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1.
Ann Oncol ; 23(12): 3129-3137, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22700994

RESUMO

BACKGROUND: Insulin-like growth factor-1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-type 2 (HER2), and c-Met are members of the receptor tyrosine kinases (RTKs). The associations between the RTK status [protein expression and gene copy number (GCN)] and patient characteristics and between the RTK status and prognosis remain undetermined. MATERIALS AND METHODS: The study included 140 patients who underwent surgery for thymic tumors. Protein expression was evaluated by immunohistochemistry (IHC) and GCN was evaluated by bright-field in situ hybridization (BISH). The correlations between the RTK status and clinicopathological findings were examined. RESULTS: IGF-1R protein was frequently detected in thymic carcinoma (83.8%) and EGFR in thymic tumors (91.4%). Thirty-six and 39 tumors were BISH high for IGF-1R and EGFR, respectively: 28 and 25 exhibited high polysomy; 8 and 14 exhibited gene amplification. No tumor was positive for HER2 or c-Met by IHC and BISH. Multivariate analysis revealed that IGF-1R gene amplification (P = 0.027), thymic carcinoma histology, and higher tumor stage were significantly correlated with an adverse prognosis. CONCLUSIONS: Thymic epithelial tumors frequently express IGF-1R and/or EGFR proteins. IGF-1R gene amplification is suggested to define an unfavorable subset for thymic epithelial tumors.


Assuntos
Receptores ErbB/genética , Dosagem de Genes , Neoplasias Epiteliais e Glandulares/genética , Receptor IGF Tipo 1/genética , Timoma/genética , Neoplasias do Timo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/cirurgia , Proteínas Proto-Oncogênicas c-met/genética , Receptor ErbB-2/genética , Timoma/cirurgia , Neoplasias do Timo/cirurgia
2.
Histopathology ; 41(1): 1-29, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12121233

RESUMO

Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein. This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n=18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with 'malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n=26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n=17) designated LCT; and cytologically malignant (n=9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer-Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n=13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%). These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n=4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD). In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin-embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered. We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.


Assuntos
Biomarcadores Tumorais , Células Dendríticas/imunologia , Histiócitos/imunologia , Transtornos Histiocíticos Malignos/classificação , Linfoma/classificação , Adulto , Idoso , Biomarcadores Tumorais/imunologia , Células Dendríticas/classificação , Feminino , Histiócitos/classificação , Histiócitos/ultraestrutura , Transtornos Histiocíticos Malignos/diagnóstico , Transtornos Histiocíticos Malignos/imunologia , Humanos , Imuno-Histoquímica , Imunofenotipagem , Linfoma/diagnóstico , Linfoma/imunologia , Linfoma/ultraestrutura , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade
3.
J Clin Oncol ; 19(22): 4238-44, 2001 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-11709567

RESUMO

PURPOSE: The management of early-stage Hodgkin's disease in the United States is controversial. To evaluate whether staging laparotomy could be safely avoided in early-stage Hodgkin's disease and whether chemotherapy should be a part of the treatment of nonlaparotomy staged patients, a phase III intergroup trial was performed. PATIENTS AND METHODS: Three hundred forty-eight patients with clinical stage IA to IIA supradiaphragmatic Hodgkin's disease were randomized without staging laparotomy to treatment with either subtotal lymphoid irradiation (STLI) or combined-modality therapy (CMT) consisting of three cycles of doxorubicin and vinblastine followed by STLI. RESULTS: The study was closed at the second, planned, interim analysis because of a markedly superior failure-free survival (FFS) rate for patients on the CMT arm (94%) compared with the STLI arm (81%). With a median follow-up of 3.3 years, 10 patients have experienced relapse or died on the chemoradiotherapy arm, compared with 34 on the radiotherapy arm (P <.001). Few deaths have occurred on either arm (three deaths on CMT and seven deaths on STLI). Treatment was well tolerated, with only one death on each arm attributed to treatment. CONCLUSION: These results demonstrate that it is possible to obtain a high FFS rate in a large group of stage IA to IIA patients without performing staging laparotomy and that three cycles of chemotherapy plus STLI provide a superior FFS compared with STLI alone. Extended follow-up is necessary to assess freedom from second relapse, overall survival, late toxicities, patterns of treatment failure, and quality of life.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Tecido Linfoide/efeitos da radiação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Dosagem Radioterapêutica , Taxa de Sobrevida , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos
4.
Blood ; 97(12): 3713-20, 2001 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-11389007

RESUMO

The Revised European-American Lymphoma classification gives Burkitt-like lymphoma (BLL) provisional status, leaving unresolved the differential diagnosis with Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). This study compared the biologic features of adult BLL and DLBCL. The phenotypic distinction between BLL and DLBCL was determined by immunohistochemical staining of frozen tissue from 13 patients with BLL and 55 patients with DLBCL by using an extensive antibody panel including Ki-67, CD10, CD11a/lymphocyte function-associated antigen 1alpha (LFA-1alpha), CD18/LFA-1beta, CD58/LFA-3, and CD54/intercellular adhesion molecule, CD8 for tumor-infiltrating cytotoxic T cells (T-TILs), CD44 homing receptor, and p53 and Bcl-2 oncogenic proteins. Compared with DLBCL, BLL had a higher proliferative rate (mean Ki-67, 88% versus 53%), greater expression of CD10 and p53 antigens, and decreased expression of Bcl-2. BLL cases had a consistent absence of one or more cell adhesion molecules (92% versus 27%), low T-TIL numbers, and absence of CD44 homing receptor (92% versus 14%). The t(8;14) translocation was identified in 80% of BLL cases, but no patients with BLL had the t(14;18) translocation. In a 10-year analysis, median survival of patients with BLL was 1.2 years, and that of patients with DLBCL was 2.5 years. Although the proportion of patients cured was similar in the 2 groups, BLL patients had an increased risk of early death. We conclude that BLL can be recognized by its combined morphologic and phenotypic features and that it represents a high-grade lymphoma much closer to BL than DLBCL. Retention of the BLL category or inclusion of BLL as a variant of BL is biologically and clinically more appropriate than absorbing the category of BLL into DLBCL. (Blood. 2001;97:3713-3720)


Assuntos
Linfoma de Burkitt/classificação , Linfoma de Burkitt/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfoma de Burkitt/patologia , Divisão Celular , Análise Citogenética , Diagnóstico Diferencial , Feminino , Secções Congeladas , Genótipo , Histocitoquímica , Humanos , Imunofenotipagem , Linfoma de Células B/classificação , Linfoma de Células B/diagnóstico , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
5.
J Clin Oncol ; 19(12): 2975-82, 2001 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-11408492

RESUMO

PURPOSE: A phase II study was conducted to determine the efficacy of paclitaxel and valspodar (PSC 833) in patients with advanced epithelial ovarian cancer. Valspodar, a nonimmunosuppressive cyclosporine D analogue that reverses P-glycoprotein-mediated multidrug resistance, in combination with paclitaxel might be active in paclitaxel-resistant and refractory ovarian cancer. PATIENTS AND METHODS: Patients received valspodar 5 mg/kg orally qid x 12 doses. Paclitaxel (70 mg/m(2) intravenously for 3 hours) was administered on day 2, 2 hours after the fifth or sixth dose of valspodar. This treatment was repeated every 21 days. One blood sample was collected before the sixth dose of valspodar for the first three cycles to evaluate valspodar trough concentration. Tumor tissue was obtained from patients for immunohistochemical staining of P-glycoprotein. RESULTS: Of 60 patients entered, 58 were assessable for response. There were five partial responses (8.6%; 90% confidence interval [CI], 3.8 to 20.0; median duration of response, 5.0 months [range, 1.9 to 10.5 months]). Median progression-free survival was 1.5 months (90% CI, 1.4 to 2.4). Grade 3 or 4 toxicities observed were neutropenia, anemia, nausea and vomiting, peripheral neuropathy, and cerebellar ataxia. The trough concentrations of valspodar were > or = 1,000 ng/mL in all but two of 40 patients in the first cycle. Immunohistochemical staining for P-glycoprotein was positive for one of two responding patients. CONCLUSION: Valspodar in combination with paclitaxel has limited activity in patients with paclitaxel-resistant ovarian carcinoma. An international randomized clinical trial of paclitaxel and carboplatin with or without valspodar as first-line therapy in advanced ovarian cancer is underway.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/mortalidade , Carcinoma/patologia , Ciclosporinas/administração & dosagem , Intervalo Livre de Doença , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Taxa de Sobrevida
6.
J Clin Oncol ; 19(10): 2714-21, 2001 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-11352964

RESUMO

BACKGROUND: Several studies have reported what seem to be false-positive results using the Food and Drug Administration (FDA)-approved HercepTest (Dako Corp, Carpinteria, CA) to profile Her-2/neu amplification and overproduction in breast carcinoma. False-positive status has been based on comparisons with gene copy enumeration by fluorescence in situ hybridization (FISH) and with comparisons to immunohistochemistry (IMH) results using a monoclonal antibody. However, simple overexpression by tumor cells that have normal gene copy has not been evaluated by profiling mRNA expression, ie, such cases could simply represent true-positive, transcriptionally upregulated overexpression. MATERIALS AND METHODS: Four hundred infiltrating ductal carcinomas of breast were evaluated by IMH using monoclonal (CB11; Ventana Medical Systems, Inc, Tucson, AZ) and polyclonal (HercepTest; Dako) antibodies after antigen retrieval (AR). A polyclonal antibody sans AR (PCA/SAR) was also used. All IMH stains were evaluated and scored according to the guidelines for the FDA-approved HercepTest. A total of 145 of 400 carcinomas were subsequently evaluated by direct and digoxigenin-labeled (Dig) FISH, and 144 of 400 were evaluated by detection of mRNA overexpression via autoradiographic RNA:RNA in situ hybridization. RESULTS: Overall HercepTest/CB11 IMH discordance was 12%. Expression of mRNA was highly concordant with FISH and DigFISH amplification and with CB11 and PCA/SAR immunohistology. IMH false-positive cases (no Her-2/neu gene amplification) occurred with both HercepTest (23%) and CB11 (17%), and the majority of false-positive results (34 of 44) were scored as 2+. All 2+ false-positive cases were mRNA-negative. Combined results of HercepTest and CB11 showed that 79% (38 of 48) of 3+ cases were Her-2/neu gene amplified, but only 17% (seven of 41) of 2+ cases had increased gene copy. CONCLUSION: Discordant HercepTest/FISH results, and to a lesser extent discordance with CB11 IMH, are most commonly false-positive results with a score of 2+. The 2+ score as defined in the guidelines for the FDA-approved HercepTest should not be used as a criterion for trastuzumab therapy unless confirmed by FISH. Determination of Her-2 gene copy number by FISH may be a more accurate and reliable method for selecting patients eligible for trastuzumab therapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Genes erbB-2/genética , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Reações Falso-Positivas , Feminino , Amplificação de Genes , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Padrões de Referência , Trastuzumab
7.
J Clin Oncol ; 19(3): 750-5, 2001 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-11157027

RESUMO

PURPOSE: Two phase II studies were conducted to evaluate infusional cyclophosphamide, doxorubicin, vincristine, and dexamethasone chemotherapy, termed the CVAD regimen, alone (Southwest Oncology Group [SWOG] 9240) and with the chemosensitizers verapamil and quinine (SWOG 9125) to assess effects on response, survival, and toxicity in intermediate- and high-grade advanced-stage non-Hodgkin's lymphoma (NHL). The results were compared with the historic group of patients randomized to CHOP chemotherapy on Intergroup (INT) 0067 (SWOG 8516). PATIENTS AND METHODS: All patients had biopsy-proven intermediate- or high-grade NHL (lymphoblastic histology excluded), were ambulatory and previously untreated, and had bulky stage II, III, or IV disease. One hundred twelve patients were registered on SWOG 9240 and received cyclophosphamide 750 mg/m(2) by intravenous bolus day 1, doxorubicin 12.5 mg/m(2)/d and vincristine 0.5 mg/d delivered as a continuous 96-hour infusion on days 1 through 4, and dexamethasone 40 mg/d orally on days 1 through 4 (CVAD). Cycles were repeated every 21 days for eight cycles. One hundred patients on SWOG 9125 received the same chemotherapy and the chemosensitizers verapamil 240 mg bid and quinine 40 mg tid. Chemosensitizers were begun 24 hours before chemotherapy and continued for a total of 6 days. RESULTS: Eighty-one patients were eligible for each study. The complete response (CR) rates were 39% on SWOG 9125 and 31% on SWOG 9240. With a median follow-up of 5.8 years on SWOG 9125 and 4.5 years on SWOG 9240, the 2-year failure-free survival (FFS) rate was 42% on SWOG 9125 and 41% on SWOG 9240. Two-year overall survival (OS) rate was 64% on SWOG 9125 and 58% on SWOG 9240. These results are comparable to a 44% CR rate, a 2-year FFS of 46%, and 2-year OS of 63% observed in 225 patients treated with CHOP on INT 0067 (SWOG 8516). CONCLUSION: CVAD combination chemotherapy alone or with the chemosensitizers verapamil and quinine is not promising therapy with respect to improved response or OS in intermediate- and high-grade advanced-stage NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Humanos , Infusões Intravenosas , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Quinina/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Taxa de Sobrevida , Verapamil/administração & dosagem , Vincristina/administração & dosagem
8.
Blood ; 97(5): 1427-34, 2001 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-11222390

RESUMO

Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with biologic effects that include regulation of hematopoietic stem cell development, extracellular matrix remodeling, and inflammatory cytokine generation. To delineate the potential role of VEGF in patients with myelodysplastic syndrome (MDS), VEGF protein and receptor expression and its functional significance in MDS bone marrow (BM) were evaluated. In BM clot sections from normal donors, low-intensity cytoplasmic VEGF expression was detected infrequently in isolated myeloid elements. However, monocytoid precursors in chronic myelomonocytic leukemia (CMML) expressed VEGF in an intense cytoplasmic pattern with membranous co-expression of the Flt-1 or KDR receptors, or both. In situ hybridization confirmed the presence of VEGF mRNA in the neoplastic monocytes. In acute myelogenous leukemia (AML) and other MDS subtypes, intense co-expression of VEGF and one or both receptors was detected in myeloblasts and immature myeloid elements, whereas erythroid precursors and lymphoid cells lacked VEGF and receptor expression. Foci of abnormal localized immature myeloid precursors (ALIP) co-expressed VEGF and Flt-1 receptor, suggesting autocrine cytokine interaction. Antibody neutralization of VEGF inhibited colony-forming unit (CFU)-leukemia formation in 9 of 15 CMML and RAEB-t patient specimens, whereas VEGF stimulated leukemia colony formation in 12 patients. Neutralization of VEGF activity suppressed the generation of tumor necrosis factor-alpha and interleukin-1beta from MDS BM-mononuclear cells and BM-stroma and promoted the formation of CFU-GEMM and burst-forming unit-erythroid in methylcellulose cultures. These findings indicate that autocrine production of VEGF may contribute to leukemia progenitor self-renewal and inflammatory cytokine elaboration in CMML and MDS and thus provide a biologic rationale for ALIP and its adverse prognostic relevance in high-risk MDS.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Fatores de Crescimento Endotelial/metabolismo , Linfocinas/metabolismo , Síndromes Mielodisplásicas/etiologia , Células Progenitoras Mieloides/efeitos dos fármacos , Anticorpos Monoclonais/farmacologia , Comunicação Autócrina , Células da Medula Óssea/química , Células da Medula Óssea/patologia , Técnicas de Cultura de Células , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Citocinas/efeitos dos fármacos , Fatores de Crescimento Endotelial/imunologia , Fatores de Crescimento Endotelial/farmacologia , Humanos , Imuno-Histoquímica , Linfocinas/imunologia , Linfocinas/farmacologia , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Células Progenitoras Mieloides/patologia , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular , Células-Tronco/efeitos dos fármacos , Células Estromais/química , Células Estromais/patologia , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
9.
Clin Cancer Res ; 6(10): 3904-9, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11051236

RESUMO

Tumor-infiltrating CD8+ T-lymphocytes (T-TILs) are thought to be relevant to immunosurveillance of several tumor types including B-cell non-Hodgkin's lymphoma. B- and T-lymphocyte interactions via cellular adhesion molecules (CAMs), recognition molecules (HLAs), and costimulatory molecules (CSMs) are necessary for optimal antigen-specific T-cell activation to occur and may be important in generating effective host T-TIL responses. We previously found that low T-TIL response (CD8+ T cells < 6%) correlates with statistically shorter relapse-free survival in patients with diffuse large-cell lymphoma (DLCL). We now extend our observations in 71 DLCL patients by analyzing malignant B-cell expression of the following molecules important in T-cell activation: (a) recognition molecules [MHC I (MAS and MCA) and MHC II (HLA-DR, -DP, -DQ)]; (b) CAMs [leukocyte function antigen 1 (CD11a and CD18) and intracellular adhesion molecule 1 (CD54)]; and (c) CSMs [B7.1 (CD80) and B7.2 (CD86)]. Eighteen patients (25%) had low a T-TIL response, and 53 patients (75%) had a high T-TIL response. Overall, expression of the MHC class H molecules HLA-DR and HLA-DQ was most conserved. The loss of B7.2 (P = 0.04), intracellular adhesion molecule 1 (P = 0.0004), MAS (P = 0.02), and HLA-DR (P = 0.0004) expression was significantly associated with decreased T-TIL response. In 100% of patients with low T-TIL responses, at least one HLA, CAM, or CSM was undetectable on the malignant B cells by immunohistochemical staining (mean number of molecules lost = 2.67). In contrast, 49% of patients with high T-TIL responses had no losses in HLA, CAM, or CSM expression (mean number of molecules lost = 0.89). The mean number of absent molecules (HLA, CAM, or CSM) was significantly associated with T-TIL response (P = 0.0001). We conclude that loss of HLA, CAM, or CSM expression on malignant B cells is associated with a poor host T-cell immune response. In addition, because patients with low T-TIL response had lost expression of multiple cellular adhesion, recognition, and costimulatory molecules, our results suggest that a combination of immunorestorative therapies may be required to generate effective antitumor T-cell responses in B-cell DLCL.


Assuntos
Antígenos CD/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Linfoma de Células B/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Glicoproteínas de Membrana/metabolismo , Antígeno B7-1/sangue , Antígeno B7-2 , Antígenos CD18/sangue , Adesão Celular , Antígenos HLA-DP/sangue , Antígenos HLA-DQ/sangue , Antígenos HLA-DR/sangue , Humanos , Imuno-Histoquímica , Antígeno-1 Associado à Função Linfocitária/sangue , Linfócitos do Interstício Tumoral/patologia , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/patologia
10.
Hum Pathol ; 31(4): 475-81, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10821495

RESUMO

Human thioredoxin is a putative oncogene that may confer both a growth and survival advantage to tumor cells. Overexpressed thioredoxin mRNA has been found in both primary human lung and colorectal cancers. To determine the intratumor distribution and amount of thioredoxin protein in human primary carcinomas, we developed an immunohistochemical assay for thioredoxin in paraffin-embedded tissue. We then studied 10 patients with primary high-risk gastric carcinoma. To further relate thioredoxin protein overexpression to cell death and survival, we used a paraffin-based in situ end-labeling (ISEL) assay. To delineate proliferation, we used the nuclear proliferation antigen detected by Ki-67. In this survey, we found that thioredoxin was localized to tumor cells and overexpressed compared with normal gastric mucosa in 8 of 10 gastric carcinomas. The thioredoxin was found at high levels in 5 of the 8 overexpressing carcinomas. The overexpression of thioredoxin was typically found in both a nuclear and cytoplasmic location in the neoplastic cells. There was a significant positive correlation (P = .0061) with cancer cell proliferation measured by Ki-67. There was a significant negative correlation (P = .0001) with DNA damage measured by the ISEL assay, suggesting decreased apoptosis and increased carcinoma cell survival. Thus, human primary gastric tumors that are highly expressive of thioredoxin have both a higher proliferative rate and a higher survival rate than tumors that do not express thioredoxin. With these newly developed assays in hand, it is now feasible to question whether this thioredoxin-related combined growth and survival advantage translates into poor clinical outcome.


Assuntos
Adenocarcinoma/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias Gástricas/metabolismo , Tiorredoxinas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Apoptose , Divisão Celular , Sobrevivência Celular , Fragmentação do DNA , DNA de Neoplasias/análise , Humanos , Técnicas Imunoenzimáticas , Marcação In Situ das Extremidades Cortadas , Antígeno Ki-67/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
11.
Leuk Lymphoma ; 34(3-4): 315-24, 1999 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10439368

RESUMO

The major vault protein (MVP), a ribonucleoprotein complex which mediates the transport of xenobiotic toxins, has been implicated in multidrug resistance (MDR) not mediated by p-glycoprotein (P-gp) or multidrug resistance related protein (MRP). We evaluated, via immunohistochemistry, the presence of MVP in plasma cells of myeloma patients. Among 73 patients registered with the Southwest Oncology Group (SWOG), 52 patients (74%) were positive for MVP. The presence of MVP and P-gp were significantly associated (p < 0.01). A univariate analysis of response versus MVP positivity showed borderline statistical significance (p = 0.043) with no association with OS or PFS. In particular, MVP positivity at first biopsy was associated with non-responsiveness to therapy (7/7 patients, 100%). MRP was not present in any of 23 samples tested. An increased proliferative rate (Ki-67 > 5%) was significantly associated with shorter OS (log rank p-value = 0.0002). The collective work indicates that MVP protein is common and abundant in myeloma with potential relevance to therapeutic response.


Assuntos
Resistência a Múltiplos Medicamentos , Mieloma Múltiplo/metabolismo , Partículas de Ribonucleoproteínas em Forma de Abóbada/biossíntese , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/biossíntese , Anticorpos , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Proteínas de Neoplasias/biossíntese , Células Tumorais Cultivadas
12.
Cancer Res ; 59(3): 728-33, 1999 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-9973224

RESUMO

Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis by acting as a potent inducer of vascular permeability as well as serving as a specific endothelial cell mitogen. The importance of angiogenic factors such as VEGF, although clearly established in solid tumors, has not been fully elucidated in human hematopoietic neoplasms. We examined the expression of mRNA and protein for VEGF in 12 human hematopoietic tumor cell lines, representing multiple lineages and diseases, including leukemia, lymphoma, and multiple myeloma. Our results revealed that VEGF message was expressed in these cells and that the corresponding protein was secreted into the extracellular environment. Five of the 12 cell lines were also found to express the Flt-1 receptor for VEGF at a moderate to strong level, suggesting an autocrine pathway. When human vascular endothelial cells were exposed to recombinant human VEGF, there was an increase in the mRNA for several hematopoietic growth factors including macrophage colony-stimulating factor, granulocyte colony-stimulating factor and interleukin 6. Plasma cells in the bone marrow from patients diagnosed with multiple myeloma were found to express VEGF, whereas both the Flt-1 and KDR high affinity VEGF receptors were observed to be markedly elevated in the normal bone marrow myeloid and monocytic cells surrounding the tumor. These data raise the possibility that VEGF may play a role in the growth of hematopoietic neoplasms such as multiple myeloma through either a paracrine or an autocrine mechanism.


Assuntos
Fatores de Crescimento Endotelial/biossíntese , Neoplasias Hematológicas/metabolismo , Linfocinas/biossíntese , Mieloma Múltiplo/metabolismo , Receptores Proteína Tirosina Quinases/biossíntese , Receptores de Fatores de Crescimento/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Fatores de Crescimento Endotelial/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/biossíntese , Neoplasias Hematológicas/ultraestrutura , Humanos , Linfocinas/metabolismo , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Receptores de Fatores de Crescimento do Endotélio Vascular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
13.
Neoplasia ; 1(5): 468-75, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10933063

RESUMO

Human skin is continually subjected to UV-irradiation with the p53 gene playing a pivotal role in repair of UV-induced DNA damage and apoptosis. Consequently, p53 alterations are early events in human UV-induced skin carcinogenesis. We studied 13 squamous cell carcinomas (SCC), 16 actinic keratoses (AK), 13 samples adjacent to an AK (chronically sun-damaged), and 14 normal-appearing skin samples for p53 mutation, p53 immunostaining (IHC), apoptosis (in situ TUNEL and morphology), and proliferation (PCNA). The frequency of p53 mutation increased from 14% in normal skin, to 38.5% in sun-damaged skin, 63% in AK, and 54% in SCC. p53 IHC increased similarly. Apoptosis (TUNEL) increased from 0.06 +/- 0.02%, to 0.1 +/- 0.2, 0.3 +/- 0.3, and 0.4 +/- 0.3 in normal skin, sun-damaged skin, AK, and SCC, respectively. Apoptosis was strongly correlated with proliferation (i.e., TUNEL and PCNA, r = 0.7, P < 0.0001), and proliferation was significantly increased in the progression from normal skin to SCC. Bax was significantly increased in SCC compared to AK. These data imply that apoptosis in samples with a high frequency of p53 mutation may not necessarily be p53-dependent. We suggest that there is a mechanism for apoptosis in response to increased cellular proliferation that is p53-independent.


Assuntos
Apoptose/genética , Células Epidérmicas , Genes p53/genética , Mutação , Neoplasias Induzidas por Radiação/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Raios Ultravioleta , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Divisão Celular/genética , Epiderme/metabolismo , Epiderme/patologia , Feminino , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Ceratose/genética , Ceratose/metabolismo , Ceratose/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/metabolismo , Neoplasias Induzidas por Radiação/patologia , Polimorfismo Conformacional de Fita Simples , Antígeno Nuclear de Célula em Proliferação/biossíntese , Neoplasias Cutâneas/metabolismo , Proteína Supressora de Tumor p53/biossíntese
14.
Cancer J Sci Am ; 4 Suppl 2: S5-12, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9672769

RESUMO

PURPOSE: In 1994, the International Lymphoma Study Group proposed a "Revised European-American Lymphoma (REAL) Classification of Lymphoid Neoplasms." This classification system was developed because (1) new lymphoid disease entities have been recognized that are not part of the National Cancer Institute Working Formulation (WF) and (2) there was a need to develop a common classification system that could be used internationally. The REAL classification itself had never been tested, however, to determine whether it was reproducible or defined distinct clinicopathologic entities. Therefore, in the past two years, two studies were conducted by the South-west Oncology Group (SWOG) Lymphoma Committee and the Non-Hodgkin's Lymphoma (NHL) Classification Project to validate the REAL classification. PATIENTS AND METHODS: The SWOG Lymphoma Committee reviewed the pathology and clinical course of 376 previously untreated patients with stage III or IV disease within WF categories A, B, C, D, or E who received full-dose cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) in SWOG studies 7204, 7426, and 7713. No patients in this database had localized mucosa-associated lymphoid tissue (MALT) lymphoma. The NHL Classification Project performed a retrospective study of 1,403 consecutive patients with previously untreated NHL seen between 1988 and 1990 at nine sites around the world. Five expert hematopathologists reached a consensus diagnosis on every case by using histologic, clinical, and immunophenotypic data, and 20% of all cases were randomly reviewed. RESULTS: The most common diagnosis was diffuse large B-cell lymphoma (31%), which combines the large-cell and immunoblastic WF categories (WF G/H). The next most common diagnosis was follicular lymphoma (22%; WF B, C, and D). Marginal zone B-cell (including MALT), peripheral T-cell, small B-lymphocytic, and mantle cell lymphoma each constituted between 5% and 10% of diagnoses. Primary mediastinal large B-cell, anaplastic large T/null cell, high-grade B-cell, Burkitt-like, and precursor T-lymphoblastic lymphoma made up the remaining 10 most frequent diagnoses. CONCLUSIONS: The analyses conducted by the SWOG Lymphoma Committee and the NHL Classification Project have demonstrated that the REAL classification does define "real" clinical entities that can be diagnosed by expert hematopathologists. The understanding gained from study of "real" entities should permit hematologists/oncologists to better predict the clinical course of their patients and also to develop improved therapy.


Assuntos
Linfoma/classificação , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma de Células B/classificação , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/microbiologia , Linfoma Difuso de Grandes Células B/classificação , Linfoma não Hodgkin/classificação , Linfoma não Hodgkin/patologia , Linfoma de Células T/classificação , Reprodutibilidade dos Testes
15.
N Engl J Med ; 339(1): 21-6, 1998 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-9647875

RESUMO

BACKGROUND: Patients with clinically localized, intermediate- or high-grade non-Hodgkin's lymphoma usually receive initial treatment with a doxorubicin-containing regimen such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Pilot studies suggest that eight cycles of CHOP alone or three cycles of CHOP followed by involved-field radiotherapy are effective in such patients. METHODS: We compared these two approaches in a prospective, randomized, multi-institutional study. The end points were progression-free survival, overall survival, and life-threatening or fatal toxic effects. Two hundred eligible patients were randomly assigned to receive CHOP plus radiotherapy, and 201 received CHOP alone. RESULTS: Patients treated with three cycles of CHOP plus radiotherapy had significantly better progression-free survival (P=0.03) and overall survival (P=0.02) than patients treated with CHOP alone. The five-year estimates of progression-free survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 77 percent and 64 percent, respectively. The five-year estimates of overall survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 82 percent and 72 percent, respectively. The adverse effects included one death in each treatment group. Life-threatening toxic effects of any type were seen in 61 of 200 patients treated with CHOP plus radiotherapy and in 80 of 201 patients treated with CHOP alone (P=0.06). The left ventricular function was decreased in seven patients who received CHOP alone, whereas no cardiac events were recorded in the group receiving CHOP plus radiotherapy (P=0.02). CONCLUSIONS: Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkin's lymphoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Humanos , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Modelos de Riscos Proporcionais , Estudos Prospectivos , Radioterapia/efeitos adversos , Radioterapia/mortalidade , Dosagem Radioterapêutica , Análise de Sobrevida , Vincristina/administração & dosagem , Vincristina/efeitos adversos
16.
J Natl Cancer Inst ; 89(22): 1706-15, 1997 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-9390540

RESUMO

BACKGROUND: Fewer than 20% of patients with bone cancer who are treated with surgery alone are cured. Even with the best current treatment, surgery combined with chemotherapy, only 60%-80% of patients with nonmetastatic bone cancer and 10% of patients with metastatic bone cancer are cured. Thus far, the reason for treatment failure in the nonresponding subset has not been identified. It has been hypothesized that P-glycoprotein, which confers multidrug resistance, might be the cause. We sought to determine whether the expression of P-glycoprotein is associated with poor treatment outcome in osteosarcoma. METHODS: In a retrospective study, we correlated P-glycoprotein expression with the outcome of conventional chemotherapy in 62 consecutive, clinically staged patients diagnosed as having osteosarcoma between 1980 and 1989. RESULTS: P-glycoprotein was overexpressed in 27 patients but not in another 34 patients, and expression was ambiguous in the sample from one patient. At a median follow-up of 8.9 years, the 34 patients whose tumors did not express P-glycoprotein had significantly better relapse-free rates than the 27 subjects whose tumors expressed the protein (87% versus 0%; P<.00001) and had improved survival rates (94% versus 35%; P<.00001). Among the 46 patients who received chemotherapy before surgery, the 23 whose tumors were negative for P-glycoprotein showed significantly better long-term outcomes (P<.00002), although differences in tumor necrosis in response to therapy were only of borderline significance (P = .057). CONCLUSIONS: P-glycoprotein expression does correlate with treatment failure in patients with osteosarcoma. This correlation raises the possibility that inhibiting the action of P-glycoprotein as part of therapy for this disease would improve outcome.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Regulação Neoplásica da Expressão Gênica , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Neoplasias Ósseas/cirurgia , Criança , Pré-Escolar , Humanos , Técnicas Imunoenzimáticas , Razão de Chances , Osteossarcoma/cirurgia , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
17.
Hematol Oncol Clin North Am ; 11(5): 819-46, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9336717

RESUMO

In recent years several new morphologic entities and a new classification system, Revised European-American Lymphoma Classification (REAL), have been proposed which affect the nomenclature and classification of lymphoid malignancies. This article reviews some of the features of the more common new entities, places these entities in immunologic context, explores the clinical utility of these entities, and provides a working clinical organization to the names.


Assuntos
Linfoma não Hodgkin/classificação , Terminologia como Assunto , Estudos de Avaliação como Assunto , Humanos , Tábuas de Vida , Linfoma não Hodgkin/mortalidade , Oncologia , Prognóstico , Taxa de Sobrevida
18.
Hematol Oncol Clin North Am ; 11(5): 893-900, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9336720

RESUMO

There has been a long history of debate as to whether histologic subtypes of follicular lymphoma are associated with unique outcomes. The controversy has been fueled by studies of small patient groups having heterogeneous prognostic factors followed for short intervals, and by a new proposal for the classification of lymphomas (REAL). The current report provides insight into the controversy by using a large group of patients of similar stage and treatment followed for up to 25 years.


Assuntos
Linfoma Folicular/patologia , Adulto , Idoso , Feminino , Humanos , Tábuas de Vida , Linfoma Folicular/classificação , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
19.
J Lab Clin Med ; 130(3): 297-306, 1997 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9341990

RESUMO

Multidrug resistance protein (MRP), like P170, confers multidrug resistance, but its clinical relevance is uncertain, whereas P170 is an accepted cause of chemotherapy failure for which ongoing reversal trials are being conducted. Because such trials have been only modestly successful, we must investigate alternative drug resistance mechanisms such as MRP, which is poorly blocked by P170 inhibitors. The significance of MRP has remained undefined because MRP mRNA is difficult to assay in archival material, does not necessarily reflect MRP levels, and is widely expressed in normal or hematopoietic cells within tumors and bone marrow. Because conventional immunoblot or immunocytochemistry may not be sensitive enough to detect low or heterogeneous MRP expression in clinical samples, we elected to score MRP in single tumor cells by modifying our P170 assays that have proven valuable for correlating P170 expression with the outcome of pediatric cancer chemotherapy. We enhanced the signal-to-noise ratio with several peroxidase-tagged secondary antibody layers and staining refinements, standardizing the assay with MRP-negative and MRP-positive but P170-negative transfected or drug-selected controls in which MRP was quantified by immunoblot. We confirmed sensitivity by staining a very low MRP-expressing revertant line and "mixed" samples containing small numbers of positive cells; we confirmed specificity by applying two antibodies directed against separate MRP epitopes. We examined neuroblastoma, osteosarcoma, rhabdomyosarcoma, and retinoblastoma samples, identifying MRP-positive malignant cells, which were distinguishable from MRP-positive normal cells. This assay may be valuable for early diagnosis of low but potentially important MRP expression, which would allow timely application of alternative therapy, perhaps with MRP-specific blockers.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/análise , Técnicas Imunoenzimáticas/normas , Proteínas de Neoplasias/análise , Células Tumorais Cultivadas/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/imunologia , Anticorpos Antineoplásicos/imunologia , Membrana Celular/química , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Células HeLa/química , Humanos , Immunoblotting , Sensibilidade e Especificidade , Transfecção/genética
20.
Leukemia ; 11(7): 1107-9, 1997 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9204998

RESUMO

The problem of tumor cell drug resistance remains a barrier to the successful treatment of many neoplastic diseases. Problems of tumor cell heterogeneity and expression of multiple mechanisms of drug resistance complicate treatment strategies. Indeed, even that form of resistance to natural product anticancer agents, multidrug resistance (MDR), can have multiple mechanisms. Compounding these problems is the use of different methodologies and different reagents to assess expression of the most widely studied form of MDR, that due to increased expression of the MDR1 gene and its product, P-glycoprotein (Pgp). In this paper, we discuss problems associated with assay variability and accurate measurement of markers of drug resistance, and summarize consensus findings of the St Jude Workshop on methods to detect Pgp in tumors.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/análise , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Calibragem , Resistência a Múltiplos Medicamentos , Humanos
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