RESUMO
For children with stage II testicular malignant germ cell tumors (MGCT), the survival is good with surgery and adjuvant chemotherapy. However, there is limited data on surgical results for cases in which there was no imaging or pathologic evidence of residual tumor, but in which serum tumor markers either increased or failed to normalize after an appropriate period of half-life time post-surgery. To determine the use of chemotherapy for children with stage II germ cell tumors, we analyzed the outcomes (relapse rate and overall survival) of patients who were treated at the Sun Yat-sen University Cancer Center between January 1990 and May 2013. Twenty-four pediatric patients with a median age of 20 months (range, 4 months to 17 years) were enrolled in this study. In 20 cases (83.3%), the tumors had yolk sac histology. For definitive treatment, 21 patients underwent surgery alone, and 3 patients received surgery and adjuvant chemotherapy. No relapse was observed in the 3 patients who received adjuvant chemotherapy, whereas relapse occurred in 16 of the 21 patients (76.2%) treated with surgery alone. There were a total of 2 deaths. Treatment was stopped for 1 patient, who died 3 months later due to the tumor. The other patient achieved complete response after salvage treatment, but developed lung and pelvic metastases 7 months later and died of the tumor after stopping treatment. For children treated with surgery alone and surgery combined with adjuvant chemotherapy, the 3-year event-free survival rates were 23.8% and 100%, respectively (P = 0.042), and the 3-year overall survival rates were 90.5% and 100%, respectively (P = 0.588). These results suggest that adjuvant chemotherapy can help to reduce the recurrence rate and increase the survival rate for patients with stage II germ cell tumors.
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Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Masculino , Quimioterapia Adjuvante , Terapia Combinada , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas , Mortalidade , Patologia , Terapêutica , Taxa de Sobrevida , Neoplasias Testiculares , Mortalidade , Patologia , TerapêuticaRESUMO
<p><b>INTRODUCTION</b>Brain metastasis is common in relapsed neuroblastoma patients, but the characteristics of brain metastasis remain largely unknown. This study aimed to investigate the status of brain metastasis with neuroblastoma in South China.</p><p><b>METHODS</b>In this retrospective case-based study, 106 patients with stage 4 neuroblastoma from the Department of Pediatric Oncology in Sun Yat-sen University Cancer Center between January 2004 and May 2013 were included. The incidence, risk factors, and survival status of these patients were reviewed and analyzed.</p><p><b>RESULTS</b>Of the 106 patients, 11 (10.4%) developed brain metastasis, accounting for 20.0% of 55 patients with relapse or progression. The age at initial diagnosis of the 11 patients ranged from 2 to 10 years (median 4 years), which was younger than that of the patients without brain metastasis (median 5 years, range 1-10 years, P=0.073). The male to female ratio of the 11 patients was 8:3, which was not significantly different from that of the patients without brain metastasis (P=0.86). Patients with brain metastasis had higher lactate dehydrogenase levels than those without brain metastasis, but the differences were not significant (P=0.076). Eight patients died, and 3 patients survived. The median interval from the initial diagnosis to the development of brain metastasis was 18 months (range 6-32 months). The median survival was 4 months (range 1 day to 29 months) after the diagnosis of brain metastasis. The median interval from the manifestation of brain metastasis to death was 3 months (range 1 day to 11 months).</p><p><b>CONCLUSIONS</b>High-risk factors for brain metastasis in cases of neuroblastoma include bone marrow involvement and a younger age at initial diagnosis. Nevertheless, multiple treatment modalities can improve disease-free survival.</p>
Assuntos
Criança , Feminino , Humanos , Masculino , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica , Encéfalo , Neoplasias Encefálicas , China , Progressão da Doença , Intervalo Livre de Doença , Incidência , L-Lactato Desidrogenase , Mortalidade , Metástase Neoplásica , Recidiva Local de Neoplasia , Neuroblastoma , Estudos Retrospectivos , Fatores de RiscoRESUMO
Primary central nervous system germ cell tumors (CNS-GCTs) in children and adolescents have unique clinical features and methods of treatment compared with those in adults. There is little information about Chinese children and adolescents with CNS-GCTs. Therefore, in this study we retrospectively analyzed the clinical features and treatment outcome of Chinese children and adolescents with primary CNS-GCTs. Between January 2002 and December 2012, 57 untreated patients from a single institution were enrolled. They were diagnosed with CNS-GCTs after pathologic or clinical assessment. Of the 57 patients, 41 were males and 16 were females, with a median age of 12.8 years (range, 2.7 to 18.0 years) at diagnosis; 43 (75.4%) had non-germinomatous germ cell tumors (NGGCTs) and 14 (24.6%) had germinomas; 44 (77.2%) had localized disease and 13 (22.8%) had extensive lesions. Fifty-three patients completed the prescribed treatment, of which 18 underwent monotherapy of surgery, radiotherapy, or chemotherapy, and 35 underwent multimodality therapies that included radiotherapy combined with chemotherapy or surgery combined with chemotherapy and/or radiotherapy. PEB (cisplatin, etoposide, and bleomycin) protocol was the major chemotherapy regimen. The median follow-up time was 32.3 months (range, 1.2 to 139 months). Fourteen patients died of relapse or disease progression. The 3-year event-free survival (EFS) and overall survival rates for all patients were 72.2% and 73.8%, respectively. The 3-year EFS was 92.9% for germinomas and 64.8% for NGGCTs (P = 0.064). The 3-year EFS rates for patients with NGGCTs who underwent monotherapy and multimodality therapies were 50.6% and 73.5%, respectively (P = 0.042). Our results indicate that multimodality therapies including chemotherapy plus radiotherapy were better treatment option for children and adolescents with CNS-GCTs.
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Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Antineoplásicos , Usos Terapêuticos , Protocolos de Quimioterapia Combinada Antineoplásica , Usos Terapêuticos , Bleomicina , Neoplasias do Sistema Nervoso Central , Terapêutica , Cisplatino , Terapia Combinada , Intervalo Livre de Doença , Etoposídeo , Recidiva Local de Neoplasia , Neoplasias Embrionárias de Células Germinativas , Terapêutica , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
<p><b>OBJECTIVE</b>To evaluate the efficacy of a modified NHL-BFM-90 protocol in childhood and adolescence with Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).</p><p><b>METHODS</b>A total of 138 de novo patients with BL and DLBCL were enrolled. All patients were stratified into low (R1), intermediate (R2) and high risk (R3) groups based on the stage, chemotherapy response and LDH level, and treated with a modified NHL-BFM 90 protocol.</p><p><b>RESULTS</b>Of the 138 patients, 105 were boys and 33 girls, with a median age at diagnosis of 7.5 yr (range 1.5 to 20.0 yr). Eighty-two cases were BL, 56 cases DLBCL. The patients with stage III/IV accounted for 76.1%. Thirty-one patients were assigned to group R1, 38 patients group R2, and 69 patients group R3. Complete remission (CR) after chemotherapy was 90.6%. At a median follow-up of 50 months(1-158 months), a total of 19 patients died of disease. The 5-year event free survival (EFS) and overall survival (OS) for the entire group were 85.8%, 85.8% respectively. 5-year EFS was 97.1% for stage I/II, 82.1% for stage III/IV respectively (P=0.039); and 96.7%, 86.8% and 80.2% for groups R1, R2 and R3 respectively (P=0.135); and 85.2% and 86.9% for BL and DLBCL respectively (P=0.635). Major toxicity was myelosuppression, which was tolerant and manageable.</p><p><b>CONCLUSION</b>That the modified NHL-BFM-90 protocol was highly effective for children and adolescents with BL and DLBCL, and especially improved the survival of the advanced patients.</p>
Assuntos
Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Adulto Jovem , Protocolos de Quimioterapia Combinada Antineoplásica , Usos Terapêuticos , Linfoma de Burkitt , Tratamento Farmacológico , Intervalo Livre de Doença , Linfoma Difuso de Grandes Células B , Tratamento Farmacológico , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Lymphoma is seen in up to 30% of patients with X-linked lymphoproliferative disease (XLP), but cerebral vasculitis related with XLP after cure of Burkitt lymphoma is rarely reported. We describe a case of a 5-year-old boy with XLP who developed cerebral vasculitis two years after cure of Burkitt lymphoma. He had Burkitt lymphoma at the age of 3 years and received chemotherapy (non-Hodgkin's lymphoma-Berlin-Frankfurt-Milan-90 protocol plus rituximab), which induced complete remission over the following two years. At the age of 5 years, the patient first developed headache, vomiting, and then intellectual and motorial retrogression. His condition was not improved after anti-infection, dehydration, or dexamethasone therapy. No tumor cells were found in his cerebrospinal fluid. Magnetic resonance imaging showed multiple non-homogeneous, hypodense masses along the bilateral cortex. Pathology after biopsy revealed hyperplasia of neurogliocytes and vessels, accompanied by lymphocyte infiltration but no tumor cell infiltration. Despite aggressive treatment, his cognition and motor functions deteriorated in response to progressive cerebral changes. The patient is presently in a vegetative state. We present this case to inform clinicians of association between lymphoma and immunodeficiency and explore an optimal treatment for lymphoma patients with compromised immune system.
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Pré-Escolar , Humanos , Masculino , Anticorpos Monoclonais Murinos , Usos Terapêuticos , Protocolos de Quimioterapia Combinada Antineoplásica , Usos Terapêuticos , Linfoma de Burkitt , Tratamento Farmacológico , Transtornos Linfoproliferativos , Imageamento por Ressonância Magnética , Rituximab , Resultado do Tratamento , Vasculite do Sistema Nervoso CentralRESUMO
In vitro amplified human leukocyte antigen (HLA)-haploidentical donor immune cell infusion (HDICI) is not commonly used in children. Therefore, our study sought to evaluate its safety for treating childhood malignancies. Between September 2011 and September 2012, 12 patients with childhood malignancies underwent HDICI in Sun Yat-sen University Cancer Center. The median patient age was 5.1 years (range, 1.7-8.4 years). Of the 12 patients, 9 had high-risk neuroblastoma (NB) [7 showed complete response (CR), 1 showed partial response (PR), and 1 had progressive disease (PD) after multi-modal therapies], and 3 had Epstein-Barr virus (EBV)-positive lymphoproliferative disease (EBV-LPD). The 12 patients underwent a total of 92 HDICIs at a mean dose of 1.6×10(8) immune cells/kg body weight: 71 infusions with natural killer (NK) cells, 8 with cytokine-induced killer (CIK) cells, and 13 with cascade primed immune cells (CAPRIs); 83 infusions with immune cells from the mothers, whereas 9 with cells from the fathers. Twenty cases (21.7%) of fever, including 6 cases (6.5%) accompanied with chills and 1 (1.1%) with febrile convulsion, occurred during infusions and were alleviated after symptomatic treatments. Five cases (5.4%) of mild emotion changes were reported. No other adverse events occurred during and after the completion of HDIDIs. Neither acute nor chronic graft versus host disease (GVHD) was observed following HDICIs. After a median of 5.0 months (range, 1.0-11.5 months) of follow-up, the 2 NB patients with PR and PD developed PD during HDICIs. Of the other 7 NB patients in CR, 2 relapsed in the sixth month of HDICIs, and 5 maintained CR with disease-free survival (DFS) ranging from 4.5 to 11.5 months (median, 7.2 months). One EBV-LPD patient achieved PR, whereas 2 had stable disease (SD). Our results show that HDICI is a safe immunotherapy for childhood malignancies, thus warranting further studies.
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Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Células Matadoras Induzidas por Citocinas , Alergia e Imunologia , Infecções por Vírus Epstein-Barr , Terapêutica , Seguimentos , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Células Matadoras Naturais , Alergia e Imunologia , Transtornos Linfoproliferativos , Terapêutica , Virologia , Neuroblastoma , Terapêutica , Transplante Homólogo , Resultado do TratamentoRESUMO
Pediatric diffuse large B-cell lymphoma (DLBCL) is a highly aggressive disease with unique clinical characteristics. This study analyzed the germinal-center type B-cell (GCB) classification and clinical characteristics of Chinese pediatric DLBCL. A total of 76 patients with DLBCL newly diagnosed in Sun Yat-sen University Cancer Center between February 2000 and May 2011, with an age younger than 18 years, were included in the analysis. The male/female ratio was 3.47:1. The median age was 12 years (range, 2 to 18 years), and 47 (61.8%) patients were at least 10 years old. Of the 76 patients, 48 (63.2%) had stage III/IV disease, 9 (11.8%) had bone marrow involvement, 1 (1.3%) had central nervous system (CNS) involvement, and 5 (6.6%) had bone involvement. The GCB classification was assessed in 45 patients: 26 (57.8%) were classified as GCB subtype, and 19 (42.2%) were classified as non-GCB subtype. The modified B-NHL-BFM-90/95 regimen was administered to 50 patients, and the 4-year event-free survival (EFS) rate was 85.8%. Among these 50 patients, 31 were assessed for the GCB classification: 17 (54.8%) were classified as GCB subtype, with a 4-year EFS rate of 88.2%; 14 (45.2%) were classified as non-GCB subtype, with a 4-year EFS rate of 92.9%. Our data indicate that bone marrow involvement and stage III/IV disease are common in Chinese pediatric DLBCL patients, whereas the percentage of patients with the GCB subtype is similar to that of patients with the non-GCB subtype. The modified B-NHL-BFM-90/95 protocol is an active and effective treatment protocol for Chinese pediatric patients with DLBCL.
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Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica , Usos Terapêuticos , Asparaginase , Usos Terapêuticos , Daunorrubicina , Usos Terapêuticos , Intervalo Livre de Doença , Seguimentos , Centro Germinativo , Patologia , Linfoma Difuso de Grandes Células B , Tratamento Farmacológico , Patologia , Prednisona , Usos Terapêuticos , Taxa de Sobrevida , Vincristina , Usos TerapêuticosRESUMO
<p><b>BACKGROUND AND OBJECTIVE</b>Precursor T lymphoblastic lymphoma (T-LBL) is a highly aggressive lymphoma. Myeloid antigen expression was found in some of the patients, and its clinical significance is worth studying. This study was to compare the clinical features, short-term efficacy and survival of T-LBL patients with or without myeloid antigen expression so as to evaluate its prognostic significance.</p><p><b>METHODS</b>Forty-five T-LBL patients, with a median age of 14 years, were treated at Sun Yet-sen University Cancer Center between January 2000 and July 2008. These patients were divided into myeloid antigen-positive group (My(+) group) and myeloid antigen-negative group (My(-) group) based on the flow cytometric (FCM) analysis in bone marrow or pleural fluid. Myeloid antigen expression and its correlation with the short-term efficacy and overall survival were assessed in the two groups.</p><p><b>RESULTS</b>There were 18 patients (40.0%) in the My(+) group and 27 (60.0%) in the My(-) group. The myeloid antigen expression was negatively correlated with the initial level of lactate dehydrogenase (LDH), but not with other clinical features. The remission rate was lower in the My(+) group than in the My(-) group (38.8% vs. 70.3%, P = 0.028). The 2-year overall survival rate was lower in the My(+) group than in the My(-) group (51.9% vs. 78.7%, P = 0.036). By age subgroup analysis, there were no differences in response and survival rate among children and adolescents with or without myeloid antigen expression. But the remission rate and the 2-year overall survival rate were significantly lower in adult patients with myeloid antigen expression than in patients without it. Univariate and multivariate analysis demonstrated that age and myeloid antigen expression were adverse prognostic factors.</p><p><b>CONCLUSION</b>Myeloid antigen expression is a predictor of a poor response to chemotherapy, and adverse prognostic factor in adult T-LBL, but not in children with T-LBL.</p>
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Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Fatores Etários , Antígenos CD7 , Metabolismo , Antígenos de Diferenciação Mielomonocítica , Metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Usos Terapêuticos , Asparaginase , Usos Terapêuticos , Ciclina D3 , Metabolismo , Ciclofosfamida , Usos Terapêuticos , Citarabina , Usos Terapêuticos , Daunorrubicina , Usos Terapêuticos , Doxorrubicina , Usos Terapêuticos , Etoposídeo , Usos Terapêuticos , Seguimentos , Mercaptopurina , Usos Terapêuticos , Metotrexato , Usos Terapêuticos , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Tratamento Farmacológico , Alergia e Imunologia , Prednisona , Usos Terapêuticos , Modelos de Riscos Proporcionais , Indução de Remissão , Taxa de Sobrevida , Fatores de Transcrição , Metabolismo , Vincristina , Usos TerapêuticosRESUMO
<p><b>OBJECTIVE</b>This study was designed to evaluate the efficacy and toxicity of modified BFM-90 regimen originated from Germany authors in the treatment of Chinese childhood and adolescent lymphoblastic lymphoma.</p><p><b>METHODS</b>Thirty-six untreated lymphoblastic lymphoma patients aged from 3 to 18 years were included, with 1 patient in stage II , 9 in stage III and 26 in stage IV. Of these 36 patients, 28 (77.7%) were diagnosed as T cell phenotype, 26 (72. 2%) were found to have mediastinal mass, 21 (58. 3%) had bone marrow involvement. All patients received chemotherapy of modified BFM-90 regimen consisting of induction remission, central nerve system prophylaxis, re-induction remission and maintenance therapy. Total treatment duration was two years. The difference from standard BFM-90 is that we omitted cranial radiotherapy but gave regular high dose methotrexate (MTX) iv infusion and intrathecal MTX therapy during maintenance therapy period. Kaplan-Meier method was used to evaluate survival rate.</p><p><b>RESULTS</b>Of 36 patients, 32 (88%) achieved complete remission (CR) , 1 (2. 7%) partial remission (PR) with an overall response rate of 90.7%. One patient had disease progression ( DP). Two patients received autologous stem cell transplantation at CR1, and two patients received radiotherapy to mediastinum. Totally, 5 patients relapsed, while 2 of them were still alive after salvage chemotherapy. The other 3 died of tumor progression. Two patients died during induction remission, 1 of fungal septicemia, the other of cerebral hemorrhage; one PR and one DP patient died of disease, therefore, totally 7 patients died at last. Median follow-up time was 28 months. Overall three-year survival rate was 78. 3%. The major toxicity was myelosuppression.</p><p><b>CONCLUSION</b>Modified BFM-90 protocol can improve the efficacy and survival of Chinese childhood and adolescent lymphoblastic lymphoma with tolerable toxicity. However, this modified protocol should only be used in experienced cancer center or hematological unit.</p>
Assuntos
Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica , Usos Terapêuticos , Povo Asiático , Asparaginase , Usos Terapêuticos , China , Ciclofosfamida , Usos Terapêuticos , Citarabina , Usos Terapêuticos , Daunorrubicina , Usos Terapêuticos , Seguimentos , Estimativa de Kaplan-Meier , Mercaptopurina , Usos Terapêuticos , Metotrexato , Usos Terapêuticos , Recidiva Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Tratamento Farmacológico , Etnologia , Prednisona , Usos Terapêuticos , Indução de Remissão , Resultado do Tratamento , Vincristina , Usos TerapêuticosRESUMO
<p><b>OBJECTIVE</b>To analyse the clinical features of patients with B cell lymphoblastic lymphoma(BCLL) and the outcomes after modified BFM-90 protocol therapy.</p><p><b>METHODS</b>The clinical features of 14 patients with BCLL were analysed, and compared with that of T cell lymphoblastic lymphoma in the same period. The efficacy and toxicity of modified BFM-90 protocol were analysed.</p><p><b>RESULTS</b>The 14 patients were aged 3 to 18 and diagnosed as BCLL by morphology and immunohistology. One case was in stage I , 2 stage III and 11 stage IV. Most common involved sites were lymph nodes (70% ), skin (50% ) and bone marrow (64% ). One patient received CHOP + HD-MTX, and 13 received modified BFM-90 protocol chemotherapy. Twelve patients (92.3%) achieved complete remission( CR) , 1 patient(7. 7% ) partial remission( PR). The median follow-up duration was 19. 5 months (2 to 44 months). At present 13 patients are alive except one PR patient who gave up treatment and died of disease. The major toxicity of the protocol was myelosuppression, but could be tolerated.</p><p><b>CONCLUSIONS</b>The most common involvement sites of BCLL were lymph nodes, skin and bone marrow. The effectiveness is improved as treated with modified BFM-90 protocol.</p>
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Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica , Usos Terapêuticos , Esquema de Medicação , Seguimentos , Linfoma de Células B , Tratamento Farmacológico , Mercaptopurina , Metotrexato , Leucemia-Linfoma Linfoblástico de Células Precursoras , Tratamento Farmacológico , Resultado do TratamentoRESUMO
<p><b>OBJECTIVES</b>To evaluate the efficacy and toxicity of the B-NHL-BFM-90 protocol in the treatment of Chinese childhood and adolescent B-cell non-Hodgkin's lymphomas (B-NHL).</p><p><b>METHODS</b>Forty-two untreated childhood and adolescent B-NHL were enrolled in the present study. Of them 18 cases were Burkitt's lymphoma, 16 diffuse large B cell lymphoma and 8 anaplastic lymphoma. There were 10 cases in stage II and 32 in stage III/IV. The patients were grouped by risk factors into low, medium and high risk groups. All patients were treated with the B-NHL-BFM 90 (Berlin-Frankfurt- Münster) protocol. The low risk group received A, B courses for 4 cycles, the medium risk group AA, BB courses for 6 cycles, and the high risk group AA, BB, CC courses for 6 cycles.</p><p><b>RESULTS</b>Complete remission (CR) was obtained in 37 patients (88%), and partial remission (PR) in 5 (12%). Of the 5 PR patients, I received autologous hematopoietic stem cell transplantation, 3 received radiotherapy for residual disease and 1 just under watching. Major toxicity was myelosuppression and mucositis, especially in AA, BB and CC cycles, but was tolerant and manageable. Median follow-up was 20 (4 - 89) months. Kaplan-Meier method was used to analyse survival data. Two year event free survival (EFS) for all patients was 86. 24%, being 100% for stage II and 80.95% for stage III/IV.</p><p><b>CONCLUSION</b>Short term and intensive chemotherapy can improves the efficacy and survival rate of childhood and adolescent B-NHL, especially for advanced stage patients.</p>
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Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica , Estudos de Viabilidade , Seguimentos , Linfoma de Células B , Tratamento Farmacológico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
To investigate the distribution of HLA-E alleles and linkage between HLA-E and HLA-A or -B loci in Chinese Han in Guangdong area, HLA-E alleles were detected by using PCR-SSP in 150 unrelated healthy individuals from Guangzhou area; HLA-A, -B antigens typing in 106 individuals was carried out with NIH standard microlymphocytoxic method. Analysis of linkage was performed between HLA-E and HLA-A, -B. The results showed that three alleles of HLA-E could be detected in this population. They are E * 0101, E * 01031, E * 01032, with the frequency of 45.33%, 32.33%, 22.33% respectively. No E * 0102 and E * 0104 could be detected in all of these individuals. The analysis of linkage on two loci between HLA-E and HLA-A or -B showed that no significant difference could be found between expected frequencies and observed frequencies except B15/E * 01032 and A2/E * 01032. In conclusion, the high conservative polymorphism of HLA-E suggests that it's biological characteristic is different from that of classical HLA class Ia molecules.