Patient satisfaction and our clinical experience with 459 microfocused ultrasound treatments.

PURPOSE: Microfocused ultrasound (MFUS) is a safe and effective method for noninvasive skin tightening. Previous clinical studies demonstrate a 60-100% patient satisfaction after MFUS. We used an anonymous online platform after MFUS to assess patient satisfaction. DESIGN: Patients treated with MFUS between January 2013 and 2016 were invited to complete an anonymous online survey at least 4 months post-treatment. Patients were asked to rate improvement in skin tightening as none (0%), mild (0-25%), moderate (26-50%), significant (51-75%), or dramatic (76-100%) and treatment satisfaction as disappointed, neutral, satisfied, or extremely satisfied. SUMMARY: Between January 2013 and 2016, 253 patients received 459 MFUS treatments at our center. A total of 83 surveys were received with data. Nearly 80% of responders reported at least mild improvement, with 14.5% indicating significant improvement, 27.7% indicating moderate, 37.3% indicating mild, and 20.5% indicating none. In addition, 53.1% of responders reported being satisfied or extremely satisfied with the results. 44.6% of responders did not feel treatment results met expectations. CONCLUSION: Patient satisfaction with elective cosmetic procedures is an important indicator of success. Our current study demonstrates a high response rate, with almost 80% of responders indicating at least mild tightening with MFUS treatment. Interestingly, only 53.1% of patients reported satisfaction after treatment, a lower satisfaction rate than reported in previous non-anonymous studies and lower than patients report in our office follow-up appointments. This discrepancy may be due to gratitude bias. Anonymous surveys likely provide a more accurate assessment of patients' perceptions and will improve physician's future counseling efforts. Lasers Surg. Med. 51:495-499, 2019. © 2019 Wiley Periodicals, Inc.

A Comparative Split-Face Trial of Plant-Based Hypoallergenic Ointment vs Petroleum-Based Ointment Following Fractionated Carbon Dioxide Laser Resurfacing of the Face

Purpose: Fractionated carbon dioxide (CO2) laser resurfacing uses fractional photothermolysis with an ablative 10,600-nm wavelength for treatment of rhytides and photodamage. Although associated with reduced side effect profile from traditional ablative lasers, fractionated lasers can lead to significant erythema, edema, crusting, and exudation for 14 days. Post-care includes regular distilled water soaks and healing ointment. This study evaluated efficacy and patient satisfaction of a novel plant-based hypoallergenic ointment (Doctor Rogers RESTORE®Healing Balm; Product 1) compared to petroleum-based lanolin-containing ointment (Aquaphor® Healing Ointment; Product 2) to accelerate wound healing post-laser resurfacing of the face. Design: This was a single-center, prospective randomized, double-blinded, split-face comparative study of 10 subjects with photo-aging and rhytids who received treatment with fractionated CO2 laser between September 2017 and January 2018. Product 1 and Product 2 were randomized to each half of the face and applied from days 0 to 7 with an option to continue to day 14. The primary outcome measures were Investigator-rated degree of erythema, edema, crusting, exudation, and percentage healing, with follow-up evaluations performed at days 2, 4, 7, 14, and 30. The secondary outcome measure was patient satisfaction. Summary: Based on investigator post-resurfacing scores, day 4 showed improved erythema (50%), edema (50%), crusting (40%), and percentage healing (60%) on the Product 1-treated side compared to Product 2, with the majority of remaining patients scoring the same as Product 2. On day 14, Product 1 demonstrated improvement in erythema (50%), edema (30%), and percentage healing (30%) compared to Product 2, with all remaining patients scoring the same as Product 2. Crusting was the same between the two products on day 14. Ninety percent of patients preferred Product 1 over Product 2, found it easier to use, and were more likely to use it in the future. Conclusion: Product 1 is a plant-based hypoallergenic ointment that is safe and effective post-laser treatment and is associated with high patient satisfaction and preference.

Evidence for Anti-Aging South Korean Cosmeceuticals.

As the market for South Korean skin care products grows in the U.S. and worldwide, consumers will increasingly seek advice from dermatologists regarding their efficacy. In this paper, the evidence behind the anti-aging and skin whitening activity of ingredients in the most popular South Korean skin care products was reviewed and critically evaluated. Industry profit data from Euromonitor was obtained to identify the top cosmeceutical brands by retail value in South Korea. The top selling products and their ingredients were then identified from individual brand websites. A comprehensive literature search was conducted using Pubmed to identify and grade the anti-aging and whitening efficacy for nine popular ingredients: licorice, niacinamide, beta-glucan, snail mucus, ginkgo biloba, ginseng, green tea, pomegranate, and soy. Of the various ingredients reviewed, niacinamide, green tea, licorice, and soy have the most published data for anti-aging and whitening activity. Although the literature shows modest results, small sample sizes limit interpretation. High-level evidence to support the use of South Korean skin care products in anti-aging and skin whitening is lacking.

J Drugs Dermatol. 2017;16(4):358-364.

Rare angioinvasive fungal infection in association with leukemia cutis.

Leukemia cutis (LC) is characterized by the infiltration of malignant neoplastic leukocytes or their precursors into the skin and is most often seen in conjunction with systemic leukemia. Patients with LC frequently are in a relative or absolute immunocompromised state. We report the case of a 52-year-old man with primary refractory acute myelogenous leukemia (AML) following allogeneic stem cell transplant (SCT) who presented with a progressive reddish purple nodule with surrounding erythema and central necrosis in the setting of leukocytosis and possible fungal pneumonia. Histopathologic examination revealed an ulcerated dense diffuse dermal infiltrate of large atypical lymphocytes consistent with LC and septate hyphae with acute-angle branching in the dermal blood vessels. Cultures from a biopsied lesion grew Paecilomyces species, a rare but emerging opportunistic infection, despite the patient being on antifungal prophylaxis. This novel report of a rare angioinvasive infection occurring within a lesion of LC supports the need to maintain a high index of suspicion for invasive infection in patients with hematologic malignancy, even those on antifungal prophylaxis.

Minimally Invasive Procedures for Gender Affirmation.

Despite an increase in the visibility of the transgender population, those who transition continue to face barriers to receiving care through traditional medical providers. Dermatologists can play an important role in the care of transgender patients, through increased understanding and awareness, better outreach, modified medical forms, improved office procedures, and safer and immediately available minimally invasive aesthetic treatments. Minimally invasive aesthetic enhancements that help align appearance with aesthetic goals and gender identity can enhance confidence and improve quality of life. This article discusses gender transition, applicable minimally invasive procedures for the face and body, and illustrative case examples.

Chronic NMDA administration to rats increases brain pro-apoptotic factors while decreasing anti-Apoptotic factors and causes cell death.

BACKGROUND: Chronic N-Methyl-d-aspartate (NMDA) administration to rats is reported to increase arachidonic acid signaling and upregulate neuroinflammatory markers in rat brain. These changes may damage brain cells. In this study, we determined if chronic NMDA administration (25 mg/kg i.p., 21 days) to rats would alter expression of pro- and anti-apoptotic factors in frontal cortex, compared with vehicle control. RESULTS: Using real time RT-PCR and Western blotting, chronic NMDA administration was shown to decrease mRNA and protein levels of anti-apoptotic markers Bcl-2 and BDNF, and of their transcription factor phospho-CREB in the cortex. Expression of pro-apoptotic Bax, Bad, and 14-3-3zeta was increased, as well as Fluoro-Jade B (FJB) staining, a marker of neuronal loss. CONCLUSION: This alteration in the balance between pro- and anti-apoptotic factors by chronic NMDA receptor activation in this animal model may contribute to neuronal loss, and further suggests that the model can be used to examine multiple processes involved in excitotoxicity.

Chronic administration of mood stabilizers upregulates BDNF and bcl-2 expression levels in rat frontal cortex.

Brain-derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2) proteins are neuroprotective factors involved in neuronal signaling, survival and plasticity. Both can be regulated by cyclic AMP response element binding (CREB) protein. Decreased levels of BDNF and Bcl-2 are implicated in the pathogenesis of bipolar disorder. The present study investigated whether chronically administered mood stabilizers would increase BDNF and/or Bcl-2 levels in rat brain. Real time RT-PCR, sandwich ELISA and Western blotting were used to measure BDNF and Bcl-2 mRNA and protein levels in the frontal cortex of rats chronically administered carbamazepine (CBZ) or lamotrigine (LTG) to produce plasma concentrations therapeutically relevant to bipolar disorder. Chronic CBZ and LTG significantly increased BDNF and Bcl-2 mRNA and protein levels in the frontal cortex. A common mechanism of action of mood stabilizers in the treatment of bipolar disorder may involve neuroprotection mediated by upregulation of brain BDNF and Bcl-2 expression.

Chronic NMDA administration increases neuroinflammatory markers in rat frontal cortex: cross-talk between excitotoxicity and neuroinflammation.

Chronic N-Methyl-D: -aspartate (NMDA) administration, a model of excitotoxicity, and chronic intracerebroventricular lipopolysaccharide infusion, a model of neuroinflammation, are reported to upregulate arachidonic acid incorporation and turnover in rat brain phospholipids as well as enzymes involved in arachidonic acid metabolism. This suggests cross-talk between signaling pathways of excitotoxicity and of neuroinflammation, involving arachidonic acid. To test whether chronic NMDA administrations to rats can upregulate brain markers of neuroinflammation, NMDA (25 mg/kg i.p.) or vehicle (1 ml saline/kg i.p.) was administered daily to adult male rats for 21 days. Protein and mRNA levels of cytokines and other inflammatory markers were measured in the frontal cortex using immunoblot and real-time PCR. Compared with chronic vehicle, chronic NMDA significantly increased protein and mRNA levels of interleukin-1beta, tumor necrosis factor alpha, glial fibrillary acidic protein and inducible nitric oxide synthase. Chronic NMDA receptor overactivation results in increased levels of neuroinflammatory markers in the rat frontal cortex, consistent with cross-talk between excitotoxicity and neuroinflammation. As both processes have been reported in a number of human brain diseases, NMDA receptor inhibitors might be of use in treating neuroinflammation in these diseases.

Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma.

The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.

Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.

Update on Epidemiology and Clinical Assessment Tools of Cutaneous Lupus Erythematosus and Dermatomyositis.

Cutaneous Lupus Erythematosus (CLE) and Dermatomyositis (DM) are cutaneous autoimmune diseases that have been among the least systematically studied, due in part to the lack of validated outcome instruments in the past. More recent epidemiologic studies have elucidated the incidence and prevalence of these diseases and their subtypes. In addition, the advent of validated clinical outcome measures, including the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), has led to an objective means of measuring activity and damage of the disease. These outcome measures have established the framework for evaluating responsiveness and therapeutic efficacy in clinical trials as well as longitudinal studies to study disease course.