5-Fluorouracil Enhances Protoporphyrin IX Accumulation and Lesion Clearance during Photodynamic Therapy of Actinic Keratoses: A Mechanism-Based Clinical Trial.

Purpose: Actinic keratoses (AK) are precancerous lesions that can progress to squamous cell carcinoma. Photodynamic therapy (PDT) and topical 5-fluorouracil (5FU) are commonly used agents for AK. Empirical reports suggest that combining them can improve the therapeutic response. However, the optimal combined regimen was not clear in terms of proper sequence, timing, and mechanism. This clinical study explored mechanisms of action for neoadjuvantal 5FU and PDT for treatment of AK.Patients and Methods: A bilaterally controlled trial (17 patients) was performed. One side of the body (face, scalp, forearms) received 5FU pretreatment for 6 days, whereas the other side served as no-pretreatment control. Methylaminolevulinate cream was applied to both sides for 3 hours, and protoporphyrin IX (PpIX) levels were measured by noninvasive fluorimetry and skin biopsy. After red light illumination, lesion clearance was assessed at 3, 6, 9, and 12 months after PDT.Results: PpIX levels were increased 2- to 3-fold in 5FU-pretreated lesions versus controls. Altered expression of heme-synthetic enzymes (coproporphyrinogen oxidase and ferrochelatase) and induction of p53 were observed, probably accounting for increased PpIX and subsequent cancer cell death. Relative clearance rates after PDT with or without 5FU pretreatment were 75% versus 45% at 3 months, and 67% versus 39% at 6 months, respectively; these differences were statistically significant.Conclusions: Serial 5FU and PDT improve AK clearance by at least two mechanisms, enhanced photosensitizer accumulation and p53 induction. Because 5FU and PDT are FDA-approved modalities, the combined regimen can be readily employed in clinical practice to reduce AK burden and reduce SCC risk. Clin Cancer Res; 24(13); 3026-35. ©2018 AACR.

Differentiating Intralymphatic Histiocytosis, Intravascular Histiocytosis, and Subtypes of Reactive Angioendotheliomatosis: Review of Clinical and Histologic Features of All Cases Reported to Date.

Reactive angioendotheliomatosis (REA) is a rare benign angioproliferative condition of the skin, which has been noted to occur in patients with a variety of underlying systemic diseases. Histopathologically, this condition is characterized by vascular proliferation, and endothelial cell hyperplasia within the lumina and around dermal vessels, without significant cellular atypia. Since the first case of RAE was reported in 1958, multiple histologic patterns of benign cutaneous vascular proliferations with similar clinical presentations to RAE have been described in the literature and have been proposed as subtypes of the originally described condition. Among these entities are diffuse dermal angiomatosis (DDA), acroangiodermatitis, glomeruloid angioendotheliomatosis, and angiomatosis associated with cryoproteins. It has also been proposed that another entity, characterized by the benign proliferation of histiocytes within the lumina of cutaneous vessels, is a subtype of RAE. Histiocytosis within dermal vessels, in conjunction with skin pathology, was first reported in 1994. Based on the appearance of involved vessels, it was initially believed that the histiocytic proliferations were within the lumina of capillaries. Hence, the term intravascular histiocytosis was introduced to describe this histologic finding. However, subsequent introduction of an immunohistochemical (IHC) marker specific for lymphatic vessels demonstrated that most cases of cutaneous histiocyte proliferation are intralymphatic, rather than truly intravascular. However, there have also been reports of IHC-confirmed cases of true intravascular (intracapillary) histiocytosis. In this study, clinical and histologic data from all of the cases of RAE and IHC-confirmed cases of intravascular histiocytosis and intralymphatic histiocytosis reported in the literature to date are examined. Through comparison of the frequency with which key clinical and histologic features present in cases of each group, the authors provide improved clarity of the similarities and differences between these 3 entities.

Evolution of skin and hair in African Americans.

Current demographic trends in the United States highlight the growing population of those who identify as having "skin of color." As such, dermatologists must have a greater comfort level and knowledge in treating some of the unique skin and hair conditions seen in this population. Understanding the scientific basis for the evolution of skin color and hair texture is necessary in order to understand the variations in the characteristics of skin and hair seen among racial and ethnic groups. This review seeks to highlight the current scientific explanation of skin color and hair texture, with special attention to people of African descent, in an attempt to give insight into the clinical presentations of hair and skin disorders seen in this group.

ILK Index and Regrowth in Alopecia Areata.

There is insufficient data in the literature concerning optimal intralesional kenalog (ILK) dosing for the treatment of alopecia areata (AA). The purpose of this pilot study was to evaluate the utility of using the ratio of ILK received to initial Severity of Alopecia Tool (SALT) score to guide ILK dosing in patients with AA. Using photographic data from patients at baseline and 4-months follow-up, hair loss in 15 patients treated with AA was retrospectively graded using the SALT scores. The ILK received/initial SALT score (ILK index) was calculated for each patient, and the mean ILK index for patients who experienced significant (≥50%) and suboptimal (<50%) hair regrowth at 4 months follow-up were compared. Patients who experienced suboptimal hair regrowth had a lower ILK index on average than patients who experienced significant improvement. Although the difference did not meet significance (<0.1), the trend suggests that the ILK index, a novel calculation, may be a useful tool for guiding ILK dosing in the treatment of AA.

Angioinvasive opportunistic filamentous mycoses in immunocompromised patients.

Immunocompromised individuals are at greater risk for disseminated fungal infections. Immunocompromised individuals in the community have increased because of medical advances, thereby increasing the incidence and prevalence of opportunistic mycoses. The following case series illustrates the importance of having a high clinical suspicion for skin manifestations concerning for deep fungal infections.

Association of lichen planopilaris with thyroid disease: a retrospective case-control study.

BACKGROUND: Studies on the precise causes and comorbidities seen with lichen planopilaris (LPP) are limited. OBJECTIVE: We sought to determine the prevalence of thyroid diseases in patients with LPP. METHODS: Medical records of 166 patients with LPP and 81 age- and gender-matched control subjects seen in the Department of Dermatology at the Cleveland Clinic Foundation in Ohio between 2000 and 2013 were reviewed. RESULTS: A diagnosis of thyroid disease was present in 34% (n = 57) of the 166 patients with LPP, and in 11% (n = 9) of the control subjects (P = .0001). When confined to hypothyroidism only, this disease was found in 29% (n = 48) of the patients with LPP and 9% (n = 7) of the control subjects (P = .0003). LIMITATIONS: This study was limited by being retrospective. CONCLUSION: In our patients, LPP was associated with thyroid disease, especially hypothyroidism.

Cutaneous manifestations of anti-angiogenic therapy in oncology: Review with focus on VEGF inhibitors.

The role of the VEGF signaling pathway in angiogenesis has been extensively investigated, and many new targeted anti-angiogenic drugs have evolved from this knowledge. The recent approval and introduction of these anti-neoplastic drugs has revolutionized the treatment of many types of cancers, but has also revealed numerous toxicities to the skin and its adnexae. Since these cutaneous side effects may have a significant impact on the physical, emotional and psychosocial health of patients, it is important for dermatologists and oncologists alike to be aware of the cutaneous complications of these drugs in order to properly diagnose and treat them. This review will detail the presentation of the cutaneous complications of the anti-angiogenic drugs, most notably bevacizumab, sorafenib and sunitinib, and shed light on the management of such adverse reactions.

Central centrifugal cicatricial alopecia - an approach to diagnosis and management.

Central centrifugal cicatricial alopecia (CCCA) occurs primarily in African-American women and is the most common cause of scarring hair loss in this population. Since the mid 20th century, hair care practices of African-American women have been associated with CCCA, although there is developing evidence that the etiology of CCCA may be multifactorial. Clinically diagnosing CCCA may be challenging because it can resemble female pattern hair loss, alopecia areata, lichen planopilaris, or telogen effluvium. Therapeutic options are limited, thus the goal of treatment is to prevent progression of disease because once scar formation occurs, it is irreversible.

Medical and environmental risk factors for the development of central centrifugal cicatricial alopecia: a population study.

OBJECTIVE: To investigate medical and environmental risk factors for central centrifugal cicatricial alopecia (CCCA), the most common type of scarring alopecia in African American women. DESIGN: A population study involving a quantitative cross-sectional survey of risk factors for CCCA. Survey results are then correlated with a clinical evaluation for CCCA using a standardized, previously published central scalp alopecia photographic scale. SETTING: Two African American churches and a health fair for African American women in Cleveland, Ohio. PARTICIPANTS: A total of 326 African American women who participated in the hair study. MAIN OUTCOME MEASURES: Prevalence of CCCA in the general African American population and risk factors associated with CCCA. RESULTS: Of the 326 responders, 28% received a grade of 2 or higher using a standardized, previously published central scalp alopecia photographic scale, a score consistent with clinically evident central hair loss. Advanced central hair loss with clinical signs of scarring (grade ≥ 3) was seen in 59% of these respondents and was interpreted as clinically consistent with CCCA. Diabetes mellitus type 2 was significantly higher in those with CCCA (P = . 01), as were bacterial scalp infections (P = .045) and hair styles associated with traction (eg, from braids and weaves) (P = .02). CONCLUSIONS: Our survey results suggest that there is a high prevalence of central hair loss among African American women. Hair styles causing traction as well as inflammation in the form of bacterial infection may be contributing to the development of CCCA. The increase in diabetes mellitus type 2 among those with CCCA is in line with the recent theory that cicatricial alopecia may be a manifestation of metabolic dysregulation.