Noninvasive treatment of cutaneous neurofibromas (cNFs): Results of a randomized prospective, direct comparison of four methods.

BACKGROUND: People with Neurofibromatosis Type 1 (NF1) suffer disfigurement and pain when hundreds to thousands of cutaneous neurofibromas (cNFs) appear and grow throughout life. Surgical removal of cNFs under anesthesia is the only standard therapy, leaving surgical scars. OBJECTIVE: Effective, minimally-invasive, safe, rapid, tolerable treatment(s) of small cNFs that may prevent tumor progression. METHODS: Safety, tolerability, and efficacy of 4 different treatments were compared in 309, 2-4 mm cNFs across 19 adults with Fitzpatrick skin types (FST) I-IV: radiofrequency (RF) needle coagulation, 755 nm alexandrite laser with suction, 980 nm diode laser, and intratumoral injection of 10 mg/mL deoxycholate. Regional pain, clinical responses, tumor height and volume (by 3D photography) were assessed before, 3 and 6 months post-treatment. Biopsies were obtained electively at 3 months. RESULTS: There was no scarring or adverse events > grade 2. Each modality significantly (P < .05) reduced or cleared cNFs, with large variation between tumors and participants. Alexandrite laser and deoxycholate were fast and least painful; 980 nm laser was most painful. Growth of cNFs was not stimulated by treatment(s) based on height and volume values at 3 and 6 months compared to baseline. LIMITATIONS: Intervention was a single treatment session; dosimetry has not been optimized. CONCLUSIONS: Small cNFs can be rapidly and safely treated without surgery.

Total ice content and lipid saturation determine adipose tissue cryolipolysis by injection of ice-slurry.

OBJECTIVES: Cryolipolysis uses tissue cooling to solidify lipids, preferentially damaging lipid-rich cells. Topical cooling is popular for the reduction of local subcutaneous fat. Injection of biocompatible ice-slurry is a recently introduced alternative. We developed and verified a quantitative model that simulates the heat exchange and phase changes involved, offering insights into ice-slurry injection for treating subcutaneous fat. METHODS: Finite element method was used to model the spatial and temporal progression of heat transfer between adipose tissue and injected ice-slurry, estimating dose-response relationships between properties of the slurry and size of tissue affected by cryolipolysis. Phase changes of both slurry and adipose tissue lipids were considered. An in vivo swine model was used to validate the numerical solutions. Oils with different lipid compositions were exposed to ice-slurry in vitro to evaluate the effects of lipid freezing temperature. Microscopy and nuclear magnetic resonance (NMR) were performed to detect lipid phase changes. RESULTS: A ball of granular ice was deposited at the injection site in subcutaneous fat. Total injected ice content determines both the effective cooling region of tissue, and the duration of tissue cooling. Water's high latent heat of fusion enables tissue cooling long after slurry injection. Slurry temperature affects the rate of tissue cooling. In swine, when 30 ml slurry injection at -3.5°C was compared to 15 ml slurry injection at -4.8°C (both with the same total ice content), the latter led to almost twice faster tissue cooling. NMR showed a large decrease in diffusion upon lipid crystallization; saturated lipids with higher freezing temperatures were more susceptible to solidification after ice-slurry injection. CONCLUSIONS: Total injected ice content determines both the volume of tissue treated by cryolipolysis and the cooling duration after slurry injection, while slurry temperature affects the cooling rate. Lipid saturation, which varies with diet and anatomic location, also has an important influence.

Injectable ice slurry for reducing pericardial adipose tissue.

OBJECTIVES: Excess pericardial adipose tissue (PAT) is associated with a higher risk of cardiovascular diseases. Currently, available methods for reducing PAT volume include weight loss through diet and exercise, weight loss with medications, and bariatric surgery. However, these methods are all limited by low patient compliance to maintain the results. We have developed an injectable ice slurry that could selectively target and reduce subcutaneous adipose tissue volume. The aim of this study was to investigate the feasibility and safety of using injectable slurry to selectively reduce PAT volume in a preclinical large animal model. METHODS: PAT in Yucatan swine was injected with slurry or room temperature control solution. All animals were imaged with baseline chest computed tomography (CT) before slurry injection and at 2 months after injection to quantify PAT volume. Specimens from injected and noninjected PAT were harvested for histology. RESULTS: Slurry treatment of PAT was well tolerated in all animals. Slurry-induced selective cryolipolysis in treated PAT. CT imaging showed decrease in PAT volume in treated area at 8 weeks posttreatment compared to baseline, that was significantly different from control solution treated group (median [range]: -29.66 [-35.07 to -27.92]% vs. -1.50 [-11.69 to 8.69]% in control animals respectively, p < 0.05). CONCLUSIONS: This study demonstrated that slurry injection into PAT is feasible in a large animal model. Slurry injection was safe and effective in inducing selective cryolipolysis in PAT and reducing PAT volume. Slurry reduction of PAT could potentially serve as a novel treatment for cardiovascular diseases.

Skin of color representation in cosmetic clinical trials: A literature review.

Despite cosmetic procedures being on the rise in the US in all demographics, cosmetic procedures remain heavily skewed towards non-skin of color patients. Cosmetic clinical trials in the United States must be representative of the ever-increasing diversity of the US population. We sought to analyze published cosmetic randomized controlled trials, both industry-sponsored and investigator-initiated, to characterize and assess representation of skin of color participants over the past three decades. Our study shows that industry sponsorship correlates with poor study participant ethnic/racial diversity in aesthetic randomized controlled trials, and should serve as a call to action for industries to increase the inclusion of skin of color participants in their studies.

Neural Selective Cryoneurolysis with Ice Slurry Injection in a Rat Model.

BACKGROUND: Postoperative pain caused by trauma to nerves and tissue around the surgical site is a major problem. Perioperative steps to reduce postoperative pain include local anesthetics and opioids, the latter of which are addictive and have contributed to the opioid epidemic. Cryoneurolysis is a nonopioid and long-lasting treatment for reducing postoperative pain. However, current methods of cryoneurolysis are invasive, technically demanding, and are not tissue-selective. This project aims to determine whether ice slurry can be used as a novel, injectable, drug-free, and tissue-selective method of cryoneurolysis and resulting analgesia. METHODS: The authors developed an injectable and selective method of cryoneurolysis using biocompatible ice slurry, using rat sciatic nerve to investigate the effect of slurry injection on the structure and function of the nerve. Sixty-two naïve, male Sprague-Dawley rats were used in this study. Advanced Coherent anti-Stokes Raman Scattering microscopy, light, and fluorescent microscopy imaging were used at baseline and at various time points after treatment for evaluation and quantification of myelin sheath and axon structural integrity. Validated motor and sensory testing were used for evaluating the sciatic nerve function in response to ice slurry treatment. RESULTS: Ice slurry injection can selectively target the rat sciatic nerve. Being injectable, it can infiltrate around the nerve. The authors demonstrate that a single injection is safe and selective for reversibly disrupting the myelin sheaths and axon density, with complete structural recovery by day 112. This leads to decreased nocifensive function for up to 60 days, with complete recovery by day 112. There was up to median [interquartile range]: 68% [60 to 94%] reduction in mechanical pain response after treatment. CONCLUSIONS: Ice slurry injection selectively targets the rat sciatic nerve, causing no damage to surrounding tissue. Injection of ice slurry around the rat sciatic nerve induced decreased nociceptive response from the baseline through neural selective cryoneurolysis.

Injectable slurry for selective destruction of neck adipose tissue in New Zealand obese mouse model.

PURPOSE: Increased neck circumference is a major risk factor for obstructive sleep apnea (OSA). New data suggest that increased adipose tissue in the neck may be a contributory cause of OSA. The aim of this study was to investigate safety and efficacy of a recently developed injectable ice slurry in selective reduction of neck adipose tissue in a mouse model. METHODS: We used the New Zealand obese mice that have increased volume of anterior neck fat, and are commonly used in OSA studies. MRI imaging was used to measure changes in fat tissue volume. RESULTS: Thirty animals were used in this study. Volumetric measurements in MRI images showed thatchanges in anterior neck adipose tissue volume from baseline in treated mice was significantly different in comparison with the control group (-1.09/kg ± 0.33/kg vs 0.68/kg ± 0.37/kg; p < 0.01 by two-tailed Student's t test). Histological analysis of samples from the treated area of the neck did not show scarring or damage to the surrounding tissues. CONCLUSIONS: Injection of ice slurry safely, effectively, and selectively reduces upper airway fat in New Zealand obese mice without scarring or damage to surrounding tissue. Our results suggest that slurry injection may be a novel and minimally invasive method of removing neck adipose tissue. This intervention should be further investigated to determine its suitability for treatment of OSA.

Skin changes and manifestations associated with the treatment of obesity.

In light of the increasing prevalence of obesity, a large proportion of patients are taking weight loss medications or undergoing weight loss procedures. The typical paradigm for treating obesity begins with lifestyle interventions and progresses to medical treatments, and when nonsurgical interventions have failed, procedural techniques are considered. The effect of these interventions on the skin and dermatologic conditions has not been reviewed in depth. Herein, we review the impact of weight loss on pre-existing dermatologic conditions, as well as the development of novel skin changes and consequences of redundant skin after these interventions.

Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice.

BACKGROUND: The B-cell receptor transmembrane activator and calcium modulator ligand interactor (TACI) is important for T-independent antibody responses. One in 200 blood donors are heterozygous for the TACI A181E mutation. OBJECTIVE: We sought to investigate the effect on B-cell function of TACI A181E heterozygosity in reportedly healthy subjects and of the corresponding TACI A144E mutation in mice. METHODS: Nuclear factor κB (NF-κB) activation was measured by using the luciferase assay in 293T cells cotransfected with wild-type and mutant TACI. TACI-driven proliferation, isotype switching, and antibody responses were measured in B cells from heterozygous TACI A144E knock-in mice. Mouse mortality was monitored after intranasal pneumococcal challenge. RESULTS: Levels of natural antibodies to the pneumococcal polysaccharide component phosphocholine were significantly lower in A181E-heterozygous than TACI-sufficient Swedish blood donors never immunized with pneumococcal antigens. Although overexpressed hTACI A181E and mTACI A144E acted as dominant-negative mutations in transfectants, homozygosity for A144E in mice resulted in absent TACI expression in B cells, indicating that the mutant protein is unstable when naturally expressed. A144E heterozygous mice, such as TACI+/- mice, expressed half the normal level of TACI on their B cells and exhibited similar defects in a proliferation-inducing ligand-driven B-cell activation, antibody responses to TNP-Ficoll, production of natural antibodies to phosphocholine, and survival after intranasal pneumococcal challenge. CONCLUSION: These results suggest that TACI A181E heterozygosity results in TACI haploinsufficiency with increased susceptibility to pneumococcal infection. This has important implications for asymptomatic TACI A181E carriers.

Three-dimensional volumetric quantification of fat loss following cryolipolysis.

BACKGROUND AND OBJECTIVES: Cryolipolysis is a noninvasive and well-tolerated treatment for reduction of localized subcutaneous fat. Although several studies demonstrate the safety and efficacy of this procedure, volumetric fat reduction from this treatment has not been quantified. This prospective study investigated the change in volume of fat after cryolipolysis treatment using three-dimensional (3D) photography. MATERIALS AND METHODS: A prospective study of subjects treated with cryolipolysis on the flank (love handle) was performed at Massachusetts General Hospital. Volume measurements were performed with a Canfield Scientific Vectra three-dimensional camera and software to evaluate the amount of post procedure volume change. Clinical outcomes were assessed with caliper measurements, subject surveys, and blinded physician assessment of photographs. RESULTS: Eleven subjects were enrolled in this study. Each subject underwent a single cycle of cryolipolysis to one flank. The untreated flank served as an internal control. The follow-up time after treatment was 2 months. The mean amount of calculated absolute fat volume loss using 3D photography from baseline to 2 months follow-up visit was 56.2 ± 25.6 from the treatment site and 16.6 ± 17.6 cc from the control (P < 0.0001). A mean absolute difference of 39.6 cc between the treated and untreated sides was calculated at 2 months post-treatment. Comparison of caliper measurements from baseline to 2 months post-treatment demonstrated significant reduction of the treated flank from 45.6 ± 5.8 mm at baseline to 38.6 ± 4.6 mm at 2 months post-treatment (P < 0.001). The untreated flank did not show significant reduction with caliper measurements demonstrating 45.3 ± 5.0 mm at baseline and 44.6 ± 5.1 mm at 2 months post-treatment (P = 0.360). No unexpected side effects or adverse events were reported. Post-treatment satisfaction surveys demonstrated 82% of subjects were satisfied with the results. CONCLUSIONS: Cryolipolysis is a safe, well-tolerated, and effective noninvasive fat removal methodology that on average leads to 39.6 cc of fat loss of the treated flank at 2 months after a single treatment cycle.

TACI is mutant in common variable immunodeficiency and IgA deficiency.

The tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells. We found that 4 of 19 unrelated individuals with common variable immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding TACI). One of the four individuals with CVID had a single nucleotide insertion in the other TNFRSF13B allele. None of these mutations were present in 50 healthy subjects. TNFRSF13B mutations cosegregated with the phenotype of CVID or IgAD in family members of four index individuals that we studied. B cells from individuals with TACI mutations expressed TACI but did not produce IgG and IgA in response to the TACI ligand APRIL, probably reflecting impaired isotype switching. These results suggest that TACI mutations can result in CVID and IgAD.

Understanding the pathophysiology of itch.

Itch is the most common symptom described by our patients. Treating this symptom can be challenging. A revolution is ongoing in understanding the pathophysiology of itch and will allow this challenge to be met. The present authors review and update the current understanding of the pathophysiology of itch.

Advanced aging skin and itch: addressing an unmet need.

Itch is the most common skin disorder in the elderly and frequently diminishes quality of life in this population. The high prevalence of pruritus in elderly patients is attributed in part to the decline in the normal physiology of the advanced aging skin, and reflects poor hydration, impaired skin barrier, and altered neural function, all ultimately contributing to inflammation and pruritus. As the elderly population continues to grow, practitioners need to be aware of how to evaluate and manage pruritus, recognizing the common conditions contributing to itch in elderly patients as well as the challenges of treatment in this group. Ultimately, management of pruritus will require an individually tailored approach that is guided by a patient's general health, severity of symptoms, and the potential adverse effects of itch therapies.

Fibrosis-associated single-nucleotide polymorphisms in TGFB1 and CAV1 are not associated with the development of nephrogenic systemic fibrosis.

OBJECTIVE: To test the hypothesis that the subset of patients with impaired renal function who are exposed to gadolinium-containing contrast agents (GCCAs) and develop nephrogenic systemic fibrosis (NSF) have a genetic predisposition for disease. METHODS: We examined whether an intronic single-nucleotide polymorphism (SNP) in caveolin-1 (CAV1 rs4730751) and 2 coding SNPs in transforming growth factor-beta 1 (TGFB1 rs1800471, codon 25; and rs1800470, codon 10) were associated with the NSF phenotype. RESULTS: Forty-one patients with a history of chronic kidney disease and GCCA administration were studied, including NSF cases (n = 17) and control subjects (n = 24) without clinical or histological evidence of NSF. No significant differences in the genotype frequencies at these SNPs in TGFB1 and CAV1 were found between patients with NSF and subjects without NSF. CONCLUSIONS: We conclude that polymorphisms in the genes encoding TGFB1 and CAV1 previously associated with the development and progression of fibrosis in several organ systems are not associated with development of NSF in this cohort of patients with renal impairment after GCCA exposure.

Cryolipolysis: The future of cryolipolysis.

BACKGROUND: Cryolipolysis has revolutionized the field of cosmetic dermatology as a nonsurgical procedure, utilizing controlled cooling to selectively destroy fat cells. AIMS AND METHODS: This review article will focus on the future prospects of cryolipolysis, considering advancements in current technology as well as innovations that hold promise for the future. We will explore emerging trends in cryolipolysis, considering novel applicator designs, combination therapies, an innovative injectable treatment approach, and the evolving role of this technology in the field of cosmetic dermatology. CONCLUSION: The future holds promise for advances in cryolipolysis using both the noninvasive topical cooling approach and the novel injectable ice-slurry technology.

Innovating on innovation training with the Virtual Magic Wand (VMW) program: a qualitative study.

To identify and solve unmet needs and bring new therapies to patients, clinicians at all levels must engage in innovation. The Magic Wand Initiative, a program based at Massachusetts General Hospital-Wellman Center for Photomedicine, created a 10-months course called the Virtual Magic Wand (VMW) program that is a curriculum that teaches the biomedical innovation pathway to dermatologists and engages them in this creative process. This study aims to identify the impact of the VMW program on participants and consider the potential benefits of an innovation curriculum. The authors conducted semi-structured interviews in which alumni of the VMW program were asked about their experiences with innovation before, during, and after the program. Using grounded theory methodology, data were analyzed using deductive coding methods. The most cited benefit of the program was the opportunity to network (n = 12, 100%)-specifically, the mentorship opportunities (n = 10, 83%) and specialty-specific peer groups (n = 9, 75%). Other benefits included a change in mindset regarding their clinical work (n = 11, 92%) and learning the process of innovation (83%). Among barriers, lack of time (n = 7, 58%), knowledge (n = 6, 50%), and resources (n = 5, 42%), were the most mentioned. All alumni interviewed have stayed engaged in the field of biomedical innovation after their completion of the VMW program. These findings show that the VMW program positively impacted the lives and careers of participants. This study identified some of the systemic reasons that deter physicians from regularly engaging in innovation and provides guidance for how to design other innovation programs and further support the advancement of medicine.

Sunscreens: Misconceptions and Misinformation.

Over the past 70 years, sunscreens have evolved from beach products designed to prevent sunburn to more cosmetically elegant skincare products intended to protect against multiple long-term adverse consequences of characteristically low-intensity daily UV and visible light exposure. Sunscreen testing and labeling intended to quantify such protection are unfortunately often misunderstood by users and have also led to illegal misleading and potentially dangerous industry practices. Changes in regulatory requirements, better policing, and more informative sunscreen labeling would benefit users and their physician advisors.

Cryoneurolysis with Injectable Ice Slurry Modulates Mechanical Skin Pain.

Cutaneous pain is a common symptom of skin disease, and available therapies are inadequate. We developed a neural selective and injectable method of cryoneurolysis with ice slurry, which leads to a long-lasting decrease in mechanical pain. The aim of this study is to determine whether slurry injection reduces cutaneous pain without inducing the side effects associated with conventional cryoneurolysis. Using the rat sciatic nerve, we examined the effects of slurry on nerve structure and function in comparison with the effects of a Food and Drug Administration‒approved cryoneurolysis device (Iovera). Coherent anti-Stokes Raman scattering microscopy and immunofluorescence staining were used to investigate histological effects on the sciatic nerve and on downstream cutaneous nerve fibers. Complete Freund's Adjuvant model of cutaneous pain was used to study the effect of the slurry on reducing pain. Structural changes in myelin induced by slurry were comparable with those induced by Iovera, which uses much colder temperatures. Compared with that of Iovera, the decrease in mechanical pain due to slurry was less profound but lasted longer without signs of dysesthesia. Slurry did not cause a reduction of epidermal nerve fibers or a change in thermal pain sensitivity. Slurry-treated rats showed reduced cutaneous mechanical pain in response to Complete Freund's Adjuvant. Slurry injection can be used to successfully reduce cutaneous pain without causing dysesthesia.

Selective reduction of visceral adipose tissue with injectable ice slurry.

Reduction in visceral adipose tissue (VAT) mass reduces body weight and metabolic disease risk in obese patients. However surgical removal of VAT is highly invasive and thus not clinically feasible. We developed an injectable ice slurry for selective reduction of adipose tissue through cryolipolysis. The aim of this study was to investigate safety, feasibility and mechanism of ice slurry-induced cryolipolysis of VAT. Perigonadal VAT in diet-induced obese mice and rats was subjected to slurry or sham treatment. Body weight and blood chemistry were monitored for 56 days post-treatment. Histological analysis and molecular studies were performed to elucidate mechanisms of fat reduction. Treatment of VAT was well tolerated in all animals. Slurry induced adipocyte cell death via selective cryolipolysis; significant weight loss was noted at day 21 post-treatment. RNA sequencing from treated VAT samples showed increased expression of genes involved in inflammation, immune response, collagen biosynthesis and wound healing, and decreased expression of adipokines. This study demonstrates that slurry treatment is safe and effective in inducing cryolipolysis of VAT and subsequent weight loss in mice. Ice slurry is promising as a minimally-invasive treatment to reduce visceral adipose tissue.