Andrew C. Walls

Gene expression profiling of anti-CTLA4-treated metastatic melanoma in patients with treatment-induced autoimmunity.

Ipilimumab (IPI) is a monoclonal antibody that targets the inhibitory CTLA4 receptor of T cells, enhancing T-cell-driven antitumor responses. IPI therapy in metastatic melanoma results in significant improvement in disease-free and overall survival, although after initial responses disease progression generally ensues. Identification of specific responses in tissue where melanoma tumor cells are subjected to IPI-driven immune attack may reveal mechanisms of treatment efficacy or resistance, permitting refinement of targeted therapeutic approaches. We used NanoString digital barcoding chemistry to identify changes in the transcriptome of metastatic melanoma cells before and after IPI treatment using two comprehensive panels containing a total of 1330 unique genes. Only patients who developed autoimmune disorders following treatment, signifying a robust immune response, were included. Despite evidence of an enhanced immune response, most patients eventually exhibited disease progression. Overall, data from five pre-IPI tumors and four post-IPI tumor samples (from three patients) permitted identification of several candidate genes that showed increased expression based on normalized counts after therapy. These included TTK (~3.1-fold, P=1.18e−4), which encodes a dual-specificity protein tyrosine kinase, a known cell cycle regulator, and BIRC5 (~3.0-fold, P=9.36e−4), which encodes the antiapoptotic protein survivin. Both TTK (MPS1) and survivin are targetable proteins against which a number of pharmacologic agents have been developed. CDK1, which encodes a protein tyrosine kinase known to phosphorylate survivin, was also upregulated (~3.2-fold, P=2.80−3). Tumor cell expression of TTK and survivin proteins was confirmed using immunohistochemistry in an expanded patient cohort. Differences in gene expression for several commonly encountered immune antigens, such as CD3, CD4, CD8, and CTLA4, were not statistically significant, likely reflecting the long length of time (average 323 days) between the last IPI dose and post-treatment biopsies. Although our sample size is limited, these results for the first time identify targetable genes that are significantly altered by interaction between a highly activated, IPI-treated immune system and melanoma cells.

Prevention of airborne propolis-induced allergic contact dermatitis with barrier cream

A 63-year-old man presented with a 4-year history of itching restricted to the scalp. Clobetasol 0.05% solution was the only effective medical intervention, although this gave him relief for no more than 1 hour after application. The patient stated that the application of rubbing alcohol to affected areas was the only other effective temporary treatment. Physical examination and histopathology revealed no specific abnormalities. Patch testing to 46 standard allergens was negative. Treatment with topical corticosteroids, oral antihistamines, antibiotics, and neuromodulatory medications failed to alleviate the ‘‘pruritus.’’ Most patients who complain of itching of the scalp present with visible lesions or dermatoses, from which a clinical or histological diagnosis can usually be made. Common causes of such scalp dermatoses include seborrheic dermatitis, contact dermatitis, psoriasis, dermatomyositis, and pediculosis. By contrast, patients with ‘‘pruritus’’ of the scalp without visible lesions also commonly present for relief of symptoms. A literature search of PubMed and Ovid databases led us to use ‘‘sensitivity’’ instead of just ‘‘pruritus’’ as the most encompassing terminology of symptoms from patients’ perspectives. The pathophysiology of skin sensitivity without visible lesions is poorly understood with an apparent reduced ‘‘tolerance threshold’’ of skin for itch but without specific immune or allergic reaction present and histopathology limited (if at all) to vasodilation or some subtle inflammatory response. Often noted, however, is increased transepidermal water loss that may allow greater entry of irritants through the skin. In contrast to other body areas, histamine may not be a mediator of itching on the scalp because in vivo analysis revealed decreased vascular and sensory sensitivity to histamine-induced pruritogenesis on the scalp as compared with the forearm, which in turn may be due to the scalp having significantly fewer histaminesensitive chemonocioceptors. Central processing of the itch stimulus could also be different, requiring a higher central threshold for itching on the scalp versus the area subserved by the trigeminal nerve. Pain may play a role in masking perceptions of itch as well because opioid administration often results counterintuitively in ‘‘pruritus’’ of the scalp. Up to 70% of patients with skin sensitivity have a psychiatric illness, and it is well known that psychiatric illnesses and psychosomatic factors can elicit ‘‘pruritus’’ and affect perception of scratching behavior. Furthermore, the scalp and face are the most common sites of involvement in localized skin sensitivity associated with psychiatric disease. Unfortunately, no high-level data exist to guide clinical practice in the treatment of scalp sensitivity. Topical corticosteroids and oral antihistamines often fail to relieve the ‘‘pruritus,’’ perhaps because of the scalp’s different local mediator of itch or different central processing of itch stimulus. More efficacious treatment modalities have been shown to focus on treatment of comorbid psychiatric disorders with use of tricyclic antidepressants, selective serotonin reuptake inhibitors, anxiolytics, and opioid antagonists. PEARL

Successful Treatment of Perianal Giant Condyloma Acuminatum in an Immunocompromised Host With Systemic Interleukin 2 and Topical Cidofovir

A 46-year-old man presented for evaluation of large recurrent growths around the anus and rectum. He had been diagnosed as having chronic lymphocytic leukemia at age 36 years and was treated with fludarabine phosphate, cyclophosphamide, and rituximab at age 42 years, with successful induction of remission. His disease returned 3 years later, and while undergoing chemotherapy with the same regimen, he developed perianal and penile skin lesions. The penile lesions cleared with serial treatment with cryotherapy, imiquimod, and sinecatechins, to which the perianal lesions were refractory. He underwent 2 surgical debulking procedures for the rapidly progressive perianal lesions, which exhibited aggressive regrowth within 2 weeks of each debulking. Physical examination revealed a large (>10 cm in diameter), circumferential (but not occluding the rectum), exophytic, friable perianal mass with punctate bleeding, consistent with giant condyloma acuminatum (GCA). An adjacent 3-mm papule with corymbiform surface consistent with a common wart was also noted (Figure 1). The patient reported considerable rectal pain and bleeding due to the anal condyloma. The perianal mass demonstrated severe squamous dysplasia, with focal areas concerning for squamous cell carcinoma in situ on histopathologic examination. The remaining findings from examination were unremarkable.

Impact of the 2009 AJCC staging guidelines for melanoma on the number of mitotic figures reported by dermatopathologists at one institution

In 2009 the revised seventh staging system for melanoma recommended the use of mitotic count to separate stage T1a from T1b. However, careful scrutiny of cases may lead to an inadvertent selection effect, with consequent increased reporting of mitotic counts.

Mohs micrographic surgery for recurrent chondroid syringoma of the eyebrow.

Three months later, the patient presented with firmness within the scar line. Intralesional triamcinolone was injected for treatment of hypertrophic scar with improvement. At 1 year, the patient presented with an enlarging nodule in the area, now thought to be recurrent tumor (Figure 2A). Because of the location and the potential for irregular or discontinuous tumor, MMS was chosen for reexcision. Four Mohs stages were required to clear the tumor, resulting in a final defect size of 1.6 by 1.3 cm. Complex repair was performed (Figure 2B, C). Review of the initial Mohs debulking revealed a 1.0by 0.7-cm tumor nodule with no significant cytological atypia, mitotic activity, or tumor necrosis (Figure 3). Mohs stages tracked a finger-like projection extending to the subcutaneous fat (Figure 4A, B). There was no evidence of recurrence at 6 months.

Abstract 5500: Phenotypic risk factors for malignant melanoma in-situ in US women and men

Malignant melanoma in-situ (MMIS) has been associated with the risk of invasive melanoma, either through invasive transformation or as a marker for de novo invasive melanoma. However, while risk of invasive melanoma has been extensively studied, very little data exists on phenotypic risk factors of MMIS. Objectives: In this study, we evaluated the risk of MMIS according to host phenotypic characteristics amongst a large population of US women and men. Methods: We used data from three prospective cohort studies, the Nurse9s Health Study 1 and 2 (NHS, NHS2), and the Health Professionals Follow-up Study (HPFS). Data were collected via biennial questionnaires from 44,998 males and 205,153 females over a 28, 20 and 22 year period for NHS1, NHS2, and HPFS, respectively. 1,097 melanoma in-situ lesions were identified and confirmed via pathology reports. Risk factors were family history of melanoma, number of atypical (>3mm) nevi on an extremity, childhood/adolescent sunburn reaction, number of childhood/adolescent sunburns and natural hair color at age 21. Age-adjusted and multivariate regression analysis was performed. Further sub-analysis in NHS evaluated MMIS risk based on Fitzpatrick skin type. Results: Individuals with a family history of melanoma had increased risk of MMIS in all three studies, NHS mvRR 1.51 (95% CI 1.13-2.02), NHS2 RR 1.95 (95% CI 1.42-2.69), HPFS RR 2.72 (95% CI 1.61-4.59). Three or more moles on the extremity were also associated with increased risk of MMIS, NHS RR 1.62 (95% CI 1.19-2.21), NHS2 RR 1.63 (95% CI 1.08-2.45), HPFS RR 1.93 (95% CI 1.21-3.08). In individuals with 6 or more moles on an extremity, the relative risk increased to reflect threefold risk, NHS mvRR 2.77 (95% CI 2.02-3.78), NHS2 mvRR 2.95 (95% CI 2.25-3.88), HPFS mvRR 2.79 (95% CI 1.75-4.46) (P for trend Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5500. doi:1538-7445.AM2012-5500