Hayes B. Gladstone

Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation

Although tissue microenvironments play critical roles in epithelial development and tumorigenesis, the factors mediating these effects are poorly understood. In this work, we used a genomic approach to identify factors produced by cells in the microenvironment of basal cell carcinoma (BCC) of the skin, one of the most common human cancers. The global gene expression programs of stromal cell cultures derived from human BCCs showed consistent, systematic differences from those derived from nontumor skin. The gene most consistently expressed at a higher level in BCC tumor stromal cells compared with those from nontumor skin was GREMLIN 1, which encodes a secreted antagonist of the bone morphogenetic protein (BMP) pathway. BMPs and their antagonists are known to play a crucial role in stem and progenitor cell biology as regulators of the balance between expansion and differentiation. Consistent with the hypothesis that BMP antagonists might have a similar role in cancer, we found GREMLIN 1 expression in the stroma of human BCC tumors but not in normal skin in vivo. Furthermore, BMP 2 and 4 are expressed by BCC cells. Ex vivo, BMP inhibits, and Gremlin 1 promotes, proliferation of cultured BCC cells. We further found that GREMLIN 1 is expressed by stromal cells in many carcinomas but not in the corresponding normal tissue counterparts that we examined. Our data suggest that BMP antagonists may be important constituents of tumor stroma, providing a favorable microenvironment for cancer cell survival and expansion in many cancers.

Continuous, Noninvasive, and Localized Microvascular Tissue Oximetry Using Visible Light Spectroscopy

Background: The authors evaluated the ability of visible light spectroscopy (VLS) oximetry to detect hypoxemia and ischemia in human and animal subjects. Unlike near-infrared spectroscopy or pulse oximetry (SpO2), VLS tissue oximetry uses shallow-penetrating visible light to measure microvascular hemoglobin oxygen saturation (StO2) in small, thin tissue volumes. Methods: In pigs, StO2 was measured in muscle and enteric mucosa during normoxia, hypoxemia (SpO2 = 40–96%), and ischemia (occlusion, arrest). In patients, StO2 was measured in skin, muscle, and oral/enteric mucosa during normoxia, hypoxemia (SpO2 = 60–99%), and ischemia (occlusion, compression, ventricular fibrillation). Results: In pigs, normoxic StO2 was 71 ± 4% (mean ± SD), without differences between sites, and decreased during hypoxemia (muscle, 11 ± 6%; P < 0.001) and ischemia (colon, 31 ± 11%; P < 0.001). In patients, mean normoxic StO2 ranged from 68 to 77% at different sites (733 measures, 111 subjects); for each noninvasive site except skin, variance between subjects was low (e.g., colon, 69% ± 4%, 40 subjects; buccal, 77% ± 3%, 21 subjects). During hypoxemia, StO2 correlated with SpO2 (animals, r2 = 0.98; humans, r2 = 0.87). During ischemia, StO2 initially decreased at −1.3 ± 0.2%/s and decreased to zero in 3–9 min (r2 = 0.94). Ischemia was distinguished from normoxia and hypoxemia by a widened pulse/VLS saturation difference (Δ < 30% during normoxia or hypoxemia vs. Δ > 35% during ischemia). Conclusions: VLS oximetry provides a continuous, noninvasive, and localized measurement of the StO2, sensitive to hypoxemia, regional, and global ischemia. The reproducible and narrow StO2 normal range for oral/enteric mucosa supports use of this site as an accessible and reliable reference point for the VLS monitoring of systemic flow.

ASDS guidelines of care: injectable fillers.

S 1 1 5 Injectable soft tissue augmentation materials available for use in the United States have proliferated during the past 5 years. In addition to bovine collagen and autologous fat, physicians can now choose between numerous other options, including hyaluronic acid derivatives, poly-L-lactic acid, injectable calcium hydroxylapatite, injectable liquid silicone, polymethylmethacrylate microspheres, and human collagen. While these materials are generally safe and versatile, each has specific features that inform its best use. The guidelines presented herein are not intended to delineate the standard of care but rather to present how most injectors commonly use these materials in patients. These guidelines are a consensus document produced by the ASDS Guidelines of Care Task Force in conjunction with recognized experts in the field who have volunteered their time. While efforts have been made to maintain accuracy and timeliness at the point of submission, these guidelines will no doubt evolve over time and should be considered in the context of the patients’ individual needs. In the 1970s, research into collagen production led to a bovine formulation that could be placed in a syringe and injected. Because of bovine collagen’s temporary persistence, and requirement for skin testing, other fillers were developed and tested in Europe, Asia, and North America in the 1990s. Today, there are a number of fillers to choose from, each with its own strengths and drawbacks.

Lack of efficacy with 1064-nm neodymium:yttrium-aluminum-garnet laser for the treatment of onychomycosis: A randomized, controlled trial

BACKGROUND Laser therapies have been Food and Drug Administration approved for temporary nail plate clearance; however, there is minimal evidence of their long-term efficacy. OBJECTIVE We sought to evaluate the clinical and mycological clearance of toenails treated with 1064-nm neodymium:yttrium-aluminum-garnet laser versus no treatment. METHODS This was a randomized, controlled, single-center trial comparing 2 treatments with 1064-nm neodymium:yttrium-aluminum-garnet laser (fluence of 5 J/cm(2), rate of 6 Hz) spaced 2 weeks apart versus no treatment in 27 patients (N = 125 affected nails) with clinical and mycological diagnosis of onychomycosis. At 3 months, patients were assessed with mycological cultures and proximal nail plate measurements. Patients treated with laser were also assessed with proximal nail plate measurements at 12 months. RESULTS At 3 months, 33% of patients treated with laser achieved a negative mycological culture compared with 20% of the control group (P = .49), and had more proximal nail plate clearance compared with control subjects (0.44 vs 0.15 mm, P = .18), which was not statistically significant. At 12 months, there was no difference in nail plate clearance between laser versus control subjects (0.24 vs 0.15 mm, P = .59). LIMITATIONS Our study was limited by the small sample size and number of treatments. CONCLUSIONS There was no significant mycological culture or clinical nail plate clearance with 1064-nm neodymium:yttrium-aluminum-garnet laser compared with control.

Management of visible granulomas following periorbital injection of poly-l-lactic Acid.

Purpose: Injectable poly-L-lactic acid (PLA) is a recently FDA-approved soft-tissue filler. Although approved only for treatment of HIV-associated lipoatrophy, there has been increased interest in its use for cosmetic purposes. Here we describe a case of a granulomatous reaction to injectable PLA in the inferior periorbital region resulting in visible papules and discuss treatment options. Methods: We review literature pertaining to medical and surgical treatment options for our patient, and we discuss relevant techniques for both the injection of PLA and the management of this complication with surgical techniques. Results: After failing several nonsurgical treatment options, our patient had excellent results with surgical excision of her persistent visible nodules. This technique is minimally invasive, provides definitive removal of the nodules, and can leave minimal residual scarring. Conclusions: Given the high frequency of subcutaneous nodule formation reported in early trials of injectable PLA, it is important for physicians to be well informed regarding its potential side-effects and how to minimize risk of adverse reactions. Based on our experience, we suggest that surgical excision is an excellent treatment option for persistent papules and nodules that arise after injection of PLA in the periorbital area.

Virtual reality for dermatologic surgery: virtually a reality in the 21st century.

In the 20th century, virtual reality has predominantly played a role in training pilots and in the entertainment industry. Despite much publicity, virtual reality did not live up to its perceived potential. During the past decade, it has also been applied for medical uses, particularly as training simulators, for minimally invasive surgery. Because of advances in computer technology, virtual reality is on the cusp of becoming an effective medical educational tool. At the University of Washington, we are developing a virtual reality soft tissue surgery simulator. Based on fast finite element modeling and using a personal computer, this device can simulate three-dimensional human skin deformations with real-time tactile feedback. Although there are many cutaneous biomechanical challenges to solve, it will eventually provide more realistic dermatologic surgery training for medical students and residents than the currently used models.

Split‐Face Comparison of the Erbium Micropeel with Intense Pulsed Light

BACKGROUND A variety of photorejuvenative techniques have been utilized to reverse the signs of cutaneous photoaging, including ablative and nonablative laser resurfacing as well as light-based devices. OBJECTIVE The purpose of this split-face randomized prospective open-label trial was to determine the effectiveness of sequential erbium:yttrium-aluminum-garnet (Er:YAG) laser versus intense pulsed light (IPL) for the treatment of mild to moderate facial photodamage. MATERIALS AND METHODS Ten subjects (ages 35–63) with facial dyschromia and rhytides were enrolled. Study patients were randomized to the two treatment arms, Er:YAG (3.8 J/cm2, 30% pattern overlap, 0% interpulse overlap, 15 μm per pass with no coagulation) and IPL (560-nm filter, 30 J/cm2, 2.4/4.0-ms pulse with 10-ms delay), each receiving three sequential treatments spaced 1 month apart. Subjective and blinded physician evaluations were performed at baseline and 4, 8, and 20 weeks posttreatment using a nominal scale from 1 to 4. Erythema and adverse events were assessed 1 week following each treatment. RESULTS Ten female subjects with mild to moderate facial photodamage were treated with one pass of either IPL or Er:YAG in a split-face fashion. Patients received three treatments each spaced 1 month apart. Nine of 10 patients completed the trial; 1 withdrew due to pain during the second Er:YAG treatment. Basline subjective and blinded physician dyschromia and rhytid scores revealed no significant difference between the IPL and Er:YAG randomly assigned sides. Up to three IPL or Er:YAG treatments did not result in a significant improvement in rhytid scores. Subjective and blinded physician dyschromia scores improved 26 and 38%, respectively, 3 months after the final IPL treatment, but only by 7 and 29%, respectively, with Er:YAG. Subjective global facial appearance scores worsened by 5% while blinded physician scores improved by 16% 3 months after 3 Er:YAG treatments, but by 28 and 20% for IPL, respectively. The overall incidence of adverse events and subsequent downtime was increased for Er:YAG (1/10 patients experienced hyperpigmentation, 3/10 exfoliation, 1/10 blistering, and 5/10 discomfort) compared to IPL (1/10 exfoliation and 1/10 discomfort), although no permanent side effects were observed with either treatment arm. CONCLUSIONS While low-fluence erbium resurfacing has a modest effect on facial photodamage, patients preferred IPL because it resulted in less downtime.

Quantifying soft tissue loss in facial aging: a study in women using magnetic resonance imaging.

BACKGROUND Facial aging involves changes in the facial skeleton and soft tissues. There is limited quantitative data on soft tissue aging of the face. OBJECTIVE Magnetic resonance imaging (MRI) was used to quantify and compare facial soft tissue loss over time. METHODS AND MATERIALS Two thousand thirty‐seven MRI scans from 58 women divided into young, middle‐aged, and older groups were screened. A blinded radiologist used MRI to measure the temporal, infraorbital, and medial and lateral cheek areas. RESULTS The mean thickness of the subcutaneous tissue in the temporal area was 12.3, 8.4, and 8.9 mm in the young, middle‐aged, and older groups, respectively (p < .001). A mean difference of 1.6 mm was seen between the young and middle‐aged groups and 2.2 mm between the young and older group (p < .001) in the infraorbital area, 3.3 mm between the young and middle‐aged groups and 3.2 mm between the young and older group in the medial cheeks (p < .001), and 2.4 mm between the young and middle‐aged groups and 2.4 mm between the young and older group in the lateral cheeks (p = .01). CONCLUSIONS Facial soft tissue undergoes significant deterioration over time, with the most dramatic changes between the ages of 30 and 60 in the temporal, infraorbital, and lateral and medial cheek areas. Soft tissue augmentation and volume correction in these areas may be an effective strategy for facial rejuvenation.

Quantifying soft tissue loss in the aging male face using magnetic resonance imaging

BACKGROUND Quantitative data on soft tissue aging of the face are scarce, particularly in men. OBJECTIVE Magnetic resonance imaging (MRI) was used to quantify and compare facial soft tissue loss in men. MATERIALS AND METHODS Two thousand thirty-seven MRIs were screened and 30 male subjects were divided into young, middle, and old-aged groups. A blinded radiologist measured temporal, infraorbital, and medial and lateral cheek areas. RESULTS The mean thickness of the subcutaneous tissue in the temporal area was 12.5, 10.9, and 9.6 mm in the young, middle, and older age groups, respectively (p < .001). A 40% reduction in the skin thickness was seen in the infraorbital areas. Finally, a decrease of 1.5 and 2.7 mm in medial cheeks (p < .001), and 0.9 and 1.6 mm (p = .03) in lateral cheeks were measured in middle and old age groups. CONCLUSION A steady and significant decline in the soft tissue thickness was noted at all measured sites in men over time. These findings are in contrast to our recently study in women showing dramatic loss of soft tissue between the ages of 30 and 60 with no significant differences between the middle and old-aged groups. These results have implications for volume correction and maintenance of a youthful appearance in the aging male face.

Nonmelanoma Skin Cancer Visits and Procedure Patterns in a Nationally Representative Sample: National Ambulatory Medical Care Survey 1995–2007

BACKGROUND The rising incidence of nonmelanoma skin cancer (NMSC) is well documented, but data are limited on the number of visits and treatment patterns of NMSC in the outpatient setting. OBJECTIVES To evaluate practice and treatment patterns of NMSC in the United States over the last decade and to characterize differences according to sex, age, race, insurance type, and physician specialty. METHODS AND MATERIALS Adults with an International Classification of Diseases, Ninth Revision, diagnosis of NMSC were included in this cross‐sectional survey study of the National Ambulatory Medical Care Survey between 1995 and 2007. Primary outcomes included population‐adjusted NMSC visit rates and odds ratios of receiving a procedure for NMSC using logistic regression. RESULTS Rates of NMSC visits increased between 1995 and 2007. The number of visits was significantly higher in men, particularly those aged 65 and older. Fifty‐nine percent of NMSC visits were associated with a procedure, and the individuals associated with that visit were more likely to be male, to be seen by a dermatologist, and to have private‐pay insurance. CONCLUSIONS Nonmelanoma skin cancer visit rates increased from 1995 to 2007 and were higher in men than women. Visits to a dermatologist are more likely to be associated with a procedure for NMSC, and there may be discrepancies in treatment patterns based on insurance type and sex.