RESUMO
Adult T-cell leukemia/lymphoma (ATLL) is a rare and often aggressive lymphoid malignancy known to be associated with human T-cell lymphotropic virus type 1. There are 2 broad categories: acute and chronic. In the acute category, there is a leukemic and a lymphomatous variant, whereas in the designated "chronic" form, there is mild peripheral blood lymphocytosis. The intermediate "smoldering" category is without peripheral blood lymphocytosis with only discernible skin involvement. We present a 68-year-old human T-cell lymphotropic virus type 1 seropositive female with a mild peripheral blood atypical lymphocytosis who had indurated nodules on her hands of 2 years duration and a new scaly ichthyosiform eruption on her lower extremities. Histopathologic examination of the hand biopsy revealed coalescing nodules of large atypical noncerebriform lymphocytes with focal areas of epidermotropism. Phenotypically, the infiltrate was positive for ß-F1, CD2, CD4, CD5, CD7, Foxp3, and CD25. In both biopsies, there was striking upregulation of TOX (thymocyte selection-associated high mobility group box factor) in the nuclei of neoplastic cells. The second biopsy taken from the ichthyotic patch on the patient's left leg showed a subtle pattern of epidermal infiltration by atypical noncerebriform lymphocytes and a distinct compact scale consistent with the clinical picture of ichthyosis. The histopathologic appearance was that of a yet undescribed ichthyosiform mycosis fungoides-like presentation of chronic ATLL. In addition, the observed upregulation of nuclear TOX may play an oncogenic role in ATLL. The course to date in this patient has been relatively indolent, although the patients believe that large cell transformation could portend more aggressive disease.
Assuntos
Biomarcadores Tumorais/análise , Proteínas de Grupo de Alta Mobilidade/análise , Ictiose/metabolismo , Leucemia-Linfoma de Células T do Adulto/metabolismo , Micose Fungoide/química , Neoplasias Cutâneas/química , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Feminino , Humanos , Ictiose/tratamento farmacológico , Ictiose/patologia , Imuno-Histoquímica , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/patologia , Micose Fungoide/tratamento farmacológico , Micose Fungoide/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Regulação para CimaRESUMO
Belinostat is a pan-histone deacetylase inhibitor with antitumour and anti-angiogenic properties. An open label, multicentre study was conducted in patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥1 prior systemic therapy and were treated with belinostat (1000 mg/m(2) intravenously ×5 d of a 21-d cycle). The primary endpoint was objective response rate (ORR). Patients with PTCL (n = 24) had received a median of three prior systemic therapies (range 1-9) and 40% had stage IV disease. Patients with CTCL (n = 29) had received a median of one prior skin-directed therapy (range 0-4) and four prior systemic therapies (range 1-9); 55% had stage IV disease. The ORRs were 25% (PTCL) and 14% (CTCL). Treatment-related adverse events occurred in 77% of patients; nausea (43%), vomiting (21%), infusion site pain (13%) and dizziness (11%) had the highest incidence. Treatment-related serious adverse events were Grade 5 ventricular fibrillation; Grade 4 thrombocytopenia; Grade 3 peripheral oedema, apraxia, paralytic ileus and pneumonitis; and Grade 2 jugular vein thrombosis. Belinostat monotherapy was well tolerated and efficacious in patients with recurrent/refractory PTCL and CTCL. This trial was registered at www.clinicaltrials.gov as NCT00274651.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Esquema de Medicação , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Infusões Intravenosas , Linfoma Cutâneo de Células T/patologia , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Recidiva , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
Fanconi anemia (FA) is a clinically heterogenous and genetically diverse disease with 22 known complementation groups (FA-A to FA-W), resulting from the inability to repair DNA interstrand cross-links. This rare disorder is characterized by congenital defects, bone marrow failure, and cancer predisposition. FANCA is the most commonly mutated gene in FA and a variety of mostly private mutations have been documented, including small and large indels and point and splicing variants. Genotype-phenotype associations in FA are complex, and a relationship between particular FANCA variants and the observed cellular phenotype or illness severity remains unclear. In this study, we describe two siblings with compound heterozygous FANCA variants (c.3788_3790delTCT and c.4199G > A) who both presented with esophageal squamous cell carcinoma at the age of 51. The proband came to medical attention when he developed pancytopenia after a single cycle of low-dose chemotherapy including platinum-based therapy. Other than a minor thumb abnormality, neither patient had prior findings to suggest FA, including normal blood counts and intact fertility. Patient fibroblasts from both siblings display increased chromosomal breakage and hypersensitivity to interstrand cross-linking agents as seen in typical FA. Based on our functional data demonstrating that the c.4199G > A/p.R1400H variant represents a hypomorphic FANCA allele, we conclude that the residual activity of the Fanconi anemia repair pathway accounts for lack of spontaneous bone marrow failure or infertility with the late presentation of malignancy as the initial disease manifestation. This and similar cases of adult-onset esophageal cancer stress the need for chromosome breakage testing in patients with early onset of aerodigestive tract squamous cell carcinomas before platinum-based therapy is initiated.
Assuntos
Neoplasias Esofágicas/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Sistemas CRISPR-Cas , Quebra Cromossômica , DNA , Reparo do DNA , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/terapia , Fibroblastos/metabolismo , Edição de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
Abstract: T cell lymphomas comprise a distinct class of non-Hodgkin's lymphomas, which include mature T and natural killer (NK) cell neoplasms. While each malignancy within this group is characterized by unique clinicopathologic features, dysregulation in the Janus tyrosine family of kinases/Signal transducer and activator of transcription (JAK/STAT) signaling pathway, specifically aberrant STAT3 activation, is a common feature among these lymphomas. The mechanisms driving dysregulation vary among T cell lymphoma subtypes and include activating mutations in upstream kinases or STAT3 itself, formation of oncogenic kinases which drive STAT3 activation, loss of negative regulators of STAT3, and the induction of a pro-tumorigenic inflammatory microenvironment. Constitutive STAT3 activation has been associated with the expression of targets able to increase pro-survival signals and provide malignant fitness. Patients with dysregulated STAT3 signaling tend to have inferior clinical outcomes, which underscores the importance of STAT3 signaling in malignant progression. Targeting of STAT3 has shown promising results in pre-clinical studies in T cell lymphoma lines, ex-vivo primary malignant patient cells, and in mouse models of disease. However, targeting this pleotropic pathway in patients has proven difficult. Here we review the recent contributions to our understanding of the role of STAT3 in T cell lymphomagenesis, mechanisms driving STAT3 activation in T cell lymphomas, and current efforts at targeting STAT3 signaling in T cell malignancies.
RESUMO
Intraoperative bleeding can be minimized with optimal preoperative preparation but cannot be completely prevented. There are circumstances when patients need emergent operative intervention, and thorough hemostatic evaluation and preparation is not possible. In this review, the authors summarize the recommendations for rapid reversal of vitamin K antagonists and direct oral anticoagulants before procedures. The authors review the potential causes for intraoperative bleeding and the methods for rapid and accurate diagnosis. The authors summarize the current evidence for treatment options, including transfusion of platelets and coagulation factors and the use of topical agents, antidotes to direct-acting anticoagulants, antifibrinolytics, and desmopressin.
Assuntos
Transtornos da Coagulação Sanguínea/prevenção & controle , Perda Sanguínea Cirúrgica/prevenção & controle , Hemostasia Cirúrgica/métodos , Procedimentos Neurocirúrgicos/métodos , Anticoagulantes/uso terapêutico , Antifibrinolíticos/uso terapêutico , Transfusão de Sangue , Humanos , Resultado do TratamentoRESUMO
Cutaneous T-cell lymphoma is a heterogeneous group of lymphomas characterized by the accumulation of malignant T cells in the skin. The molecular and cellular etiology of this malignancy remains enigmatic, and what role antigenic stimulation plays in the initiation and/or progression of the disease remains to be elucidated. Deep sequencing of the tumor genome showed a highly heterogeneous landscape of genetic perturbations, and transcriptome analysis of transformed T cells further highlighted the heterogeneity of this disease. Nonetheless, using data harvested from high-throughput transcriptional profiling allowed us to develop a reliable signature of this malignancy. Focusing on a key cytokine signaling pathway previously implicated in cutaneous T-cell lymphoma pathogenesis, JAK/STAT signaling, we used conditional gene targeting to develop a fully penetrant small animal model of this disease that recapitulates many key features of mycosis fungoides, a common variant of cutaneous T-cell lymphoma. Using this mouse model, we show that T-cell receptor engagement is critical for malignant transformation of the T lymphocytes and that progression of the disease is dependent on microbiota.
Assuntos
Citocinas/fisiologia , Linfoma Cutâneo de Células T/etiologia , Transdução de Sinais/fisiologia , Neoplasias Cutâneas/etiologia , Animais , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/imunologia , Camundongos , Microbiota , Receptores de Antígenos de Linfócitos T/fisiologia , Fator de Transcrição STAT3/fisiologia , Síndrome de Sézary/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologiaRESUMO
Mycosis fungoides is responsive to treatment in the early stages; patients have a long duration of survival but are rarely cured of the disease. Therefore, patients require long-term, sequential therapies with as little toxicity as possible. In the early stages, skin-directed therapies, such as psoralen plus ultraviolet A in combination with retinoids or interferon, generally produce good, long-term responses. Once the disease progresses, systemic agents such as cytokines and retinoids are introduced. The cytokines provide a rational treatment approach for cutaneous T-cell lymphoma (CTCL) and produce good, long-lasting responses with few immunosuppressant effects. Denileukin diftitox (Ontak) has also been shown to produce good treatment effects, and its toxic effects can usually be controlled using prophylactic therapies. The synthetic retinoid bexarotene (Targretin) is taken orally and produces high response rates in CTCL, with a good long-term tolerability profile. Conventional systemic chemotherapies produce rapid responses and high response rates in CTCL, but these are generally of short duration and accompanied by myelosuppression and immunosuppression. Current treatment strategies therefore consist of the use of initial skin-directed therapies, with the addition of low-toxicity systemic biologic agents as the disease progresses; patients who do not respond to biologic agents should then receive conventional chemotherapies, starting with single agents and progressing to combination therapies.
Assuntos
Antineoplásicos/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bexaroteno , Citocinas/uso terapêutico , Toxina Diftérica/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Interleucina-2/uso terapêutico , Linfoma Cutâneo de Células T/patologia , Estadiamento de Neoplasias , Purinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Retinoides/uso terapêutico , Neoplasias Cutâneas/patologia , Tetra-Hidronaftalenos/uso terapêuticoRESUMO
Bexarotene (Targretin, Ligand Pharmaceuticals Inc.) is a synthetic retinoid analog with specific affinity for the retinoid X receptor and belongs to a group of compounds called rexinoids. Early clinical trials of this drug demonstrated activity in cutaneous T-cell lymphoma. Subsequent Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of cutaneous T-cell lymphoma who were refractory or intolerant to the previous therapy. The principal toxicities of bexarotene include central hypothyroidism, xeroderma and elevation of cholesterol and triglycerides. These toxicities can be managed with dose attenuation or addition of atorvastatin (Lipitor, Pfizer) or fenofibrate (TriCor, Abbott Laboratories). Since bexarotene has little bone marrow toxicity, it is an excellent candidate for combination therapy with other modalities useful in the treatment of cutaneous T-cell lymphoma. These include ultraviolet B irradiation, psoralen and ultraviolet A photochemotherapy, interferons, denileukin diftitox (Ontak, Ligand Pharmaceuticals Inc.) and cytotoxic chemotherapy. Bexarotene has also been investigated in the treatment of breast cancer and non-small cell carcinoma of the lung with promising early results.
Assuntos
Anticarcinógenos/uso terapêutico , Neoplasias/tratamento farmacológico , Tetra-Hidronaftalenos/uso terapêutico , Bexaroteno , Neoplasias da Mama/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
INTRODUCTION: Hemolysis from naturopathic remedies remains poorly reported in the medical literature, although it is most commonly noted in the patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. We report a case of massive intravascular hemolysis following the infusion of a naturopathic preparation that contains vitamins. CASE REPORT: A 47-year-old African-American man presented to the hospital with 3 days of fever, dyspnea, emesis, dark urine, and progressive confusion. His symptoms began 1 day following an infusion of a vitamin complex. His physical examination was significant for lethargy and scleral icterus. Initial laboratory studies were notable for anemia (hemoglobin, 3.3 g/dL and hematocrit, 11%), brisk reticulocytosis (33%), acute renal insufficiency (creatinine, 2.8 mg/dL), and indirect hyperbilirubinemia (total bilirubin, 4.4 mg/dL). His peripheral smear demonstrated "blister cells," erythrocytes that have been left devoid of precipitated hemoglobin by the spleen, which are commonly seen in patients with G6PD deficiency. His physician revealed that the infusion contained vitamins B and D complex, free amino acids, magnesium, and taurine. The patient clinically improved and was discharged to home. G6PD concentration was significantly reduced to 4.7 U/g Hb upon recovery. DISCUSSION: Life-threatening intravascular hemolysis may occur following a naturopathic vitamin infusion and may identify previously unknown G6PD deficiency. Since most properly formulated naturopathic treatments have few toxic ingredients, the possibilities of improper formulation, toxic diluents, or contaminants should be considered. Inadequate regulatory oversight of naturopathic remedies has the potential to allow serious toxicity especially in genetically predisposed individuals.
Assuntos
Hemólise/efeitos dos fármacos , Naturologia , Vitaminas/intoxicação , Contagem de Células Sanguíneas , Membrana Eritrocítica/enzimologia , Eritrócitos/patologia , Glucosefosfato Desidrogenase/sangue , Deficiência de Glucosefosfato Desidrogenase/complicações , Hemodinâmica , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-IdadeRESUMO
The term epigenetics refers to modifications in gene activity that occur without directly affecting the DNA sequence, and irregularities in cellular epigenetics have been implicated in the development of a number of malignancies. As such, there is considerable interest in the anticancer effects of agents that can modify cellular epigenetics. Histone deacetylase (HDAC) inhibitors represent a class of anticancer agents that have shown promise in the treatment of both solid and hematologic malignancies. Although there are a number of HDAC inhibitors in advanced stages of clinical development, vorinostat, and more recently, romidepsin, are currently the only HDAC inhibitors approved for use. Vorinostat was approved in the United States in 2006 for the treatment of cutaneous manifestations of T-cell lymphoma in patients with progressive, persistent, or recurrent disease on or following 2 systemic therapies. Romidepsin was approved in the United States in 2009 for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received >/= 1 prior systemic therapy. This review aims to assess the clinical progress that vorinostat and other HDAC inhibitors have made in symptom relief and treatment of patients with CTCL and to provide practical advice for the management of associated toxicities.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Histona Desacetilases , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Depsipeptídeos , Neoplasias Hematológicas/patologia , Humanos , Ácidos Hidroxâmicos , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/patologia , Linfoma Cutâneo de Células T/patologia , Neoplasias/patologia , Estados Unidos , VorinostatRESUMO
Cutaneous T-cell lymphoma/mycosis fungoides (CTCL/MF) is a rare lymphoproliferative disorder which can present as an indolent or as an aggressive process involving skin, lymph nodes, and blood. In stages IA, IB and IIA, it is usually managed with topical medications and phototherapy. If there is progression despite application of these treatments, or if the patient presents with a higher stage of disease, systemic chemotherapy or retinoids, rexinoids, biologic response modifiers are often necessary. Consequently, patients are often treated with a sequence of modalities and drugs. Denileukin diftitox (DD, Ontak(R)) is a targeted immunotoxin which has biological activity against malignancies expressing the IL-2 receptor. In addition to its unique mechanism of action, DD has a toxicity profile which does not overlap with most commonly used chemotherapeutic agents. CTCL/MF has been found be particularly susceptible to treatment with this agent. This review will describe the development DD, its proposed mechanism of action, the clinical trials which identified its utility in the treatment of CTCL/MF, the common toxicities encountered with this agent, and the management of these toxicities. In addition the incorporation of DD in the sequential treatment of CTCL/MF and data suggesting potential combination therapies employing this novel agent will be discussed.