There have been major developments in targeted therapeutics with the clinical development of selective BRAF inhibitors (BRAFi) for patients with metastatic BRAF V600E mutant melanoma. Objective response rate of almost 50% has been witnessed in BRAFi clinical trials. Frequent side effects range from squamoproliferative lesions, including hyperplasia, keratoacanthomas, and squamous cell carcinomas to second primary melanomas. We describe a 50-year-old Hispanic woman with BRAF V600E mutant metastatic melanoma who was treated with surgery, radiation therapy, interleukin-2, and was enrolled on a BRAFi (dabrafenib) trial. Two months after initiation, she developed multiple erythematous, indurated, tender subcutaneous nodules bilaterally on the anterior thighs, posterior arms, and left dorsal forearm without overlying epidermal change. Punch biopsy revealed panniculitis with necrotizing granulomata. Infectious and other causes for panniculitis were excluded. We believe the histology likely represents a reaction to BRAFi therapy based on the temporal relationship of its onset to initiation of BRAFi therapy and previously reported cases of neutrophilic panniculitis associated with BRAFi therapy. Panniculitis has been emerging as an important unusual side effect of BRAFi therapy. Our case illustrates a unique presentation of BRAFi-associated panniculitis demonstrating necrotizing granulomata.

Dabrafenib

Panniculitis

Trametinib

V600E

10.1097/dad.0000000000000230

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Citations (19)

Data from Mutational Landscape of Aggressive Cutaneous Squamous Cell Carcinoma

Curtis R. Pickering Jane H. Zhou J. Jack Lee Jennifer Drummond S. Andrew Peng

<div>AbstractPurpose: Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC.Experimental Design: Whole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias.Results: Despite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion.Conclusions: The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC. Clin Cancer Res; 20(24); 6582–92. ©2014 AACR.</div>

10.1158/1078-0432.c.6523832

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Summary of expression of SPARC protein in cutaneous vascular neoplasms and mimickers

Annals of Diagnostic Pathology (2018)

Shakuntala H. Mauzo Denái R. Milton Víctor G. Prieto Carlos A. Torres‐Cabala Wei‐Lien Wang

Matricellular protein

Osteonectin

10.1016/j.anndiagpath.2018.03.005

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Citations (3)

Beyond BRAF V600

Alan Siroy Genevieve M. Boland Denái R. Milton Jason Roszik Silva Frankian

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Citations (86)

HUMAN KERATINOCYTES EXPRESS FUNCTIONAL α-MSH (MC1-R) RECEPTORS

In Vitro Cellular & Developmental Biology - Animal (2001)

Jonathan L. Curry Wilfred Pinto Brian J. Nickoloff Andrzej Słomiński

10.1290/1071-2690(2001)037<0234:hkefmm>2.0.co;2

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Interleukin-6 Blockade Abrogates Immunotherapy Toxicity and Promotes Tumor Immunity

SSRN Electronic Journal (2021)

Yared Hailemichael Daniel H. Johnson Noha Abdel‐Wahab Wai Chin Foo May Daher

Immune checkpoint blockade (ICB) for cancer is associated with high response rates but also high rates of adverse events. To elucidate the underlying immunobiology, we profiled gene expression in intestinal, colitis, and tumor tissue from ICB-treated patients, with parallel studies in preclinical models, and validated our findings in a review of clinical cohort treated with interleukin-6 blockade. Expression of interleukin-6, neutrophil and chemotactic markers was higher in colitis than in normal intestinal tissue. The genes upregulated in colitis were not upregulated in responding tumors from patients receiving ICB. In murine models, interleukin-6 blockade was associated with improved tumor control and a higher density of CD4/CD8 effector T-cells, with reduced Th17, macrophages, and myeloid cells. In an experimental autoimmune encephalomyelitis (EAE) model with tumors, combined interleukin-6 blockade and ICB enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone. Interleukin-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.

10.2139/ssrn.3808296

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The spectrum of hair loss in patients with mycosis fungoides and Sézary syndrome

Journal of the American Academy of Dermatology (2010)

Ming Yang Bi Jonathan L. Curry Angela M. Christiano Maria Hordinsky David A. Norris

Cutaneous lymphoma

Erythroderma

10.1016/j.jaad.2009.12.056

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Citations (44)

Human keratinocytes express functional α-MSH (MC1-R) receptors

In Vitro Cellular & Developmental Biology - Animal (2001)

Jonathan L. Curry Wilfred Pinto Brian J. Nickoloff Andrzej Słomiński

10.1007/bf02577535

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Citations (21)

Aberrant DNA Methylation Predicts Melanoma-Specific Survival in Patients with Acral Melanoma

Cancers (2019)

Dinesh Pradhan George Jour Denái R. Milton Varshini Vasudevaraja Michael T. Tetzlaff

Acral melanoma (AM) is a rare, aggressive type of cutaneous melanoma (CM) with a distinct genetic profile. We aimed to identify a methylome signature distinguishing primary acral lentiginous melanoma (PALM) from primary non-lentiginous AM (NALM), metastatic ALM (MALM), primary non-acral CM (PCM), and acral nevus (AN). A total of 22 PALM, nine NALM, 10 MALM, nine PCM, and three AN were subjected to genome-wide methylation analysis using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites. A prominent finding was that the methylation profiles of PALM and NALM were distinct. Four of the genes most differentially methylated between PALM and NALM or MALM were HHEX, DIPK2A, NELFB, and TEF. However, when primary AMs (PALM + NALM) were compared with MALM, IFITM1 and SIK3 were the most differentially methylated, highlighting their pivotal role in the metastatic potential of AMs. Patients with NALM had significantly worse disease-specific survival (DSS) than patients with PALM. Aberrant methylation was significantly associated with aggressive clinicopathologic parameters and worse DSS. Our study emphasizes the importance of distinguishing the two epigenetically distinct subtypes of AM. We also identified novel epigenetic prognostic biomarkers that may serve to risk-stratify patients with AM and may be leveraged for the development of targeted therapies.

Acral lentiginous melanoma

CpG site

10.3390/cancers11122031

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Citations (22)

Bullous pemphigoid secondary to bintrafusp alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1

JAAD Case Reports (2021)

BS Claire J. Wiggins Van K. Morris Natasha Klimas Priyadharsini Nagarajan Jonathan L. Curry

10.1016/j.jdcr.2021.04.027

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Citations (2)