Prognostic Significance of Subungual Anatomic Site in Acral Lentiginous Melanoma.

CONTEXT.­: Acral lentiginous melanoma is a rare and aggressive type of cutaneous melanoma that arises on the acral skin and the nail unit. The prognostic significance of subungual anatomic site in acral lentiginous melanoma is not established. OBJECTIVE.­: To assess the impact of subungual anatomic site on overall survival and disease-specific survival in acral lentiginous melanoma. DESIGN.­: Retrospective cohort analysis. Clinicopathologic characteristics of 627 primary acral lentiginous melanomas (45 [7%] subungual and 582 [93%] nonsubungual) were summarized, and the impact of these characteristics on overall survival and disease-specific survival was determined using univariate and multivariable analyses. RESULTS.­: No significant differences in clinicopathologic features were identified between the subungual and nonsubungual acral lentiginous melanomas. The 1-, 5-, and 10-year overall survival rates were 81%, 40%, and 28%, respectively, for subungual acral lentiginous melanoma and 94%, 59%, and 38%, respectively, for nonsubungual acral lentiginous melanoma (P = .04); risk of death was significantly higher for subungual tumors (hazard ratio [95% confidence interval] = 1.59 [1.02-2.50]; P = .04). The 1-, 5-, and 10-year disease-specific survival rates were 94%, 56%, and 48%, respectively, for subungual acral lentiginous melanoma versus 96%, 69%, and 55%, respectively, for nonsubungual acral lentiginous melanoma (P = .18). By multivariable analysis, independent poor prognostic factors included older age and ulceration for overall survival and greater Breslow thickness and sentinel lymph node positivity for overall survival and disease-specific survival. Subungual anatomic site was not an independent prognostic factor for overall or disease-specific survival. CONCLUSIONS.­: Subungual anatomic site is not an independent prognostic factor for acral lentiginous melanoma.

Surgical site identification with personal digital device: A prospective pilot study.

BACKGROUND: Various means to facilit ate accurate biopsy site identification have been proposed. OBJECTIVE: To determine the accuracy of biopsy site identification by using photographs taken with a patient's digital device by a dermatologist versus professional medical photography. METHODS: Photographs of circled biopsy sites were taken with personal digital devices by the principal investigator (PI). Another set of photographs was taken by a professional photographer. Secondary photographs were taken of the biopsy site location pointed to by the staff and PI on the basis of the personal digital device image and professional medical photography, respectively. On the basis of secondary photographs, 2 independent dermatologists determined whether the skin biopsy locations pointed out by the staff were consistent with the ones pointed out by PI. RESULTS: Per dermatologist A, the staff correctly identified all 53 biopsy sites. Per dermatologist B, the staff were correct on 51 of 53 observations. Dermatologist C, the final arbiter, concurred with dermatologist A on the 2 cases in which dermatologist B was not certain of the location of the biopsy site. LIMITATIONS: The mean interval from initial biopsy to reidentification of the site was 36.2 days. CONCLUSION: Utilizing patients' personal digital devices is a cost-effective, Health Insurance Portability and Accountability Act-compliant, and readily available means to identify skin biopsy sites.

Case of vemurafenib-induced Sweet's syndrome.

Vemurafenib is a targeted therapy that has become standard treatment for patients with advanced melanoma with a V600E BRAF mutation. It has been associated with frequent skin toxicity, including photosensitivity, rash and squamous cell carcinomas. We present an 83-year-old woman with an advanced V600E BRAF-mutant melanoma who developed a severe skin rash and fatigue after taking vemurafenib. The dose was reduced from 960 to 720 to 480 mg twice a day; however, she was subsequently admitted to the hospital with fever, chills, fatigue, confusion and a diffuse skin eruption. She then developed hypoxia and acute renal failure that required hemodialysis. A biopsy of her skin lesions revealed a neutrophilic dermatitis with papillary dermal edema, consistent with Sweet's syndrome. Her symptoms resolved upon discontinuation of vemurafenib and treatment with prednisone. This constellation of symptoms and clinical course are consistent with drug-induced Sweet's syndrome caused by vemurafenib.

Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK.

Sorafenib is U.S. Food and Drug Adminstration-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal-regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor-induced cSCC. Here, we report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun-NH(2)-kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif-containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis.

BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling.

Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates and increased survival in melanoma. Approximately 22% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) during therapy. The prevailing explanation for this is drug-induced paradoxical ERK activation, resulting in hyperproliferation. Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling is suppressed in multiple contexts, including in cSCC of vemurafenib-treated patients, as well as in mice. Expression of a mutant ZAK that cannot be inhibited reverses the suppression of JNK activation and apoptosis. Our results implicate suppression of JNK-dependent apoptosis as a significant, independent mechanism that cooperates with paradoxical ERK activation to induce cSCC, suggesting broad implications for understanding toxicities associated with BRAF inhibitors and for their use in combination therapies. DOI: http://dx.doi.org/10.7554/eLife.00969.001.

Cutaneous and systemic adverse reactions to antibiotics.

Antibiotics cause a variety of cutaneous and systemic reactions. Reactions can range from mild exanthems to life-threatening toxic epidermal necrolysis. For this reason, it is important for dermatologists to recognize common cutaneous adverse reactions caused by specific antibiotics. This review highlights the clinical features and management of common adverse reactions to antibiotics.