Ethical Issues of Medical Schools and their Academic Departments Accepting Gifts from Pharma.

The ethical implications of medical schools or any of their academic departments accepting large corporate donations, mainly from pharmaceutical companies, have been long debated. While such contributions are common in other graduate institutions, medical schools must be convinced about potential conflicts of interest and public opinion. We re-explore the benefits these kinds of gifts would afford for improved educational and research resources against the ethical dilemmas this kind of donation would present and concerns about public perception and actual conflict of interest. Utilizing the principles of beneficence, non-maleficence, autonomy, and distributive justice, we discuss the physicians' obligations and conceivable patient backlash that may ensue. Ultimately, we recognize the necessity for financial resources to support academic missions but contend that healthcare facilities and medical education must be equipped to ensure a complete lack of bias in sponsorship.

Equivalent efficacy of indoor daylight and lamp-based 5-aminolevulinic acid photodynamic therapy for treatment of actinic keratosis.

Background: Photodynamic therapy (PDT) is widely used as a treatment for actinic keratoses (AK), with new sunlight-based regimens proposed as alternatives to lamp-based treatments. Prescribing indoor daylight activation could help address the seasonal temperature, clinical supervision, and access variability associated with outdoor treatments. Objective: To compare the AK lesion clearance efficacy of indoor daylight PDT treatment (30 min of 5-aminolevulinic acid (ALA) pre-incubation, followed by 2 h of indoor sunlight) versus a lamp-based PDT treatment (30 min of ALA preincubation, followed by 10 min of red light). Methods: A prospective clinical trial was conducted with 41 patients. Topical 10% ALA was applied to the entire treatment site (face, forehead, scalp). Patients were assigned to either the lamp-based or indoor daylight treatment. Actinic keratosis lesion counts were determined by clinical examination and recorded for pre-treatment, 1-month, and 6-month follow-up visits. Results: There was no statistical difference in the efficacy of AK lesion clearance between the red-lamp (1-month clearance = 57 ± 17%, 6-month clearance = 57 ± 20%) and indoor daylight treatment (1-month clearance = 61 ± 19%, 6-month clearance = 67 ± 20%). A 95% confidence interval of the difference of the means was measured between -4.4% and 13.4% for 1-month, and -2.2% and +23.6% for 6-month timepoints when comparing the indoor daylight to the red-lamp treatment, with a priori interval of equivalence of ±20%. Limitations: Ensuring an equivalent dose between the indoor and lamp treatment cohorts limited randomisation since it required performing indoor daylight treatments only during sunny days. Conclusion: Indoor-daylight PDT provided equivalent AK treatment efficacy to a lamp-based regimen while overcoming temperature limitations and UV-block sunscreen issues associated with outdoor sunlight treatments in the winter. Clinical trial registration: Clinicaltrials.gov listing: NCT03805737.

Effective fluence and dose at skin depth of daylight and lamp sources for PpIX-based photodynamic therapy.

SIGNIFICANCE: Skin-based photodynamic therapy (PDT) is used for the clinical treatment of actinic keratosis (AKs) and other skin lesions with continued expansion into the standard of care. Due to the spectral dependency of photosensitizer activation and skin optical fluence, there is a need for more accurate methods to estimate the delivered dose at depth from different PDT light sources and treatment regimens. AIM: Develop radiometric methods for calculating photosensitizer-effective fluence and dose at depth and determine differences between red-lamp, blue-lamp, and daylight-based PDT treatments. METHODS: Radiometric measurements of FDA-approved PDT lamp sources, outdoor daylight, and indoor daylight were performed for clinically relevant AK treatments. The protoporphyrin IX (PpIX) equivalent irradiance, fluence, and dose for each light source were calculated from the PpIX absorption spectrum and a 7-layer skin fluence model. The effective fluence and dose at depth was estimated by combining the spectral attenuation predicted at each wavelength and depth with the source fluence at each wavelength. RESULTS: The red-lamp source had the highest illuminance (112,000 lumen/m2), but lowest PpIX-effective irradiance (9.6 W/m2), and highest effective fluence at depth (10.8 W/m2 at 500 µm). In contrast, the blue light source had the lowest illuminance (2300 lumen/m2), but highest PpIX effective irradiance (37.0 W/m2), and ultimately the lowest effective fluence at depth (0.18 W/cm2 at 500 µm). The daylight source had values of (outdoor | indoor) illuminance of (49,200 | 37,800 lumen/m2), effective irradiance of (19.2 | 10.7 W/m2), and effective fluence of (1.50 | 1.08 W/m2 at 500 µm). The effective fluence and dose at depth facilitated the comparison of treatment regimens, for example, calculating an equivalent dose for a 2 hr indoor daylight treatment and a 10 min red-light treatment for the 300-1000 µm depth range. CONCLUSIONS: The consideration of PpIX-effective fluence at varying depths is necessary to provide adequate comparisons of the delivered dose from PDT light sources. Methods for calculating radiometric fluence and delivered dose at depth were introduced, with open source MATLAB code, to help overcome the limitations of commonly used photometric and irradiance-based reporting.

Ultracompact fluorescence smartphone attachment using built-in optics for protoporphyrin-IX quantification in skin.

Smartphone-based fluorescence imaging systems have the potential to provide convenient quantitative image guidance at the point of care. However, common approaches have required the addition of complex optical attachments, which reduce translation potential. In this study, a simple clip-on attachment appropriate for fluorescence imaging of protoporphyrin-IX (PpIX) in skin was designed using the built-in light source and ultrawide camera sensor of a smartphone. Software control for image acquisition and quantitative analysis was developed using the 10-bit video capability of the phone. Optical performance was characterized using PpIX in liquid tissue phantoms and endogenously produced PpIX in mice and human skin. The proposed system achieves a very compact form factor (<30 cm3) and can be readily fabricated using widely available low-cost materials. The limit of detection of PpIX in optical phantoms was <10 nM, with good signal linearity from 10 to 1000 nM (R2 >0.99). Both murine and human skin imaging verified that in vivo PpIX fluorescence was detected within 1 hour of applying aminolevulinic acid (ALA) gel. This ultracompact handheld system for quantification of PpIX in skin is well-suited for dermatology clinical workflows. Due to its simplicity and form factor, the proposed system can be readily adapted for use with other smartphone devices and fluorescence imaging applications. Hardware design and software for the system is made freely available on GitHub (https://github.com/optmed/CompactFluorescenceCam).

Topical Imiquimod for Lentigo Maligna: Survival Analysis of 103 Cases With 17 Years Follow-up.

Topical imiquimod 5% cream has been investigated as off-label primary or adjuvant treatment for melanoma in situ, lentigo maligna type (LM). Herein, we present the largest known case series of lentigo maligna treated with topical imiquimod, with up to 17 years of follow-up, and include a recurrence-free survival analysis. In this case series, 103 lesions were retrospectively evaluated for treatment response and recurrence following a course of topical imiquimod with or without tazarotene gel 0.1% pretreatment between January 1, 2002 and March 31, 2019, and prospectively followed through November 15, 2019. Over median follow-up of 5.1 years (mean = 6.2 years, S = 5.2 years, range, 0.08–17.1 years), including 29.1% LM with >10 years follow-up, we observed a response rate of 97.1% (100/103), with 8 local recurrences (8/100, 8.0%) developing at mean 2.9 years (SD: 2.7 years). Local recurrence was significantly associated with a history of failed excision (P= 0.001), <60 applications of imiquimod (P= 0.04) and partial clinical clearance (P= 0.0003). Recurrence-free survival analysis demonstrated significant risk-stratification for low and high-risk groups (P= 0.0001). Long term risk for recurrence showed significant differences among low- and high-risk cases, with low-risk cases demonstrating favorable long-term outcomes, comparable to conventional and staged surgery. Our observed low recurrence in a large case series with long-term follow-up suggests the efficacy of topical 5% imiquimod for LM and emphasizes the need for randomized control trials comparing imiquimod with, or as an adjunct to, surgical treatment. J Drugs Dermatol. 2021;20(3):346-348. doi:10.36849/JDD.5660.

Cutaneous leishmaniasis successfully treated with miltefosine.

Leishmaniasis is a neglected tropical disease with notable worldwide burden and increasing prevalence in the United States due to globalization. We describe 2 cases of cutaneous leishmaniasis in New England, United States, both caused by the New World subgenus Viannia, in adults returning from Central America. Both patients underutilized preventive measures against bites from phlebotomine sand flies while abroad. They were successfully treated with oral miltefosine, which was well tolerated. Avoidance of vector transmission is the most important preventive measure. Prompt identification and treatment of cutaneous leishmaniasis caused by species with potential for mucocutaneous spread are key to limiting morbidity and mortality. This responsibility should be shared among medical specialties, including dermatologists. Partnering with the Centers for Disease Control and Prevention (CDC) is critical for timely diagnosis and thus treatment. Miltefosine should be considered a first-line agent for cutaneous leishmaniasis given its efficacy, tolerability, availability, and ease of administration. Ondansetron can be prescribed concurrently.

Smartphone fluorescence imager for quantitative dosimetry of protoporphyrin-IX-based photodynamic therapy in skin.

Significance: While clinical treatment of actinic keratosis by photodynamic therapy (PDT) is widely practiced, there is a well-known variability in response, primarily caused by heterogeneous accumulation of the photosensitizer protoporphyrin IX (PpIX) between patients and between lesions, but measurement of this is rarely done. Aim: Develop a smartphone-based fluorescence imager for simple quantitative photography of the lesions and their PpIX levels that can be used in a new clinical workflow to guide the reliability of aminolevulinic acid (ALA) application for improved lesion clearance. Approach: The smartphone fluorescence imager uses an iPhone and a custom iOS application for image acquisition, a 3D-printed base for measurement standardization, an emission filter for PpIX fluorescence isolation, and a 405-nm LED ring for optical excitation. System performance was tested to ensure measurement reproducibility and the ability to capture photosensitizer accumulation and photobleaching in pre-clinical and clinical settings. Results: PpIX fluorescence signal from tissue-simulating phantoms showed linear sensitivity in the 0.01 to 2.0 µM range. Murine studies with Ameluz® aminolevulinic acid (ALA) gel and initial human testing with Levulan® ALA cream verified that in-vivo imaging was feasible, including that PpIX production over 1 h is easily captured and that photobleaching from the light treatment could be quantified. Conclusions: The presented device is the first quantitative wide-field fluorescence imaging system for PDT dosimetry designed for clinical skin use and for maximal ease of translation into clinical workflow. The results lay the foundation for using the system in clinical studies to establish treatment thresholds for the individualization of PDT treatment.

Spontaneous Hair Repigmentation in an 80-Year-Old Man: A Case of Melanoma-Associated Hair Repigmentation and Review of the Literature.

Spontaneous hair repigmentation of physiologically white or gray hair is a rare occurrence that may be associated with melanoma in elderly individuals. We present the first case of this phenomenon in a man. A gray-haired, 80-year-old man presented to dermatology clinic with a 3-cm lock of black hair on his vertex scalp that developed over 1 year. Punch biopsies showed an increase in junctional dendritic melanocytes with rare pagetoid cells and extension along the follicular outer root sheath epithelium and interfollicular epidermis, associated with prominent dendritic melanocytic hyperplasia and pigment-containing melanocytes within the hair bulbs. Although the findings on the biopsies were not diagnostic of melanoma in situ, an irregular interfollicular distribution of melanocytes was concerning for an adjacent atypical process. A complete excision was performed and revealed melanoma in situ, lentigo maligna type. Rare reports describe spontaneous hair repigmentation as a harbinger of lentigo maligna in women. Repigmentation can occur in the setting of proliferation of malignant pigment-producing melanocytes or by paracrine stimulation of benign bulbar melanocytes through receptor tyrosine kinase KIT activation. Presence of prominent dendritic melanocytic hyperplasia and pigment-containing melanocytes within the hair bulbs in our patient's biopsies was suggestive of paracrine or physiologic stimulation of bulbar melanocytes. Given the importance of early melanoma detection and the low visibility of the scalp, this report raises awareness of an extraordinary presentation of lentigo maligna and exemplifies the importance of close clinicopathologic correlation to ensure optimal clinical management and patient outcome.

Modeling PpIX effective light fluence at depths into the skin for PDT dose comparison.

BACKGROUND: Daylight-activated PDT has seen increased support in recent years as a treatment method for actinic keratosis and other non-melanoma skin cancers. The inherent variability observed in broad-spectrum light used in this methodology makes it difficult to plan and monitor light dose, or compare to lamp light doses. METHODS: The present study expands on the commonly used PpIX-weighted effective surface irradiance metric by introducing a Monte Carlo method for estimating effective fluence rates into depths of the skin. The fluence rates are compared between multiple broadband and narrowband sources that have been reported in previous studies, and an effective total fluence for various treatment times is reported. A dynamic estimate of PpIX concentration produced during pro-drug incubation and treatment is used with the fluence estimates to calculate a photodynamic dose. RESULTS: Even when there is up to a 5x reduction between the effective surface irradiance of the broadband light sources, the effective fluence below 250 µm depth is predicted to be relatively equivalent. An effective threshold fluence value (0. 70Jeff/cm2) is introduced based on a meta-analysis of previously published ALA-PpIX induced cell death. This was combined with a threshold PpIX concentration (50 nM) to define a threshold photodynamic dose of 0.035 u M Jeff/cm2. CONCLUSIONS: The threshold was used to generate lookup tables to prescribe minimal treatment times to achieve depth-dependent cytotoxic effect based on incubation times and irradiance values for each light source.

Comparison of Blue and White Lamp Light with Sunlight for Daylight-Mediated, 5-ALA Photodynamic Therapy, in vivo.

Daylight-mediated photodynamic therapy (d-PDT) as a treatment for actinic keratosis (AK) is an increasingly common technique due to a significant reduction in pain, leading to better patient tolerability. While past studies have looked at different light sources and delivery methods, this study strives to provide equivalent PpIX-weighted light doses with the hypothesis that artificial light sources could be equally as effective as natural sunlight if their PpIX-weighted fluences were equalized. Normal mouse skin was used as the model to compare blue LED light, metal halide white light and natural sunlight, with minimal incubation time between topical ALA application and the onset of light delivery. A total PpIX-weighted fluence of 20 Jeff cm-2 was delivered over 2 h, and the efficacy of response was quantified using three acute bioassays for PDT damage: PpIX photobleaching, Stat3 crosslinking and quantitative histopathology. These bioassays indicated blue light was slightly inferior to both sunlight and white light, but that the latter two were not significantly different. The results suggest that metal halide white light could be a reasonable alternative to daylight PDT, which should allow a more controlled treatment that is independent of weather and yet should have similar response rates with limited pain during treatment.

Atypical herpes zoster presentation in a healthy vaccinated pediatric patient.

We report the case of a 6-year-old girl with no notable medical history who presented to the dermatology clinic for evaluation of left leg pain with an overlying erythematous rash of 4 days' duration. Clinical examination revealed pink patches and plaques in a unilateral L5 distribution with an isolated pinpoint vesicle. Direct fluorescent antibody testing confirmed varicella-zoster virus (VZV) infection, establishing a diagnosis of herpes zoster (HZ). The patient previously had received the VZV vaccine in the left leg and arm and had no history of primary VZV infection. We summarize this case and discuss the epidemiology and clinical characteristics of HZ in vaccinated children.

Assessing daylight & low-dose rate photodynamic therapy efficacy, using biomarkers of photophysical, biochemical and biological damage metrics in situ.

BACKGROUND: Sunlight can activate photodynamic therapy (PDT), and this is a proven strategy to reduce pain caused byconventional PDT treatment, but assessment of this and other alternative low dose rate light sources, and their efficacy, has not been studied in an objective, controlled pre-clinical setting. This study used three objective assays to assess the efficacy of different PDT treatment regimens, using PpIX fluorescence as a photophysical measure, STAT3 cross-linking as a photochemical measure, and keratinocyte damage as a photobiological measure. METHODS: Nude mouse skin was used along with in vivo measures of photosensitizer fluorescence, keratinocyte nucleus damage from pathology, and STAT3 cross-linking from Western blot analysis. Light sources compared included a low fluence rate red LED panel, compact fluorescent bulbs, halogen bulbs and direct sunlight, as compared to traditional PDT delivery with conventional and fractionated high fluence rate red LED light delivery. RESULTS: Of the three biomarkers, two had strong correlation to the PpIX-weighted light dose, which is calculated as the product of the treatment light dose (J/cm2) and the normalized PpIX absorption spectra. Comparison of STAT3 cross-linking to PpIX-weighted light dose had an R=0.74, and comparison of keratinocyte nuclear damage R=0.70. There was little correlation to PpIX fluorescence. These assays indicate most of the low fluence rate treatment modalities were as effective as conventional PDT, while fractionated PDT showed the most damage. CONCLUSIONS: Daylight or artificial light PDT provides an alternative schedule for delivery of drug-light treatment, and this pre-clinical assay demonstrated that in vivo assays of damage could be used to objectively predict a clinical outcome in this altered delivery process.

Long-Term Outcomes of Melanoma In Situ Treated With Topical 5% Imiquimod Cream: A Retrospective Review.

BACKGROUND: Melanoma in situ (MIS) is a noninvasive form of melanoma for which nonsurgical therapeutic options continue to be explored. The off-label use of topical 5% imiquimod cream in the management of MIS has shown potential but reported recurrence rates vary considerably between 0% and 40%. Furthermore, the long-term efficacy of imiquimod is not well established. OBJECTIVE: To determine the recurrence rate of MIS among patients treated with topical 5% imiquimod cream at Dartmouth-Hitchcock Medical Center with at least 1 year of follow-up. METHODS: A retrospective chart review identified 12 patients with MIS who have been treated with topical 5% imiquimod cream for 6 to 12 weeks. Patients who underwent surgical treatment for MIS were excluded from analysis. RESULTS: Of 12 patients with histologically confirmed MIS treated with topical 5% imiquimod cream, there were 2 recurrences (17%) during a median follow-up time of 5.5 years. CONCLUSION: Although surgery is still considered the gold standard for the treatment of MIS, imiquimod may represent a potentially effective noninvasive treatment option for patient who are not surgical candidates.

Cutaneous adverse effects of the immune checkpoint inhibitors.

The immune checkpoint targeted agents, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and anti-programed cell death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) inhibitors are frequently associated with cutaneous side effects that are often dose limiting and can lead to discontinuation of therapy. Ipilimumab, a CTLA-4 inhibitor, is most commonly associated with a morbilliform eruption on the trunk and extremities and pruritus. More severe cutaneous toxicities reported include toxic epidermal necrolysis and severe drug rash with eosinophila and systemic symptoms. Recent case reports of Sweet syndrome and cutaneous sarcoidosis have also recently been described after treatment with ipilimumab. The cutaneous events usually occur early in the course of treatment and are dose dependent. PD-1 inhibitors, nivolumab and pembrolizumab, induce similar but less severe toxicities compared with the CTLA-4 inhibitors. The most common cutaneous adverse events include lichenoid reactions, eczema, vitiligo, and pruritus. Lichenoid oral mucosal lesions located on the tongue, buccal mucosa, lips, or gingivae or located on all of these have also recently been described. The time of onset of the cutaneous events with the PD-1 inhibitors occurs later than that seen with the CTLA-4 inhibitors. Anti-PD-L1 antibodies, such as atezolizumab, have a similar side effect profile compared with the PD-1 inhibitors. Combination of immune checkpoint inhibitors, ipilimumab and nivolumab, has recently been approved for the treatment of advanced melanoma. The combination therapy is associated with a more severe side effect profile compared with the agents used as monotherapy. We discuss the most frequently encountered cutaneous side effects of the immune checkpoint inhibitors and review the recommended management strategies.

Comparing desferrioxamine and light fractionation enhancement of ALA-PpIX photodynamic therapy in skin cancer.

BACKGROUND: Aminolevulinic acid (ALA)-based photodynamic therapy (PDT) provides selective uptake and conversion of ALA into protoporphyrin IX (PpIX) in actinic keratosis and squamous cell carcinoma, yet large response variations in effect are common between individuals. The aim of this study was to compare pre-treatment strategies that increase the therapeutic effect, including fractionated light delivery during PDT (fPDT) and use of iron chelator desferrioxamine (DFO), separately and combined. METHODS: Optical measurements of fluorescence were used to quantify PpIX produced, and the total amount of PpIX photobleached as an implicit measure of the photodynamic dose. In addition, measurements of white light reflectance were used to quantify changes in vascular physiology throughout the PDT treatment. RESULTS: fPDT produced both a replenishment of PpIX and vascular re-oxygenation during a 2 h dark interval between the first and second PDT light fractions. The absolute photodynamic dose was increased 57% by fPDT, DFO and their combination, as compared with PDT group (from 0.7 to 1.1). Despite that light fractionation increased oedema and scab formation during the week after treatment, no significant difference in long-term survival has been observed between treatment groups. However, outcomes stratified on the basis of measured photodynamic dose showed a significant difference in long-term survival. CONCLUSIONS: The assessment of implicit photodynamic dose was a more significant predictor of efficacy for ALA-PDT skin cancer treatments than prescription of an enhanced treatment strategy, likely because of high individual variation in response between subjects.