Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers.

PURPOSE: Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because of immunosuppression and risk of treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers. METHODS: Adult KTR with advanced melanoma or basal, cutaneous squamous, or Merkel cell carcinomas were eligible. Immunosuppression was standardized to TACRO (serum trough 2-5 ng/mL) + PRED 5 mg once daily. Patients then received NIVO 480 mg IV once every 4 weeks. The primary composite end point was partial or complete (tumor) response (CR) or stable disease per RECIST v1.1 without allograft loss at 16W. Patients with progressive disease (PD) could receive IPI 1 mg/kg IV + NIVO 3 mg/kg once every 3 weeks × 4 followed by NIVO. Donor-derived cell-free DNA (dd-cfDNA) levels were measured approximately once every 2 weeks as a potential predictor of allograft rejection. RESULTS: Among eight evaluable patients, none met the trial's primary end point. All eight patients experienced PD on NIVO + TACRO + PRED; TRAL occurred in one patient. Six patients then received IPI + NIVO + TACRO + PRED. Best overall responses: two CR (one with TRAL) and four PD (one with TRAL). In total, 7 of 8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. In total, 2 of 5 on-NIVO biopsies demonstrated moderate immune infiltrates; both patients later experienced a CR to IPI + NIVO. In 2 of 3 patients with TRAL, dd-cfDNA elevations occurred 10 and 15 days before increases in serum creatinine. CONCLUSION: In most KTR with advanced skin cancer, TACRO + PRED provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of NIVO ± IPI. Elevated dd-cfDNA levels can signal treatment-related allograft rejection earlier than rises in serum creatinine.

Biomarkers of Tretinoin Precursors and Tretinoin Efficacy in Patients With Moderate to Severe Facial Photodamage: A Randomized Clinical Trial.

Importance: Topical formulations of tretinoin precursors (retinol and its ester derivatives) are widely available over the counter and may offer similar clinical benefits to those of tretinoin for treatment of photoaging. However, which of the many purported molecular effects of retinoids most strongly drives clinical improvements in tretinoin-treated skin remains unclear. Objectives: To evaluate the clinical efficacy of topical tretinoin precursors (TTP) vs tretinoin (RA) in treating moderate to severe facial photodamage and to identify potential biomarkers that correlate with clinical efficacy. Design, Setting, and Participants: This randomized, double-blind, single-center, parallel-arm study of 24 patients with moderate to severe facial photodamage was conducted at an academic referral center from November 2010 to December 2011, with data analysis performed from January 2012 to December 2021. Interventions: Daily topical application of 0.02% RA or 1.1% TTP formulation containing retinol, retinyl acetate, and retinyl palmitate for 24 weeks. Main Outcomes and Measures: Photoaging and tolerability were assessed by dermatologist evaluations and patient-reported outcomes. Target gene expression was assessed by real-time quantitative polymerase chain reaction of biopsied tissue from treated areas. Results: A total of 20 White women were ultimately analyzed (9 randomized to TTP, 11 randomized to RA). At week 24, there was no significant difference in Griffiths photoaging scores among patients receiving TTP vs RA (median, 4 vs 5) (TTP - RA difference: -1; 95% CI, -2 to 1; P = .27). Treatment with TTP was associated with erythema 6 times less frequently than RA (11% vs 64%) (TTP - RA difference: -0.53; 95% CI, -0.88 to -0.17; P = .01). Target gene analysis showed significant CRABP2 messenger RNA (mRNA) induction (confirming retinoic acid receptor signaling) but no significant changes in procollagen I or MMP1/3/9 mRNA in TTP-treated samples. Instead, MMP2 mRNA, which encodes a type IV collagenase, was significantly reduced in TTP-treated samples (week 24 - baseline mRNA difference: -5; 96% CI, -33 to 1.6; P = .02), and changes in MMP2 were strongly correlated with changes in fine wrinkles (r = 0.54; 95% CI, 0.12 to 0.80; P = .01). Interestingly, patients with severe baseline wrinkles exhibited greater improvements (r = -0.74; 95% CI, -0.89 to -0.43; P < .001). This trend was mirrored in MMP2 mRNA, with initial expression strongly predicting subsequent changes (r = -0.78; 95% CI, -0.89 to -0.43; P < .001). Conclusions and Relevance: In this randomized clinical trial, there was no significant difference in efficacy between this particular formulation of TTP and tretinoin 0.02%. However, the results of these mechanistic studies highlight MMP2 as a possible mediator of retinoid efficacy in photoaging. Trial Registration: ClinicalTrials.gov Identifier: NCT01283464.

Consensus-Based Recommendations on the Prevention of Squamous Cell Carcinoma in Solid Organ Transplant Recipients: A Delphi Consensus Statement.

IMPORTANCE: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs). OBJECTIVE: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs. EVIDENCE REVIEW: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses. FINDINGS: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC. CONCLUSIONS AND RELEVANCE: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

Community Testing and SARS-CoV-2 Rates for Latinxs in Baltimore.

INTRODUCTION: Latinxs have been disproportionately impacted by COVID-19. Latinx immigrants, in particular, face significant barriers to SARS-CoV-2 testing, including lack of insurance, language barriers, stigma, work conflicts, and limited transportation. METHODS: In response to a disproportionately high SARS-CoV-2 positivity rate among Latinxs at the Johns Hopkins Health System, investigators implemented free community-based testing by partnering with religious leaders and leveraging the skill of trusted community health workers. Data were extracted from the electronic health record and a Research Electronic Data Capture database. SARS-CoV-2 positivity was evaluated per event stratified by race/ethnicity. Total rates of SARS-CoV-2 positivity and categorical patient characteristics were compared between groups using chi-square tests. RESULTS: Between June 25, 2020 and October 15, 2020, a total of 1,786 patients (57.5% Latinx, 31.2% non-Hispanic White, 5.9% non-Hispanic Black, and 5.3% non-Hispanic other) were tested for SARS-CoV-2 in 18 testing events. Among them, 355 (19.9%) tested positive. The positivity rate was 31.5% for Latinxs, 7.6% for non-Hispanic Blacks, 3.4% for non-Hispanic Whites, and 5.3% for patients of other races/ethnicities. Compared with Latinxs who tested negative, Latinxs who tested positive were more likely to report Spanish as their preferred language (91.6% vs 81.7%, p<0.001), be younger (30.4 vs 33.4 years, p<0.008), and have a larger household size (4.8 vs 4.3 members, p<0.002). CONCLUSIONS: Community-based testing identified high levels of ongoing SARS-CoV-2 transmission among primarily Latinxs with limited English proficiency. During this period, the overall positivity rate at this community testing site was almost 10 times higher among Latinxs than among non-Hispanic Whites.

Noninflammatory comedones have greater diversity in microbiome and are more prone to biofilm formation than inflammatory lesions of acne vulgaris.

BACKGROUND: The ability of Cutibacterium acnes strains to form biofilms has been correlated with their virulence. OBJECTIVE: This study examined biofilm and skin microbiota in acne patients in order to understand their role in the development of acne lesions. METHODS: Thin sections of punch biopsy specimens of (i) uninflamed comedones, (ii) inflammatory lesions, and (iii) uninvolved adjacent skin of acne patients were examined. Epiflourescence and confocal laser scanning microscopy were used for biofilm detection, and pyrosequencing with taxonomic classification of 16s rRNA gene amplicons was used for microbiota analysis. RESULTS: Of the 39 skin specimens from patients with mild-moderate acne (n = 13) that were studied, nine (23%) contained biofilm. Among these specimens, biofilm was most frequently detected in comedones (55.6%) and less frequently in inflammatory papules (22.2%) and uninvolved skin (22.2%). Comedones demonstrated the highest mean alpha diversity of all the lesion subtypes. The relative abundance of Staphylococcus was significantly higher in comedones (11.400% ± 12.242%) compared to uninvolved skin (0.073% ± 0.185%, P = 0.024). CONCLUSIONS: The microenvironment of the comedone differs from that of inflammatory lesions and unaffected skin. The increased frequency of biofilm in comedones may account for the lack of host inflammatory response to these lesions.

Kidney retransplantation after anti-programmed cell death-1 (PD-1)-related allograft rejection.

In this report, we describe the first kidney retransplantation performed after anti-programmed cell death-1 (PD-1)-related allograft rejection. In 2014, we administered pembrolizumab (anti-PD-1) for ~9 months to a 57-year-old kidney transplant recipient with metastatic cutaneous squamous cell carcinoma (CSCC). The patient experienced both a complete antitumor response and T cell-mediated allograft rejection requiring reinitiation of hemodialysis. Four-and-a-half years after initiating pembrolizumab, the patient remained without evidence of CSCC relapse and received a kidney transplant from a living-unrelated donor. Ten-and-a-half months after kidney retransplantation, the allograft is functioning well and the patient's CSCC remains in remission. This case illustrates the potential for PD-1 blockade to bring about durable immune-mediated tumor control in chronically immunosuppressed patients, and begins to address the feasibility of kidney retransplantation in patients who have previously received immune checkpoint inhibitor therapy for cancer. Results from this and future cases may help elucidate mechanisms of antitumor immunity and allograft tolerance, and inform updates to transplant decision models. Our report also underscores the need for clinical trials testing novel immunotherapy combinations in solid organ transplant recipients designed to uncouple antitumor and anti-allograft immunity.

Cutaneous Complications in Recipients of Lung Transplants: A Pictorial Review.

Lung transplant is now an established modality for a broad spectrum of end-stage pulmonary diseases. According to the International Society for Heart and Lung Transplantation Registry, more than 50,000 lung transplants have been performed worldwide, with nearly 11,000 recipients of lung transplants alive in the United States. With the increasing use of lung transplant, pulmonologists must be cognizant of the common as well as the unique posttransplant dermatologic complications. Immunosuppression, infections, and a variety of medications and environmental exposures can contribute to these complications. This review aims to provide representative pictures and describe the pathogenesis, epidemiologic characteristics, and clinical manifestations of dermatologic complications encountered among recipients of lung transplants.

Lymphocytic Thrombophilic Arteritis: A Review.

Macular lymphocytic arteritis or lymphocytic thrombophilic arteritis (LTA) is a recently described cutaneous arteritis that is characterized by asymptomatic macules and patches of the extremities associated with lymphocytic arteritis at the deep dermal/subcuticular junction for which little information exists on demographics, evaluation, and management. There has been recent debate in the literature whether this disease is a new distinct entity, misdiagnosed cutaneous polyarteritis nodosa (cPAN), or a disease on a spectrum with cPAN. We systematically review the literature on demographic information, medical history, histopathology findings, and treatment management to analyze trends and clarify controversies in characterizations of LTA. Forty detailed cases of LTA have been published. We submit that, although literature is limited, a review of the data still suggests that LTA is distinct from cPAN and systemic PAN. In addition, to better reflect the pathophysiologic natural history of this condition and correct for the historical artifact of how the disease was identified, we encourage the disease to be referred to as LTA and discourage ongoing use of macular lymphocytic arteritis.

Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Merkel Cell Carcinoma (MCC) focuses on areas impacted by recently emerging data, including sections describing MCC risk factors, diagnosis, workup, follow-up, and management of advanced disease with radiation and systemic therapy. Included in these sections are discussion of the new recommendations for use of Merkel cell polyomavirus as a biomarker and new recommendations for use of checkpoint immunotherapies to treat metastatic or unresectable disease. The next update of the complete version of the NCCN Guidelines for MCC will include more detailed information about elements of pathology and addresses additional aspects of management of MCC, including surgical management of the primary tumor and draining nodal basin, radiation therapy as primary treatment, and management of recurrence.

Adapalene 0.3% Gel Shows Efficacy for the Treatment of Atrophic Acne Scars.

INTRODUCTION: Scarring is an unfortunate clinical outcome of acne. Current treatment options for atrophic acne scars are dominated by non-pharmacological, invasive procedures which may not be suitable or affordable to all patients. This phase II, single-center, open-label, exploratory study assessed the efficacy, safety and subject-reported outcomes of adapalene 0.3% gel in the treatment of atrophic acne scars. METHODS: The study included subjects aged 18-50 years with past history of acne and moderate to severe facial atrophic acne scars. Subjects received adapalene 0.3% gel once daily for the first 4 weeks and twice daily for the following 20 weeks. Assessments were performed at baseline, day 10 and weeks 4, 8, 16 and 24, and at post-treatment follow-ups (weeks 36 and 48-72). RESULTS: At week 24, investigator and subject assessments reported improvement in skin texture/atrophic scars in 50% and > 80% of subjects, respectively. Subjects were satisfied with the treatment and reported improvements in quality of life. CONCLUSION: Daily use of adapalene 0.3% gel for the treatment of atrophic acne scars showed promising clinical efficacy, a favorable tolerability profile, and improvement in quality of life. FUNDING: Nestlé Skin Health-Galderma R&D. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01213199.

Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.

Human polyomavirus-7-associated rash and pruritus (PVARP) is a chronic superficial viral skin infection, which primarily impacts immunocompromised individuals. We report on a case of PVARP in a lung transplant recipient. Our patient developed symptoms 13 years after being on his immunosuppressive regimen, with an insidious course of progressive gray lichenification with marked islands of sparing and quality of life-altering pruritus. Treatment for PVARP is not established; however, topical cidofovir combined with immunomodulation may offer sustained therapeutic benefit.

Cutaneous Eruptions in Patients Receiving Immune Checkpoint Blockade: Clinicopathologic Analysis of the Nonlichenoid Histologic Pattern.

Cutaneous eruptions are among the most common immune-related adverse events (irAEs) associated with anti-programmed cell death protein 1/programmed cell death ligand 1 therapy, and are often clinically and histologically characterized as lichenoid. Nonlichenoid patterns may also occur and are likely to be encountered by surgical pathologists, given the increasing clinical use of these agents. The purpose of this study is to describe the histopathologic features of nonlichenoid cutaneous irAEs from patients receiving anti-programmed cell death protein 1/programmed cell death ligand 1 therapies for a variety of underlying advanced malignancies. Sixteen patients with 17 biopsied eruptions were included from 2 academic institutions with extensive experience administering and monitoring responses to immune checkpoint blockade as well as treating the potential side effects. Eruptions occurred a median of 10 days (range, 1 d to 11.4 mo) after treatment initiation. Nearly half of specimens demonstrated either a psoriasiform/spongiotic or an urticarial-type reaction pattern on histologic review. Patterns consistent with Grover disease, bullous pemphigoid, and granulomatous dermatitis were also observed. Nearly two-thirds of patients required systemic corticosteroids for treatment of the cutaneous irAE, and 19% of patients discontinued immunotherapy due to their skin eruptions. 75% of patients showed an objective antitumor response. The diverse array of nonlichenoid cutaneous irAE presented here should reflect and inform the scope of histologic patterns encountered by the practicing surgical pathologist. Such eruptions are seen in patients with a variety of underlying tumor types, many of whom ultimately demonstrate a favorable response to immune checkpoint blockade.

Eruptive sebaceous hyperplasia as a side effect of oral tacrolimus in a renal transplant recipient.

Sebaceous hyperplasia, a benign proliferation ofsebaceous glands, has been well documented in organ transplant recipients treated with cyclosporine. Sebaceous hyperplasia has not been strongly associated with any other immunosuppressive medications. We report a case of eruptive sebaceous hyperplasia in a renal transplant recipient with no previous exposure to cyclosporine that was recently started on tacrolimus, mycophenolate mofetil, and prednisone. To our knowledge, this is the first report of eruptive sebaceous hyperplasia in a renal transplant recipient who was immunosuppressed with tacrolimus and had no prior exposure to cyclosporine.