instruction and evaluation decrease learning time and improve skill acquisition.To determine the amount of practice needed to attain simple suture proficiency and to identify the optimal teaching schedule for retention of skill.First-year and second-year medical students at the Icahn School of Medicine at Mount Sinai with little to no suturing experience were randomly divided into 2 equal groups, with one being taught on day 1 and tested for proficiency on day 30 (control group) and the other being taught on day 1 and tested for proficiency on days 10, 20, and 30 (experimental group). Students were evaluated using the objective structured assessment of technical skills method and a checklist. Those initially not proficient on a given day were immediately prompted to practice and retest. This cycle continued until proficiency was achieved for that day. The study was conducted from April 7, 2014, to June 30, 2014.Simple suture proficiency at 30 days and the mean number of practice sutures needed for proficiency on day 1.All students ultimately achieved proficiency. The mean (SD) number of practice sutures required to achieve proficiency at the initial training was 41 (15). Students in the control group had a 0% pass rate at the 30-day initial proficiency test, while students in the experimental group had a 91.7% pass rate at day 30 (P .001). There were no differences in instructional time, cumulative number of sutures, or objective structured assessment of technical skills scores at proficiency between groups across the study.Single instructional sessions may not be sufficient to maintain simple suture proficiency over the course of a 30-day elective. We propose the use of preparatory instructional videos, followed by instructor demonstration to introduce the technique. Independent practice with intermittent evaluation and critique allows for skill acquisition and time efficiency at the initial training. Students should view instructional videos and practice at least 10 repetitions every 10 days to maintain their skill.

We sought to define cellular immune mechanisms of synergy between tumor-antigen–targeted monoclonal antibodies and chemotherapy. Established B16 melanoma in mice was treated with cytotoxic doses of cyclophosphamide in combination with an antibody targeting tyrosinase-related protein 1 (αTRP1), a native melanoma differentiation antigen. We find that Fcγ receptors are required for efficacy, showing that antitumor activity of combination therapy is immune mediated. Rag1−/− mice deficient in adaptive immunity are able to clear tumors, and thus innate immunity is sufficient for efficacy. Furthermore, previously treated wild-type mice are not significantly protected against tumor reinduction, as compared with mice inoculated with irradiated B16 alone, consistent with a primarily innate immune mechanism of action of chemo-immunotherapy. In contrast, mice deficient in both classical natural killer (NK) lymphocytes and nonclassical innate lymphocytes (ILC) due to deletion of the IL2 receptor common gamma chain IL2γc−/−) are refractory to chemo-immunotherapy. Classical NK lymphocytes are not critical for treatment, as depletion of NK1.1+ cells does not impair antitumor effect. Depletion of CD90+NK1.1− lymphocytes, however, both diminishes therapeutic benefit and decreases accumulation of macrophages within the tumor. Tumor clearance during combination chemo-immunotherapy with monoclonal antibodies against native antigen is mediated by the innate immune system. We highlight a novel potential role for CD90+NK1.1− ILCs in chemo-immunotherapy. Cancer Immunol Res; 3(3); 296–304. ©2015 AACR.

We designed an imagery mnemonic to help medical students and residents learn the porphyrin pathway and associated diseases. Fourth year medical students at the Icahn School of Medicine at Mount Sinai in the spring of 2014 participated. One group (n=11) received the porphyrin pathway in a lecture explaining a mnemonic, whereas a second group (n=11) was simply taught the steps of the pathway. A pre-intervention assessment before the lectures was given to assess baseline differences in knowledge of the porphyrin pathway between the groups. Immediately following the lecture, 1 week after the lecture, and 3 weeks after the lecture, the students were given quizzes to assess their knowledge. Students were aware of the week 1 quiz and were asked not to study for it. The week 3 quiz was a surprise. There were no statistically significant differences in knowledge of the pathway at baseline (p=.45), at the immediate post-intervention (p=.22), or one week post-intervention (p=.40). Three weeks after the lecture, students in the mnemonic group scored 20% higher than controls (p=.02). Students who had learned the mnemonic demonstrated better long-term retention of information than students learning by the control method. This mnemonic minimizes study time while improving long-term retention.

Purpose: Tremelimumab (ticilimumab, Pfizer), is a monoclonal antibody (mAb) targeting cytotoxic T lymphocyte–associated antigen-4 (CTLA-4). Ipilimumab (Yervoy, BMS), another anti-CTLA-4 antibody, is approved by the U.S. Federal Drug Administration (FDA). Biomarkers are needed to identify the subset of patients who will achieve tumor control with CTLA-4 blockade. Experimental Design: Pretreatment peripheral blood samples from 218 patients with melanoma who were refractory to prior therapy and receiving tremelimumab in a multicenter phase II study were measured for 169 mRNA transcripts using reverse transcription polymerase chain reaction (RT-PCR). A two-class latent model yielded a risk score based on four genes that were highly predictive of survival (P < 0.001). This signature was validated in an independent population of 260 treatment-naïve patients with melanoma enrolled in a multicenter phase III study of tremelimumab. Results: Median follow-up was 297 days for the training population and 386 days for the test population. Expression levels of the 169 genes were closely correlated across the two populations (r = 0.9939). A four-gene model, including cathepsin D (CTSD), phopholipase A2 group VII (PLA2G7), thioredoxin reductase 1 (TXNRD1), and interleukin 1 receptor–associated kinase 3 (IRAK3), predicted survival in the test population (P = 0.001 by log-rank test). This four-gene model added to the predictive value of clinical predictors (P < 0.0001). Conclusions: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral blood are predictive of survival in patients with melanoma treated with tremelimumab. Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy. Clin Cancer Res; 20(12); 3310–8. ©2014 AACR.

Patients with resected stage II-III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin-fixed and paraffin-embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II-III FFPE primary melanomas was analyzed and a 53-immune-gene panel predictive of non-progression (area under the curve (AUC)=0.920) was defined. The signature predicted disease-specific survival (DSS P