Immune biomarkers are more accurate in prediction of survival in ulcerated than in non-ulcerated primary melanomas.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Defining the role of CD2 in disease progression and overall survival among patients with completely resected stage-II to -III cutaneous melanoma.

BACKGROUND: Accurate assessment of prognosis remains clinically challenging in stage II to III cutaneous melanoma. Studies have implicated CD2 in immune surveillance, T-cell activation, and antitumor immunity, but its role in melanoma progression warrants further investigation. OBJECTIVE: We sought to investigate the prognostic role of CD2 in primary cutaneous melanoma. METHODS: Patients with American Joint Committee on Cancer stage II and III cutaneous melanoma were identified by retrospective review of dermatopathology databases from 2001 to 2010 at Mount Sinai Medical Center and Geisinger Medical Center. Additional patients were provided by New York University Medical Center based on retrospective review and tissue availability. Immunohistochemistry was performed on tumors from 90 patients with known recurrence status and documented follow-up. RESULTS: Primary tumors from patients who developed recurrent disease had fewer CD2(+) cells (P = .0003). In multivariable analyses including standard clinicopathologic predictors, CD2 was an independent predictor of disease recurrence (P = .008) and overall survival (P = .007). CD2 count correlated with characterization of tumor-infiltrating lymphocytes (P = .0004). Among the intermediate prognosis group of patients with nonbrisk tumor-infiltrating lymphocytes, CD2 count was predictive of disease recurrence (P = .0006) and overall survival (P = .0318). LIMITATIONS: Our retrospective design may have resulted in incomplete representation of patients lacking documented follow-up. CONCLUSIONS: CD2 may be an independent predictor of disease recurrence and overall survival among patients with primary cutaneous melanoma.

Urea: a comprehensive review of the clinical literature.

INTRODUCTION: Urea is an organic compound that has been used clinically for dermatological diseases for more than a century. Urea is a potent emollient and keratolytic agent, making urea an effective monotherapy for conditions associated with dry and scaly skin. A systematic review of the literature is needed to provide clinicians with evidence-based applications of urea in the treatment of dermatological diseases. METHODS: A PubMed search was conducted using the term "urea" combined with "skin," "ichthyosis," "psoriasis," "xerosis," "emollient," "onychomycosis," "dermatitis," and "avulsion." A total of 81 publications met inclusion criteria and were evaluated. Treatment indication(s), test agents, number of subjects, treatment protocols, results, and side effects were recorded. RESULTS: Effective treatment with urea has been reported for the following conditions: ichthyosis, xerosis, atopic dermatitis/eczema, contact dermatitis, radiation induced dermatitis, psoriasis/seborrheic dermatitis, onychomycosis, tinea pedis, keratosis, pruritus, and dystrophic nails. Furthermore, urea has been used with other medications as a penetration enhancing agent. Mild irritation is the most common adverse event, proving urea to be a safe and tolerable topical drug without systemic toxicity. DISCUSSION/CONCLUSION: Urea is a safe, effective dermatologic therapy with wide-ranging clinical utility and minimal, non-systemic side effects. In order to optimize patient care, dermatologists should be well informed with regards to urea's indications and efficacy.

Teaching the Simple Suture to Medical Students for Long-term Retention of Skill.

IMPORTANCE: 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. OBJECTIVES: To determine the amount of practice needed to attain simple suture proficiency and to identify the optimal teaching schedule for retention of skill. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: Simple suture proficiency at 30 days and the mean number of practice sutures needed for proficiency on day 1. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.

Requirement for innate immunity and CD90⁺ NK1.1⁻ lymphocytes to treat established melanoma with chemo-immunotherapy.

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.

Instructional video for teaching venepuncture.

BACKGROUND: Safe venepuncture technique is a critical skill for health care professionals, to avoid accidental occupational injury. This study investigates whether watching an instructional video improves medical students' ability to perform venepuncture safely. METHODS: This was a randomised, controlled, assessor-blinded trial that evaluated the utility of an instructional video, with the primary outcome of the ability to perform venepuncture safely. Forty-two second-year medical students were recruited and randomised to receive either video instruction (group A, n = 20) or no intervention (group B, n = 22). Prior to the study, all students attended an instructor-led workshop on venepuncture. During the study, students were paired and instructed to perform venepuncture on a partner. Performance was assessed using a points-based checklist. Pre- and post-study surveys were conducted to assess confidence with technique. RESULTS: The mean total checklist score was higher in group A than in group B, with values of 14.15 and 9.18, respectively (p < 0.0001, maximum 18 points). Mean scores were also higher in group A than in group B among students who performed first (p = 0.008) and students who performed second (p = 0.005) within the pair. From the post-procedure survey, only group A rated increased confidence in performing venepuncture after the study (p = 0.008). DISCUSSION: Students who watched an instructional video performed venepuncture more effectively and reported greater confidence with the technique. Medical students can benefit from having access to an instructional video on venepuncture as an adjunct to the standard curriculum. Safe venepuncture technique is a critical skill for health care professionals.

Dissection of immune gene networks in primary melanoma tumors critical for antitumor surveillance of patients with stage II-III resectable disease.

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<0.001) and recurrence-free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a coexpression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally, the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001), and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger data set annotated on the basis of prospectively gathered data.

Urticaria multiforme.

Urticaria multiforme is a benign cutaneous hypersensitivity reaction seen in pediatric patients that is characterized by the acute and transient onset of blanchable, annular, polycyclic, erythematous wheals with dusky, ecchymotic centers in association with acral edema. It is most commonly misdiagnosed as erythema multiforme, a serum-sickness-like reaction, or urticarial vasculitis. Since these three diagnoses represent distinct clinical entities with unique prognoses and management strategies, it is important that physicians distinguish urticaria multiforme from its clinical mimics in order to optimize patient care. By performing a thorough history and physical examination, the astute clinician can make the correct diagnosis and develop an appropriate, effective treatment plan while avoiding unnecessary biopsies and laboratory evaluations. The authors report a case of urticaria multiforme in a four-year-old girl in order to emphasize the distinctive morphological manifestations of this rare, albeit unique, disease seen in the pediatric population.

Oncolytic virus therapy for cancer.

The use of oncolytic viruses to treat cancer is based on the selection of tropic tumor viruses or the generation of replication selective vectors that can either directly kill infected tumor cells or increase their susceptibility to cell death and apoptosis through additional exposure to radiation or chemotherapy. In addition, viral vectors can be modified to promote more potent tumor cell death, improve the toxicity profile, and/or generate host antitumor immunity. A variety of viruses have been developed as oncolytic therapeutics, including adenovirus, vaccinia virus, herpesvirus, coxsackie A virus, Newcastle disease virus, and reovirus. The clinical development of oncolytic viral therapy has accelerated in the last few years, with several vectors entering clinical trials for a variety of cancers. In this review, current strategies to optimize the therapeutic effectiveness and safety of the major oncolytic viruses are discussed, and a summary of current clinical trials is provided. Further investigation is needed to characterize better the clinical impact of oncolytic viruses, but there are increasing data demonstrating the potential promise of this approach for the treatment of human and animal cancers.

Elevated rates of transaminitis during ipilimumab therapy for metastatic melanoma.

Melanoma is the deadliest form of skin cancer. Ipilimumab, a novel immunotherapy, is the first treatment shown to improve survival in patients with metastatic melanoma in large randomized controlled studies. The most concerning side effects reported in clinical studies of ipilimumab fall into the category of immune-related adverse events, which include enterocolitis, dermatitis, thyroiditis, hepatitis, hypophysitis, uveitis, and others. During the course of routine clinical care at Mount Sinai Medical Center, frequent hepatotoxicity was noted when ipilimumab was administered at a dose of 3 mg/kg according to Food and Drug Administration (FDA) guidelines. To better characterize these adverse events, we conducted a retrospective review of the first 11 patients with metastatic melanoma treated with ipilimumab at the Mount Sinai Medical Center after FDA approval. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevation, as defined by the National Cancer Institute's Common Terminology Criteria for Adverse Events, each occurred in six of 11 cases (≥grade 1), a notably higher frequency than could be expected on the basis of the FDA licensing study where elevations were reported in 0.8 and 1.5% of patients for AST and ALT, respectively. Grade 3 elevations in AST occurred in three of 11 patients as compared with 0% in the licensing trial. All cases of transaminitis resolved when ipilimumab was temporarily withheld without administration of immunosuppressive medication. During routine clinical care of late-stage melanoma patients with ipilimumab, physicians should monitor patients closely for hepatotoxicity and be aware that toxicity rates may differ across populations during ipilimumab therapy.

Hypertrophic osteoarthropathy presenting as unilateral cellulitis with successful treatment using pamidronate disodium.

Hypertrophic pulmonary osteoarthropathy is a paraneoplastic syndrome seen in patients with lung cancer. This condition is characterized by the presence of digital clubbing, periosteal thickening, synovial thickening, and severe pain of the affected joints. Other syndromes exhibiting clubbing may or may not have underlying diseases causing their manifestation. An example is primary hypertrophic osteoarthropathy, or pachydermoperiostosis. While clubbing makes up part of the clinical picture in both hypertrophic pulmonary osteoarthropathy and hypertrophic osteoarthropathy, the latter has no underlying disease associations. Rather, primary hypertrophic osteoarthropathy is familial, idiopathic, and has a chronic course often beginning during puberty in males. Secondary hypertrophic osteoarthropathy is an acquired form of clubbing that is classically associated with lung disease. However, it has also been associated with diseases of the heart, liver, and intestines. In the setting of pulmonary malignancy, secondary hypertrophic osteoarthropathy is known as hypertrophic pulmonary osteoarthropathy. Hypertrophic pulmonary osteoarthropathy has a distinct constellation of clinical findings that includes intractable pain often refractory to treatments other than resolution of the underlying disease process. The authors herein report a case of hypertrophic pulmonary osteoarthropathy masquerading as recurrent lower extremity cellulitis with chronic hand and foot pain in the setting of pulmonary malignancy that responded dramatically to intravenous pamidronate disodium (a bisphosphonate). Given the rarity of hypertrophic osteoarthropathy associated with lung cancer and the difficulty with pain management in such circumstances, the authors present the following case in which pain was mitigated by treatment with bisphosphonate therapy.