IMPORTANCE: Mogamulizumab is a monoclonal antibody against CCR4 approved for treatment for mycosis fungoides (MF) and Sézary syndrome (SS). Mogamulizumab-associated rash (MAR) is difficult to ...differentiate from cutaneous MF or SS, which can lead to unnecessary discontinuation of drug use because of concern for severe drug reaction or incorrect presumption of disease relapse or progression in the skin. OBJECTIVE: To examine the most common clinical presentations of MAR in patients with MF or SS and the diagnostic and management challenges. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series assessed patients from a multidisciplinary cutaneous lymphoma clinic and supportive oncodermatology clinic at a major academic referral center who had a diagnosis of MF or SS and received mogamulizumab from January 1, 2013, to January 1, 2020. Treatment was followed by new or worsening rash with skin biopsy results compatible with drug eruption determined by clinicopathologic correlation and molecular testing to exclude active malignant disease. EXPOSURES: At least 1 dose of mogamulizumab. MAIN OUTCOMES AND MEASURES: Mogamulizumab-associated rash was characterized by clinical features, including time to onset, clinical presentation, histopathologic features, and management approach. RESULTS: The study included 19 patients with MF or SS who developed MAR (median age, 65 years; age range, 38-82 years; 10 52.6% male). Median time to MAR onset was 119 days (range, 56 days to 3.8 years). Patients with MAR exhibited 4 predominant clinical presentations: (1) folliculotropic MF–like scalp plaques with alopecia, (2) papules and/or plaques, (3) photoaccentuated dermatitis, and (4) morbilliform or erythrodermic dermatitis. The most common anatomical region involved was the head and neck, including the scalp. Histopathologic findings were variable and did not correspond to primary clinical morphologic findings. Immunohistochemistry and T-cell clonality ancillary testing were helpful to distinguish MAR from disease. Most patients with MAR (14 of 19) discontinued mogamulizumab treatment; however, no life-threatening severe cutaneous adverse drug reactions occurred, and the decision for drug therapy cessation was usually multifactorial. Four patients were treated again with mogamulizumab with no life-threatening drug-related events. Approaches to management of MAR include topical corticosteroids, systemic corticosteroids, and/or methotrexate. CONCLUSIONS AND RELEVANCE: This case series found that mogamulizumab-associated rash had a heterogeneous clinical presentation with variable and delayed onset in patients with MF or SS. Mogamulizumab-associated rash exhibited a predilection for the head and neck and was difficult to clinically distinguish from relapse or progression of disease. Recognition of the most common clinical presentations can help prevent unnecessary discontinuation of mogamulizumab treatment. The presence of MAR does not necessitate permanent discontinuation of or avoidance of retreatment with mogamulizumab.
The influence of air pollutants originating from the Chinese region on air quality over South Korea has been a major concern for policymakers. To investigate the inter-annual trends of the ...long-distance transport of air pollutants from China to South Korea, multi-year trend analysis was carried out for Aerosol Optical Depth (AOD, as a proxy of particulate matter), and CO (a water-insoluble air pollutant) and SO2 (a partially water-soluble air pollutant), over three regions in Northeast Asia. Air pollutants are typically long-range transported from the highly polluted parts of China to South Korea through the Yellow Sea. Taking advantage of this geographical merit, we carried out the multi-year trend analysis with a special focus on the Yellow Sea region. Decreasing trends of about 5–10%, 13–17% and 55–61% during the last decade were observed in surface CO, AOD and tropospheric SO2 columns over the North China Plain (NCP), Yellow Sea (YS), and South Korea (SK), respectively. Such decreasing trends were also found consistently during the last three, five, and seven years, indicating that the changes in pollution levels are likely in response to recent policy measures taken by the Chinese and Korean governments to improve air quality over the regions. Due to these efforts, the amounts of air pollutants transported from China to South Korea are expected to decrease in future years, to the likely rates of 1.50 ppb yr−1, 0.05 DU yr−1, and 0.56 μg m−3 yr−1 over the YS region for CO, SO2, and PM2.5, respectively. Given the ambitious plans recently announced by the Chinese government for the 21st meeting of Conference of Parties (COP21) and its co-control effects, the suggested percentage rates may even be conservative numbers. This analysis is expected to provide South Korean policymakers with valuable information to establish new air pollution policies in South Korea.
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•The decrease in air pollutants over the Yellow Sea suggested a decrease in LRT air pollutants from NCP to South Korea.•Likely annual reduction rates of 1.50 ppb, 0.05 DU, and 0.56 μg/m3 for CO, SO2, and PM2.5 are expected over the Yellow Sea.•Recent emission reductions in NCP suggested a future decrease in the LRT air pollutants from China (NCP).
This paper presents a new mixed demand model for measuring the value of public goods in an intertemporal optimization framework. From the specification of an indirect utility function allowing for ...public goods, direct demand functions for private goods are derived and estimated jointly with the Euler equation for intertemporal consumption behavior, using US data. This allows us to identify the marginal utility of private consumption and to obtain the inverse demand or shadow price of a public good, which is then related to its observed price to assess whether the public good is efficiently provided. There is evidence, though suggestive, that the public good as measured by national defense in the USA has been inefficiently provided over the past decades.
Consumer demands and consumption, though seemingly disjoint, are inextricably linked together via intertemporal two-stage budgeting, and cannot be separated. This paper elucidates this budgeting ...procedure with an illustration using the Linear Expenditure System, and evaluates the traditional analysis of consumer behavior that treats them as independent. We find that the dichotomous treatment of consumption expenditure and relative commodity prices in the traditional analysis creates a bias in the estimation of consumer demands and consumption. We argue that a proper understanding of consumer behavior entails an integration of consumer demands and consumption within a unifying framework, which can be achieved by utilizing the intertemporal two-stage budgeting procedure.
Here, we survey variation and dynamics of active regulatory elements genome-wide using longitudinal samples from human individuals. We applied Assay of Transposase Accessible Chromatin with ...sequencing (ATAC-seq) to map chromatin accessibility in primary CD4+ T cells isolated from standard blood draws from 12 healthy volunteers over time, from cancer patients, and during T-cell activation. Over 4,000 predicted regulatory elements (7.2%) showed reproducible variation in accessibility between individuals. Gender was the most significant attributable source of variation. ATAC-seq revealed previously undescribed elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately affect genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide a foundational reference for comparing disease-associated regulomes.
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•ATAC-seq identifies personal gene regulatory landscapes of T cells over time•Sexual dimorphism in chromatin accessibility coordinately impacts immune genes•Noisy enhancers are enriched for disease enhancers in autoimmunity•Foundational resource is provided for comparison to human disease or perturbations
Qu et al. identify personal variations in accessible chromatin landscape in human T cells and trace their genetic, epigenetic, and disease associations.
We have developed and previously reported on a therapeutic vaccination strategy for indolent B-cell lymphoma that combines local radiation to enhance tumor immunogenicity with the injection into the ...tumor of a TLR9 agonist. As a result, antitumor CD8+ T cells are induced, and systemic tumor regression was documented. Because the vaccination occurs in situ, there is no need to manufacture a vaccine product. We have now explored this strategy in a second disease: mycosis fungoides (MF). We treated 15 patients. Clinical responses were assessed at the distant, untreated sites as a measure of systemic antitumor activity. Five clinically meaningful responses were observed. The procedure was well tolerated and adverse effects consisted mostly of mild and transient injection site or flu-like symptoms. The immunized sites showed a significant reduction of CD25+, Foxp3+ T cells that could be either MF cells or tissue regulatory T cells and a similar reduction in S100+, CD1a+ dendritic cells. There was a trend toward greater reduction of CD25+ T cells and skin dendritic cells in clinical responders versus nonresponders. Our in situ vaccination strategy is feasible also in MF and the clinical responses that occurred in a subset of patients warrant further study with modifications to augment these therapeutic effects. This study is registered at www.clinicaltrials.gov as NCT00226993.
Primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the latest 2016 ...World Health Organization Classification of Cutaneous lymphomas. We sought to better characterize and provide diagnostic and therapeutic guidance of this rare cutaneous lymphoma. Thirty-four patients with a median age of 77 years (range 19–89 years) presented primarily with extensive annular necrotic plaques or tumor lesions with frequent mucous membrane involvement. The 5-year survival was 32% with a median survival of 12 months. A subset of 17 patients had a prodrome of chronic patches prior to the development of aggressive ulcerative lesions. We identified cases with lack of CD8 or αβ T-cell receptor expression yet with similar clinical and pathological presentation. Allogeneic stem cell transplantation provided partial or complete remissions in 5/6 patients. We recommend the term primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma as this more broad designation better describes this clinical-pathologic presentation, which allows the inclusion of cases with CD8 negative and/or αβ/γδ T-cell receptor chain double-positive or double-negative expression. We have identified early skin signs of chronic patch/plaque lesions that are often misdiagnosed as eczema, psoriasis, or mycosis fungoides. Our experience confirms the poor prognosis of this entity and highlights the inefficacy of our standard therapies with the exception of allogeneic stem cell transplantation in selected cases.
Abstract
This study aims to determine the optimal range of A-scan data that enables the detection of cavities in reinforced concrete structures using ground-penetrating radar (GPR). GPR is commonly ...used as a nondestructive testing method for detecting cavities. However, the identification of cavities using B-scan data is challenging when the cavities are obscured by highly reflective objects such as reinforcements. To address this issue, the B-scan data can be substituted with the A-scan data by adopting an area estimation approach. However, this approach requires the determination of the location and range of the A-scan data. In this study, we analyzed GPR A-scan data obtained from a large-scale concrete block with cavities adjacent to a complex reinforcement layout. The location and range were varied to investigate their effects on the accuracy of object detection using the area estimation approach, and an appropriate range was suggested.
Rash is one of the most common adverse events observed with mogamulizumab, an anti-C-C chemokine receptor 4 monoclonal antibody approved for previously treated mycosis fungoides (MF) and Sezary ...syndrome (SS). Given the nonspecific clinical presentations of this rash, histopathologic distinction from MF/SS is critical for informing clinical management. We performed a comprehensive characterization of the histopathologic findings in mogamulizumab-associated rash (MAR) with the integration of high-throughput sequencing of T-cell receptor (TCR) genes. Fifty-two biopsy specimens from 19 patients were evaluated retrospectively. Three major histologic reaction patterns were identifiedspongiotic/psoriasiform dermatitis (33/52), interface dermatitis (11/52), and granulomatous dermatitis (8/52). Almost half of the specimens (21/52) showed at least 2 of these reaction patterns concurrently. Dermal eosinophils were not a consistent feature, being present in only half (27/52) of specimens and prominent in only 3. Features mimicking MF/SS, including lymphocyte exocytosis, lamellar fibroplasia, and adnexal involvement, were commonly seen but tended to be focal and mild. In 38/43 specimens with available immunohistochemistry, intraepidermal lymphocytes demonstrated a CD4:CD8 ratio ≤1 : 1. Low background levels of the patient’s previously identified MF/SS-associated TCR sequence(s) were demonstrated in 20/46 specimens analyzed by high-throughput sequencing of TCR. We conclude that MAR may demonstrate diverse histologic features. Findings that may distinguish MAR from MF/SS include the inverted or normalized CD4:CD8 ratio within intraepidermal lymphocytes and demonstration of absent or nondominant levels of disease-associated TCR sequences. Correlation with the clinical findings and immunohistochemical and molecular characterization of the patient’s MF/SS before mogamulizumab, when possible, may facilitate recognition of MAR.
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