Utility of topical agents for radiation dermatitis and pain: a randomized clinical trial.

PURPOSE: Although topical agents are often provided during radiation therapy, there is limited consensus and evidence for their use prophylactically to prevent or reduce radiation dermatitis. METHODS: This was a multi-site, randomized, placebo-controlled, blinded study of 191 breast cancer patients to compare the prophylactic effectiveness of three topical agents (Curcumin, HPR Plus™, and Placebo) for reducing radiation dermatitis and associated pain. Patients applied the topical agent to their skin in the radiation area site three times daily starting the first day of radiation therapy (RT) until 1 week after RT completion. RESULTS: Of the 191 randomized patients, 171 patients were included in the final analyses (87.5% white females, mean age = 58 (range = 36-88)). Mean radiation dermatitis severity (RDS) scores did not significantly differ between study arms (Curcumin = 2.68 [2.49, 2.86]; HPR Plus™ = 2.64 [2.45, 2.82]; Placebo = 2.63 [2.44, 2.83]; p = 0.929). Logistic regression analyses showed that increased breast field separation positively correlated with increased radiation dermatitis severity (p = 0.018). In patients with high breast field separation (≥ 25 cm), RDS scores (Curcumin = 2.70 [2.21, 3.19]; HPR Plus™ = 3.57 [3.16, 4.00]; Placebo = 2.95 [2.60, 3.30]; p = 0.024) and pain scores (Curcumin = 0.52 [- 0.28, 1.33]; HPR Plus™ = 0.55 [- 0.19, 1.30]; Placebo = 1.73 [0.97, 2.50]; p = 0.046) significantly differed at the end of RT. CONCLUSIONS: Although there were no significant effects of the treatment groups on the overall population, our exploratory subgroup analysis suggests that prophylactic treatment with topical curcumin may be effective for minimizing skin reactions and pain for patients with high breast separation (≥ 25 cm) who may have the worst skin reactions.

Chronic social stress Ameliorates psoriasiform dermatitis through upregulation of the Hypothalamic-Pituitary-Adrenal axis.

Acute stress is a physiological response of an organism to adverse conditions, contributing to survival; however, persistence through time may lead to disease. Indeed, exacerbation of inflammatory conditions such as psoriasis has been reported to follow stressors in susceptible patients. Because chronic stress cannot ethically be elicited in patients under controlled laboratory conditions, we studied genetically modified mice that naturally develop psoriasiform dermatitis, and subjected them to an ethological chronic social contact stress paradigm. Although we found elevated pro-inflammatory neuropeptide production of substance P (SP), calcitonin-gene-related peptide (CGRP) and nerve-growth factor (NGF) mRNA in the dorsal root ganglia (DRG) as well as pro-inflammatory cytokines in response to the social stressor, stress paradoxically prevented the development of the skin lesions. This effect of stress could be reversed by the treatment with glucocorticoid (GC) receptor blockers, suggesting that it was mediated through the upregulation of corticosterone secretion. Extrapolating to humans, the worsening of disease in susceptible patients with psoriasis could be attributed to a defect in the Hypothalamic-Pituitary-Adrenal (HPA) axis with an impaired production of GC during situations of adversity, thus rendering them unable to counteract the pro-inflammatory effects of chronic stressors.

Oral curcumin for radiation dermatitis: a URCC NCORP study of 686 breast cancer patients.

PURPOSE: Despite advances in medical technology, radiation dermatitis occurs in 95% of patients receiving radiation therapy (RT) for cancer. Currently, there is no standard and effective treatment for the prevention or control of radiation dermatitis. The goal of the study was to determine the efficacy of oral curcumin, one of the biologically active components in turmeric, at reducing radiation dermatitis severity (RDS) at the end of RT, using the RDS scale, compared to placebo. METHODS: This was a multisite, randomized, double-blinded, placebo-controlled trial of 686 breast cancer patients. Patients took four 500-mg capsules of placebo or curcumin three times daily throughout their prescribed course of RT until 1 week post-RT. RESULTS: A total of 686 patients were included in the final analyses (87.5% white females, mean age = 58). Linear mixed-model analyses demonstrated that curcumin did not reduce radiation dermatitis severity at the end of RT compared to placebo (B (95% CI) = 0.044 (- 0.101, 0.188), p = 0.552). Fewer curcumin patients with RDS > 3.0 suggested a trend toward reduced severity (7.4 vs. 12.9%, p = 0.082). Patient-reported changes in pain, symptoms, and quality of life were not statistically significant between arms. CONCLUSIONS: Oral curcumin did not significantly reduce radiation dermatitis severity compared to placebo. The skin rating variation and broad eligibility criteria could not account for the undetectable therapeutic effect. An objective measure for radiation dermatitis severity and further exploration for an effective treatment for radiation dermatitis is warranted.

Successful Treatment of Pemphigus Vulgaris With Ofatumumab

Rituximab is a chimeric anti-CD20 monoclonal antibody that is very effective in treating patients with pemphigus vulgaris. Though infrequent, the development of human anti-chimeric antibodies in patients receiving rituximab results in loss of efficacy. Ofatumumab is a second-generation fully-human anti-CD20 monoclonal antibody currently used to treat chronic lymphocytic leukemia. We report a case of a patient with pemphigus vulgaris successfully treated with ofatumumab after developing human anti-chimeric antibodies to rituximab. J Drugs Dermatol. 2018;17(12):1338-1339.

Aldo-keto reductase 1C3 is overexpressed in skin squamous cell carcinoma (SCC) and affects SCC growth via prostaglandin metabolism.

Aldo-keto reductase 1C3 (AKR1C3) is an enzyme involved in metabolizing prostaglandins (PGs) and sex hormones. It metabolizes PGD2 to 9α11ß-PGF2 , diverting the spontaneous conversion of PGD2 to the PPARγ agonist, 15-Deoxy-Delta-12, 14-prostaglandin J2 (15d-PGJ2 ). AKR1C3 is overexpressed in various malignancies, suggesting a tumor promoting function. This work investigates AKR1C3 expression in human non-melanoma skin cancers, revealing overexpression in squamous cell carcinoma (SCC). Effects of AKR1C3 overexpression were then evaluated using three SCC cell lines. AKR1C3 was detected in all SCC cell lines and its expression was upregulated in response to its substrate, PGD2 . Although attenuating AKR1C3 expression in SCC cells by siRNA did not affect growth, treatment with PGD2 and its dehydration metabolite, 15d-PGJ2 , decreased SCC proliferation in a PPARγ-dependent manner. In addition, treatment with the PPARγ agonist pioglitazone profoundly inhibited SCC proliferation. Finally, we generated an SCC cell line that stably overexpressed AKR1C3 (SCC-AKR1C3). SCC-AKR1C3 metabolized PGD2 to 9α11ß-PGF2 12-fold faster than the parent cell line and was protected from the antiproliferative effect mediated by PGD2 . This work suggests that PGD2 and its metabolite 15d-PGJ2 attenuate SCC proliferation in a PPARγ-dependent manner, therefore activation of PPARγ by agonists such as pioglitazone may benefit those at high risk of SCC.

Exposure to ionizing radiation induces the migration of cutaneous dendritic cells by a CCR7-dependent mechanism.

In the event of a deliberate or accidental radiological emergency, the skin would likely receive substantial ionizing radiation (IR) poisoning, which could negatively impact cellular proliferation, communication, and immune regulation within the cutaneous microenvironment. Indeed, as we have previously shown, local IR exposure to the murine ear causes a reduction of two types of cutaneous dendritic cells (cDC), including interstitial dendritic cells of the dermis and Langerhans cells of the epidermis, in a dose- and time-dependent manner. These APCs are critical regulators of skin homeostasis, immunosurveillance, and the induction of T and B cell-mediated immunity, as previously demonstrated using conditional cDC knockout mice. To mimic a radiological emergency, we developed a murine model of sublethal total body irradiation (TBI). Our data would suggest that TBI results in the reduction of cDC from the murine ear that was not due to a systemic response to IR, as a loss was not observed in shielded ears. We further determined that this reduction was due, in part, to the upregulation of the chemoattractant CCL21 on lymphatic vessels as well as CCR7 expressed on cDC. Migration as a potential mechanism was confirmed using CCR7(-/-) mice in which cDC were not depleted following TBI. Finally, we demonstrated that the loss of cDC following TBI results in an impaired contact hypersensitivity response to hapten by using a modified contact hypersensitivity protocol. Taken together, these data suggest that IR exposure may result in diminished immunosurveillance in the skin, which could render the host more susceptible to pathogens.

Implementation of a postgraduate dermatology fellowship program for nurse practitioners.

ABSTRACT: Transition to practice programs (also referred to as fellowship, residency, or postgraduate training programs) for nurse practitioners (NPs) are becoming more popular, especially in specialties such as dermatology. A nationwide shortage of dermatology clinicians, which had led to long appointment wait times and inadequate patient access to care, has led to more NPs practicing dermatology to help meet the demand for care. New graduate NPs may struggle in their transition to practice, and fellowship programs have been shown to support NPs as they transition from novice to expert. In this article, the University of Rochester Medical Center shares its experience in developing, implementing, and managing a postgraduate dermatology fellowship program for NPs.

ItchyQoL reveals differences in itch symptom experience in routine dermatologic care.

Itch is a common symptom of dermatologic diseases associated with significant impairment of health-related quality of life (QoL). This study reveals disparities in itch symptom experience and itch impact on QoL. A retrospective study of patient-reported outcome measure (PRO) data (ItchyQoL, Itch NRS, Pain Interference, Anxiety) for 387 outpatient dermatology visits to characterize the impact of itch on patients' QoL and itch symptom experience based on skin color in patients with dermatologic disease. Most patients were Caucasian females (67%) with mean age of 48 years. Correlative analyses showed mild itch associated with emotional impacts on QoL (p < 0.01), while severe itch associated with functional and emotional impacts on QoL (p < 0.01). African American (AA) patients reported more "severe-range" answers for 15 (68%) ItchyQoL items and had higher ItchyQoL mean scores (p = 0.001). ItchyQoL demonstrated an emotional impact on QoL by mild itch, but a functional and emotional impact on QoL by severe itch. Further, AAs suffered from greater itch-related impairment in QoL than Caucasian patients, especially due to scarring and sleeplessness.

Identifying Care Gaps and Referral Patterns in Acute Dermatology at Urgent Care Centers.

Limited urgent access to board-certified dermatologists drives patients to seek dermatologic care at urgent care centers (UCC). UCC are staffed by clinicians with comparatively limited dermatology training, often resulting in lower quality care for acute dermatology conditions. This study investigates health care referral outcomes of patients seeking dermatologic care at UCC, examine the appropriateness of UCC dermatologic care, and assess the feasibility of referral management by eConsult. We utilize a retrospective cohort of 807 patients and a provider survey to examine referral outcomes of patients referred to University of Rochester Dermatology (UR-Derm), a tertiary care university-based teaching hospital, from UR UCC between January 1, 2021, and August 31, 2022. Outcomes for healthcare referrals included patient demographics, referral completion rates, UR-Derm appointment wait times, and diagnostic concordance rates between UCC and UR-Derm. Outcomes from the provider survey included appropriateness of UCC treatment plans, appropriateness of UCC referral to UR-Derm, and feasibility of referral management by eConsult. Patients who utilized UCC were predominately white (77.0%) females (53.9%) with a mean age of 37.9 years. Most patients referred by UCC did not complete an in-person UR-Derm evaluation (58.6%). Of those who did complete a UR-Derm visit, the average wait time was 38.3 days. Only 56% of UCC and UR-Derm diagnoses were concordant. Our surveyed dermatologists deemed 30% of the UCC treatment plans appropriate. The majority of referrals (83.5%) were viewed as manageable with an eConsult with only 10% of referrals requiring in-person visit. Several practice gaps exist in specialty care delivery in UCC and additional inefficiencies exist in the urgent referral process. These gaps could be addressed by targeted educational interventions and availability of dermatology consultation to support urgent care.

The utility of PROMIS domain measures in dermatologic care.

Patient-reported outcome (PRO) measures play an important role in clinical care. Currently, a broad-spectrum, validated PRO measure suitable for all dermatology patients, as part of clinical care, does not exist. Patient-reported Outcome Measures Information System (PROMIS) measures track specific domain outcomes across all diseases. To assess the relevance and utility of a computer-adaptive health assessment consisting of three PROMIS domains in routine dermatologic care. This retrospective study evaluated a PROMIS health assessment, consisting of three computer-adaptive test domains (pain interference, anxiety, and depression), administered as part of routine clinical care in three dermatology clinics at an academic medical center. The primary objective was to identify clinically significant associations between high PROMIS domain scores (i.e., t score > 55) and dermatologic disease, as well as change in PROMIS domain scores in response to treatment. The majority of patients who initiated the assessment completed all domains (88.7%). In patients with atopic dermatitis, acne, hidradenitis suppurativa, and psoriasis, high PROMIS scores correlated with clinically relevant outcomes, such as severe disease, unsuccessful treatment, uncontrolled disease, and the presence of a mental health condition. PROMIS Pain Interference, anxiety and depression identified patients with severe disease, unsuccessful treatment regimens, poorly-controlled disease, and/or mental health comorbidities for multiple skin conditions. Further utilization of PROMIS domains in routine clinical care will promote patient-centered care and improve quality of care.

Sequential down-regulation of E-cadherin with squamous cell carcinoma progression: loss of E-cadherin via a prostaglandin E2-EP2 dependent posttranslational mechanism.

The incidence of skin cancer is on the rise, with over 1 million new cases yearly. Although it is known that squamous cell cancers (SCC) are caused by UV light, the mechanism(s) involved remains poorly understood. In vitro studies with epithelial cells or reports examining malignant skin lesions suggest that loss of E-cadherin-mediated cell-cell contacts may contribute to SCCs. Other studies show a pivotal role for cyclooxygenase-dependent prostaglandin E2 (PGE2) synthesis in this process. Using chronically UV-irradiated SKH-1 mice, we show a sequential loss of E-cadherin-mediated cell-cell contacts as lesions progress from dysplasia to SCCs. This E-cadherin down-regulation was also evident after acute UV exposure in vivo. In both chronic and acute UV injury, E-cadherin levels declined at a time when epidermal PGE2 synthesis was enhanced. Inhibition of PGE2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo abrogated this UV-induced E-cadherin down-regulation. In contrast, addition of PGE2 or the EP2 receptor agonist butaprost to PMK produced a dose- and time-dependent decrease in E-cadherin. We also show that UV irradiation, via the PGE2-EP2 signaling pathway, may initiate tumorigenesis in keratinocytes by down-regulating E-cadherin-mediated cell-cell contacts through its mobilization away from the cell membrane, internalization into the cytoplasm, and shuttling through the lysosome and proteasome degradation pathways. Further understanding of how UV-PGE2-EP2 down-regulates E-cadherin may lead to novel chemopreventative strategies for the treatment of skin and other epithelial cancers.

Effects of continuous-wave (670-nm) red light on wound healing.

BACKGROUND: Recent work suggests that injuries can heal faster if treated by lasers emitting 670-nm red light. LED lights emitting 670-nm light are now available. This suggests that inexpensive and easy-to-use 670-nm LED lights might help accelerate cutaneous wound healing. OBJECTIVE: The objective was to evaluate the effect of 670-nm LED light on wound healing in SKH-1 hairless mice. METHODS: To study 670-nm light effects on incisional injury, animals were left unexposed or exposed to equal doses of high-, medium-, or low-flux light. Burn injuries were treated with high-flux light or left unexposed. Healing was assessed by measurement of the burn area and the gap remaining to closure of incisional injury. RESULTS: Mice exposed to 670-nm red light showed significantly faster healing than control mice. High, medium, and low fluxes of light were all effective after incisional injury. In burn injury, there was improvement in wound healing initially, but the time to repair was unchanged. CONCLUSIONS: A 670-nm LED red light source accelerates healing in skin of SKH-1 hairless mice after incisional injuries, but is not as effective for burn injuries. These data that suggest red light exposure may be helpful in postoperative wound repair.

sPLA2-X stimulates cutaneous melanocyte dendricity and pigmentation through a lysophosphatidylcholine-dependent mechanism.

Photoprotection of the skin is provided by melanocytes, neural crest derived cells that synthesize melanin in specialized organelles that are transferred to keratinocytes. Secretory phospholipases comprise a large family of Ca2+-dependent enzymes that liberate arachidonic acid (AA), a precursor of prostaglandins, as well as lysophospholipids. The predominant secretory phospholipase expressed by keratinocytes is group X secretory phospholipase A2 (sPLA2), which liberates large amounts of AA and the lysophospholipid lysophosphatidylcholine (LPC), from membrane preparations. Recent work by our laboratory has shown that melanocytes express receptors for prostaglandins that upon activation stimulate melanocyte dendricity and activity of tyrosinase, a key enzyme in melanin biosynthesis. In the present study, we have treated human melanocytes with recombinant sPLA2-X and show that low levels of sPLA2-X stimulate both tyrosinase activity and melanocyte dendricity. We found that the effects of sPLA2-X are mediated predominantly by LPC, not AA, and we have demonstrated expression of the phospholipase A2 receptor and two G-protein-coupled receptors for LPC (G2A and GPR119) in human melanocytes. Because secretory phospholipases are released during inflammation and are regulated by UV irradiation, our data suggest an important role for sPLA2-X in cutaneous pigmentation through the release of LPC.

Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines.

PURPOSE: To determine whether curcumin ameliorates acute and chronic radiation skin toxicity and to examine the expression of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-18, IL-1Ra, tumor necrosis factor [TNF]-alpha, and lymphotoxin-beta) or fibrogenic cytokines (transforming growth factor [TGF]-beta) during the same acute and chronic phases. METHODS AND MATERIALS: Curcumin was given intragastrically or intraperitoneally to C3H/HeN mice either: 5 days before radiation; 5 days after radiation; or both 5 days before and 5 days after radiation. The cutaneous damage was assessed at 15-21 days (acute) and 90 days (chronic) after a single 50 Gy radiation dose was given to the hind leg. Skin and muscle tissues were collected for measurement of cytokine mRNA. RESULTS: Curcumin, administered before or after radiation, markedly reduced acute and chronic skin toxicity in mice (p < 0.05). Additionally, curcumin significantly decreased mRNA expression of early responding cytokines (IL-1 IL-6, IL-18, TNF-alpha, and lymphotoxin-beta) and the fibrogenic cytokine, TGF-beta, in cutaneous tissues at 21 days postradiation. CONCLUSION: Curcumin has a protective effect on radiation-induced cutaneous damage in mice, which is characterized by a downregulation of both inflammatory and fibrogenic cytokines in irradiated skin and muscle, particularly in the early phase after radiation. These results may provide the molecular basis for the application of curcumin in clinical radiation therapy.

Case reports: nodular vasculitis responsive to mycophenolate mofetil.

Mycophenolate mofetil is commonly used as a steroid-sparing agent effective in the management of erythema nodosum, idiopathic nodular panniculitis (Pfiefer-Weber-Christian disease), bullous pemphigoid, pemphigus vulgaris, and psoriasis. We report a case of nodular vasculitis responsive to mycophenolate mofetil. The clinical presentation, etiology, and management options for nodular vasculitis are discussed.

Cyclooxygenase-1 deletion enhances apoptosis but does not protect against ultraviolet light-induced tumors.

Inhibition or deletion of cyclooxygenase (COX)-2 has been demonstrated to protect against squamous cell cancer in many studies. Although much effort has focused on COX-2 inhibition, recent work indicates that COX-1 deletion may be nearly as protective. In this study, we used SKH-1 hairless mice in which COX-1 was selectively deleted to examine the role of COX-1 in photocarcinogenesis. After UV exposure, 40-60% less prostaglandin E2 was detected in COX-1-/- animals compared with wild-type (WT) controls. A 4-fold induction of keratinocyte apoptosis was observed in knockouts relative to WT animals, as documented by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling and caspase-3 staining. Proliferation was not significantly different in COX-1+/+, COX-1+/-, and COX-1-/- animals. When susceptibility to UV-induced tumor formation was studied, tumor number, average tumor size, and time of tumor onset in COX-1-/- animals were identical to WT controls. Thus, enhanced apoptosis did not alter UV-induced skin carcinogenesis, suggesting other effects are key to nonsteroidal anti-inflammatory drug chemoprevention. These results contrast sharply with data obtained using the classic 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate cancer model in which a prominent protective effect of COX-1-/- is present. The lack of protection observed here confirms cancer mechanisms are distinct in UV- and tumor promotor-induced cancer models and indicates that chemoprevention strategies must specifically address cancer causes to be effective.

Impact of Cosmetic Lotions on Nanoparticle Penetration through ex vivo C57BL/6 Hairless Mouse and Human Skin: A Comparison Study.

Understanding the interactions of nanoparticles (NPs) with skin is important from a consumer and occupational health and safety perspective, as well as for the design of effective NP-based transdermal therapeutics. Despite intense efforts to elucidate the conditions that permit NP penetration, there remains a lack of translatable results from animal models to human skin. The objectives of this study are to investigate the impact of common skin lotions on NP penetration and to quantify penetration differences of quantum dot (QD) NPs between freshly excised human and mouse skin. QDs were mixed in 7 different vehicles, including 5 commercial skin lotions. These were topically applied to skin using two exposure methods; a petri dish protocol and a Franz diffusion cell protocol. QD presence in the skin was quantified using Confocal Laser Scanning Microscopy. Results show that the commercial vehicles can significantly impact QD penetration in both mouse and human skin. Lotions that contain alpha hydroxyl acids (AHA) facilitated NP penetration. Lower QD signal was observed in skin studied using a Franz cell. Freshly excised human skin was also studied immediately after the sub-cutaneous fat removal process, then after 24 hours rest ex vivo. Resting human skin 24 hours prior to QD exposure significantly reduced epidermal presence. This study exemplifies how application vehicles, skin processing and the exposure protocol can affect QD penetration results and the conclusions that maybe drawn between skin models.

Total-Body Irradiation Exacerbates Dissemination of Cutaneous Candida Albicans Infection.

Exposure to radiation, particularly a large or total-body dose, weakens the immune system through loss of bone marrow precursor cells, as well as diminished populations of circulating and tissue-resident immune cells. One such population is the skin-resident immune cells. Changes in the skin environment can be of particular importance as the skin is also host to a number of commensal organisms, including Candida albicans , a species of fungus that causes opportunistic infections in immunocompromised patients. In a previous study, we found that a 6 Gy sublethal dose of radiation in mice caused a reduction of cutaneous dendritic cells, indicating that the skin may have a poorer response to infection after irradiation. In this study, the same 6 Gy sublethal radiation dose led to a weakened response to a C. ablicans cutaneous infection, which resulted in systemic dissemination from the ear skin to the kidneys. However, this impaired response was mitigated through the use of interleukin-12 (IL-12) administered to the skin after irradiation. Concomitantly with this loss of local control of infection, we also observed a reduction of CD4+ and CD8+ T cells in the skin, as well as the reduced expression of IFN-γ, CXCL9 and IL-9, which influence T-cell infiltration and function in infected skin. These changes suggest a mechanism by which an impaired immune environment in the skin after a sublethal dose of radiation increases susceptibility to an opportunistic fungal infection. Thus, in the event of radiation exposure, it is important to include antifungal agents, or possibly IL-12, in the treatment regimen, particularly if wounds are involved that result in loss of the skin's physical barrier function.