RESUMO
BACKGROUND: Mantle cell lymphoma (MCL) is aggressive, and relapsed/refractory disease has poor outcomes. PATIENTS AND METHODS: Thirty-nine patients (men = 34, women = 5) at 64 (41-82) years of age with relapsed/refractory MCL, ineligible for high-dose chemotherapy and had received 2 (1-5) prior regimens, were treated with a continuous oral regimen, comprising oral arsenic trioxide (oral-As2O3), chlorambucil and ascorbic acid. RESULTS: Overall response rate was 49% (complete response, CR = 28%; partial response, PR = 21%). Only grade 1/2 toxicities were observed (hematologic: 56%, hepatic: 8%). Response was maintained in 11 patients (CR = 8; PR = 3), after a median of 24 (2-108) months. Independent prognostic factors for response were increased lactate dehydrogenase (P = 0.04) and unfavorable MCL international prognostic index (P = 0.04). At a median follow-up of 21 (1-118) months, the median progression-free survival (PFS) was 16 months, and overall survival (OS) 38 months. Independent prognostic factors for PFS were female gender (P = 0.002), and Eastern Cooperative Oncology Group (ECOG) performance score of 2 (P = 0.009). Independent prognostic factors for OS were female gender (P < 0.001), ECOG performance score of 2 (P = 0.03), non-response (P < 0.001), and disease progression after initial response (P = 0.05). CONCLUSION: An oral regimen of oral-As2O3, chlorambucil and ascorbic acid was active with minimal toxicity in relapsed/refractory MCL, achieving durable responses in â¼30% of cases.
Assuntos
Arsenicais/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Óxidos/uso terapêutico , Terapia de Salvação , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Trióxido de Arsênio , Arsenicais/administração & dosagem , Humanos , Linfoma de Célula do Manto/diagnóstico por imagem , Pessoa de Meia-Idade , Óxidos/administração & dosagem , Tomografia por Emissão de Pósitrons , Recidiva , Análise de SobrevidaAssuntos
Transplante de Células-Tronco Hematopoéticas , Imunossupressores/administração & dosagem , Doadores Vivos , Mieloma Múltiplo/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Talidomida/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
Arsenic trioxide has been used in traditional Chinese medicine for over 5000 years, but lost its appeal due to its toxicity. It was rediscovered in western medicine and enjoyed a renaissance from 1830 to 1930, as the first effective chemotherapy against syphilis, parasites and leukaemia. These years were also a time of political turmoil in China. The Nanking treaty (29 August 1842) turned Hong Kong into a colony, while the Xinhai Revolution (10 October 1911) gave birth to a republic of China. Arsenic returned to China and Hong Kong with the establishment of the first medical schools from 1887 to 1920. Until 1950, oral arsenic trioxide was the standard anti-leukaemic treatment in Queen Mary Hospital. The advent of alkylating chemotherapeutic agents replaced arsenic trioxide in Hong Kong and around the world. In the 1970s, however, the specific activity of arsenic trioxide against acute promyelocytic leukaemia was re-discovered during the Cultural Revolution in Harbin, China. In 1997, Hong Kong was returned to China. In the same year, arsenic trioxide returned to the world stage. Intravenous arsenic trioxide became the worldwide standard therapy for relapsed acute promyelocytic leukaemia. Oral administration of arsenic trioxide was revived in Hong Kong in 2000. This resulted in the first locally produced, registered, patented prescription drug in Hong Kong. Pending imminent manufacture, this product is poised to revolutionise acute promyelocytic leukaemia care and may hold the key to saving the lives of acute promyelocytic leukaemia patients worldwide. The remarkable journey of arsenic in the setting of medical history of China and Hong Kong is reviewed.
Assuntos
Arsênio/história , Medicina Tradicional Chinesa/história , China , História do Século XVI , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , Hong Kong , HumanosRESUMO
Bronchiolitis obliterans syndrome (BOS) is an important complication after hematopoietic SCT (HSCT). Recent observations suggested that azithromycin might improve lung function in BOS after HSCT. We conducted a randomized double-blinded placebo-controlled study on azithromycin in patients with BOS after HSCT. The treatment group (n=10) received oral azithromycin 250 mg daily while the control group (n=12) received placebo daily for 12 weeks. Respiratory symptoms were assessed by the St George Respiratory Questionnaires and spirometry at baseline (drug commencement), 1, 2, 3 (drug cessation) and 4 months (1 month after drug cessation). There was no significant difference in the baseline demographic characteristics between the treatment and the control groups in age, gender, time from HSCT to BOS, time since diagnosis of BOS, chronic GVHD, baseline respiratory symptom scores and baseline forced expiratory volume in 1 s (FEV(1)). Throughout and after 3 months of treatment, there were no significant changes in respiratory symptom scores and FEV(1) measurements between the treatment and the control groups. In conclusion, there was no significant benefit of 3 months of oral azithromycin on the respiratory symptoms and lung function in patients with relatively late BOS after HSCT in this randomized placebo-controlled study.
Assuntos
Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Bronquiolite Obliterante/tratamento farmacológico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Administração Oral , Adulto , Bronquiolite Obliterante/etiologia , Doença Crônica , Método Duplo-Cego , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome , Fatores de Tempo , Transplante HomólogoRESUMO
Natural killer (NK) cell lymphomas/leukemias are rare neoplasms with an aggressive clinical behavior. The majority of the cases belong to extranodal NK/T-cell lymphoma, nasal type (ENKTL) in the current WHO classification scheme. Gene-expression profiling (GEP) of 21 ENKTL and NK-cell lymphoma/leukemia patients, 17 NK- and T-cell lines and 5 indolent NK-cell large-granular-lymphocytic proliferation was performed and compared with 125 peripheral T-cell lymphoma (PTCL) patients previously studied. The molecular classifier derived for ENKTL patients was comprised of 84 transcripts with the majority of them contributed by the neoplastic NK cells. The classifier also identified a set of γδ-PTCLs both in the ENKTL cases as well as in cases initially classified as PTCL-not otherwise specified. These γδ-PTCLs expressed transcripts associated with the T-cell receptor (TCR)/CD3 complex, suggesting T cell rather than NK-cell lineage. They were very similar to NK-cell tumors by GEP, but were distinct from cytotoxic (αß)-PTCL and hepatosplenic T-cell lymphoma, indicating derivation from an ontogenically and functionally distinct subset of γδ T cells. They showed distinct expression of Vγ9, Vδ2 transcripts and were positive for TCRγ, but negative for TCRß by immunohistochemistry. Targeted inhibition of two oncogenic pathways (AURKA and NOTCH-1) by small-molecular inhibitors induced significant growth arrest in NK-cell lines, thus providing a rationale for clinical trials of these inhibitors in NK-cell malignancies.
Assuntos
Células Matadoras Naturais/patologia , Linfoma não Hodgkin/patologia , Linfoma de Células T Periférico/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T gama-delta , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aurora Quinase A , Aurora Quinases , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacologia , Receptores Notch/antagonistas & inibidores , Transdução de Sinais , Células Tumorais Cultivadas , Adulto JovemAssuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Sistema Hematopoético , Agonistas Mieloablativos/uso terapêutico , Regeneração , Adolescente , Adulto , Feminino , Humanos , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Quimeras de Transplante , Transplante Homólogo , Adulto JovemAssuntos
Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Linfoma Extranodal de Células T-NK/complicações , RNA Viral/genética , Neoplasias Cutâneas/complicações , Carcinoma , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/genética , Humanos , Linfoma Extranodal de Células T-NK/diagnóstico , Linfoma Extranodal de Células T-NK/genética , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/complicações , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/genética , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genéticaRESUMO
The first case of haematopoietic stem cell transplant (HSCT) was performed at the Bone Marrow Transplant Center, Queen Mary Hospital (QMH) in 1990. Since then three more transplant centres have been established: Prince of Wales Hospital (1991) mainly in paediatric transplant, Queen Elizabeth Hospital (1995) and Tuen Mun Hospital (2006) in adult autologous transplant. Up to the end of 2008, a little over 2000 transplants have been performed in Hong Kong, and QMH takes up about 85% of the total number of cases. A unified HSCT registry in Hong Kong is desirable and is yet to be established. At QMH, by the end of 2008, a total of 1708 transplant procedures have been performed with 83% (1417) being first-time transplants and the rest (291, 17%) are repeat transplants mostly for relapsed patients. The numbers of male and female patients are 955 and 753, respectively. The median age is 35.4 years (range, 3 months to 67 years) with 85.8% of the transplants performed in adults (> 18 years). The type of donor includes 34% autologous, 1% syngeneic, 38% related allogeneic and 27% unrelated allogeneic. The top five indications of the first-time transplants are acute myeloid leukaemia (25.8%), chronic myeloid leukaemia (15.9%), lymphoma (14.6%), acute lymphoblastic leukaemia (14.5%), and myeloma (8.6%). With the development of peripheral blood stem cell collection, in recent years it is performed in 50% of the allogeneic and 80% of the autologous cases. Bone marrow harvest in autologous cases is only for patients who fail peripheral blood stem cell mobilisation. Transplant outcomes are reported to the Center for International Blood and Marrow Transplant Research and long-term survivals are in general comparable to international standard.
Assuntos
Transplante de Células-Tronco Hematopoéticas/tendências , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/etnologia , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Hong Kong/epidemiologia , Humanos , Incidência , Lactente , Leucemia/terapia , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/estatística & dados numéricos , Transplante de Células-Tronco de Sangue Periférico/tendências , Transplante Homólogo/tendências , Adulto JovemRESUMO
Deficiency in glucose-6-phosphate dehydrogenase (G6PD), an X-linked recessive red cell enzymopathy, is endemic in Southern Chinese. Universal screening of newborn is done in Hong Kong, Taiwan and Singapore, among other places. In Hong Kong, 4.8% of males are affected and seven common G6PD alleles account for over 99% of all defects. Male hemizygotes suffer from severe deficiency, while female heterozygotes may also be affected. Deficiency of G6PD may affect haematopoietic stem cell transplantation (HSCT) recipients and donors, before and after HSCT. Female patients with clonal erythropoiesis (eg myelodysplasia/myeloproliferative diseases) will have the male population incidence of G6PD. Quantitative enzyme level screening is prudent for donors and recipients, and should be repeated after engraftment. Cotrimoxazole prophylaxis should be avoided in known male and female carriers, including those with low-normal G6PD enzyme levels. Our experience suggested that G6PD-deficient marrow, stem cell and cord blood donor units have no engraftment problems. Post-engraftment G6PD levels correlate with those in donors. An acquired change in G6PD status may serve as a surrogate marker for engraftment. For female heterozygote donors with normal G6PD levels, skewing of lyonized X-chromosome ratio during engraftment may result in over-expression of the deficient allele. This can result in unexpected significant G6PD deficiency. Hence, a repeat G6PD screening at stable engraftment is recommended, especially before commencement of oxidative medications.
Assuntos
Deficiência de Glucosefosfato Desidrogenase/etnologia , Transplante de Células-Tronco Hematopoéticas/etnologia , Células-Tronco Hematopoéticas/enzimologia , China/epidemiologia , Seleção do Doador , Feminino , Deficiência de Glucosefosfato Desidrogenase/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , PrevalênciaRESUMO
Natural killer (NK)-cell malignancies are among the most aggressive lymphoid neoplasms with very poor prognosis. We performed array comparative genomic hybridization analysis on a number of NK cell lines and primary tumors to gain better understanding of the pathogenesis and tumor biology of these malignancies. We also obtained transcriptional profiles of genes residing in these regions and compared them with normal and activated NK cells. Only 30-50% of the genes residing in the gained or deleted regions showed corresponding increased or decreased expression. However, many of the upregulated genes in regions of gain are functionally important for the proliferation and growth of the neoplastic population. Genes downregulated in regions of loss included many transcription factors or repressors, tumor suppressors or negative regulators of the cell cycle. The minimal common region of deletion in 6q21 included three known genes (PRDM1, ATG5 and AIM1) showing generally low expression. Mutations resulting in truncated PRDM1 and changes in conserved amino-acid sequences of AIM1 were detected. Highly methylated CpG islands 5' of PRDM1 and AIM1 correlated with low expression of the transcripts. Reversal of methylation by Decitabine induced expression of PRDM1 and cell death. In conclusion, we have shown a general tumor-promoting effect of genetic alterations and have identified PRDM1 as the most likely target gene in del6q21. ATG5, an essential gene for autophagy and AIM1, a gene implicated in melanoma, may also participate in the functional abnormalities.
Assuntos
Hibridização Genômica Comparativa , Cristalinas/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Células Matadoras Naturais/patologia , Linfoma/genética , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Repressoras/genética , Adulto , Idoso , Proteína 5 Relacionada à Autofagia , Proliferação de Células , Cromossomos Humanos Par 6 , Perfilação da Expressão Gênica , Humanos , Linfoma/patologia , Pessoa de Meia-Idade , Fator 1 de Ligação ao Domínio I Regulador Positivo , Células Tumorais CultivadasAssuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Deficiência de Glucosefosfato Desidrogenase/genética , Sobrevivência de Enxerto , Leucemia Mieloide Aguda/terapia , Quimeras de Transplante/genética , Condicionamento Pré-Transplante , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-IdadeAssuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Antineoplásicos/administração & dosagem , Citomegalovirus/efeitos dos fármacos , Ganciclovir/análogos & derivados , Alemtuzumab , Anticorpos Monoclonais Humanizados , Avaliação de Medicamentos , Ganciclovir/administração & dosagem , Humanos , Pré-Medicação , Valganciclovir , Ativação Viral/efeitos dos fármacosAssuntos
Predisposição Genética para Doença , Linfoma de Células B/complicações , Linfoma de Células B/genética , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/genética , Idoso , Humanos , Linfoma de Células B/patologia , Masculino , Transtornos Mieloproliferativos/patologiaRESUMO
PURPOSE: To assess the feasibility of one-stop evaluation of iron load of myocardium, liver, and anterior pituitary gland in thalassemia patients. MATERIALS AND METHODS: Fifty thalassemia major patients underwent a breath-hold magnetic resonance imaging (MRI) sequence for assessment of T2* for liver and myocardium, a short axis cine trueFISP sequence covering base to apex to assess the ejection fraction of left ventricle, and a turbo spin echo T2-weighted sequence for the anterior pituitary gland. The MRI parameters were correlated with serum growth hormone, insulin growth factor-1 (IGF-1), insulin growth factor binding protein-3 (IGFBP-3), and endocrine failure. RESULTS: Ferritin was found to be associated with T2* liver (P < 0.005), T2SI (signal intensity) pituitary (P = 0.001), and T2 pituitary/fat (P = 0.001), but not with T2* heart. There was significant correlation of T2SI pituitary with IGF-1 and IGFBP-3. T2* liver (P < 0.001), T2* heart (P < 0.001), pituitary SI (P < 0.001) and pituitary/fat SI (P = 0.002) were also found to be significantly correlated with a history of hypogonadism. T2* heart was also found to be significantly correlated with IGF-1. CONCLUSION: A quick MRI protocol for assessment of T2* liver, T2* heart, and T2SI pituitary is technically feasible. This might form an objective basis to monitor the response to different organs to chelation therapy.
Assuntos
Ferro/análise , Fígado/química , Imageamento por Ressonância Magnética , Miocárdio/química , Adeno-Hipófise/química , Talassemia/metabolismo , Adolescente , Adulto , Criança , Estudos de Viabilidade , Feminino , Humanos , MasculinoRESUMO
Graft-versus-host disease (GVHD) often complicates allogeneic stem cell transplantation (SCT) and affects mainly the gut, liver, lung and skin. The microscopic morphological features of late-phase sclerodermatous chronic GVHD in the skin, namely epidermal atrophy, lymphoplasmacytic infiltration, dense dermal fibrosis and adnexal atrophy, are histologically indistinguishable from those in sporadic systemic sclerosis, morphoea and the related condition of lichen sclerosus. Mucosal orifices including those of the genitourinary system may be severely affected. We present three SCT recipients with chronic GVHD and severe posthitis leading to phimosis requiring surgery. The excised prepuces showed features of lichen sclerosus including epidermal atrophy and a subepidermal zone of eosinophilic, homogeneous and hyalinized collagen above a band-like lymphoplasmacytic infiltrate. These cases add further evidence to support the notion that penile lichen sclerosus should be included within the expanding sclerodermoid spectrum of late-stage cutaneous chronic GVHD.
Assuntos
Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Líquen Escleroso e Atrófico/etiologia , Fimose/etiologia , Adulto , Doença Crônica , Doença Enxerto-Hospedeiro/patologia , Humanos , Líquen Escleroso e Atrófico/patologia , Masculino , Pessoa de Meia-Idade , Fimose/patologiaRESUMO
We performed a study of magnetic resonance imaging (MRI) assessment of hemosiderosis in the heart (T2/T2*), liver (T2*), pancreas (T2*), and pituitary gland (T2/T2*/SIR) in 20 hemopoietic stem cell transplant (HSCT) recipients (median peak ferritin levels 7615 pmol/L, range 3411 to 33000 pmol/L). MRI reading was abnormal in the heart (5%), liver (85%), pancreas (40%), and pituitary gland (55%). The heart T2 correlated with peak ferritin levels (P=.024), while the liver T2* correlated with current ferritin (P=.038) values only. Pancreatic T2* values correlated with pituitary T2 and signal intensity ratio values. The ejection fraction was abnormal in 10% of cases and did not correlate with ferritin level or heart T2. The peak liver enzymes correlated with peak ferritin (P=.025), but the current liver enzymes were mostly normal. Pancreatic assessments (fasting glucose, insulin, beta cell function, insulin reserve, and C-peptide) and pituitary growth hormone axis assessments (growth hormone, insulin growth factor-1, and insulin growth factor binding protein-3) were abnormal in 40% to 70% of cases. They were unrelated to pancreas or pituitary MRI values. Interestingly, endocrine assessments correlated with heart T2 values and peak (but not current) ferritin levels. We concluded that iron overload may contribute to organ damage after HSCT, and MRI assessment may be useful in its detection and treatment monitoring.
Assuntos
Ferritinas/metabolismo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Sobrecarga de Ferro/etiologia , Leucemia/terapia , Adulto , Anemia Aplástica/patologia , Anemia Aplástica/terapia , Feminino , Cardiopatias/patologia , Cardiopatias/terapia , Hemossiderose/patologia , Hemossiderose/terapia , Humanos , Leucemia/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/patologia , Mielofibrose Primária/terapia , Transplante Homólogo/fisiologiaRESUMO
To determine whether during hematopoietic stem cell transplantation (HSCT), X-chromosome inactivation (lyonization) of donor HSC might change after engraftment in recipients, the glucose-6-phosphate dehydrogenase (G6PD) gene of 180 female donors was genotyped by PCR/allele-specific primer extension, and MALDI-TOF mass spectrometry/Sequenom MassARRAY analysis. X-inactivation was determined by semiquantitative PCR for the HUMARA gene before/after HpaII digestion. X-inactivation was preserved in most cases post-HSCT, although altered skewing of lyonization might occur to either of the X-chromosomes. Among pre-HSCT clinicopathologic parameters analyzed, only recipient gender significantly affected skewing. Seven donors with normal G6PD biochemically but heterozygous for G6PD mutants were identified. Owing to lyonization changes, some donor-recipient pairs showed significantly different G6PD levels. In one donor-recipient pair, extreme lyonization affecting the wild-type G6PD allele occurred, causing biochemical G6PD deficiency in the recipient. In HSCT from asymptomatic female donors heterozygous for X-linked recessive disorders, altered lyonization might cause clinical diseases in the recipients.
Assuntos
Deficiência de Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adulto , Pré-Escolar , Cromossomos Humanos X , Primers do DNA , Feminino , Triagem de Portadores Genéticos , Genótipo , Glucosefosfato Desidrogenase/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Genético , Receptores Androgênicos/genética , Valores de Referência , Mapeamento por Restrição , Irmãos , Doadores de Tecidos/estatística & dados numéricosRESUMO
We analyzed the outcome of 108 adult acute lymphoblastic leukemia patients undergoing allogeneic bone marrow transplantation (BMT). Philadelphia (Ph) chromosome occurred in 35.2% patients at diagnosis. Two-thirds of patients received allogeneic BMT in first complete remission (CR1) BMT. Salvage BMT was performed in 21 and 16 patients at second complete remission (CR2) and beyond CR2. Donors were human leukocyte antigen-identical siblings in 87 patients, and match-unrelated donors in 21 patients. Conditioning contained total body irradiation (TBI) in 92.6% patients. Overall survival (OS) for BMT at CR1 and BMT beyond CR1 were 46.2 and 20.3% at 15 years. Multivariate analyses (including age, sex, disease status, donor type, acute graft-versus-host disease (aGVHD), stem cell source, cytogenetics, grade 1/2 aGVHD and TBI-containing conditioning regimen) identified age<35, BMT at CR1 and grade 1/2 aGVHD as favorable factors for OS. Disease-free survival (DFS) for BMT at CR1 and beyond CR1 were 45.8 and 15.9% at 15 years, respectively, with BMT at CR1, age<35 and grade 1/2 aGVHD being favorable factors for DFS. Importantly, conventional adverse risk factors such as the Ph chromosome, B-cell phenotype and high leukocyte count were not associated with inferior survivals. In summary, the adverse impact of Ph chromosome, B-cell phenotype and high leukocyte count was overcome by allogeneic BMT. Matched unrelated donor transplantation appears promising.