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.

Steroid-sparing properties of emollients in dermatology.

Topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs) are very effective treatments in inflammatory dermatoses, but carry risks with long-term use. TCS are associated with cutaneous atrophy and tachyphylaxis and TCIs can be irritating and contain a black box warning of an increased risk of cancers including lymphoma and non-melanomatous skin cancers. Nevertheless, they are appropriate treatments for inflammatory conditions such as psoriasis and atopic dermatitis (AD) and should be used more often with disease flares and less as maintenance therapy. Given the associated risks of long-term continuous use with these pharmacologic agents, alternatives are needed with similar anti-inflammatory and barrier repair properties that can be used indefinitely without risk. Some over-the-counter (OTC) ingredients such as colloidal oatmeal and petrolatum, as well as anti-inflammatory prescription moisturizers (medical device creams), have demonstrated efficacy with little complications in skin barrier repair and symptom relief in steroid-responsive conditions. With regimented application, these non-drug options are safe and effective and can limit the longterm continuous use of TCS or TCIs.

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.

Blood mRNA expression profiling predicts survival in patients treated with tremelimumab.

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.

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.

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.