RESUMEN
CD47 is frequently overexpressed on tumor cells and is an attractive therapeutic target. The mechanism by which anti-CD47 immunotherapy eliminates cutaneous lymphoma has not been explored. We utilized CRISPR/Cas-9 CD47 knock-out, depletion of NK cells, and mice genetically deficient in IFN-γ to elucidate the mechanism of anti-CD47 therapy in a murine model of cutaneous T cell lymphoma (CTCL). CD47 was found to be a crucial factor for tumor progression since CD47 KO CTCL exhibited a delay in tumor growth. The treatment of CD47 WT murine CTCL with anti-CD47 antibodies led to a significant reduction in tumor burden as early as four days after the first treatment and accompanied by an increased percentage of cytotoxic NK cells at the tumor site. The depletion of NK cells resulted in marked attenuation of the anti-tumor effect of anti-CD47. Notably, the treatment of CD47 WT tumors in IFN-γ KO mice with anti-CD47 antibodies was efficient, demonstrating that IFN-γ was not required to mediate anti-CD47 therapy. We were able to potentiate the therapeutic effect of anti-CD47 therapy by IFN-α. That combination resulted in an increased number of cytotoxic CD107a + IFN-γ-NK1.1 cells and intermediate CD62L + NKG2a-NK1.1. Correlative data from a clinical trial (clinicaltrials.gov, NCT02890368) in patients with CTCL utilizing SIRPαFc to block CD47 confirmed our in vivo observations.
Asunto(s)
Micosis Fungoide , Neoplasias Cutáneas , Animales , Antígeno CD47 , Humanos , Interferón gamma , Células Asesinas Naturales , Ratones , Micosis Fungoide/tratamiento farmacológico , Micosis Fungoide/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
The signal transducer and activator of transcription 6 (STAT6) is a critical up-stream mediator of interleukin-13 (IL-13) and IL-4 signaling and is constitutively activated in malignant lymphocytes from Sezary syndrome (SS) and mycosis fungoides (MF), the most common subtypes of cutaneous T-cell lymphomas. By combining genome-wide expression profiling with pharmacological STAT6 inhibition, we have identified the genes regulated by STAT6 in MF/SS tumors. We found that STAT6 regulates several common pathways in MF/SS malignant lymphocytes that are associated with control of cell-cycle progression and genomic stability as well as production of Th2 cytokines. Using ex vivo skin explants from cutaneous MF tumors as well as Sezary cells derived from the blood of SS patients, we demonstrated that inhibition of STAT6 activation downregulates cytokine production and induces cell-cycle arrest in MF/SS malignant lymphocytes, inhibiting their proliferation but not their survival. Furthermore, we show that STAT6 promotes the protumoral M2-like phenotype of tumor-associated macrophages in the tumor microenvironment of advanced stage MF by upregulating the expression of genes associated with immunosuppression, chemotaxis, and tumor matrix remodeling. Thus, we show STAT6 to be a major factor in the pathogenesis and progression of MF/SS, promoting proliferation and invasion of the malignant lymphocytes while inducing a progressive depression of the antitumor immune response. Together, our results provide new insights into disease pathogenesis and offer new prospective targets for therapeutic intervention.
Asunto(s)
Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Linfoma Cutáneo de Células T/genética , Linfoma Cutáneo de Células T/metabolismo , Factor de Transcripción STAT6/metabolismo , Transcriptoma , Biomarcadores de Tumor , Ciclo Celular/genética , Estudio de Asociación del Genoma Completo , Humanos , Linfoma Cutáneo de Células T/inmunología , Linfoma Cutáneo de Células T/patología , Metástasis de la Neoplasia , Estadificación de Neoplasias , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/patologíaRESUMEN
Six out of 12 Sézary patients shared one clonotype (TRAV13-1*01-TRAJ49*01-TRBV20-1*01-TRBJ2-3*01). TRBV20-1*01 (also known as Vb2) that binds toxic shock syndrome toxin-1 was utilized by Sézary cells among half of the cohort, which would be expected for a common unifying origin.
Asunto(s)
Síndrome de Sézary , Neoplasias Cutáneas , Humanos , Linfocitos , Fenotipo , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
B-cell lymphoma of the central nervous system (CNS) is a rare malignancy with diffuse large B-cell lymphoma (DLBCL) variant being most common. Although DLBCL has a high propensity to relapse locally within the CNS, only a few cases of cutaneous metastasis have been described in the literature. We present a unique case of cutaneous metastasis of a primary DLBCL of the CNS in a 79-year-old man who was in clinical remission for 4 years until presenting with a lesion in the left adrenal gland and cutaneous nodules on the left flank. Skin biopsy specimen revealed a diffuse dermal infiltrate of atypical B-cell lymphocytes with expression of CD20, BCL-2, BCL-6, and MUM-1, suggestive of DLBCL. For differentiation between another primary or a recurrent process, immunoglobulin kappa (IgK) light chain gene rearrangement was performed and demonstrated that the DLBCL of the skin and CNS were of the same clonal origin. Restaging computerized tomography after initiating chemotherapy and daily ibrutinib showed complete resolution of the left adrenal mass and resolving cutaneous lesions. Our case demonstrates the rare, late cutaneous metastasis of DLBCL of the CNS and highlights the importance of genetic testing for the distinction between the primary and secondary lesions.
Asunto(s)
Neoplasias Encefálicas , Linfoma de Células B Grandes Difuso , Neoplasias Cutáneas , Anciano , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Masculino , Metástasis de la Neoplasia , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/secundarioRESUMEN
Literature regarding the effect of biologics on the course of mycosis fungoides (MF) is scarce. This multicentre study analysed retrospective data on 19 patients with MF, who were treated with biologics; 12 for inflammatory conditions coexisting with MF, and 7 for MF misdiagnosed as an inflammatory skin disease. Eight patients were treated with anti-tumour necrosis factor-α-monotherapy; 6 had early-stage MF, in 3 patients MF preceded and in 3 MF was diagnosed after initiation of biologics, with no stage-progression or with stable disease, respectively (median treatment time concurrent with MF 57 months). Two patients had advanced stage MF: IIB, treated for 15 months with no stage-progression, and IVA1, treated for 8 months, died of disease 10 months later. The other 11/19 patients received anti-interleukin-17A and/or anti-interleukin-12/23 or anti-interleukin-23 (with/without anti-tumour necrosis factor-α/anti-interleukin-4/13), with stage-progression in 8 patients after a median of 8 months' treatment. Although, in general, biologics should be avoided in patients with MF, these results indicate that anti-tumour necrosis factor-α-monotherapy might not aggravate the disease course in early-stage patients. Interleukin-17A, interleukin-12/23 and interleukin-23 pathway-blockers may prompt progression of MF.
Asunto(s)
Micosis Fungoide , Neoplasias Cutáneas , Citocinas , Humanos , Interleucinas , Micosis Fungoide/diagnóstico , Micosis Fungoide/tratamiento farmacológico , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
BACKGROUND: The onychodystrophies associated with Sézary syndrome (SzS) have rarely been described in the literature. We performed a retrospective analysis of SzS patients at a single institution and compared our data with previous publications. OBJECTIVES: The objectives of this study were to identify and describe the most frequent nail alterations in patients with SzS. METHODS: A retrospective analysis was performed with some prospective observations at the University of Pittsburgh from 1989 to 2017. RESULTS: We identified 54 patients with SzS out of 535 patients with cutaneous T-cell lymphoma. Nineteen patients with SzS had photos of their nail. All those patients exhibited some type of onychodystrophy. The most common types were paronychia (63.2%; 12/19), leukonychia (42.1%; 8/19), onycholysis (42.1%; 8/19), trachyonychia (31.6%; 6/19), and subungual hyperkeratosis (26.3; 5/19). Cluster analysis of our data in comparison with published data on the psoriatic nails indicated that while leukonychia, onycholysis, subungual hyperkeratosis, and nail discoloration were frequently observed in psoriasis, onychauxis, anonychia, distal notching, and onychoschizia occurred more commonly in patients with SzS. CONCLUSIONS: The most common nail manifestations in SzS patients included paronychia, leukonychia, and onycholysis. The nail manifestations in SzS patients appeared to be heterogeneous, while onychauxis, anonychia, distal notching, and onychoschizia seem to be specific to SzS in comparison with psoriasis.
Asunto(s)
Enfermedades de la Uña/etiología , Uñas Malformadas/etiología , Síndrome de Sézary/complicaciones , Neoplasias Cutáneas/complicaciones , Anciano , Femenino , Humanos , Hipopigmentación/etiología , Queratosis/etiología , Masculino , Persona de Mediana Edad , Onicólisis/etiología , Paroniquia/etiología , Estudios Prospectivos , Psoriasis/complicaciones , Estudios RetrospectivosRESUMEN
BACKGROUND: Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas. METHODS: In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499. FINDINGS: Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p<0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group. INTERPRETATION: Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene. FUNDING: Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.
Asunto(s)
Linfoma Cutáneo de Células T , Calidad de Vida , Protocolos de Quimioterapia Combinada Antineoplásica , Brentuximab Vedotina , Humanos , Inmunoconjugados , Recurrencia Local de NeoplasiaRESUMEN
Tumor progression is associated with progressive immunosuppression mediated in part by T regulatory cell(s) (Treg) and/or myeloid-derived suppressor cell(s) (MDSC). Development of strategies to reduce populations of immune cells with suppressive function in cancer patients may enable the induction or recovery of immunity against tumor cells, which may limit or reverse disease progression. With a goal of developing Treg and MDSC neutralizing strategies to treat mycosis fungoides (MF) and Sézary syndrome (SzS), we determined the association between disease stage and suppressor cell populations in patients with MF/SzS, including those responding to therapy. We found elevations in Treg populations, across Treg subtypes, in patients with SzS, and these Treg markedly suppressed proliferation of autologous CD4+CD25- responder T cells. Interestingly, while MDSC numbers were not increased in MF/SzS patients, MDSC from patients with stage IB and above produced significantly more reactive oxygen species than those from stage IA MF patients and control cohorts. Therapy with the CD25-targeting agent denileukin diftitox or IFN-α2b was associated with a reduction in Treg numbers or MDSC function, respectively. These studies identify potential mechanisms of action for these therapies and support the development of coordinated strategies targeting both Treg and MDSC activities in patients with MF/SzS.
Asunto(s)
Antineoplásicos/farmacología , Tolerancia Inmunológica/inmunología , Terapia de Inmunosupresión , Micosis Fungoide/tratamiento farmacológico , Síndrome de Sézary/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Linfocitos T Reguladores/inmunología , Anciano , Anciano de 80 o más Años , Células Cultivadas , Toxina Diftérica/farmacología , Combinación de Medicamentos , Femenino , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Interferón alfa-2 , Interferón-alfa/farmacología , Interleucina-2/farmacología , Masculino , Persona de Mediana Edad , Micosis Fungoide/inmunología , Micosis Fungoide/patología , Proteínas Recombinantes de Fusión/farmacología , Síndrome de Sézary/inmunología , Síndrome de Sézary/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
While mycosis fungoides (MF) is typically an indolent malignancy, it may infrequently undertake an aggressive course. We used proteomic analyses to identify a biomarker of the aggressive course of MF. Results of this investigation demonstrated that PARP-1, heat-shock protein family A (Hsp70) member 1 like (HSAP1L), Hsp70 member 1A (HSPA1A), ATP-depending RNA helicase (DDX17) and the α-isoform of lamina-associated polypeptide 2 (TMPO) had higher expression in aggressive disease versus non-aggressive. Moreover, PARP-1 was overexpressed in patients with early stage of MF who developed later an aggressive disease. PARP-1 was evaluated as a new target for therapy, demonstrating the selective dose-dependent cytotoxic effect of PARP inhibitors on Sézary cells in comparison with non-malignant lymphocytes. In conclusion, we believe that PARP-1 may serve not only as a biomarker at initial biopsies for a disease that may become aggressive but also as a new therapeutic target of advanced MF and Sézary syndrome.
Asunto(s)
Micosis Fungoide/diagnóstico , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Síndrome de Sézary/diagnóstico , Biomarcadores , Biopsia , Óxidos N-Cíclicos/metabolismo , Progresión de la Enfermedad , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Linfocitos/metabolismo , Micosis Fungoide/metabolismo , Estadificación de Neoplasias , Proteómica , Estudios Retrospectivos , Factores de Riesgo , Síndrome de Sézary/metabolismo , Neoplasias Cutáneas/metabolismoAsunto(s)
COVID-19 , Linfoma Cutáneo de Células T , Neoplasias Cutáneas , Humanos , Pandemias , Estudios Retrospectivos , Linfoma Cutáneo de Células T/epidemiología , Linfoma Cutáneo de Células T/terapia , Linfoma Cutáneo de Células T/patología , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patologíaRESUMEN
Cutaneous peripheral T-cell lymphoma, not otherwise specified represents a "waste basket" of all cases that cannot be put into another of the categories of mature cutaneous T-cell lymphoma. Previously, the sudden multifocal development of cutaneous CD4 tumors without preceding a patch or plaque stage was classified as d'emblée form of mycosis fungoides (MF). Currently, the term "MF" reserved only for the classic Alibert-Bazin type characterized by the evolution of patches, plaques, and tumors or for variants showing a similar clinical course. The authors describe a 75-year-old white woman who presented with a solitary skin tumor in the right supraclavicular region, with no lymph node or systemic involvement. Local external beam radiation treatment resulted in a complete response. The patient relapsed after 5 months with new tumors in the left neck and left upper chest. Biopsy of the lesions showed a dermal infiltrate of atypical small- to medium-sized T-lymphocytes, and immunohistochemical staining showed coexpression of CD4/CD8 in a subset of these cells, which was confirmed with flow cytometry of the tumor. Although the patient had no preceding patch or plaque stage, the authors herein report this extremely rare case of CD4/CD8 dual-positive peripheral T-cell lymphoma, not otherwise specified presented as MF d'emblée and discuss the seldom similar cases published previously.
Asunto(s)
Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Linfoma Cutáneo de Células T/patología , Micosis Fungoide/patología , Neoplasias Cutáneas/patología , Anciano , Femenino , Humanos , Linfoma Cutáneo de Células T/inmunología , Micosis Fungoide/inmunología , Neoplasias Cutáneas/inmunologíaRESUMEN
The practice of pre-emptive individualized medicine is predicated on the discovery, development and application of biomarkers in specific clinical settings. Mycosis fungoides and Sézary syndrome are the two most common type of cutaneous T-cell lymphoma, yet diagnosis, prognosis and disease monitoring remain a challenge. In this review, we discuss the current state of biomarker discovery in mycosis fungoides and Sézary syndrome, highlighting the most promising molecules in different compartments. Further, we emphasize the need for continued multicentre efforts to validate available and new biomarkers and to develop prospective combinatorial panels of already discovered molecules.
Asunto(s)
Biomarcadores/sangre , Micosis Fungoide/diagnóstico , Síndrome de Sézary/diagnóstico , Expresión Génica , Humanos , Micosis Fungoide/sangre , Síndrome de Sézary/sangreRESUMEN
Hypopigmented mycosis fungoides (HMF) is the most common variant of mycosis fungoides (MF) in children. Large-cell transformation in HMF has never been reported. Herein we report a case of HMF in an 8-year-old boy who presented with a 6-year history of hypopigmented patches on the bilateral arms, lower back, buttocks, posterior thighs, and lower legs. Biopsy revealed an abnormal CD8+ epidermotropic T-cell infiltrate consistent with the diagnosis of MF. The T-cell clonality study was positive. The patient was started on narrowband ultraviolet B (NBUVB) phototherapy and topical steroids. He had a 50% reduction in his patches after 10 months of treatment, after which he developed a single annular plaque on his left thigh. The biopsy specimen demonstrated large cells that were diffusely CD8+ and CD30- . Clobetasol propionate ointment was prescribed, which led to complete resolution of the plaque within 2 weeks. NBUVB phototherapy was continued and the patient had a complete response within the following 5 months. The case is an example of exceptionally rare large-cell transformation in pediatric MF and stresses the importance of regular follow-up of these patients.
Asunto(s)
Hipopigmentación/patología , Micosis Fungoide/patología , Neoplasias Cutáneas/patología , Linfocitos T/patología , Biopsia , Transformación Celular Neoplásica , Niño , Clobetasol/uso terapéutico , Glucocorticoides/uso terapéutico , Humanos , Masculino , Micosis Fungoide/terapia , Piel/patología , Neoplasias Cutáneas/terapia , Terapia Ultravioleta/métodosRESUMEN
CD4+ small/medium pleomorphic T-cell lymphoma is a relatively rare subtype of cutaneous lymphoproliferative disorder with an indolent clinical behavior. The place of this condition among lymphomas is debatable. The authors describe a rare case of the direct association of CD4 small/medium pleomorphic T-cell lymphoma-like solitary nodule with Borrelia burgdorferi infection in a 5-year-old boy, discuss the reactive nature of this condition, and emphasize the importance of clinicopathological correlation.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Eritema Crónico Migrans/inmunología , Eritema Crónico Migrans/patología , Linfoma Cutáneo de Células T/patología , Neoplasias Cutáneas/patología , Preescolar , Diagnóstico Diferencial , Humanos , Linfoma Cutáneo de Células T/inmunología , Masculino , Neoplasias Cutáneas/inmunologíaAsunto(s)
Infecciones por Coronavirus/inmunología , Linfoma Cutáneo de Células T/terapia , Micosis Fungoide/terapia , Neumonía Viral/inmunología , Síndrome de Sézary/terapia , Neoplasias Cutáneas/terapia , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Betacoronavirus/inmunología , Betacoronavirus/aislamiento & purificación , COVID-19 , Quimioradioterapia/métodos , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Servicios de Atención a Domicilio Provisto por Hospital , Humanos , Linfoma Cutáneo de Células T/complicaciones , Linfoma Cutáneo de Células T/inmunología , Micosis Fungoide/complicaciones , Micosis Fungoide/inmunología , Pandemias , Selección de Paciente , Fotoféresis , Neumonía Viral/diagnóstico , Neumonía Viral/mortalidad , Neumonía Viral/virología , Medición de Riesgo , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Síndrome de Sézary/complicaciones , Síndrome de Sézary/inmunología , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/inmunología , Telemedicina/métodos , Terapia Ultravioleta , Estados UnidosRESUMEN
Immunological functions decline with age. Because MS/SzS predominately affects the elderly, it is important to distinguish age-related from cancer-specific changes. Also, MF and SzS are malignancies of CD4(+) T-lymphocytes, further compromising an immune state of the patients. The objectives of this study were to distinguish disease-specific immunological deterioration by performing comparative age-matched Luminex multiplex assessment of 34 serum biomarkers between patients with MF/SzS, HIV-infected individuals and normal controls. Controlling for age, expression level appears to significantly differ between patients with MF/SzS and controls for the following biomarkers: G-CSF, IL-5, MIP-1ß, TNF-α, VEGF, EOTAXIN, IL-8, IL-12, IL-2R, IP10, MCP-1, MIG, TNFR1 and TNFR2 (P < 0.05), while others showed normal age-related changes. Interestingly, cluster analysis placed MF/SzS profiles closer to HIV. This further underscores an immunologically compromised state of patients with MF/SzS and suggests its potential self-perpetuating role in disease progression.
Asunto(s)
Envejecimiento/sangre , Quimiocina CCL4/sangre , Factor Estimulante de Colonias de Granulocitos/sangre , Interleucina-5/sangre , Síndrome de Sézary/sangre , Neoplasias Cutáneas/sangre , Factores de Edad , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Progresión de la Enfermedad , Infecciones por VIH/sangre , Humanos , Micosis Fungoide/sangre , Síndrome de Sézary/diagnóstico , Neoplasias Cutáneas/diagnósticoRESUMEN
We present the case of a 20-month-old boy with congenital neutropenia for which he was being treated with granulocyte colony-stimulating factor (G-CSF) who developed bullous Sweet's syndrome. Because of the challenging and extensive differential diagnosis of an acute bullous eruption in an immunocompromised child, we highlight the importance of a prompt and precise diagnosis before initiation of any systemic therapy in children with Sweet's syndrome.
Asunto(s)
Vesícula/inducido químicamente , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Neutropenia/congénito , Síndrome de Sweet/inducido químicamente , Biopsia , Vesícula/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Humanos , Lactante , Masculino , Neutropenia/tratamiento farmacológico , Síndrome de Sweet/tratamiento farmacológicoRESUMEN
BACKGROUND: Environmental hazards may play a role in the etiology of cutaneous T-cell lymphoma (CTCL). Some studies have found an increased incidence of CTCL among workers in chemical science, transportation, and manufacturing industries, but other studies have not. This discrepancy may be attributable to population migration, complicating accurate assessment of lifetime exposures. The Pittsburgh population has very low migration rates and most CTCL patients seen at the University of Pittsburgh Medical Center (UPMC) Cutaneous Lymphoma Center are life-long local residents. The Greater Pittsburgh Area used to be an industrial hub. There are residential communities positioned within close proximity to inactive industrial sites that continue to contain pollutants. OBJECTIVE: To determine whether CTCL patients' residences cluster within specific Pittsburgh regions, in particular, those with high levels of environmental pollutants. METHODS: Our study included patients diagnosed with CTCL at the UPMC Cutaneous Lymphoma Center between 2000 and 2012. We mapped the longitudinal and latitudinal coordinates of patients' residences at diagnosis, superfund sites, toxic release inventory sites, particular matter levels, and dermatologists' offices using ArcMap 10.1. We then performed a SaTScan analysis using zip codes to assess for geographic clustering of patients' residences in the Pittsburgh metropolitan statistical area. We assessed for a correlation between case distribution and both environmental hazards sites and dermatologist density in the area. RESULTS: We identified 274 patients with CTCL in the Greater Pittsburgh area. We identified a statistically significant geographic cluster (p<.001) in zip code 15213, which is the most densely populated neighborhood in Pittsburgh and the site of the region's only CTCL clinic. We observed no relationship between the locations of superfund sites, toxic release inventory sites, or particular matter levels and CTCL case distribution. CONCLUSION: Our findings do not support an association between exposure to environmental toxins and CTCL. CTCL cases clustered in areas with the highest population density, which also happen to include a regional CTCL center. To evaluate a possibility of urban pollutants playing a role in etiology of CTCL, dermatologist density and access to care need to be addressed as potential confounders in the future studies.
Asunto(s)
Linfoma Cutáneo de Células T/epidemiología , Neoplasias Cutáneas/epidemiología , Adulto , Anciano , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pennsylvania/epidemiología , Estudios RetrospectivosRESUMEN
ABSTRACT: Sézary syndrome (SS) is an aggressive leukemic expansion of skin-derived malignant CD4+ T cells. Drug monotherapy often results in disease relapse because of the heterogenous nature of malignant CD4+ T cells, but how therapies can be optimally combined remains unclear because of limitations in understanding the disease pathogenesis. We identified immunologic transitions that interlink mycosis fungoides with SS using single-cell transcriptome analysis in parallel with high-throughput T-cell receptor sequencing. Nascent peripheral CD4+ T cells acquired a distinct profile of transcription factors and trafficking receptors that gave rise to antigenically mature Sézary cells. The emergence of malignant CD4+ T cells coincided with the accumulation of dysfunctional monocytes with impaired fragment crystallizable γ-dependent phagocytosis, decreased responsiveness to cytokine stimulation, and limited repertoire of intercellular interactions with Sézary cells. Type I interferon supplementation when combined with a monoclonal antibody targeting the chemokine receptor type 4 (CCR4), unleashed monocyte induced phagocytosis and eradication of Sézary cells in vitro. In turn, coadministration of interferon-α with the US Food and Drug Administration-approved anti-CCR4 antibody, mogamulizumab, in patients with SS induced marked depletion of peripheral malignant CD4+ T cells. Importantly, residual CD4+ T cells after Sézary cell ablation lacked any immunologic shifts. These findings collectively unveil an auxiliary role for augmenting monocytic activity during mogamulizumab therapy in the treatment of SS and underscore the importance of targeted combination therapy in this disease.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Interferón alfa-2 , Monocitos , Micosis Fungoide , Síndrome de Sézary , Síndrome de Sézary/inmunología , Síndrome de Sézary/metabolismo , Síndrome de Sézary/patología , Síndrome de Sézary/terapia , Micosis Fungoide/inmunología , Micosis Fungoide/metabolismo , Micosis Fungoide/patología , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Análisis de Expresión Génica de una Sola Célula , Macrófagos/inmunología , Interferón Tipo I/inmunología , Monocitos/inmunología , Inflamación/inmunología , Inflamación/patología , Interferón alfa-2/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Terapia Combinada , Linfocitos T CD4-Positivos/inmunologíaRESUMEN
There are no established maintenance protocols for cutaneous lymphomas. We aim to determine patient treatments and outcomes during the COVID-19 pandemic in order to uncover the most effective maintenance protocols for cutaneous lymphomas and impact of treatment interruption. Data was collected retrospectively from nine international institutions, including 149 patients. Younger patients had earlier stages of disease and were most frequently treated with skin-directed therapies including topical steroids, mechlorethamine gel, and phototherapy. Treatment interruption varied by treatment type and stage, with patients on topical therapies and earlier stages of disease being least likely to experience interruption. Treatment interruption was significantly associated with progression of disease and worse outcomes, with twice as many patients progressing who had interruption compared to those without interruption. This study may demonstrate the significance of continuous maintenance therapies, even in younger patients with early stages of disease.