RESUMO
Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose-dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.
Assuntos
Bexaroteno , Dislipidemias , Hipotireoidismo , Humanos , Bexaroteno/efeitos adversos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Dislipidemias/induzido quimicamente , Japão/epidemiologia , Tiroxina/sangue , Triglicerídeos/sangue , Adulto , Tetra-Hidronaftalenos/efeitos adversos , Tetra-Hidronaftalenos/uso terapêutico , Idoso de 80 Anos ou mais , Anticarcinógenos/uso terapêutico , Anticarcinógenos/efeitos adversos , Hipertrigliceridemia/induzido quimicamenteRESUMO
Brentuximab vedotin (BV), a conjugate of anti-CD30 antibody and monomethyl auristatin E, has emerged as a promising treatment option for refractory CD30+ mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL). BV has been shown to be safe and effective in treating Hodgkin's lymphoma and peripheral T-cell lymphoma. This multicenter, prospective, single-arm phase I/II study evaluated the efficacy of BV in Japanese patients with CD30+ cutaneous lymphomas, namely CD30+ cutaneous T-cell lymphoma. Participants were divided into two groups: those with CD30+ MF or pcALCL (cohort 1, n = 13) and those with CD30+ lymphoproliferative disorders other than those in cohort 1 (cohort 2, n = 3). The studied population included the full analysis set (FAS), modified FAS (mFAS), and safety analysis set (SAF). These sets were identified in cohorts 1 and 1 + 2 and labeled FAS1 and FAS2, mFAS1 and mFAS2, and SAF1 and SAF2, respectively. Each treatment cycle lasted 3 weeks, and BV was continued for up to 16 cycles after the third cycle based on treatment response. The primary endpoint was the 4-month objective response rate (ORR4) determined by the Independent Review Forum (IRF). ORR4 was 69.2% for FAS1 and 62.5% for FAS2 (P < 0.0001). Secondary endpoints of ORR, assessed using the global response score (53.8% in FAS1) and modified severity-weighted assessment tool (62.5% in FAS1), using the IRF, provided results comparable to the primary findings. The incidence of ≥grade 3 adverse events (≥15%) in SAF1 was peripheral neuropathy in three patients (23%) and fever and eosinophilia in two patients (15%). In conclusion, BV showed favorable efficacy, tolerability, and safety profile in Japanese patients with relapsed or refractory CD30+ primary cutaneous T-cell lymphoma. The trial was registered with University Hospital Medical Information Network Clinical Trials Registry, Japan (protocol ID: UMIN000034205).
Assuntos
Brentuximab Vedotin , Antígeno Ki-1 , Neoplasias Cutâneas , Humanos , Brentuximab Vedotin/administração & dosagem , Brentuximab Vedotin/uso terapêutico , Masculino , Pessoa de Meia-Idade , Antígeno Ki-1/imunologia , Antígeno Ki-1/análise , Feminino , Idoso , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/imunologia , Estudos Prospectivos , Japão , Adulto , Idoso de 80 Anos ou mais , Micose Fungoide/tratamento farmacológico , Micose Fungoide/patologia , Micose Fungoide/imunologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/patologia , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Imunoconjugados/administração & dosagem , Imunoconjugados/uso terapêutico , Imunoconjugados/efeitos adversos , Resultado do Tratamento , População do Leste AsiáticoRESUMO
Systemic sclerosis (SSc) is a collagen disease with immune abnormalities, vasculopathy, and fibrosis. Ca blockers and prostaglandins are used to treat peripheral circulatory disturbances. Chronic limb-threatening ischemia (CLTI) is a disease characterized by extremity ulcers, necrosis, and pain due to limb ischemia. Since only a few patients present with coexistence of CLTI and SSc, the treatment outcomes of revascularization in these cases are unknown. In this study, we evaluated the clinical characteristics and treatment outcomes of seven patients with CLTI and SSc, and 35 patients with uncomplicated CLTI who were hospitalized from 2012 to 2022. A higher proportion of patients with uncomplicated CLTI had diabetes and male. There were no significant differences in the age at which ischemic ulceration occurred, other comorbidities, or in treatments, including antimicrobial agents, revascularization and amputation, improvement of pain, and the survival time from ulcer onset between the two subgroups. EVT or amputation was performed in six or two of the seven patients with CLTI and SSc, respectively. Among those who underwent EVT, 33% (2/6) achieved epithelialization and 67% (4/6) experienced pain relief. These results suggest that the revascularization in cases with CLTI and SSc should consider factors such as infection and general condition, since revascularization improve the pain of these patients.
Assuntos
Isquemia Crônica Crítica de Membro , Escleroderma Sistêmico , Humanos , Masculino , Feminino , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/terapia , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Isquemia Crônica Crítica de Membro/cirurgia , Isquemia Crônica Crítica de Membro/complicações , Isquemia Crônica Crítica de Membro/etiologia , Isquemia Crônica Crítica de Membro/diagnóstico , Isquemia Crônica Crítica de Membro/terapia , Amputação Cirúrgica/estatística & dados numéricos , Procedimentos Endovasculares , Estudos Retrospectivos , Isquemia/etiologia , Isquemia/terapia , Isquemia/diagnóstico , Idoso de 80 Anos ou mais , AdultoAssuntos
Foliculite , Imunoglobulina G , Gravidez , Feminino , Humanos , Membrana Basal , Foliculite/diagnóstico , Prurido/diagnóstico , Prurido/etiologiaRESUMO
BACKGROUND: The clinical implications of DUSP22 rearrangement and the association between DUSP22 rearrangement and lymphoid enhancer-binding factor 1 (LEF1) expression pattern in CD30+ cutaneous T-cell lymphomas (CTCLs) are unknown. OBJECTIVES: This study assessed the incidence of DUSP22 rearrangement and its clinical and immunohistochemical implications in primary cutaneous anaplastic large-cell lymphoma (pcALCL), lymphomatoid papulosis (LyP) and CD30+ mycosis fungoides with large-cell transformation (MF-LCT), focusing especially on the association with the prognosis and LEF1 expression pattern. Prognostic factors of pcALCL were also examined. METHODS: We conducted a multicentre retrospective study including patients with pcALCL, LyP and MF-LCT diagnosed between 1 January 2000 and 31 December 2018 in Japan. Baseline data at diagnosis, treatment course, overall survival (OS) and disease-specific survival (DSS) were collected. Immunohistochemical analysis and fluorescence in situ hybridization to detect DUSP22 and TP63 rearrangement were performed using skin samples at diagnosis. We investigated the association between staining pattern and these gene rearrangements. We also assessed the prognostic implications of clinical status, immunohistochemical results and the presence of gene rearrangements. RESULTS: DUSP22 rearrangement was detected in 50% (11 of 22) of cases of pcALCL, but not in any cases with LyP (0 of 14) or MF-LCT (0 of 11). TP63 rearrangement was not detected in any case. Clinically, patients with pcALCL with DUSP22 rearrangement did not tend to develop ulcers (P = 0.081). There was no significant association between DUSP22 rearrangement status and immunohistochemical results, including LEF1 expression pattern. T3 stage and the presence of lower limb lesions were significantly associated with shorter OS (P = 0.012 and 0.021, respectively, by log-rank test). Similarly, they were significantly correlated with shorter DSS (P = 0.016 and 0.0001, respectively). CONCLUSIONS: DUSP22 rearrangement is relatively specific to pcALCL among CD30+ CTCLs in Japan. Although the LEF1 expression pattern was not related to DUSP22 rearrangement in pcALCL, there was no rearrangement if LEF1 was not expressed. We confirmed that T3 stage and the lower limb involvement were significantly associated with decreased OS and DSS. The presence or absence of lower limb lesions should be included in T-stage subcategorization in the future.
Assuntos
Linfoma Anaplásico de Células Grandes , Papulose Linfomatoide , Micose Fungoide , Neoplasias Cutâneas , Humanos , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Antígeno Ki-1 , Prognóstico , Hibridização in Situ Fluorescente , Japão/epidemiologia , Micose Fungoide/patologiaRESUMO
Hydroa vacciniforme lymphoproliferative disorder (HV-LPD) is a cutaneous variant of chronic active Epstein-Barr virus disease. We examined the coexpression of T- and natural killer (NK)-cell antigens in five patients with classic HV (cHV) and five with systemic HV (sHV). T-cell receptor (TCR) repertoire analysis was performed with highthroughput sequencing. All five cHV patients had increased γδT cells (> 5%), whereas five sHV patients showed γδT- and αßT-cell dominance in two patients each, and a mixture of abnormal γδT and αßT cells in one. Circulating CD3 + T cells expressed CD16/CD56 at 7.8-42.3% and 1.1-9.7% in sHV and cHV, respectively. The percentage of CD16/CD56 + T cells was higher in the large granular lymphocyte or atypical T-cell fractions in sHV, but no TCR Vα24 invariant chain characteristic of NKT cells was detected. Considerable numbers of CD3 + cells expressing CD56 were observed in sHV skin infiltrates. Of the circulating γδT cells tested, TCR Vδ1 + cells characteristic of the epithelial type of γδT cells were dominant in two sHV cases. Thus, atypical αßT and γδT cells in HV-LPD can express NK-cell antigens, such as CD16 and CD56, and Vδ1 + epithelial-type γδT cells are a major cell type in some HV-LPD cases.
Assuntos
Infecções por Vírus Epstein-Barr , Hidroa Vaciniforme , Transtornos Linfoproliferativos , Humanos , Herpesvirus Humano 4 , Células Matadoras NaturaisRESUMO
Hydroa vacciniforme lymphoproliferative disorder (HV-LPD) and severe mosquito bite allergy (SMBA) are both cutaneous forms of Epstein-Barr virus (EBV)-associated T/natural killer (NK) cell LPDs and are closely related to chronic active EBV disease (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). HV-LPD is further divided into classic HV, a benign subtype mediated by EBV-positive γδT cells, and systemic HV, another life-threatening subtype mainly associated with EBV-positive αßT or γδT cells. The vast majority of patients with SMBA have increased numbers of EBV-infected NK cells in the blood. Clinical symptoms of HV-LPD and SMBA often overlap in the same patient and may progress to more serious disease conditions equivalent to the systemic form of CAEBV. To define the disease spectrum of HV-LPD and SMBA, we propose the diagnostic criteria and the determination criteria for disease severity. The proposed diagnostic criteria are consistent with those for CAEBV and EBV-HLH in the guidelines for the management for CAEBV and related disorders 2023.
Assuntos
Infecções por Vírus Epstein-Barr , Hidroa Vaciniforme , Hipersensibilidade , Mordeduras e Picadas de Insetos , Transtornos Linfoproliferativos , Humanos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4 , Hidroa Vaciniforme/diagnóstico , Hidroa Vaciniforme/complicações , Mordeduras e Picadas de Insetos/complicações , Mordeduras e Picadas de Insetos/diagnóstico , Gravidade do Paciente , Transtornos Linfoproliferativos/diagnóstico , Hipersensibilidade/diagnóstico , Hipersensibilidade/complicaçõesRESUMO
This was a multicenter clinical trial of rituximab, a chimeric monoclonal IgG antibody directed against CD20, for the treatment of refractory pemphigus vulgaris and pemphigus foliaceus. In total, 20 patients were treated with two doses of rituximab (1000 mg; 2 weeks apart) on days 0 and 14. The primary end point was the proportion of patients who achieved complete or partial remission on day 168 following the first rituximab dose. Of the 20 enrolled patients, 11 (55%) and four (20%) achieved complete and partial remission, respectively; therefore, remission was achieved in a total of 15 patients (75.0% [95% confidence interval, 50.9%-91.3%]). It was demonstrated that the remission rate was greater than the prespecified threshold (5%). In addition, a significant improvement in clinical score (Pemphigus Disease Area Index) and decrease in serum anti-desmoglein antibody level were observed over time. Four serious adverse events (heart failure, pneumonia, radial fracture, and osteonecrosis) were recorded in two patients, of which only pneumonia was considered causally related with rituximab. The level of peripheral blood CD19-positive B lymphocytes was decreased on day 28 after rituximab treatment and remained low throughout the study period until day 168. Our results confirm the efficacy and safety of rituximab therapy for refractory pemphigus in Japanese patients.
Assuntos
Pênfigo , Humanos , População do Leste Asiático , Fatores Imunológicos/uso terapêutico , Pênfigo/tratamento farmacológico , Estudos Prospectivos , Rituximab/uso terapêutico , Resultado do TratamentoRESUMO
To establish real-world evidence about the safety and efficacy of bexarotene for Japanese patients with cutaneous T-cell lymphoma, we conducted a nationwide cohort study using data from post-marketing surveillance for bexarotene treatment. In total, 294 patients with cutaneous T-cell lymphoma were identified between June 2016 and June 2018. Of these, 267 patients were included as the safety analysis set. Of the 267 patients, 175 were included in the efficacy analysis set. Of these, 139 patients had mycosis fungoides, including 46 with early stage disease and 93 with advanced stage disease. Among the 139 patients with mycosis fungoides, the objective response rate was 46.8%. A significant difference in objective response rate was detected between patients who started with bexarotene at 300 mg/m2 (61.6%) and patients who started with bexarotene at less than 300 mg/m2 (22.6%, p < 0.001). Of the 139 patients with mycosis fungoides, 92 were treated with a combination of bexarotene plus photo(chemo)therapy. A significant difference in objective response rate was seen between bexarotene with a combination of photo(chemo)therapy (57.6%) and bexarotene without a combination of photo(chemo)therapy (25.5%, p < 0.001). Starting bexarotene at 300 mg/m2 and combination with photo(chemo)therapy were detected as independent factors influencing response. Common treatment-related adverse events included hypothyroidism (85.8%), hypertriglyceridemia (68.5%), hypercholesterolemia (43.8%), and neutropenia (21.3%). Hypertriglyceridemia, hypercholesterolemia, and neutropenia occurred more frequently in patients who started with bexarotene at 300 mg/m2 than patients who started with bexarotene at less than 300 mg/m2 (hypertriglyceridemia, 76.4% vs. 57.0%, p = 0.001; hypercholesterolemia, 49.0% vs. 36.4%, p = 0.045; neutropenia, 28.0% vs. 12.1%, p = 0.002; respectively). The present study indicates that starting bexarotene at 300 mg/m2 and combination of photo(chemo)therapy offer a promising efficacy for the treatment of patients with mycosis fungoides. Efficacy of low-dose bexarotene plus photo(chemo)therapy should be evaluated in future.
Assuntos
Linfoma Cutâneo de Células T , Micose Fungoide , Neutropenia , Neoplasias Cutâneas , Bexaroteno , Estudos de Coortes , Humanos , Japão/epidemiologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Micose Fungoide/tratamento farmacológico , Vigilância de Produtos Comercializados , Resultado do TratamentoRESUMO
To identify clonal neoplastic cells in skin affected by B-cell lymphoma using skin flow cytometry (FCM) techniques, we investigated light-chain restriction using skin FCM with clonality assessed by polymerase chain reaction and light-chain restriction by in situ hybridization (ISH). We retrospectively analyzed 16 cases of B-cell lymphoma with cutaneous involvement: primary cutaneous diffuse large B-cell lymphoma, leg type (pcDLBCL-LT) (n = 7), DLBCL-not otherwise specified (DLBCL-NOS) (n = 6), primary cutaneous follicle center lymphoma (pcFCL) (n = 1), and follicular lymphoma (n = 2), as well as cutaneous B-cell pseudolymphoma (n = 9). Results of skin FCM light-chain restriction analyses were compared with immunoglobulin H (IgH) gene rearrangement and κ/λ ISH findings. Skin FCM detected light-chain restriction in 11 of 14 B-cell lymphoma patients but none of the B-cell pseudolymphoma patients. The sensitivity of skin FCM for distinguishing B-cell lymphoma and B-cell pseudolymphoma was 79%, and the specificity was 100%. Eleven of 13 B-cell lymphoma patients exhibited gene rearrangement (sensitivity 85%), whereas six of seven pseudolymphoma patients were negative (specificity 86%). ISH was positive in three of 16 B-cell lymphoma cases (sensitivity 19%) but none of the B-cell pseudolymphoma cases (specificity 100%). ISH sensitivity was 29% for pcDLBCL-LT, 17% for DLBCL-NOS, and 0% for pcFCL and follicular lymphoma. Skin FCM therefore appears to be more sensitive than ISH in detecting light-chain restriction in DLBCL and follicular lymphoma, and as sensitive as IgH gene rearrangement analysis in detecting clonality. Skin FCM is thus a promising diagnostic tool for identifying monoclonal neoplastic B-cell populations.
Assuntos
Linfoma Difuso de Grandes Células B , Pseudolinfoma , Citometria de Fluxo , Rearranjo Gênico , Humanos , Imunofenotipagem , Pseudolinfoma/diagnóstico , Pseudolinfoma/genética , Estudos RetrospectivosRESUMO
Toxic shock syndrome (TSS) is caused by toxic shock syndrome toxin 1 or enterotoxins secreted by Staphylococcus aureus. Lipopolysaccharide (LPS) has also been shown to play a major role in the development of sepsis. Staphylococcal superantigens and LPS operate synergistically in conditioning cytokine release and lethal shock in mice. An 80-year-old woman was admitted because of a 20% mixed-depth flame burn. Despite two excisions and grafts, necrotic ulcers with methicillin-resistant Staphylococcus aureus (MRSA) colonization remained. On the 7th day after the operation, she developed shock with an erythematous rash. Blood examination revealed evidence of disseminated intravascular coagulation, and liver and renal dysfunction. A blood culture revealed a staphylococcal enterotoxin B (SEB)-producing strain of MRSA and Klebsiella pneumoniae. The septic symptoms were prolonged, but the condition gradually improved with extensive treatment. T-cell receptor analysis demonstrated a marked accumulation of SEB-mediated Vß T cells. Stimulation of peripheral blood mononuclear cells in the recovery phase with SEB and LPS induced additive effects on tumor necrosis factor-α, interferon-γ, and interleukin-6 production. Although the present case did not fulfill the clinical criteria for TSS, the additive effects of SEB and LPS might have caused the severe septic shock.