Treatment of oral graft-versus-host disease with intraoral nbUVB phototherapy.

PURPOSE: There are limited treatment options available for hematopoietic stem-cell transplant patients (HSCT) with oral graft-versus-host disease (GVHD). Intraoral phototherapy is a novel, yet promising therapeutic regimen. RESEARCH QUESTION: To assess the safety and effectiveness of intraoral narrowband UVB (nbUVB) phototherapy in the treatment of oral GVHD. METHODS: This case series evaluated 10 patients with refractory oral GVHD, who were treated at Northwestern Memorial Hospital with nbUVB between July 2019 and October 2023. Primary outcomes were to evaluate the safety and efficacy of phototherapy. Efficacy was measured by objective improvement in symptom scores and subjective improvement in patient reported symptoms. Safety was determined by the withdrawal due to adverse events. Total nbUVB exposure, number of treatments, and change in systemic immunosuppressive medications were also examined. RESULTS: The study cohort comprised 10 patients who developed oral GVHD at a median of 9.5 months after HSCT. The total median dose of nbUVB was 36 J/cm2, and the median number of sessions was 55. All 10 patients demonstrated some degree of improvement in symptoms. Notably, there was a reduction in the number of patients who reported symptoms of oral pain (83%), bleeding (67%), xerostomia (50%), and oral sensitivity (78%) after initiating phototherapy. There was also a statistically significant decrease in the levels of pain, erythema, and edema (p ≤ 0.001, < 0.001, 0.01, respectively). Most patients tolerated phototherapy well, but 1 patient withdrew from treatment due to adverse effects. Seventy-five percent of patients who were on immunosuppressive medications were able to decrease or stop these medications. CONCLUSION: This case series suggests that nbUVB phototherapy is well tolerated and efficacious in patients with oral GVHD.

Melanoma: Clinical Presentations.

The malignant cell in melanoma is the melanocyte. Because melanocytes are located in the basal layer of the epidermis, melanoma is most commonly seen on the skin. However, melanoma can also arise on mucosal surfaces such as the oral cavity, the upper gastrointestinal mucosa, the genital mucosa, as well as the uveal tract of the eye and leptomeninges. Melanomas tend to be pigmented but can also present as pink or red lesions. They can mimic benign or other malignant skin lesions. This chapter presents the spectrum of typical and less typical presentations of melanoma, as well as patterns of spread. It is divided into (1) cutaneous lesions; (2) patterns of regional spread, (3) non-cutaneous lesions; and (4) distant metastases.

Dermatologic adverse events to chemotherapeutic agents, Part 2: BRAF inhibitors, MEK inhibitors, and ipilimumab.

The advent of novel targeted chemotherapeutic agents and immunotherapies has dramatically changed the arena of cancer treatment in recent years. BRAF inhibitors, MEK inhibitors, and ipilimumab are among the newer chemotherapy drugs that are being used at an increasing rate. Dermatologic adverse events to these medications are common, and it is important for dermatologists and oncologists alike to learn to recognize and treat such side effects in order to maintain both patients' quality of life and their anticancer treatment. This review describes the cutaneous side effects seen with BRAF inhibitors (eg, maculopapular eruption, photosensitivity, squamoproliferative growths, melanocytic proliferations), MEK inhibitors (eg, papulopustular eruption), and ipilimumab (eg, maculopapular eruption, vitiligo), with a mention of vismodegib and anti-PD-1 agents.

A randomized Phase I pre-operative window trial of transdermal endoxifen in women planning mastectomy: Evaluation of dermal safety, intra-mammary drug distribution, and biologic effects.

Breast cancer prevention only requires local exposure of the breast to active drug. However, oral preventive agents entail systemic exposure, causing adverse effects that limit acceptance by high-risk women. Drug-delivery through the breast skin is an attractive option, but requires demonstration of dermal safety and drug distribution throughout the breast. We formulated the tamoxifen metabolite (E/Z)-endoxifen for transdermal delivery and tested it in a placebo-controlled, double-blinded Phase I trial with dose escalation from 10 to 20 mg daily. The primary endpoint was dermal toxicity. Thirty-two women planning mastectomy were randomized (2:1) to endoxifen-gel or placebo-gel applied to both breasts for 3-5 weeks. Both doses of endoxifen-gel incurred no dermal or systemic toxicity compared to placebo. All endoxifen-treated breasts contained the drug at each of five sampling locations; the median per-person tissue concentration in the treated participants was 0.6 ng/g (IQR 0.4-1.6), significantly higher (p < 0.001) than the median plasma concentration (0.2 ng/mL, IQR 0.2-0.2). The median ratio of the more potent (Z)-isomer to (E)-isomer at each breast location was 1.50 (IQR 0.96-2.54, p < 0.05). No discernible effects of breast size or adiposity on tissue concentrations were observed. At the endoxifen doses and duration used, and the tissue concentration achieved, we observed a non-significant overall reduction of tumor proliferation (Ki67 LI) and significant downregulation of gene signatures known to promote cancer invasion (FN1, SERPINH1, PLOD2, PDGFA, ITGAV) (p = 0.03). Transdermal endoxifen is an important potential breast cancer prevention agent but formulations with better dermal penetration are needed.

Dermatological adverse events from BRAF inhibitors: a growing problem.

The development of targeted therapies has ushered in a new era in the management of melanoma. Inhibitors of the RAS-RAF-MEK-ERK pathway have taken the center stage with development at a rapid pace. Vemurafenib was recently approved by regulatory agencies, and other agents (e.g. dabrafenib) are in various stages of clinical testing. These agents are producing remarkable results for patients, but are also presenting new challenges. Clinical toxicities and drug resistance are topmost issues. Some of the most common and vivid representations of adverse events to these agents are the dermatologic manifestations. Published trials and initial observations reflect a toxicity profile (e.g. squamous cell carcinomas/keratoacanthomas, maculopapular rashes, hyperkeratosis) that is distinct from cutaneous toxicities from EGFR and mTOR inhibitors (acneiform rash, paronychia, xerosis). Their management extends beyond conservative treatment and includes specific physical and surgical treatment modalities, skill sets unique to dermatologists. All these pose significant challenges to clinicians, and sound knowledge of such toxicities and their management will likely result in improved patient outcomes and quality of life. In this manuscript, we provide an overview of the emerging scientific literature on dermatological adverse events arising out of BRAF inhibition.

Unique presentations of epidermal growth factor receptor inhibitor-induced papulopustular eruption related to bacterial superinfection.

Epidermal growth factor receptor (EGFR) inhibitors have been reported to induce numerous cutaneous side effects, the most notable of which is a papulopustular eruption on the face, scalp, and central chest. The typical presentation consists of inflamed papules, often with pustules, favoring a seborrheic distribution. The pustules of the EGFR inhibitor-induced papulopustular eruption are commonly sterile but bacterial superinfection is not uncommon. We report two unique presentations of the papulopustular eruption that were found to be associated with Staphylococcus aureus superinfection. One patient presented with an abrupt onset of nearly confluent red plaques on the cheeks, forehead, chin, and neck, with innumerable studded pinpoint pustules. The other patient had a long-standing untreated papulopustular eruption on the scalp, which resulted in widespread erythema, large thick plaques of serous crust, pustular exudate, and associated alopecia. Both patients quickly resolved with non-tetracycline oral antibiotics combined with topical steroid treatment.

Fatal HHV6 infection in an immunocompromised patient presenting with skin involvement.

Infection with human herpesvirus-6 (HHV6) has a broad distribution in the human population, with a seroprevalence approaching 100% worldwide. Primary infection takes place during childhood, after which the virus remains latent mostly in lymphocytes and monocytes at various sites. Immunosuppression can result in viral reactivation, associated with clinical sequelae and even death. We report a case of a disseminated HHV6 infection in a 53-year-old patient, who was immunocompromised after allogeneic bone marrow transplant treatment for acute lymphocytic leukemia. Initially, he presented with a macular eruption of the skin, followed by involvement of other sites. Histopathologic analysis of skin biopsies revealed superficial perivascular large atypical mononuclear cells with intranuclear and intracytoplasmic inclusions. Most affected cells labeled with antibodies to CD3 and CD43 as lymphocytes, and some labeled with CD68 as macrophages. Polymerase chain reaction (PCR) studies of the blood, skin, liver, colon, cerebrospinal fluid and brain were positive for HHV6 virus. Additionally, the serologic titers for HHV6 were high. Viral particles were also detected by electron microscopy (EM) in the colon. Although rare, HHV6 virus may be an important pathogen in immunocompromised patients, and may present initially in the skin. Awareness of this infection is critical to diagnosis in acute settings.

Using topical imiquimod for the management of positive in situ margins after melanoma resection.

The treatment of melanoma in situ (MIS) is controversial with current standard of care being surgical excision with clear margins. Alternative topical therapy with imiquimod has been proposed in recent studies as a possible treatment for MIS. This study aimed to evaluate the use of topical 5% imiquimod as an alternative approach for the treatment of residual melanoma in situ after surgical resection of the primary lesion. A retrospective chart review of all patients treated with topical 5% imiquimod for residual MIS following standard resection with 5-10 mm margins at Yale-New Haven Hospital from 2008 through 2013 was performed. The pre- and posttreatment results were confirmed by diagnostic tissue biopsy. Twenty-two patients were included in the study. One of these 22 patients was lost to follow up. Twenty patients (95%) had complete resolution of their residual MIS and 1 patient did not respond to imiquimod (5%). No reports of recurrences were noted at the treatment sites. For patients with residual melanoma in situ after the initial excision, topical 5% imiquimod appears to be a reasonable alternative treatment with good clinical and histopathologic success rates.

Neutrophilic dermatosis after azathioprine exposure.

IMPORTANCE: Azathioprine hypersensitivity syndrome can present clinically and histopathologically like Sweet syndrome. Shared clinical features include fever, constitutional symptoms, prompt response to systemic corticosteroid therapy, neutrophilia, and abrupt onset of erythematous cutaneous lesions. Histologically, both azathioprine hypersensitivity syndrome and Sweet syndrome are rich in neutrophils. OBSERVATIONS: An 81-year-old woman with Crohn disease presented with fever and an acute eruption of plaques on her extremities within 2 weeks of starting treatment with azathioprine. Laboratory evaluation was notable for leukocytosis and neutrophilia. Skin biopsy of an erythematous plaque on the thigh demonstrated a suppurative folliculitis. Azathioprine treatment was discontinued resulting in resolution of the clinical lesions within 5 days. Our case was compared with 18 cases with similar clinical features. CONCLUSIONS AND RELEVANCE: We report a case of azathioprine hypersensitivity syndrome and review the literature on azathioprine-induced eruptions with features of Sweet syndrome. Our patient's distribution of lesions on the extremities and the finding of suppurative folliculitis on histopathology were not classical for Sweet syndrome. Azathioprine hypersensitivity syndrome seems to be a neutrophil-driven dermatosis; therefore, many overlapping features with Sweet syndrome are not surprising. Due to the potential for anaphylaxis with azathioprine rechallenge, a better term for a Sweetlike presentation in the setting of azathioprine administration is azathioprine hypersensitivity syndrome.

Chemotherapy-induced iatrogenic injury of skin: new drugs and new concepts.

Chemotherapy and its cutaneous side effects are an increasingly common source of iatrogenic injury to the skin, hair, and nails. Cutaneous changes are among the most common side effects from treatment with particular targeted chemotherapeutic agents, especially those that target the epidermal growth factor receptor and small molecule multikinase inhibitors. Less common, but growing in recognition, are the development of secondary cutaneous neoplasms and subacute cutaneous lupus erythematosus as a result of chemotherapy. There is considerable overlap of the multiple entities described as a side effect from conventional chemotherapeutic agents; therefore, the term "toxic erythema of chemotherapy" can be used as an easily understood name.