RESUMO
Our studies in chronic lymphocytic leukemia (CLL) are directed at understanding which signals maintain viability in vivo and become lost upon removal of leukemic cells from the body, such that they immediately begin to undergo apoptosis ex vivo. In this report, we examine changes in gene expression observed between freshly isolated CLL B cells and after maintenance in vitro with and without Fludara. We compare these effects with an Epstein-Barr virus (EBV)-transformed cell line treated similarly. Kinetic effects of drug treatment on apoptosis and cell division were examined with DNA laddering, radioisotopic labeling, and flow cytometry using the fluorescent dye carboxyfluorescein diacetate succinimidyl ester. Reverse transcriptase polymerase chain reaction and hybridization blots of microarray cDNA analyses were performed to examine gene expression. We demonstrate that many genes, especially cyclin D1, were downregulated after culture of CLL cells. Anti-apoptotic genes BAG-1 and Akt2 were upregulated. The greatest positive effect with Fludara was the upregulation of JNK1. The EBV-transformed cell line was resistant to classic DNA laddering induced with Fludara. Although DNA synthesis was blocked, the EBV-transformed cell line had some ability to recover from treatment following drug washout. CLL cells express cell cycle regulatory genes that are specific for activated cells in the G(1)-S phase of the cell cycle. Growth regulatory signals are lost when the leukemic cells are isolated from the body. Fludara enhances kinetics of apoptosis and induces expression of a gene responsive to stress that regulates expression of a kinase involved in initiation of the apoptotic pathway.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Apoptose/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Fosfato de Vidarabina/análogos & derivados , Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Transformação Celular Viral , Herpesvirus Humano 4 , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Células Tumorais Cultivadas , Fosfato de Vidarabina/farmacologiaRESUMO
OBJECTIVE: To describe the two variants of Castleman's disease--the hyaline-vascular type and the plasma-cell type--and discuss the associated histologic features. DESIGN: We present a case of the hyaline-vascular type and review the literature. RESULTS: Castleman's disease was once thought to be localized and self-limited, but in recent years, reports have described a multicentric variety with severe systemic manifestations and, at times, an inexorable clinical course. Unlike the localized type for which surgical excision is curative regardless of the histologic type, multicentric disease often necessitates aggressive systemic therapy and portends a poor outcome. Little is known about the cause of this disorder, but the bulk of evidence points toward faulty immunoregulation that results in excessive proliferation of B lymphocytes and plasma cells in lymphoid organs. CONCLUSION: Castleman's disease is rare and poorly understood. The diagnosis is "contextual" and must be considered in the appropriate clinical setting and only after all other causes of lymphadenopathy have been investigated and excluded. The optimal therapeutic regimen is unknown.
Assuntos
Hiperplasia do Linfonodo Gigante , Idoso , Hiperplasia do Linfonodo Gigante/complicações , Hiperplasia do Linfonodo Gigante/patologia , Humanos , MasculinoRESUMO
Dissemination of lung cancer beyond the intrathoracic lymph nodes (stage IV disease) implies surgical unresectability. However, solitary brain metastases (SBMs) from non-small cell lung cancer (NSCLC) have often been treated by combined resection of the primary tumor and its metastasis. Such an aggressive approach appears to substantively improve patient outcome and provide better quality of life in selected cases. A search of the literature reveals extended survival (10 years or longer) in 16 patients following combined surgical excision. We report three patients with NSCLC and isolated central nervous system involvement who achieved exceptionally long survival. The existing literature on SBMs from NSCLC is reviewed.
Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/cirurgia , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Adulto , Neoplasias Encefálicas/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Segunda Neoplasia Primária/patologia , Qualidade de Vida , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Interferon-alfa in combination with cytotoxic chemotherapy has been shown to be effective in treating certain types of non-Hodgkin's lymphoma (NHL) (1). However, there is no published data on upfront induction treatment of aggressive NHL with IFN-alfa containing regimens. Studies have also shown that one can overcome regrowth resistance by administering mid-cycle agents which slow tumor proliferation between courses of cytotoxic therapy (2). Based on this, we treated 32 consecutive patients between 1/93 and 9/96 with a regimen containing cyclophosphamide 750 mg/m2, mitoxantrone 12 mg/m2, and teniposide 60 mg/m2 IV on day 1 with prednisone 100 mg PO given on days 1-5. On day 15, patients received vincristine 1.4 mg/m2 (2 mg max.) and bleomycin 10 units/m2 IV. Interferon-alfa-2b 5x10(6) units/m2 SQ was administered on days 22-26. The median age was 55 (range 26-83), M:F ratio was 2.5:1, and the median International Prognostic Index was 2. 38% of patients had stages I-II and 62% had stages III-IV disease. Fifty-nine percent of the patients achieved a complete response, 22% a partial response, and 19% had progressive disease. The overall survival (OS) was 81% and the progression free survival (PFS) was 56% at 4.3 years. There were no severe (grade IV) hematologic, flu-like, GI and infectious toxicities from IFN-alpha. Leukopenia was the main severe toxicity related to the chemotherapy regimen (days 1-15), but not IFN-alpha. Severe infection secondary to the chemotherapy regimen occurred in one patient. Interferon-alfa-2b and mid-cycle chemotherapy added to an anthracycline based regimen is effective induction treatment for patients with aggressive NHL. The OS and PFS using this regimen, based on regrowth resistance, appears to be at least as or more effective than CHOP therapy for this group of patients. Severe toxicities were rare.
Assuntos
Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Interferon-alfa/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Esquema de Medicação , Feminino , Humanos , Interferon-alfa/toxicidade , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Índice de Gravidade de Doença , Análise de Sobrevida , Equivalência Terapêutica , Resultado do TratamentoRESUMO
The clinical manifestations of Wegener's granulomatosis (WG) may be varied and easily overlooked. Awareness of distinguishing signs and symptoms allows early recognition and appropriate management. The body of literature dealing with the various facets of this disorder has grown in the past few years. Development of new diagnostic markers and successful therapies has rekindled interest in this disease. To assure early diagnosis and optimal prognosis the physician must maintain a high index of suspicion for WG. Although introduction of immunosuppressive therapy has dramatically improved the course of this disorder, treatment-related morbidity is often profound.
Assuntos
Granulomatose com Poliangiite , Adulto , Anticorpos Anticitoplasma de Neutrófilos , Autoanticorpos/análise , Biomarcadores/análise , Ciclofosfamida/uso terapêutico , Diagnóstico Diferencial , Quimioterapia Combinada , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , Masculino , Prednisona/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/uso terapêuticoRESUMO
Nitric oxide is an uncharged free radical that mediates a range of physiologic processes in the vasculature. As a principal determinant of vascular tone, the overproduction of nitric oxide has been implicated in the pathogenesis of sepsis- and cytokine-induced hypotension. The enzyme that produces nitric oxide, nitric oxide synthase, exists in three isoforms. One of the three isoforms, inducible nitric oxide synthase, is expressed in many cell types only after stimulation by cytokines and/or endotoxin. Compared to the constitutive nitric oxide synthase enzymes, the inducible enzyme generates larger quantities of nitric oxide for longer periods. Expression of the inducible isoform in vitro requires stimulation by a mixture of cytokines including interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta. These proinflammatory cytokines are known mediators of sepsis and are also produced in the serum of cancer patients during interleukin-2 therapy, thereby leading to excessive production of nitric oxide. Interleukin-2 therapy is associated with a spectrum of cardiovascular toxicities and hemodynamic alterations that are indistinguishable from those seen in septic shock. Many of these hemodynamic effects have been linked to the overproduction of nitric oxide via a cytokine-inducible nitric oxide pathway. In this regard, inhibition of nitric oxide synthesis represents a novel approach to limit the cardiovascular toxicity associated with interleukin-2 therapy and to improve its therapeutic index. Clinical trials to evaluate the efficacy of nitric oxide synthase inhibitors in reversing the hypotension associated with IL-2 therapy are now underway.
Assuntos
Hipotensão/induzido quimicamente , Óxido Nítrico/fisiologia , Animais , Indução Enzimática , Humanos , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase Tipo IIRESUMO
Fas ligand triggers cell death after interaction with its receptor Fas. Altered expression of Fas has been associated with lymphoproliferation and autoimmune disorders in both mice and man. Apoptosis of lung and liver tissue is seen in Fas ligand transgenic mice. It is not known whether constitutive expression of Fas ligand can cause a similar human disease. Four patients with aggressive large granular lymphocyte (LGL) leukaemia involving lung and liver were studied. All four patients were severely ill with pulmonary involvement. Two patients presented with hypoxia and were oxygen dependent; the other two patients had severe pulmonary hypertension. Lung biopsies showed interstitial infiltration by leukaemic LGL. The infiltrating lymphocytes expressed both Fas and Fas ligand, whereas normal pneumocytes expressed only Fas. Similar findings were observed in liver biopsies from these patients. Features mimicking the pathological changes of graft-versus-host disease were observed, including pneumocyte apoptosis. All four patients had high levels of circulating Fas ligand. Successful treatment with oral methotrexate or 2-chlorodeoxyadenosine was associated with disappearance or marked reduction of circulating Fas ligand. These results suggest that dysregulated expression of Fas ligand can lead to human disease with pathological features resembling graft-versus-host disease.
Assuntos
Leucemia Linfoide/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Glicoproteínas de Membrana/genética , Receptor fas/genética , Adulto , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose , Proteína Ligante Fas , Feminino , Expressão Gênica , Humanos , Imunofenotipagem , Leucemia Linfoide/tratamento farmacológico , Leucemia Linfoide/patologia , Infiltração Leucêmica , Fígado/patologia , Pulmão/patologia , Masculino , Metotrexato/uso terapêutico , Camundongos , Camundongos Transgênicos , Pessoa de Meia-IdadeRESUMO
The human glucocorticoid receptor (GR) is expressed as two alternatively spliced isoforms, GRalpha and GRbeta. Whereas GRalpha is a hormone-activated transcription factor, GRbeta does not bind glucocorticoids (GCs), is transcriptionally inactive, and is a potential inhibitor of activated GRalpha. Differential expression of GR isoforms may play a role in generalized or tissue-specific GC resistance. GCs induce apoptosis in neoplastic lymphoid cells; and, defective apoptosis is implicated in the genesis of chronic lymphocytic leukemia (CLL). We studied a patient with generalized GC resistance and CLL. GR number in the patient's transformed lymphocytes was approximately one half that of control cells with a approximately 10-fold reduction in binding affinity for dexamethasone. In vitro apoptosis induction in CLL cells was delayed in response to GCs, but not to other apoptosis inducers. Sequencing of the GR cDNA and gene including the 2.3-kb coding region, the intron/exon junctions, the known 5'-regulatory region, and approximately 300 bp of the 3'-region revealed no alterations. Western blot with an N-terminal antibody showed normal levels of immunoreactive GR, but quantitative analysis with isoform-specific C-terminal antibodies revealed a markedly reduced GRalpha expression, and high GRbeta expression. These findings indicate that imbalanced expression of the GR isoforms may be a mechanism of GC resistance, and may have implications for tumorigenesis by enhancing cell survival.