Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12-dimethylbenzaanthracene (DMBA) is a model PAH widely used to study tumorigenesis. Mice lacking Langerhans cells (LCs), a ...signatory epidermal dendritic cell (DC), are protected from cutaneous chemical carcinogenesis, independent of T cell immunity. Investigation of the underlying mechanism revealed that LC-deficient skin was relatively resistant to DMBA-induced DNA damage. LCs efficiently metabolized DMBA to DMBA-trans-3,4-diol, an intermediate proximal to oncogenic Hras mutation, and DMBA-treated LC-deficient skin contained significantly fewer Hras mutations. Moreover, DMBA-trans-3,4-diol application bypassed tumor resistance in LC-deficient mice. Additionally, the genotoxic impact of DMBA on human keratinocytes was significantly increased by prior incubation with human-derived LC. Thus, tissue-associated DC can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between immune cells and carcinogenesis.
Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic cell transplantation (allo-HCT) and is the main cause of late non-relapse mortality (NRM). Three new agents are ...now approved to treat cGVHD, of which belumosudil has a unique and dual mechanism of action of i) targeting the Rho-GTPase-associated coiled-coil kinase 2 (ROCK2) in T helper follicular cells (TFH) and TH17 cells, this results in downregulation of proinflammatory cytokines (interleukin -21 and 17), the former in a STAT3-dependent mechanism, ii) inhibition of tissue fibrosis by targeting stress-induced polymerization of G-actin fibrils by inhibiting the Rho-ROCK-MRTF pathway.
In this review we describe the epidemiology of cGVHD, its cardinal symptoms, preventive and therapeutic options, including second-line approved therapies in the United States (US). Clinical trial data that led to approval of belumosudil is discussed, in addition to the clinical scenarios in which the approved drugs may be most applicable.
Belumosudil is approved for treatment of adult and pediatric patients ≥ 12 years with cGVHD after failing two lines of therapy based on results of the ROCKstar study that showed high overall response rates (ORR), favorable adverse effect profiles, and low rates of severe infections. With the availability of three new agents for treatment of cGVHD, treating physicians have more therapeutic options for patients and have additional options of development new clinical trials using a combination of recently approved drugs.
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin's lymphoma that may variably involve the skin, lymph nodes, and peripheral blood. Malignant burden ranges from cutaneous patches and ...plaques with little evidence of blood involvement to erythroderma often in association with frank leukemia, as in Sézary syndrome. Toward a better understanding of the pathogenesis of this CD4+ T-cell malignancy, we conducted a high-resolution genomic analysis combining DNA (23 samples) and mRNA (12 samples) data of peripheral blood isolates from CTCL patients across a spectrum of stages. Strikingly, even patients with limited involvement, e.g., normal CD4 counts, contained significant copy-number alterations. Defining genomic characteristics of CTCL blood involvement included gains on 8q and 17q, and deletions on 17p and chromosome 10. A consensus analysis of 108 leukemic CTCL samples demonstrated global similarities among patients with varied blood involvement, narrowing 38 of 62 loci. Toward an annotated framework for in vitro testing, we also characterized genomic alterations in five CTCL cell lines (HH, HUT78, PNO, SeAx, and Sez4), revealing intact core features of leukemic CTCL. Together, these studies produce the most comprehensive view of the leukemic CTCL genome to date, with implications for pathogenesis, molecular classification, and potential future therapeutic developments.
Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12-dimethylbenzaanthracene (DMBA) is a model PAH widely used to model epithelial carcinogenesis. To achieve mutagenic ...effects, DMBA must be activated to DMBA-trans-3,4-diol via cytochrome p450 (CYP) 1B1, and this intermediate is the penultimate carcinogen responsible for inducing the signature mutation in the Hras oncogene. Recently, we observed that mice deficient in Langerhans cells (LCs), an epidermal dendritic cell (DC), are almost completely resistant to cutaneous chemical carcinogenesis, independent of αβ and γδ T cell influences. Investigations to identify the LC contribution to carcinogenesis revealed that DMBA-exposed LC-intact skin harbor more Hras mutations than LC-deficient skin, implying an early effect on tumor initiation. In vitro XS106 cells, a cell line derived from murine LCs, efficiently metabolized DMBA to DMBA-trans-3,4-diol as detected by liquid chromatography and tandem mass spectrometry. Moreover, initiation with DMBA-trans- 3,4-diol bypassed tumor resistance and restored tumorigenesis in LC-deficient mice. Consistent with previous reports, murine and human LCs expressed a higher CYP1B1:CYP1A1 ratio than keratinocytes, conferring an advantage in the ability to metabolize to mutagenic intermediates. Thus, our data suggest a cooperative carcinogenesis scenario in which LC generate DMBA-trans- 3,4-diol which moves into keratinocytes for further metabolism and mutagenesis. Tissue-associated DCs – which are also found in other epithelial surfaces – can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between immune cells and carcinogenesis.
BackgroundCemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell ...carcinoma (CSCC) expansion cohort (NCT02383212) and the pivotal Phase 2 study (NCT02760498). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study (NCT02760498).MethodsThe primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability.ResultsFor Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan–Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%).ConclusionIn patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses.Trial registration numberClinicaltrials.gov, NCT02760498. Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498
Peripheral edema with painful erythema is an increasingly recognized but poorly understood cutaneous adverse reaction to the antifolate agent pemetrexed. It is frequently misdiagnosed as cellulitis, ...and when it occurs, it is often dose-limiting. The authors report the case of a patient with preexisting lower extremity edema who developed extensive painful, bilateral erythema 5 days after administration of pemetrexed. An eosinophil-rich dermal inflammatory infiltrate was noted histologically. The authors review previously reported cases of pemetrexed-induced pseudocellulitis and discuss possible pathophysiology.
Post‐vaccinial non‐viral folliculitis has been recognized in the past decade as a new adverse cutaneous reaction to smallpox vaccination. Contrary to more serious smallpox vaccine reactions, ...post‐vaccinial non‐viral folliculitis has a benign course and resolves spontaneously within approximately 7 days. We describe additional histopathologic findings associated with post‐vaccinial non‐viral folliculitis, which has only been described once previously. New findings include the presence of a neutrophilic or lymphohistiocytic infiltrate that is concentrated around the hair follicles. We compare our findings to the follicular nature of varicella and herpes zoster infections, generating the hypothesis of deposition of vaccinia protein within folliculosebaceous units as a potential pathophysiologic mechanism behind post‐vaccinial non‐viral folliculitis.
Postvaccinial non-viral folliculitis has been recognized in the past decade as a new adverse cutaneous reaction to the smallpox vaccination. Contrary to more serious smallpox vaccine reactions, ...postvaccinial non-viral folliculitis has a benign course resolving spontaneously within approximately seven days. We describe additional histopathological findings associated with postvaccinial non-viral folliculitis, which has only been described once previously. New findings include the presence of neutrophilic or lymphohistiocytic infiltrates that concentrate around the hair follicles. We compare our findings to the follicular nature of varicella and herpes zoster infections, generating the hypothesis of deposition of vaccinia protein within folliculosebaceous units as a potential pathophysiologic mechanism behind postvaccinial non-viral folliculitis.
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