Evaluating the efficacy of combination and single-agent immunotherapies in real-world patterns of disease progression and survival of metastatic melanoma patients.

The objective of this study is to describe survival outcomes in patients with metastatic melanoma in a real-world setting receiving combination and single-agent immunotherapy outside the clinical trial context. We conducted a retrospective single-institution study of patients with metastatic melanoma in a real-world setting. Survival was calculated using log-rank test. Contingency tables were analyzed using Fisher's Exact test. CD8 + T-cell densities were measured using quantitative immunofluorescence and analyzed using Mann-Whitney U test. The median overall survival (OS) for 132 patients was 45.3 months. Brain metastasis did not confer a higher risk of death relative to liver and/or bone disease (39.53 versus 30.00 months, respectively; P  = 0.687). Anti-PD-1 monotherapy was the most common first-line treatment, received by 49.2% of patients. There was no significant difference in OS between patients receiving single-agent anti-PD-1 and combination anti-PD-1 plus CTLA-4 (39.4 months versus undefined; P  = 0.643). Patients treated with combination therapy were more likely to be alive without progression at the last follow-up than those who received monotherapy (70.4% versus 49.2%; P  = 0.0408). Median OS was 21.8 months after initiation of second-line therapy after anti-PD-1 monotherapy. CD8+ T-cell densities were higher in patients who achieved disease control on first-line immunotherapy ( P  = 0.013). In a real-world setting, patients with metastatic melanoma have excellent survival rates, and treatment benefit can be achieved even after progression on first-line therapy. Combination immunotherapy may produce more favorable long-term outcomes in a real-world setting. High pretreatment CD8+ T-cell infiltration correlates with immunotherapy efficacy.

INDIVIDUAL ARTICLE: USCOM Algorithm for the Prevention and Management of Cutaneous Immunotherapy-Related Adverse Events.

BACKGROUND: In 2023, nearly 2 million patients will be diagnosed with cancer in the United States and at least 40% will be eligible for treatment with an immune checkpoint inhibitor (ICI). Cutaneous immune related adverse events (cirAEs) from ICIs are common and include pruritus as well as maculopapular, eczematous, bullous, lichenoid, and psoriasiform reactions. All clinicians interfacing with cancer patients must expedite proper evaluation and diagnosis, treatment, and/or consultation that supports the need for evidence-directed guidelines. MATERIALS AND METHODS: A panel of advisors was selected, and a systematic literature review generated foundational evidence to develop a treatment algorithm for cirAEs via a modified Delphi process. Iterations of the algorithm were performed until the group met consensus. RESULTS: An algorithm that tailors the management of cirAEs was developed based on the CTCAE v.5 grading of skin disorders. Representative clinical images and suggested diagnostic measures, supplement the algorithm. CONCLUSION: Recognition and treatment of cirAEs guided through a multidisciplinary, physician-developed algorithm will limit disruption of immunotherapy, optimize quality of life, and enhance overall outcomes in patients treated with ICIs. J Drugs Dermatol. 2023;22:11(Suppl 1):s3-10.

Addressing the Need for Diversity in Scalp Cooling Trials.

This Viewpoint emphasizes the importance of diverse representation in research on scalp cooling to avoid hair loss during chemotherapy.

Diagnosis and Management of Dermatologic Adverse Events from Systemic Melanoma Therapies.

The advent of protein kinase inhibitors and immunotherapy has profoundly improved the management of advanced melanoma. However, with these therapeutic advancements also come drug-related toxicities that have the potential to affect various organ systems. We review dermatologic adverse events from targeted (including BRAF and MEK inhibitor-related) and less commonly used melanoma treatments, with a focus on diagnosis and management. As immunotherapy-related toxicities have been extensively reviewed, herein, we discuss injectable talimogene laherparepvec and touch on recent breakthroughs in the immunotherapy space. Dermatologic adverse events may severely impact quality of life and are associated with response and survival. It is therefore essential that clinicians are aware of their diverse presentations and management strategies.

Detection of novel therapies using a multi-national, multi-institutional registry of cutaneous immune-related adverse events and management.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) remain a prevalent and common sequelae of immune checkpoint inhibitor (ICI) therapy, often necessitating treatment interruption and prolonged immune suppression. Treatment algorithms are still poorly defined, based on single-institution case reports without adequate safety assessments, and subject to publication bias. METHODS: Data in this registry were collected through a standardized REDCap form distributed to dermatologists via email listserv. RESULTS: Ninety-seven cirAEs were reported from 13 institutions in this registry. Topical and systemic steroids were the most common treatments used; however, targeted treatment matched to disease morphology was identified at numerous sites. Novel cirAE therapy uses that to our knowledge have not been previously described were captured including tacrolimus for the treatment of follicular, bullous, and eczematous eruptions and phototherapy for eczematous eruptions. Moreover, further evidence of cirAE treatment applications sparsely described in literature were also captured in this study including dupilumab and rituximab for bullous eruptions, phototherapy for lichenoid and psoriasiform eruptions, and acitretin for psoriasiform eruptions, among others. No serious adverse events were reported. Numerous targeted therapeutics including dupilumab, rituximab, and psoriasis biologics, among others, were associated with a cirAE grade improvement of ≥2 grades in every patient treated. CONCLUSION: This study suggests that a multi-institutional registry of cirAEs and management is not only feasible but that the information collected can be used to detect, evaluate, and rigorously assess targeted treatments for cirAEs. Further expansion and modification to include treatment progression may allow for sufficient data for specific treatment recommendations to be made.

Bacterial Decolonization for Prevention of Radiation Dermatitis: A Randomized Clinical Trial.

Importance: Evidence-based approaches for the prevention of acute radiation dermatitis (ARD) are limited, and additional strategies are necessary to optimize care. Objective: To determine the efficacy of bacterial decolonization (BD) to reduce ARD severity compared with standard of care. Design, Setting, and Participants: This phase 2/3 randomized clinical trial was conducted from June 2019 to August 2021 with investigator blinding at an urban academic cancer center and enrolled patients with breast cancer or head and neck cancer receiving radiation therapy (RT) with curative intent. Analysis was performed on January 7, 2022. Interventions: Intranasal mupirocin ointment twice daily and chlorhexidine body cleanser once daily for 5 days prior to RT and repeated for 5 days every 2 weeks through RT. Main Outcomes and Measures: The primary outcome as planned prior to data collection was the development of grade 2 or higher ARD. Based on wide clinical variability of grade 2 ARD, this was refined to grade 2 ARD with moist desquamation (grade 2-MD). Results: Of 123 patients assessed for eligibility via convenience sampling, 3 were excluded, and 40 refused to participate, with 80 patients in our final volunteer sample. Of 77 patients with cancer (75 patients with breast cancer [97.4%] and 2 patients with head and neck cancer [2.6%]) who completed RT, 39 were randomly assigned BC, and 38 were randomly assigned standard of care; the mean (SD) age of the patients was 59.9 (11.9) years, and 75 (97.4%) were female. Most patients were Black (33.7% [n = 26]) or Hispanic (32.5% [n = 25]). Among patients with breast cancer and patients with head and neck cancer (N = 77), none of the 39 patients treated with BD and 9 of the 38 patients (23.7%) treated with standard of care developed ARD grade 2-MD or higher (P = .001). Similar results were observed among the 75 patients with breast cancer (ie, none treated with BD and 8 [21.6%] receiving standard of care developed ARD grade ≥2-MD; P = .002). The mean (SD) ARD grade was significantly lower for patients treated with BD (1.2 [0.7]) compared with patients receiving standard of care (1.6 [0.8]) (P = .02). Of the 39 patients randomly assigned to BD, 27 (69.2%) reported regimen adherence, and only 1 patient (2.5%) experienced an adverse event related to BD (ie, itch). Conclusions and Relevance: The results of this randomized clinical trial suggest that BD is effective for ARD prophylaxis, specifically for patients with breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03883828.

Association of Staphylococcus aureus Colonization With Severity of Acute Radiation Dermatitis in Patients With Breast or Head and Neck Cancer.

Importance: Pathogenesis of acute radiation dermatitis (ARD) is not completely understood. Pro-inflammatory cutaneous bacteria may contribute to cutaneous inflammation after radiation therapy. Objective: To evaluate whether nasal colonization with Staphylococcus aureus (SA) before radiation therapy is associated with ARD severity in patients with breast or head and neck cancer. Design, Setting, and Participants: This prospective cohort study with observers blinded to colonization status was conducted from July 2017 to May 2018 at an urban academic cancer center. Patients aged 18 years or older with breast or head and neck cancer and plans for fractionated radiation therapy (≥15 fractions) with curative intent were enrolled via convenience sampling. Data were analyzed from September to October 2018. Exposures: Staphylococcus aureus colonization status before radiation therapy (baseline). Main Outcomes and Measures: The primary outcome was ARD grade using the Common Terminology Criteria for Adverse Event Reporting, version 4.03. Results: Among 76 patients analyzed, mean (SD) age was 58.5 (12.6) years and 56 (73.7%) were female. All 76 patients developed ARD: 47 (61.8%) with grade 1, 22 (28.9%) with grade 2, and 7 (9.2%) with grade 3. The prevalence of baseline nasal SA colonization was higher among patients who developed grade 2 or higher ARD compared with those who developed grade 1 ARD (10 of 29 [34.5%] vs 6 of 47 [12.8%]; P = .02, by χ2 test). Conclusions and Relevance: In this cohort study, baseline nasal SA colonization was associated with development of grade 2 or higher ARD in patients with breast or head and neck cancer. The findings suggest that SA colonization may play a role in the pathogenesis of ARD.

An Unexpected Postsurgical Phenomenon After Total Knee Arthroplasty: Nummular Eczema: A Case Report and Literature Review.

CASES: Two elderly women each presented with a unilateral, erythematous rash 1 year after total knee arthroplasty (TKA) for osteoarthritis. Both cases were diagnosed as postsurgical nummular eczema (NE) and treated successfully with topical corticosteroids. CONCLUSION: We highlight a novel clinical presentation of postsurgical NE associated with TKA, previously reported only with breast reconstruction. Postsurgical NE may mimic periprosthetic infection or implant-related allergic contact dermatitis. Timely diagnosis and appropriate treatment in these cases prevented unnecessary testing and hospital admission for revision surgery. This case series highlights the varied presentation and wide differential diagnosis associated with postsurgical NE.

United States Cutaneous Oncodermatology Management (USCOM) II: A Multidisciplinary-Guided Algorithm for the Prevention and Management of Acute Radiation Dermatitis in Cancer Patients.

BACKGROUND: Among the 1,918,030 patients in the United States estimated to be diagnosed with cancer in 2022, approximately 50% will require radiation therapy (RT) as part of their treatment plan. Radiation dermatitis (RD) is the most common side effect of RT, particularly in patients with breast, head, neck, and anal cancers, with a wide spectrum in the severity and degree of RD that develops in an individual and considerable heterogeneity in the management of RD. In addition, few contemporaneous treatment algorithms exist for the prevention and treatment of RD, underscoring the need to develop uniform, evidence-directed guidelines. MATERIALS AND METHODS: A modified Delphi process was used to develop a treatment algorithm (USCOM II) that expanded upon a previous algorithm (USCOM I) for the management of RD. A panel of multidisciplinary advisors was selected, and a systematic literature search with key terms was conducted to identify publications on RD. Subsequently, the literature was graded according to the strength of evidence for the recommendation. The advisors convened to review the results and assemble the algorithm. Further iterations on the algorithm were obtained until 100% group consensus was achieved. RESULTS: An algorithm that tailors the management of RD, based on the CTCAE v.5 grading of RD and the presence of moist desquamation, was developed. Unique features include photographs illustrating the clinical spectrum of RD to supplement the algorithm and the integration of medically based recommendations with over-the-counter (OTC) skincare regimens that include cleansing, moisturizing, and photoprotection. CONCLUSION: Acute RD, when suboptimally managed, can lead to symptoms of pruritus and pain, decreased quality of life and morbidity, and treatment interruptions. When RD is severe or prolonged, it can delay the receipt of a full therapeutic course of RT. Enhanced patient education on the prevention of RD and clarity of treatment recommendations through a multidisciplinary, physician-developed algorithm may help prevent and manage the various adverse effects and improve the overall care of patients receiving RT. J Drugs Dermatol. 2022;21:11(Suppl 1):s3-14.

Immune Checkpoint Inhibitor-Induced Psoriasiform, Spongiotic, and Lichenoid Dermatitis: A Novel Clinicopathological Pattern.

Immune checkpoint inhibitors (ICIs), a class of anticancer agents that upregulate T-cell response to tumor cells, are associated with immune-related adverse events (irAEs), and the skin is one of the most commonly affected organs. We report the first two cases of a unique ICI-induced clinicopathological entity. A psoriasiform-appearing eruption with psoriasiform, spongiotic, and lichenoid dermatitis pattern on histopathology. A 73-year-old male with stage IV melanoma treated with nivolumab and a 63-year-old female with stage IV colorectal cancer treated with pembrolizumab and TAK-981 separately presented to our clinic with a psoriasiform rash. In both patients, punch biopsy revealed an unusual combination of psoriasiform, spongiotic, and lichenoid dermatitis. Treatment with apremilast in the first patient yielded some improvement, while treatment with ixekizumab in the second patient yielded a complete resolution of the eruption. Our cases add to the growing body of reported immune toxicities related to ICI use and illustrate the utility of targeted immune suppression of pathways in disease phenotype to allow for ICI continuation and optimization of cancer treatment.

Verruca Vulgaris Eruption Arising in the Setting of a Tyrosine Kinase Inhibitor.

A 71-year-old female with breast cancer presented with a generalized papular rash that began following the initiation of rebastinib. Examination revealed scattered pink to skin-colored verrucous papules on the forehead, extremities, and back. A biopsy showed hyperkeratosis, hypergranulosis, digitated epidermal hyperplasia, and dilated blood vessels at the tips of dermal papillae consistent with verruca vulgaris. The patient discontinued rebastinib due to muscle weakness and the lesions resolved. Rebastinib is an antineoplastic agent that targets several tyrosine kinases. Tyrosine kinase inhibitors (TKI) frequently cause cutaneous adverse events, but to date, there have been no reported cases of a verruca vulgaris eruption arising in the setting of TKI treatment. Recent studies indicate that TKIs can have immunosuppressive effects by decreasing T-cell levels. We postulate that rebastinib induced an immunosuppressive state in our patient which permitted human papillomavirus (HPV) proliferation. To our knowledge, this is the first report describing a verruca vulgaris eruption with TKI therapy.

Safe use of donated positive airway pressure devices to increase access to treatment for obstructive sleep apnea: a clinical outreach program.

Coverage to provide positive airway pressure (PAP) therapy for patients with obstructive sleep apnea (OSA) by the Centers for Medicare and Medicaid Services (CMS) and most private insurers is limited to those patients who meet diagnostic criteria for OSA based on a sleep study. Despite PAP therapy being a covered benefit by most insurers, many patients have high out-of-pocket costs due to copays and deductibles. Also, a subset of patients may be diagnosed per the American Academy of Sleep Medicine (AASM) recommended rule (H3A), while not meeting the diagnosis using the acceptable rule (H4) that their insurer requires.1 To help patients such as these, our sleep medicine program envisioned and developed a PAP device donation program for patients with diagnosed or suspected OSA. Through our novel initiative, we were able to safely provide patients with donated and refurbished PAP devices at no cost to them. Here we outline the complexity involved in the provision of PAP therapy for patients with OSA and describe our PAP device donation program. CITATION: Skiba V, McLellan B. Safe use of donated positive airway pressure devices to increase access to treatment for obstructive sleep apnea: a clinical outreach program. J Clin Sleep Med. 2022;18(5):1455-1457.

The Role of Fat Reducing Agents on Adipocyte Death and Adipose Tissue Inflammation.

Deoxycholic Acid (DCA), which is an FDA-approved compound for the reduction of submental fat, has evolved through an unanticipated and surprising sequence of events. Initially, it was used as a solvent for Phosphatidylcholine (PDC), which was thought to promote lipolysis, but it was later proven to be the bioactive component of the formula and is currently widely used as Kybella. It has also been used off-label to treat other types of fat deposits like lipomas, HIV lipodystrophy, and excess orbital fat. Despite widespread clinical use, there has been no consensus clarifying the mechanisms of DCA and PDC alone or in combination. Furthermore, despite PDC's removal from the FDA-approved formula, some studies do suggest it plays an important role in fat reduction. To provide some clarity, we conducted a PubMed search and reviewed 41 articles using a comprehensive list of terms in three main categories, using the AND operator: 1) Phosphatidylcholines 2) Deoxycholic Acid, and 3) Lipoma. We isolated articles that studied PDC, DCA, and a PDC/DCA compound using cell biology, molecular and genetic techniques. We divided relevant articles into those that studied these components using histologic techniques and those that utilized specific cell death and lipolysis measurement techniques. Most morphologic studies indicated that PDC/DCA, DCA, and PDC, all induce some type of cell death with accompanying inflammation and fibrosis. Most morphologic studies also suggest that PDC/DCA and DCA alone are non-selective for adipocytes. Biochemical studies describing PDC and DCA alone indicate that DCA acts as a detergent and rapidly induces necrosis while PDC induces TNF-α release, apoptosis, and subsequent enzymatic lipolysis after at least 24 hours. Additional papers have suggested a synergistic effect between the two compounds. Our review integrates the findings of this growing body of literature into a proposed mechanism of fat reduction and provides direction for further studies.