Treatment of Post-Inflammatory Hyperpigmentation in Patients With Darker Skin Types Using a Low Energy 1,927 nm Non-Ablative Fractional Laser: A Retrospective Photographic Review Analysis.

BACKGROUND AND OBJECTIVES: Post inflammatory hyperpigmentation (PIH) can be difficult to treat especially in patients with darker skin types as darker skin carries increased epidermal melanin content. Various treatments available to improve the appearance of PIH may incite further pigmentation thus making treatment extremely difficult and frustrating. The purpose of this study was to perform a retrospective chart and photographic review to evaluate the efficacy and safety profile of a low energy low density non-ablative fractional1927 nm wavelength laser treatment for PIH in patients with Fitzpatrick skin types IV-VI. STUDY DESIGN: A retrospective evaluation of 61 patients with PIH treated with a 1927 nm laser was conducted at a single center. Inclusion criteria required at least 2 treatment sessions so that before and after treatment photographs would be available for comparison and study purposes. Two blinded physician-evaluators using a visual analog scale for percentage of pigmentary clearance in standard photographs assessed treatment efficacy. RESULTS: The mean percent improvement after treatment, evaluated by two dermatologists was 43.24%. The correlation between raters was statistically significant (Pearson's correlation coefficienct of r = 0.59, p < 0.0001). No side effects were observed in the patients treated with the 1927 nm laser. CONCLUSION: The low energy low density non-ablative fractional 1927 nm wavelength laser is a safe and effective modality for improving post inflammatory hyperpigmentation in patients with darker skin types. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Pulsed Dye Laser Treatment of Port-Wine Stains in Infancy Without the Need for General Anesthesia.

Importance: Recent concerns regarding repetitive use of general anesthesia in children younger than 3 years have placed greater importance on the controversy surrounding the timing of the initiation of port-wine stain (PWS) laser treatment. Objective: To evaluate the use of PWS treatments at the age of 1 year or younger in the office setting without general anesthesia. Design, Setting, and Participants: Retrospective cohort study based on medical record reviews at a single, high-volume laser center for children who started pulsed dye laser treatment at the age of 1 year or younger for their PWS between 2000 and 2017. The data cutoff was at 1 year after the initial treatment to have comparable data points. Main Outcomes and Measures: The primary outcome was improvement of PWSs using before and after photographs, which were reviewed by 4 physicians independently and graded using the following 5-point visual analog scale (VAS): poor (grade 1: 0%-25% improvement), fair (grade 2: 26%-50% improvement), good (grade 3: 51%-75% improvement), excellent (grade 4: 76%-99% improvement), and complete (grade 5: 100% improvement) clearance. Results: Of the 197 patients (73 [37.1%] boys; 124 [62.9%] girls), most (149 [75.6%]) had facial lesions. The mean age at the time of first treatment was 3.38 months (range, 5-355 days) and the mean number of treatments was 9.8 (range, 2-23; median, 10). Per the mean physician VAS grading of 197 patients, 51 patients (25.9%) showed 100% clearance (mean [range] VAS score of 4.78 [4.5 - 5]); 81 patients (41.1%) showed 76 to 99% improvement (mean [range] VAS score of 3.91 [3.5 to <4.5]); 44 patients (22.3%) showed 51% to 75% improvement (mean [range] VAS score of 2.86 [2.5 to <3.5]); 13 patients (6.6%) showed 26% to 50% improvement (mean [range] VAS score of 2.12 [1.5 to <2.5]); and 8 patients (4.1%) showed 0 to 25% improvement (mean [range] VAS score of 0.78 [0 to <1.5]). The presence of a V1 (first branch of the trigeminal nerve [ophthalmic nerve]) lesion was associated with a statistically significantly higher clearance rate by a VAS grade of 0.55 (95% CI, 0.25-0.84; P < .001). The mean (SD) VAS grade for all patients was 3.65 (1.26), corresponding to excellent clearance. None of the patients experienced scarring or permanent pigmentary change. Conclusions and Relevance: In this study, treatment of PWSs in infancy was both safe and effective. Early intervention allows for treatment without general anesthesia, maximizing the chance to achieve clearance before school age and thereby minimizing the negative outcome of PWSs for both the patient and the family.

Pulsed Dye Laser at Subpurpuric Settings for the Treatment of Pulsed Dye Laser-Induced Ecchymoses in Patients With Port-Wine Stains.

BACKGROUND: Post-procedure purpura is a major complaint of patients with port-wine stains (PWSs) treated with pulsed dye laser (PDL). OBJECTIVE: To assess the safety and efficacy of using PDL at nonpurpuric settings to treat ecchymoses that develop within PWSs after treatment with PDL. MATERIALS AND METHODS: Prospective, randomized, controlled study using 595-nm PDL for treatment of PWSs and laser-induced ecchymoses. Port-wine stains were treated in entirety at baseline. Two days later, ecchymoses on randomly selected half of the lesion were re-treated with PDL at subpurpuric settings. Treatment series was repeated 4 to 8 weeks later, and follow-up was at 1 month. Reduction in bruising and PWS clearance were assessed. Three masked evaluators graded clinical improvement using a 4-point scale (1 = 1%-25% improvement, 2 = 26%-50% improvement, 3 = 51%-75% improvement, and 4 = 76%-100% improvement). RESULTS: Twenty adults with 21 PWSs on the head, trunk, and extremities were treated. After first treatment, reduction of bruising was graded a mean value of 2.43 for the treatment side, compared with 1.93 for the control side (p = .012); after the second treatment, 2.83 compared with 2.40 (p = .021). No significant adverse events occurred. CONCLUSION: Pulsed dye laser can be used safely and effectively to reduce treatment-induced purpura in patients with PWSs.

Effect of General Anesthesia on Neurodevelopmental Abnormalities in Children Undergoing Treatment of Vascular Anomalies With Laser Surgery: A Retrospective Review.

BACKGROUND: Multiple exposures to general anesthesia may be neurotoxic to the developing brain. This relationship has not been evaluated in children undergoing laser surgery for vascular anomalies. OBJECTIVE: To evaluate the prevalence of neurodevelopmental abnormalities in children who received multiple laser procedures under general anesthesia before the age of 4 years for the treatment of vascular anomalies. METHODS AND MATERIALS: Retrospective chart review of patients with contact of parents for telephone interview. RESULTS: Thirty-three patients were eligible. Average age at the time of survey was 7.8 years. Twenty-three (84.8%) patients were female, with average age at the time of first treatment at 1.9 years. Average number of treatments received before the age of 4 years was 6.7. Anesthetics included inhalational nitrous oxide and isoflurane and intravenous propofol. Seven patients carried one or more of the following diagnoses: attention-deficit hyperactivity disorder (3.0%), anxiety (6.1%), behavioral disorder (3.0%), language disorder (3.0%), speech disorder (3.0%), and motor disorder (6.1%). These prevalence rates are similar to those found in the US population. CONCLUSION: This is the first report on the prevalence of neurodevelopmental disorders in children undergoing multiple laser treatments under general anesthesia. Although the study sample is small, no increased risks when comparing with prevalence rates reported in the literature were noted.

The Photodynamic Therapy Experience of a High Volume Laser and Dermatologic Surgery Center.

BACKGROUND: Photodynamic therapy (PDT) is an FDA approved treatment for actinic keratoses (AK's) although multiple off-label indi- cations are reported. Despite frequent use for AK's, no clear consensus exists regarding protocols for overall treatment parameters. METHODS: Retrospective chart review of 1,491 subjects who underwent PDT between 2007 and 2011 at a high volume laser surgery center. Demographic information, clinical history, treatment data, and subsequent diagnosis of skin cancers were recorded. An ex- ploratory subgroup analysis was performed for patients treated for AK and/or squamous cell carcinoma (SCC) that developed SCC or remained SCC-free one year after treatment. RESULTS: The most common indications for PDT were actinic keratoses (n=1404, 94.9%) then NMSC (n=45, 3.0%) The most common treatment site was the head and neck (n=1274, 86.1%). Blue light activation (405-420nm) was used more frequently than red light and visible light. (73.8% vs. 22.8% vs. 6.8%). The most commonly used photosensitizer was aminolevulinic acid (ALA) (98.6%, n=1456). Topical application (97.7% n=1437) of photosensitizer was used more frequently than intralesional administration (2.0%, n=29). 580 patients met subgroup analysis criteria. 66 developed SCC at treatment site (11%). Factors associated with developing SCC were older age, SCC history, Fitzpatrick skin-type 1, and sixty-minute or less incubation times (P less than 0.05 for all factors). The SCC subgroup had a unique distribution of treatment sites (P less than.001). No statistically significant differences were observed for gender or wavelength. CONCLUSION: There are differences in protocols based on indication and location of lesion. Blue light is preferable for superFIcial lesions and red light for deeper lesions. Intralesional delivery is used more commonly for NMSC. Extremities require longer incubation times. PDT may be more effective with younger patients and longer than sixty-minute incubation times. PDT chemoprevention is independent of light source used. J Drugs Dermatol. 2016;15(11):1420-1426..

Use of a picosecond pulse duration laser with specialized optic for treatment of facial acne scarring.

IMPORTANCE: Fractional laser technology is routinely used in the treatment of acne scarring, with thermal injury resulting in collagen synthesis and remodeling. Use of a picosecond pulse duration with a diffractive lens array may be a new technologic advancement in the treatment of acne scarring. OBJECTIVE: To investigate the safety and efficacy of a 755-nm alexandrite picosecond pulse duration laser with diffractive lens array for the treatment of facial acne scarring. DESIGN, SETTING, AND PARTICIPANTS: This single-center, prospective study performed in a private practice with a dedicated research department included patients with clinically diagnosed scarring secondary to inflammatory or cystic acne. INTERVENTIONS: Patients received 6 treatments with a 755-nm picosecond laser with a spot size of 6 mm, fluence of 0.71 J/cm2, repetition rate of 5 Hz, and pulse width of 750 picoseconds in combination with a diffractive lens array, allowing for greater surface area and pattern density per pulse. MAIN OUTCOMES AND MEASURES: The pain and satisfaction scores for overall appearance and texture were recorded. Masked assessment of clinical photographs and analysis of 3-dimensional volumetric data were performed. Biopsy specimens were obtained for independent histologic evaluation by 2 investigators at baseline and at 3 months after last treatment. RESULTS: Fifteen women and 5 men (mean age, 44 years; age range, 27-61 years) with Fitzpatrick skin types I through V and facial acne scarring were enrolled. The mean pain score was 2.83 of 10. Patients were satisfied to extremely satisfied with improvement in appearance and texture at their final treatment and follow-up visits. The masked assessment scores of 17 patients were 1.5 of 3 and 1.4 of 3 at 1 and 3 months, respectively (a score of 0 indicates 0%-25% improvement and a score of 3 indicates >75% improvement). A 3-dimensional analysis revealed a mean 24.3% improvement in scar volume, maintained at 1 (24.0%) and 3 (27.2%) months after treatment. Histologic analysis revealed elongation and increased density of elastic fibers, with an increase in dermal collagen and mucin. CONCLUSIONS AND RELEVANCE: Treatment of facial acne scars with a diffractive lens array and 755-nm picosecond laser produced improvement in appearance and texture at 3 months after the last treatment, with objective findings similar to those published for a series of fractional ablative laser treatments. Histologic findings suggest that improvement in scarring from this treatment goes beyond remodeling of collagen.

Multicenter prospective cohort study of the incidence of adverse events associated with cosmetic dermatologic procedures: lasers, energy devices, and injectable neurotoxins and fillers.

IMPORTANCE: Common noninvasive to minimally invasive cosmetic dermatologic procedures are widely believed to be safe given the low incidence of reported adverse events, but reliable incidence data regarding adverse event rates are unavailable to date. OBJECTIVE: To assess the incidence of adverse events associated with noninvasive to minimally invasive cosmetic dermatologic procedures, including those involving laser and energy devices, as well as injectable neurotoxins and fillers. DESIGN, SETTING, AND PARTICIPANTS: A multicenter prospective cohort study (March 28, 2011, to December 30, 2011) of procedures performed using laser and energy devices, as well as injectable neurotoxins and soft-tissue augmentation materials, among 8 geographically dispersed US private and institutional dermatology outpatient clinical practices focused on cosmetic dermatology, with a total of 23 dermatologists. Participants represented a consecutive sample of 20 399 cosmetic procedures. Data acquisition was for 3 months (13 weeks) per center, with staggered start dates to account for seasonal variation. EXPOSURES: Web-based data collection daily at each center to record relevant procedures, by category type and subtype. Adverse events were detected by (1) initial observation by participating physicians or staff; (2) active ascertainment from patients, who were encouraged to self-report after their procedure; and (3) follow-up postprocedural phone calls to patients by staff, if appropriate. When adverse events were not observed by physicians but were suspected, follow-up visits were scheduled within 24 hours to characterize these events. Detailed information regarding each adverse event was entered into an online form. MAIN OUTCOMES AND MEASURES: The main outcome was the total incidence of procedure-related adverse events (total adverse events divided by total procedures performed), as verified by clinical examination. RESULTS: Forty-eight adverse events were reported, for a rate of 0.24% (95% CI, 0.18%-0.31%). Overall, 36 procedures resulted in at least 1 adverse event, for a rate of 0.18% (95% CI, 0.13%-0.25%). No serious adverse events were reported. Adverse events were infrequently associated with known risk factors. CONCLUSIONS AND RELEVANCE: Noninvasive to minimally invasive cosmetic dermatologic procedures, including energy, neurotoxin, and filler procedures, are safe when performed by experienced board-certified dermatologists. Adverse events occur in less than 1% of patients, and most of these are minor and transient.

Nonablative 1927 nm fractional resurfacing for the treatment of facial photopigmentation.

BACKGROUND: Long-term exposure to sunlight, including ultraviolet A and B, produces signs associated with photoaging and photodamage, including laxity and discoloration of the skin. Initial laser treatment for dyspigmentation included the use of ablative lasers, followed by Q-switched lasers and more recently fractional lasers. OBJECTIVE: We investigated the safety and efficacy of a fractionated 1927nm non-ablative thulium laser for the treatment of photo-induced pigmentation. METHODS: Prospective multi-center study of subjects with clinically identifiable photopigmentation. The study protocol was approved by BioMed Institutional Review Board (San Diego, CA). Subjects received two treatments with a non-ablative 1927nm fractionated thulium laser (Fraxel Dual 1550/1927 Laser System, Solta, Hayward CA), energy level of 10mJ, coverage of 40% and 4-6 passes. Subject pain, erythema and edema were recorded immediately after treatment. Two dimensional photography was obtained before each treatment and at one and three month follow up visits. Independent blinded physician assessment was performed evaluating overall improvement in appearance as well as pigment specific improvement. RESULTS: Forty men and women, ages 30 to 80 years, Fitzpatrick skin types I-IV, with photo-induced facial pigmentation were enrolled and treated, and 39 completed the three month follow up visit. Mean pain sensation for subjects during laser treatments was reported to be 4.3 on a 10-point scale. Mean scores for erythema, edema, and skin roughness throughout all treatments indicated moderate erythema, mild edema and mild skin roughness. Assessment of overall improvement was graded as moderate to very significant in 82% of subjects at one month and in 69% of subjects at three months after the second treatment. Assessment of lentigines and ephelides demonstrated moderate to very significant improvement in approximately 68% of subjects at the one month and in 51% of subjects at three months after the second treatment. Independent blinded physician assessment of randomized photography also demonstrated a durable response at three month follow up visit. Treatment was well tolerated and no serious adverse events related to treatment were observed or reported. Study limitations included a limited number of male subjects, lack of Fitzpatrick skin types V and VI, and decrease in improvement at 3 months post-treatment. CONCLUSIONS: Two treatments with a 1927nm non-ablative fractionated thulium laser produced moderate to marked improvement in overall appearance and pigmentation with high patient satisfaction. The response to treatment was maintained at one and three months follow up.

Retrospective study of the treatment of infantile hemangiomas using a combination of propranolol and pulsed dye laser.

BACKGROUND: Infantile hemangioma (IH) clearance may be slow or incomplete in response to pulsed dye laser (PDL) or propranolol alone. OBJECTIVES: To evaluate whether IH treated with PDL and propranolol displayed more rapid and complete clearance than IH treated with propranolol alone. MATERIALS AND METHODS: Retrospective review of facial-segmental IH treated with propranolol and PDL and controls treated with propranolol was conducted. Blinded physicians used patient photographs to select clearance level and the earliest date of near-complete clearance. Days of propranolol, PDL sessions, and propranolol dose, each until date of near-complete clearance; total days of propranolol; and total propranolol dose were recorded. RESULTS: Infantile hemangiomas treated concurrently with propranolol and PDL achieved complete clearance (6/12) more often than IH treated with propranolol followed by PDL (2/5) or IH treated with propranolol alone (1/8; difference in clearance scores p = .01) and achieved near-complete clearance after fewer days of propranolol (mean 92 days for concurrent propranolol and PDL vs 288 days for propranolol; p < .001). Cumulative propranolol dose until near-complete clearance was lowest in the concurrent propranolol and PDL group (149.16 vs. 401.25 mg/kg for propranolol; p < .001). CONCLUSION: Facial-segmental IH treated with propranolol and PDL displayed morerapid and complete clearance and required a lower cumulative propranolol dose to achieve near-complete clearance.

Treatment of port-wine stains with a short pulse width 532-nm Nd:YAG laser.

BACKGROUND AND OBJECTIVE: Pulsed dye laser treatment often results in port-wine stain (PWS) improvement; however, results vary. A frequency-doubled neodymium-doped yttrium aluminum garnet (Nd:YAG) laser that allows for shorter pulse widths along with large spot sizes and high fluences has been developed for the treatment of cutaneous vascular lesions. STUDY DESIGN: A prospective, controlled study was performed in 5 adults with PWS using a frequency-doubled Nd:YAG laser (Excel V; Cutera Inc, Brisbane, CA) in 4 quadrants, using spot sizes of 6 to 10 mm, fluences of 4.8 to 9 J/cm2, and pulse durations of 3 to 6 ms. An adjacent control area was not treated. Each was assessed immediately posttreatment for purpura and edema and at 1 month for PWS color, size, texture, and thickness. Skin biopsies obtained immediately after and at 1 month posttreatment were evaluated. RESULTS: All treatment quadrants displayed purpura. At 1-month follow-up, all treatment quadrants showed at least 1 grade of color improvement, from a minimum of 1% to 25% to a maximum of 51% to 75% improvement (12/20 quadrants with 1%-25% improvement, 3/20 with 26%-50%, 5/20 with 51%-75%, and 0/20 with 76%-100%). Histologic evaluation of treatment quadrants revealed vascular changes ranging 0.35 to 4 mm in depth. Immediately posttreatment, thrombi and extravasated red blood cells were observed in treatment quadrants. Histology at 1 month revealed decreased number and diameter of vessels in treatment quadrants (superficial vessels decreased by mean 1.1 vessels per section [13%], and diameter by 3.0 µm [47%], midlevel vessels decreased in number by 2.3 [20%], diameter by 2.42 µm [25%], and deep vessels decreased in number by 1.5 [83%], and diameter by 7.44 µm [88%]). CONCLUSIONS: A single treatment with a short pulse width, frequency-doubled Nd:YAG laser resulted in safe and effective improvement of PWS, with up to 75% improvement in color observed at 1 month. Histologic evaluation demonstrated vascular injury at depths of 0.35 to 4 mm with a reduction in vessel number and size at multiple dermal levels.

1927-nm fractional resurfacing of facial actinic keratoses: a promising new therapeutic option.

BACKGROUND: Actinic keratoses (AK) are precancerous epidermal proliferations commonly present on chronically sun-damaged skin. These lesions are among the most often treated dermatologic conditions. OBJECTIVE: We sought to investigate the 6-month safety, tolerance, and efficacy of nonablative 1927-nm fractional resurfacing of facial AK. METHODS: This was a prospective clinical trial of 24 individuals with facial photodamage and AK receiving up to 4 treatments with the fractionated 1927-nm nonablative thulium laser. RESULTS: At 6 months, an 86.6% reduction in absolute number of lesions was noted by independent physician assessment. In addition, at this same time point, patients reported marked or noticeable improvement in overall photodamage. LIMITATIONS: This prospective study does not provide safety, tolerance, and efficacy data beyond 6 months of follow-up, nor does it identify the precise mechanism of action involved in AK clearance after 1927-nm resurfacing. CONCLUSION: The clinical and histologic findings, as well as the reported patient satisfaction and safety, suggest that the treatment of AK and photodamage with a fractionated 1927-nm nonablative thulium laser is a promising new therapeutic option.

Topical perfluorodecalin resolves immediate whitening reactions and allows rapid effective multiple pass treatment of tattoos.

BACKGROUND AND OBJECTIVE: Laser tattoo removal using multiple passes per session, with each pass delivered after spontaneous resolution of whitening, improves tattoo fading in a 60-minute treatment time. Our objective was to evaluate the safety and efficacy of topical perfluorodecalin (PFD) in facilitating rapid effective multiple-pass tattoo removal. STUDY DESIGN: In a randomized, controlled study using Q-switched ruby or Nd:YAG laser, 22 previously treated tattoos were treated with 3 passes using PFD to resolve whitening after each pass ("R0 method"). In previously untreated symmetric tattoos, seven were treated over half of the tattoo with the R20 method, and the opposite half with 4 passes using PFD (R0 method); two were treated over half with a single pass and the opposite half with 4 passes using PFD (R0 method); and six treated over half with a single pass followed by PFD and the opposite half with a single pass alone. Blinded dermatologists rated tattoo fading at 1-3 months. Optical coherence tomography (OCT) imaging of whitening was performed in two tattoos. RESULTS: Topical PFD clinically resolved immediate whitening reactions within a mean 5 seconds (range 3-10 seconds). Tattoos treated with the R0 method demonstrated excellent fading in an average total treatment time of 5 minutes. Tattoo areas treated with the R0 method demonstrated equal fading compared to the R20 method, and improved fading compared to a single pass method. OCT imaging of whitening demonstrated epidermal and dermal hyper-reflective "bubbles" that dissipated until absent at 9-10 minutes after PFD application, and at 20 minutes without intervention. CONCLUSIONS: Multiple-pass tattoo removal using PFD to deliver rapid sequential passes (R0 method) appears equally effective as the R20 method, in a total treatment time averaging 5 minutes, and more effective than single pass treatment. OCT-visualized whitening-associated "bubbles," upon treatment with PFD, resolve twice as rapidly as spontaneous resolution.

Ablative fractional resurfacing for involuted hemangioma residuum.

BACKGROUND Given the natural tendency for 15% to 40% of infantile hemangiomas to spontaneously involute over time, much debate surrounds the issue of treatment. Until recently, effective therapies to improve the appearance of residual textural skin changes in these patients were lacking. We suggest the use of ablative fractional resurfacing for the treatment of textural skin changes resulting from involuted hemangiomas. OBSERVATIONS All patients treated with an ablative fractional carbon dioxide laser experienced considerable flattening of the fibrofatty residual tissue, with at least 50% to 75% improvement in color, texture, and overall appearance. CONCLUSION While additional future studies are needed, we believe that ablative fractional resurfacing should be considered for the treatment of textural skin changes associated with involuted infantile hemangiomas.

Successful and rapid treatment of blue and green tattoo pigment with a novel picosecond laser.

BACKGROUND: While the understanding and technology of laser tattoo removal has advanced much over the last 5 decades, treatments and results remain far from perfect. With currently available devices, treatment courses are often painful and prolonged with mixed results. We describe the successful and rapid treatment of 12 tattoos containing blue and/or green pigment with a novel, picosecond, 755-nm alexandrite laser. OBSERVATIONS: All previously untreated multicolored tattoos as well as tattoos recalcitrant to treatment demonstrated at least 75% clearance of blue and green pigment after 1 or 2 treatments with a novel, picosecond, 755-nm alexandrite laser. More than two-thirds of these tattoos approached closer to 100% clearance. CONCLUSIONS: While additional future studies are needed, we believe that this new technology is more effective in targeting blue and green pigment, resulting in expedited clearance with less collateral injury to surrounding tissue.

Calcium hydroxylapatite nodule resolution after fractional carbon dioxide laser therapy.

BACKGROUND: Injection of calcium hydroxylapatite filler may result in nodule formation owing to superficial placement of the filler. Calcium hydroxylapatite nodules are difficult to reverse. Previously reported therapeutic options are limited and include intralesional triamcinolone, massage, needling, and excision, each with inconsistent results or potential for scarring. OBSERVATION: We have observed complete resolution of calcium hydroxylapatite nodules after a single treatment with fractional carbon dioxide laser. CONCLUSIONS: A single session of fractional carbon dioxide laser treatment may resolve selected cases of calcium hydroxylapatite nodules. The mechanism of action may involve conversion of the product into tricalcium phosphates which dissolve readily. This novel therapeutic technique may enhance treatment options for a difficult clinical problem.