Evaluating the Safety and Efficacy of a Topical Formulation Containing Epidermal Growth Factor, Tranexamic Acid, Vitamin C, Arbutin, Niacinamide and Other Ingredients as Hydroquinone 4% Alternatives to Improve Hyperpigmentation: A Prospective, Randomized, Controlled Split Face Study.

Hyperpigmentation is a common concern of patients in aesthetic practice. There are various treatment options, but topical depigmenting agents such as hydroquinone (HQ) are usually a first-line option. Given HQ's side effects and potential controversy over its long-term use from prior animal studies, there is a consumer demand for non-HQ topical formulations that provide similar efficacy, but with a reduced adverse reaction profile to HQ. There is increasing evidence to support the use of selective growth factors, tranexamic acid, niacinamide, arbutin, and Vitamin C in improving hyperpigmentation. This study sought to determine whether a non-HQ topical formulation, composed of the aforementioned ingredients, could provide similar or improved efficacy to topical HQ, but with a reduced adverse reaction profile. This single-center, prospective, randomized, controlled split face study investigated the safety and efficacy of a proprietary product SKNB19 compared with hydroquinone 4% (HQ4%) in treating hyperpigmentation. Eighteen adult subjects with facial pigmentation were randomly assigned to have one side of their face treated with SKNB19 twice a day (morning and night application) and the other treated with HQ4% applied nightly. Patients used a 5-point scale to self-assess their overall appearance, and a 4-point scale to assess redness, irritation, and tolerability to the skin-brightening creams. A Wilcoxon signed-rank test was used to test whether there was a statistical difference between the two treatments. Three-dimensional imaging was performed before treatment was administered and again 1 month following treatment initiation using a Canfield Vectra 3D imaging system. Five independent reviewers comprising two dermatologists, two facial plastic surgeons, and one oculoplastic surgeon graded and performed a qualitative comparative assessment of each side of the face using the before and after images. A Wilcoxon signed-rank test was used to test whether there was a statistical difference in overall appearance between SKNB19- and HQ4%-treated sides. SKNB19-treated hyperpigmentation had a statistically significant improvement in the overall appearance of hyperpigmentation and was shown to be 28.5% better than HQ4%-treated skin in the patient self-assessment and 27% better than HQ4%-treated skin in the independent reviewer assessment. On pair-wise comparison, the independent reviewer assessment also showed that 88.2% of the SKNB19-treated sides appeared equal or better than the HQ4%-treated sides. One patient dropped out of the study because of severe intolerance to HQ4%. No patients experienced intolerance to SKNB19, and all were able to continue its use without adverse effects. SKNB19-treated hyperpigmentation also had a statistically significant reduction in irritation when compared with HQ4%-treated hyperpigmentation. Patients reported a reduction in redness when using SKNB19 as opposed to HQ4%, but these figures did not reach statistical significance. This study supports that SKNB19, a recently developed non-HQ proprietary product, is safe and effective in improving hyperpigmentation. SKNB19 significantly improved the appearance of hyperpigmentation when compared with HQ4% in both patient self-assessment and independent reviewer assessment. SKNB19 exhibited a lower adverse reaction profile and was significantly better tolerated than HQ4%. SKNB19 should be considered as a safe and effective non-HQ alternative for the management of hyperpigmentation.

Retrospective review of delayed adverse events secondary to treatment with a smooth, cohesive 20-mg/mL hyaluronic acid filler in 4500 patients.

BACKGROUND: Recent publications have suggested an increased risk of delayed adverse events (DAEs) with a smooth, cohesive 20-mg/mL hyaluronic acid filler, Juvéderm Voluma (HA-V). OBJECTIVE: To examine the occurrence of HA-V DAEs and identify patterns and characteristics. METHODS: Charts from patients who received HA-V between February 1, 2009, and February 28, 2018 from 2 clinics were analyzed. RESULTS: In 4500 patients who received 9324 treatments with HA-V, 44 DAEs were identified, for a combined incidence of 0.98% per patient, 0.47% per treatment, and 0.23% per syringe. Patients with DAEs received a slightly larger cumulative amount of HA-V than those who did not. Delayed swelling and nodule formation were the most common reactions and occurred a median of 4 months after treatment, with an increase in frequency between October and January. About a third were preceded by an identifiable immunologic stimulus. DAEs were transient and resolved without incident. LIMITATIONS: The retrospective nature made it difficult to capture time to resolution or remember potential triggers. CONCLUSION: In this large, long-term, retrospective review, HA-V DAEs occurred at a rate of 0.98% per patient. Although the exact cause has yet to be elucidated, we hypothesize that an increase in fragmentation during the HA-V degradation process may trigger an inflammatory response after an immunologic trigger.

Ten-Year and Beyond Follow-up After Treatment With Highly Purified Liquid-Injectable Silicone for HIV-Associated Facial Lipoatrophy: A Report of 164 Patients.

BACKGROUND: Highly purified liquid-injectable silicone (LIS) has been established as a permanent agent for off-label correction of HIV-associated facial lipoatrophy (HIV-FLA). However, controversy exists about long-term safety. OBJECTIVE: To establish the safety and efficacy at 10 years or greater of LIS for HIV-FLA. METHODS: Patients from 3 practices with 10-year or greater in-person office follow-up were analyzed to determine the number of LIS treatments and total volume required to achieve optimal correction. The nature of any treated adverse events was noted. RESULTS: One hundred sixty-four patients had 10-year or greater in-office follow-up. All subjects maintained long-term correction with an average of 9 treatments, average of 1.56 mL per treatment, and an average total of 14.1 mL. Two patients had severe adverse events manifesting as temporary facial edema. Four patients experienced mild-to-moderate excess fibroplasia presenting as perceived overcorrection, and 6 patients had nondisfiguring subcutaneous firmness. All adverse events were successfully treatable, mostly with intralesional 5-fluorouracil and triamcinolone. CONCLUSION: Liquid-injectable silicone is an effective long-term treatment option for HIV-FLA. When injected in small quantities with the microdroplet serial puncture technique at monthly or greater intervals, optimal correction appears durable for more than 10 years. Adverse events consisted mostly of excess fibroplasia and were treatable.

Merkel cell carcinoma.

A 92-year-old man presented for evaluation with a 1-month history of a rapidly growing asymptomatic pink nodule on his forearm. Biopsy results of the lesion demonstrated pathology consistent with Merkel cell carcinoma (MCC). Immunohistochemical studies displayed positive cytoplasmic staining for cytokeratin AE1/AE3, positive dot-like perinuclear staining for cytokeratin-20, diffuse cytoplasmic staining for neuron specific enolase, and no significant staining for S-100. Subsequent positron emission tomography did not reveal evidence of metastatic disease. Wide excision of the lesion was performed along with a sentinel node biopsy of his left axilla. The sentinel nodes were negative for MCC. Adjuvant radiation treatment of the tumor site was provided because the pathologist noted MCC within 2 mm of the deep margin.

Unique biological function of cathepsin L in secretory vesicles for biosynthesis of neuropeptides.

Neuropeptides are essential for cell-cell communication in the nervous and neuroendocrine systems. Production of active neuropeptides requires proteolytic processing of proneuropeptide precursors in secretory vesicles that produce, store, and release neuropeptides that regulate physiological functions. This review describes recent findings indicating the prominent role of cathepsin L in secretory vesicles for production of neuropeptides from their protein precursors. The role of cathepsin L in neuropeptide production was discovered using the strategy of activity-based probes for proenkephalin-cleaving activity for identification of the enzyme protein by mass spectrometry. The novel role of cathepsin L in secretory vesicles for neuropeptide production has been demonstrated in vivo by cathepsin L gene knockout studies, cathepsin L gene expression in neuroendocrine cells, and notably, cathepsin L localization in neuropeptide-containing secretory vesicles. Cathepsin L is involved in producing opioid neuropeptides consisting of enkephalin, ß-endorphin, and dynorphin, as well as in generating the POMC-derived peptide hormones ACTH and α-MSH. In addition, NPY, CCK, and catestatin neuropeptides utilize cathepsin L for their biosynthesis. The neuropeptide-synthesizing functions of cathepsin L represent its unique activity in secretory vesicles, which contrasts with its role in lysosomes. Interesting evaluations of protease gene knockout studies in mice that lack cathepsin L compared to those lacking PC1/3 and PC2 (PC, prohormone convertase) indicate the key role of cathepsin L in neuropeptide production. Therefore, dual cathepsin L and prohormone convertase protease pathways participate in neuropeptide production. Significantly, the recent new findings indicate cathepsin L as a novel 'proprotein convertase' for production of neuropeptides that mediate cell-cell communication in health and disease.

Cathepsin L participates in dynorphin production in brain cortex, illustrated by protease gene knockout and expression.

Dynorphin opioid neuropeptides mediate neurotransmission for analgesia and behavioral functions. Dynorphin A, dynorphin B, and alpha-neoendorphin are generated from prodynorphin by proteolytic processing. This study demonstrates the significant role of the cysteine protease cathepsin L for producing dynorphins. Cathepsin L knockout mouse brains showed extensive decreases in dynorphin A, dynorphin B, and alpha-neoendorphin that were reduced by 75%, 83%, and 90%, respectively, compared to controls. Moreover, cathepsin L in brain cortical neurons was colocalized with dynorphins in secretory vesicles, the primary site of neuropeptide production. Cellular coexpression of cathepsin L with prodynorphin in PC12 cells resulted in increased production of dynorphins A and B. Comparative studies of PC1/3 and PC2 convertases showed that PC1/3 knockout mouse brains had a modest decrease in dynorphin A, and PC2 knockout mice showed a minor decrease in alpha-neoendorphin. Overall, these results demonstrate a prominent role for cathepsin L, jointly with PC1/3 and PC2, for production of dynorphins in brain.

Saposin C stimulates growth and invasion, activates p42/44 and SAPK/JNK signaling pathways of MAPK and upregulates uPA/uPAR expression in prostate cancer and stromal cells.

AIM: To determine the effect of saposin C (a known trophic domain of prosaposin) on proliferation, migration and invasion, as well as its effect on the expression of urokinase plasmonogen activator (uPA), its receptor (uPAR) and matrix metalloproteinases (MMP)-2 and -9 in normal and malignant prostate cells. In addition, we tested whether saposin C can activate p42/44 and stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) signal transduction pathways of the mitogen-activated protein kinase (MAPK) superfamily. METHODS: We employed Western blot analysis, phospho-specific antibodies, cell proliferation assay, reverse transcriptase-polymerase chain reaction, in vitro kinase assays and migration and invasion to determine the effect of saposin C on various biological behaviors of prostate stromal and cancer cells. RESULTS: Saposin C, in a cell type-specific manner, upregulates uPA/uPAR and immediate early gene c-Jun expression, stimulates cell proliferation, migration and invasion and activates p42/44 and SAPK/JNK MAPK pathways in prostate stromal and cancer cells. Normal prostate epithelial cells were not responsive to saposin C treatment in the above studies. CONCLUSION: Saposin C functions as a multipotential modulator of diverse biological activities in prostate cancer and stromal cells. These results strongly suggest that saposin C functions as a potent growth factor for prostatic cells and may contribute to prostate carcinogenesis and/or the development of hormone-refractory prostate cancer.

Prosaptide TX14A stimulates growth, migration, and invasion and activates the Raf-MEK-ERK-RSK-Elk-1 signaling pathway in prostate cancer cells.

BACKGROUND: Prosaposin is a neurotrophic factor. Prosaposin knock-out mice have been reported to develop a number of abnormalities, including atrophy of the prostate gland and mitogen-activated protein kinase (MAPK)-inactivation in prostate epithelial cells. These abnormalities underscore a potential fundamental role in prostate development. The trophic factor activity of prosaposin has been localized at a specific amino terminal portion of the molecule that has been the source for a number of biologically active peptides called prosaptides (e.g., TX14A). The expression and function of prosaposin in prostate cancer is not known. METHODS: Using conventional protein expression analysis, immunohistochemical staining, cell proliferation assays, and in vitro invasion assays, we determined the expression of prosaposin and the effect of prosaptide TX14A on cell growth/death protection, motility, invasion, and MAPK signal transduction pathway in prostate cancer cells. RESULTS: We found a higher expression of prosaposin in androgen-independent (AI) prostate cancer cells (PC-3 and DU-145) than in androgen-dependent (AD) LNCaP or normal prostate epithelial cells. Immunohistochemical staining on benign and malignant prostate tissues revealed an intense cytoplasmic anti-prosaposin immunoreactivity in tumor cells, as well as stromal, endothelial, and inflammatory mononuclear cells. The intensity of staining was proportional to the overall Gleason's score. In addition, we demonstrated that TX14A stimulates cell proliferation/survival, migration, and invasion, and activates the Raf-MEK-ERK-RSK-Elk-1 signaling cascade of the MAPK pathway. CONCLUSIONS: These results are suggestive of a potential pleuripotent regulatory function for prosaposin in prostate cancer.