Two congenital cases of pigmented epithelioid melanocytoma with unique clinical and genetic features.

Pigmented epithelioid melanocytomas (PEM) are intermediate-grade melanocytic lesions with frequent lymph node involvement and rare metastases that tend to follow an indolent course with a favorable outcome. We report two unique cases of congenital PEM with PRKCA fusion transcripts: a multifocal PEM with an aggressive incompletely resectable scalp tumor and a solitary palmar PEM with newly reported ITGB5-PRKCA fusion. Through these case reports and a summary of previously reported cases, we outline the spectrum of disease of PEM and highlight the key clinical and histopathologic features associated with PEM with PRKCA fusion transcripts. We also discuss the treatment options and suggest that surgical excision without further adjuvant systemic treatment is reasonable first-line therapy given the favorable prognosis.

A case of recalcitrant silicone granuloma treated with adalimumab: A case report.

Liquid silicone is a relatively inexpensive injectable used for soft tissue augmentation. Injection of silicone is associated with a risk of delayed granuloma formation associated with elevated levels of tumour necrosis factor-α. We report a case of recalcitrant silicone granulomas following facial injections of silicone successfully treated with tumour necrosis factor-α blockade. Our case, as well as previous reports, demonstrates the effectiveness of this therapy for the treatment of foreign body granulomas from due to silicone.

Paradoxical psoriasis in pediatric patients: A systematic review.

BACKGROUND: Paradoxical psoriasis occurs in pediatric patients following treatment with biologic agents. These presentations are not well described, and optimal treatment strategies have not been established. OBJECTIVE: To describe the reported rates, demographic characteristics, clinical presentation, and treatment options for TNF-α inhibitor-induced psoriasis. METHODS: Systematic review of published cases and cohort studies of paradoxical psoriasis induced by biologic agents, with specific reference to TNF-α inhibitors. RESULTS: We identified 4564 pediatric patients treated with TNF-α inhibitors, of whom 210 (4.6%) developed paradoxical psoriasis. Infliximab was the drug most likely to induce psoriasis (8.3%), followed by adalimumab (3.3%). Individual-level data were acquired from 129 individuals with a mean age of 13.6 years (SD: 4.0); 45.0% were male. The scalp was the most commonly affected area (47.5%), followed by the ears (30.8%). Most (63.3%) patients were continued on TNF-α inhibitor therapy. Among those who switched TNF-α inhibitors, only 32.0% had complete clearance of their skin lesions. Among patients who were switched to a non-TNF-α inhibitor, 81% had complete clearance of their paradoxical psoriasis. LIMITATIONS: Data were acquired from retrospective studies including case reports and case series. CONCLUSION: TNF-α inhibitor-induced psoriasis is a common adverse effect; however, most patients can continue their original therapy and be managed with skin-directed topical or systemic medications. If a patient requires medication discontinuation, switching to a new TNF-α inhibitor is unlikely to lead to resolution of their skin lesions.

BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition.

While several systemic therapies are approved for cutaneous T cell lymphoma (CTCL), a non-Hodgkin lymphoma of skin-homing T cells that may involve lymph nodes and peripheral blood in advanced stages, relapses are common. Mutational analysis of CTCL cells has revealed frequent amplification of the MYC oncogene, and bromodomain and extraterminal (BET) protein inhibitors have been shown to repress MYC expression in various malignancies. Towards a potential novel therapy, we thus sought to examine the effect of BET inhibition on CTCL cells in vitro. Each of the four tested BET inhibitors (JQ1, ABBV-075, I-BET762, CPI-0610) consistently induced dose-dependent decreases in viability of isolated patient-derived CTCL cells and established CTCL cell lines (MyLa, Sez4, HH, Hut78). This effect was synergistically potentiated by combination of BET inhibition with BCL2 inhibition (e.g. venetoclax) or histone deacetylase (HDAC) inhibition (e.g. vorinostat or romidepsin). There was also a marked increase in caspase 3/7 activation when JQ1 was combined with either vorinostat or romidepsin, confirming that the observed synergies are due in major part to induction of apoptosis. Furthermore, MYC and BCL2 expression were each synergistically repressed when CTCL cells were treated with JQ1 plus HDAC inhibitors, suggesting cooperative activities at the level of epigenetic regulation. Taken together, these data indicate that targeting BET proteins in CTCL represents a promising novel therapeutic strategy that may be substantially potentiated by combination with BCL2 or HDAC inhibition.

Transplantation in the Treatment of Primary Cutaneous Aggressive Epidermotropic Cytotoxic CD8-Positive T-Cell Lymphoma.

BACKGROUND: Primary cutaneous aggressive epidermotropic cytotoxic CD8 positive T-cell lymphoma (CD8+ PCAETL) is a rare subtype of peripheral T-cell lymphoma with poor outcomes and without a standardized treatment strategy. Allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested as a potential curative therapy. PATIENTS AND METHODS: We conducted a retrospective case series. We identified 8 patients with the diagnosis of CD8+ PCAETL, 4 of whom also underwent allogeneic HSCT. RESULTS: Eight patients were treated at our center with combination chemotherapy and several novel agents, including histone deacetylase inhibitors, brentuximab, and pralatrexate. Patients underwent a median of 8.5 treatments before HSCT. Six of the 8 patients examined, including all 4 who received an HSCT, were alive at their last follow-up. CONCLUSION: Allogeneic HSCT is a promising treatment modality for CD8+ PCAETL. Because of the aggressive nature of this disease and lack of sustained remission with currently available therapies, HSCT should be considered early in the course of treatment. Two novel agents, brentuximab and pralatrexate, showed significant activity against CD8+ PCAETL, and may be incorporated earlier in the treatment course.

Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients.

The presence and degree of peripheral blood involvement in patients with cutaneous T-cell lymphoma (CTCL) portend a worse clinical outcome. Available systemic therapies for CTCL may variably decrease tumor burden and improve quality of life, but offer limited effects on survival; thus, novel approaches to the treatment of advanced stages of this non-Hodgkin lymphoma are clearly warranted. Mutational analyses of CTCL patient peripheral blood malignant cell samples suggested the antiapoptotic mediator B-cell lymphoma 2 (BCL2) as a potential therapeutic target. To test this, we developed a screening assay for evaluating the sensitivity of CTCL cells to targeted molecular agents, and compared a novel BCL2 inhibitor, venetoclax, alone and in combination with a histone deacetylase (HDAC) inhibitor, vorinostat or romidepsin. Peripheral blood CTCL malignant cells were isolated from 25 patients and exposed ex vivo to the 3 drugs alone and in combination, and comparisons were made to 4 CTCL cell lines (Hut78, Sez4, HH, MyLa). The majority of CTCL patient samples were sensitive to venetoclax, and BCL2 expression levels were negatively correlated (r = -0.52; P =018) to 50% inhibitory concentration values. Furthermore, this anti-BCL2 effect was markedly potentiated by concurrent HDAC inhibition with 93% of samples treated with venetoclax and vorinostat and 73% of samples treated with venetoclax and romidepsin showing synergistic effects. These data strongly suggest that concurrent BCL2 and HDAC inhibition may offer synergy in the treatment of patients with advanced CTCL. By using combination therapies and correlating response to gene expression in this way, we hope to achieve more effective and personalized treatments for CTCL.