Disseminated punctate keratoderma: a rare case report and review of the literature.

We report a rare case of a 53-year-old womanpresenting with diffuse, late-onset disseminatedhyperkeratotic papules. Biopsy showed massivehyperkeratosis overlying a crateriform epidermaldepression and hypergranulosis with mild epidermalhyperplasia. There was no parakeratosis, cornoidlamella, or dyskeratosis. Based on the clinical findingsand histopathological features, a diagnosis ofdisseminated punctate keratoderma was made. Thisis a rare subtype of palmoplantar keratoderma, whichhas a putative increased risk of malignancy. This casereport emphasizes the importance of identifyingthe clinical and histological presentation of this rarecondition; referral of the patient for age-appropriatemalignancy screening is appropriate. We also presenta concise review of treatment options.

Transforming growth factor beta (TGF-ß) isoforms in wound healing and fibrosis.

Scar formation, with persistent alteration of the normal tissue structure, is an undesirable and significant result of both wound healing and fibrosing disorders. There are few strategies to prevent or to treat scarring. The transforming growth factor beta (TGF-ß) superfamily is an important mediator of tissue repair. Each TGF-ß isoform may exert a different effect on wound healing, which may be context-dependent. In particular, TGF-ß1 may mediate fibrosis in adults' wounds, while TGF-ß3 may promote scarless healing in the fetus and reduced scarring in adults. Thus, TGF-ß3 may offer a scar-reducing therapy for acute and chronic wounds and fibrosing disorders.

Ustekinumab for treatment of cutaneous Crohn's disease.

Cutaneous Crohn disease (CD) affecting the vulva, perineum, and perianal skin, is a rare entity, which may accompany or precede gastrointestinal CD. Vulvar involvement, if untreated, may ultimately require extensive surgery including vulvectomy to gain control of the disease. Both gastrointestinal and cutaneous CD respond to biologics, which block TNF. In addition, ustekinumab, which targets both IL-12 and IL-23 cytokines, is effective in patients with gastrointestinal CD who fail TNF blockade. However, it is unclear if ustekinumab is effective for cutaneous CD. Herein we present a patient with cutaneous CD affecting the vulva and perianal skin, which, at seven months, had a marked response to ustekinumab administered at higher doses than typically used for psoriasis.

In the clinic. Common cutaneous parasites.

This issue provides a clinical overview of Common Cutaneous Parasites focusing on prevention, diagnosis, treatment, practice improvement, and patient information. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including ACP Smart Medicine and MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of science writers and physician writers. Editorial consultants from ACP Smart Medicine and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult http://smartmedicine.acponline.org, http://mksap.acponline.org, and other resources referenced in each issue of In the Clinic.

Nitric oxide-producing myeloid-derived suppressor cells inhibit vascular E-selectin expression in human squamous cell carcinomas.

Squamous cell carcinomas (SCCs) are sun-induced skin cancers that are particularly numerous and aggressive in immunosuppressed individuals. SCCs evade immune detection at least in part by downregulating E-selectin on tumor vessels, thereby restricting entry of skin-homing T cells into tumors. We find that nitric oxide (NO) potently suppresses E-selectin expression on human endothelial cells and that SCCs are infiltrated by NO-producing iNOS(+) CD11b(+) CD33(+) CD11c(-) HLA-DR(-) myeloid-derived suppressor cells (MDSCs). MDSCs from SCCs produced NO, transforming growth factor-ß (TGF-ß), and arginase, and inhibited endothelial E-selectin expression in vitro. MDSCs from SCCs expressed the chemokine receptor CCR2 (chemokine (C-C motif) receptor 2) and tumors expressed the CCR2 ligand human ß-defensin 3 (HBD3), suggesting that CCR2/HBD3 interactions may contribute to MDSC recruitment to SCCs. Treatment of SCCs in vitro with the inducible nitric oxide synthase (iNOS) inhibitor N(ω)-nitro-L-arginine(L-NNA) induced E-selectin expression at levels comparable to imiquimod-treated SCCs undergoing immunologic destruction. Our results suggest that local production of NO in SCCs may impair vascular E-selectin expression. We show that MDSCs are critical producers of NO in SCCs and that NO inhibition restores vascular E-selectin expression, potentially enhancing T-cell recruitment. The iNOS inhibitors and other therapies that reduce NO production may therefore be effective in the treatment of SCCs and their premalignant precursor lesions, actinic keratoses.

IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells.

IL-15 and IL-2 possess similar properties, including the ability to induce T cell proliferation. However, whereas IL-2 can promote apoptosis and limit CD8(+) memory T cell survival and proliferation, IL-15 helps maintain a memory CD8(+) T cell population and can inhibit apoptosis. We sought to determine whether IL-15 could enhance the in vivo function of tumor/self-reactive CD8(+) T cells by using a T cell receptor transgenic mouse (pmel-1) whose CD8(+) T cells recognize an epitope derived from the self/melanoma antigen gp100. By removing endogenous IL-15 by using tumor-bearing IL-15 knockout hosts or supplementing IL-15 by means of exogenous administration, as a component of culture media or as a transgene expressed by adoptively transferred T cells, we demonstrate that IL-15 can improve the in vivo antitumor activity of adoptively transferred CD8(+) T cells. These results provide several avenues for improving adoptive immunotherapy of cancer in patients.