Cost-effectiveness of the regimen proposed by the International Consortium on Acute Promyelocytic Leukemia for the treatment of newly diagnosed patients with Acute Promyelocytic Leukemia

ABSTRACT Introduction: We performed cost-effectiveness and cost-utility analyses of the modified International Consortium on Acute Promyelocytic Leukemia protocol in Mexico for the treatment of acute promyelocytic leukemia Acute Promyelocytic Leukemia. Methods: We performed a three-state Markov analysis: stable disease (first line complete response [CR]), disease event (relapse, second line response and CR) and death. The modified IC-APL protocol is composed of three phases: induction, consolidation and maintenance. Cost and outcomes were used to calculate incremental cost-effectiveness ratios (ICERs); quality-adjusted life-years were used to calculate incremental cost-utility ratios (ICURs). Results: The CR was achieved in 18 patients (90%), treated with the IC-APL protocol as the first-line option; one patient (5%) died in induction, another one never achieved CR (5%); of the 18 patients that achieved CR, 1 relapsed (5.5%). The median treatment cost of the IC-APL protocol was $21,523 USD. The average life-year in our study was 7.8 years, while the average quality-adjusted life-year (QALY) was 6.1 years. When comparing the ICER between the IC-APL and the all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) protocols, we found the different costs of $6497, $19,133 and $17,123 USD in Italy, the USA and Canada, respectively. In relation to the ICUR, we found the different costs to be $13,955 and $11,979 USD in the USA and Canada, respectively. Conclusion: Taking into account the similar response rates, lower cost and easy access to the modified IC-APL regimen, we consider it a cost-effective and cost-utility protocol, deeming it the treatment of choice for our population.

BRD4 interacts with PML/RARα in acute promyelocytic leukemia / 医学前沿

Bromodomain-containing 4 (BRD4) has been considered as an important requirement for disease maintenance and an attractive therapeutic target for cancer therapy. This protein can be targeted by JQ1, a selective small-molecule inhibitor. However, few studies have investigated whether BRD4 influenced acute promyelocytic leukemia (APL), and whether BRD4 had interaction with promyelocytic leukemia-retinoic acid receptor α (PML/RARα) fusion protein to some extent. Results from cell viability assay, cell cycle analysis, and Annexin-V/PI analysis indicated that JQ1 inhibited the growth of NB4 cells, an APL-derived cell line, and induced NB4 cell cycle arrest at G1 and apoptosis. Then, we used co-immunoprecipitation (co-IP) assay and immunoblot to demonstrate the endogenous interaction of BRD4 and PML/RARα in NB4 cells. Moreover, downregulation of PML/RARα at the mRNA and protein levels was observed upon JQ1 treatment. Furthermore, results from the RT-qPCR, ChIP-qPCR, and re-ChIP-qPCR assays showed that BRD4 and PML/RARα co-existed on the same regulatory regions of their target genes. Hence, we showed a new discovery of the interaction of BRD4 and PML/RARα, as well as the decline of PML/RARα expression, under JQ1 treatment.

Survival and treatment response in adults with acute promyelocytic leukemia treated with a modified International Consortium on Acute Promyelocytic Leukemia protocol

ABSTRACT Acute promyelocytic leukemia has good prognosis in view of the high complete remission and survival rates achieved with therapies containing all-trans retinoic acid or arsenic trioxide. However, there is a significant risk of death during induction due to hemorrhage secondary to disseminated intravascular coagulation. This has contributed to a gap in the prognosis of patients between developed and developing countries. The International Consortium on Acute Promyelocytic Leukemia was created in 2005 and proposed a treatment protocol based on daunorubicin and all-trans retinoic acid stratified by risk geared toward developing countries. Herein are presented the results from the first patient cohort treated in a single developing country hospital employing a slightly modified version of the International Consortium protocol in a real life setting. Twenty patients with acute promyelocytic leukemia were enrolled: 27.8% had low-risk, 55.6% intermediate risk and 16.7% high-risk. The complete remission rate was 94.4% after a median of 42 days. Both relapse rates and death rates were one patient (5.5%) each. No deaths were observed during consolidation. After a median follow-up of 29 months, the overall survival rate was 89.1%. Efficacy and safety of the International Consortium on Acute Promyelocytic Leukemia protocol has been reproduced in acute promyelocytic leukemia patients from a developing country.

Onco-microRNA miR-130b promoting cell growth in children APL by targeting PTEN

Objective: To study the expression of microRNA-130b (miR-130b) in children acute promyelocytic leukemia (APL) and its role for regulating PTEN expression. Methods: A total of 50 children APL marrow tissues and 15 normal marrow tissues between January and December in 2012 were collected into our study. The expression of miR-130b in APL and normal marrow tissues were detected by quantitative real-time polymerase chain reaction. MiR-130b inhibitor was transfected into HL-60 cells. Cell Counting Kit-8 assay and flow cytometry were used to measure cell proliferation and apoptosis, respectively. The expression of PTEN, a potential target of miR-130b, and its downstream genes, Bcl-2 and Bax, in transformed cells were detected by quantitative real-time polymerase chain reaction and western-blot. Results: The expression of miR-130b was significantly higher in children APL marrow tissues than in normal marrow tissues (P < 0.05). Down-regulation of miR-130b could significantly suppress cell proliferation and induce apoptosis in HL-60 cells (P < 0.05). PTEN expression was upregulated when miR-130b was knocking-down (P < 0.05). As downstream genes of PTEN, the expression of Bcl-2 and Bax were regulated as well. Conclusions: MiR-130b is overexpressed in children APL marrow tissues and associated with cell growth. MiR-130b may promote children APL progression by inducing cell proliferation and inhibiting apoptosis.

Onco-microRNA miR-130b promoting cell growth in children APL by targeting PTEN

OBJECTIVE@#To study the expression of microRNA-130b (miR-130b) in children acute promyelocytic leukemia (APL) and its role for regulating PTEN expression.@*METHODS@#A total of 50 children APL marrow tissues and 15 normal marrow tissues between January and December in 2012 were collected into our study. The expression of miR-130b in APL and normal marrow tissues were detected by quantitative real-time polymerase chain reaction. MiR-130b inhibitor was transfected into HL-60 cells. Cell Counting Kit-8 assay and flow cytometry were used to measure cell proliferation and apoptosis, respectively. The expression of PTEN, a potential target of miR-130b, and its downstream genes, Bcl-2 and Bax, in transformed cells were detected by quantitative real-time polymerase chain reaction and western-blot.@*RESULTS@#The expression of miR-130b was significantly higher in children APL marrow tissues than in normal marrow tissues (P < 0.05). Down-regulation of miR-130b could significantly suppress cell proliferation and induce apoptosis in HL-60 cells (P < 0.05). PTEN expression was upregulated when miR-130b was knocking-down (P < 0.05). As downstream genes of PTEN, the expression of Bcl-2 and Bax were regulated as well.@*CONCLUSIONS@#MiR-130b is overexpressed in children APL marrow tissues and associated with cell growth. MiR-130b may promote children APL progression by inducing cell proliferation and inhibiting apoptosis.

Cloning and expression analysis of TcAPLs in Taxus chinensis / 中草药

Objective: To clone altered phloem development (APL) genes from Taxus chinensis and reveal their potential regulatory role in tissues regeneration after bark girdling by investigating the expression profiles of these APLs. Methods: The full-length three APL genes were isolated using reverse transcription-polymerase chain reaction (RT-PCR) and were named as TcAPL1, TcAPL2, and TcAPL3, respectively. The expression profiles of these genes in different tissues and at different regeneration stages after bark girdling were analyzed by semi-quantitative RT-PCR and quantitative real-time PCR (qRT-PCR), respectively. Results: Phylogenetic tree analysis suggested that TcAPL1 and TcAPL2 could be clustered together with APL protein of Morus notabilis, which are closest in genetic relationship; TcAPL3 could be clustered with APL proteins of another big independent branch. The analysis of gene expression patterns in different tissues showed that the transcript abundances of TcAPL1 and TcAPL2 were mainly expressed in the roots, stems, leaves, and phloem with cambium; While TcAPL3 was higher in the leaves than that in the roots and xylem with cambium. Through analysis of the expression patterns in regeneration tissues after bark girdling, the mRNA expressions of TcAPL1 and TcAPL2 showed a up-down trend in the following periods and were found to decrease notably at 36 d after bark girdling, while the expression of TcAPL3 was repressed at all stages after bark girdling. Conclusion: In this study, three TcAPLs genes are cloned from T. chinensis, and their expressions are regulated in the regeneration processes after bark girdling. Our results demonstrate that APL might play a regulatory role in tissue regeneration after bark girdling in T. chinensis.

The experimental progress on arsenic trioxide for non-APL and solid tumor / 实用肿瘤学杂志

Arsenic trioxide(As2O3)effectively triggers apoptosis in acute promyelocytic leukemia (APL) cells and induces complete remission and cure in most APL patients ,if they can refrain from early mortality .In the last few years,it has been under investigation as a potential treatment for non -APL leukemia and a variety of sol-id tumors.In the meantime,it has been found that As2O3 also inhibits proliferation of non -APL leukemia cell and several solid tumor cell such as liver ,esophageal ,and gastric cancer cell in vitro or in vivo in the more and more studies .The molecular mechanisms that As 2 O3 induces cellular apoptosis in non APL leukemia cell and solid tumor cells have been discussed ,which also includes building new targeting preparation in order to obtain much more satisfying therapeutic effect and relieve its cellular toxic and side effect and so on.Here, we give a summary which is connected with the research progress above .

Characterizing PML/RARα Isoforms of Acute Promyelocytic Leukemia (APL) in Malay patients.

Aim: Reciprocal translocation between retinoic acid receptor alpha (RARα) gene on chromo- some 17 and promyelocytic leukemia (PML) gene on chromosome 15 is the hallmark for acute promyelocytic leukemia (APL). Three different PML/RARα isoforms have been described; S-form, L-form and V-form. Our aims were to characterize the different types of PML/RARα iso- forms in Malay patients with APL and to determine the outcome of these different types of iso- forms. Materials and methods: RT-PCR analysis was performed on 20 patients recruited from hematology-oncology ward. RT-PCR detected fusion transcript of PML/RARα in all patients. Results and Discussion: Of these patients, 65% (13 patients) exhibited L/V-form, and 35% (7 patients) S-form. Total white blood cell count (TWBC) was higher in L/V-form (25 x 109/l) compared to S-form (2.1 x 109/l) (p < 0.05). Five years survival rate was 100% and 33.3% for L/V-forms and S-forms respectively (p<0.005). Conclusion: We conclude that L/V- forms is the commonest isoform among Malays. They presented at younger age with higher TWBC counts. Although the sample size is small, our preliminary data showed an interestingly longer survival outcome among L/V-forms compared to S-form. PML/RARα isoforms could be used in future as risk stratification feature in patients diagnosed as APL. Further study with more number of patients is required.

Afasia logopénica: presentación de un caso y revisión de la literatura / Logopenic Aphasia: a case report an review of the literature

With the progressive aging of the Chilean population the diagnosis of neurodegenerative disorders is increasingly common, and among them is Primary Progressive Aphasia (PPA), with specific symptoms but late consultation. PPA is a clinical syndrome characterized by the degeneration of language regions in the dominant hemisphere that determines an insidious and progressive loss of language. Two types of PPA were recognized: Progressive non-fluent Aphasia (APnF) and Progressive Semantic Aphasia (DS), and was recently identified as a new type, Logopénica Progressive Aphasia (APL). We describe a case evaluated at the University of Chile Clinical Hospital of a woman of 54 years who have a history of 2-3 years of fluent speech with reduced speed due to the difficulty in finding words, had shortcomings in repetition of complex words, phrases and sentences, presence of phonemic paraphasias and impaired episodic memory. What in the phonological assessment supports a diagnosis of APL. Despite the above, the neurological examination was normal. The APL has been associated with Alzheimer's disease because it presents impaired episodic memory and the neuropathological changes most frequently encountered are amyloid plaques and neurofibrillary tangles. Through this article you may learn more about this disease and who to go if you or some colleague have symptoms to receive some guidance.

Con el progresivo envejecimiento de la población Chilena el diagnóstico de enfermedades neurodegenerativas es cada vez más com ún, y entre ellas está la afasia progresiva primaria (PPA), de síntomas específicos pero consulta tardía. PPA es un síndrome clínico caracterizado por la degeneración de las regiones del lenguaje en el hemisferio dominante que determina una pérdida insidiosa y progresiva del lenguaje. Fueron reconocidos dos tipos de PPA: Afasia Progresiva no fluente (APnF) y Afasia Progresiva Semántica (DS), y recientemente fue identificado un nuevo tipo como, Afasia Progresiva Logopénica (APL). Se describe un caso evaluado en el Hospital Clínico Universidad de Chile de una mujer de 54 años que presenta una historia de 2-3 años de habla fluida, con disminución de la velocidad debido a la dificultad para encontrar palabras, presentaba fallas en repetición de palabras complejas, frases y oraciones, presencia de parafasias fonémicas y problemas de memoria episódica. Lo que en la evaluación fonológica es compatible con un diagnóstico de APL. A pesar de todo lo anterior el examen neurológico fue normal. La APL se ha asociado con la enfermedad de Alzheimer, ya que presenta deterioro de la memoria episódica y los cambios neuropatológicos más frecuentes son las placas amiloides y los ovillos neurofibrilares. A través de este artículo podrán conocer más acerca de esta enfermedad y a quien acudir en caso de presentar síntomas usted o algún conocido para recibir alguna orientación.

Characterization of cryptic rearrangements, deletion, complex variants of PML, RARA in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation t(15;17)(q22;q21) leading to the disruption of Promyelocytic leukemia (PML) and Retionic Acid Receptor Alpha (RARA) followed by reciprocal PML–RARA fusion in 90% of the cases. Fluorescence in situ hybridization (FISH) has overcome the hurdles of unavailability of abnormal and/or lack of metaphase cells, and detection of cryptic, submicroscopic rearrangements. In the present study, besides diagnostic approach we sought to analyze these cases for identification and characterization of cryptic rearrangements, deletion variants and unknown RARA translocation variants by application of D-FISH and RARA break-apart probe strategy on interphase and metaphase cells in a large series of 200 cases of APL. Forty cases (20%) had atypical PML–RARA and/or RARA variants. D-FISH with PML/RARA probe helped identification of RARA insertion to PML. By application of D-FISH on metaphase cells, we documented that translocation of 15 to 17 leads to 17q deletion which results in loss of reciprocal fusion and/or residual RARA on der(17). Among the complex variants of t(15;17), PML–RARA fusion followed by residual RARA insertion closed to PML–RARA on der(15) was unique and unusual. FISH with break-apart RARA probe on metaphase cells was found to be a very efficient strategy to detect unknown RARA variant translocations like t(11;17)(q23;q21), t(11;17)(q13;q21) and t(2;17)(p21;q21). These findings proved that D-FISH and break-apart probe strategy has potential to detect primary as well as secondary additional aberrations of PML, RARA and other additional loci. The long-term clinical follow-up is essential to evaluate the clinical importance of these findings.

Análise do desenvolvimento de Arranjos Produtivos Locais (APLs): um estudo de caso do município de Paraty (RJ) / Development analysis of local productive arrangements (LPA): a study case of Paraty (RJ)

Este trabalho aborda o desenvolvimento local no município de Paraty, através da formação de APLs, especificamente neste caso voltados para a atividade turística. Através de informações obtidas por análise documental e entrevistas, pode-se analisar as potencialidades da região e apontar caminhos para incremento de sua competitividade, principalmente no que tange à integração e à formação de parcerias entre empresas, comunidade e poder público. Além disso, foram feitas sugestões para superar obstáculos, vencer desafios e aproveitar oportunidades, baseadas na vocação turística, para que a região se torne competitiva no mercado de destinos turísticos, fidelizando e ampliando a base de turistas, através do melhor aproveitamento de seus encantos naturais, históricos e culturais. Os principais resultados mostram que Paraty carece de melhorias de infraestrutura para desenvolver o turismo local, que vão desde o saneamento básico até o melhor treinamento e capacitação de mão de obra. Além disso, toda a estrutura existente ainda não pode ser considerada efetivamente um APL, apesar de já se observar uma organização da rede de pequenas e médias empresas voltada para o desenvolvimento turístico sustentável do município. O que se encontra, em termos de organização em rede, é um APL ainda informal, onde praticamente inexiste a liderança e a confiança interna.

This paper discusses the development in the municipality of Paraty, through the formation of LPAs, specifically in this case focused on tourism. By the information obtained through interviews and document analysis, we can analyze the region's potential and show ways to improve their competitiveness, especially regarding the integration and formation of partnerships between business, community and government. In addition, suggestions were made to overcome obstacles, overcome challenges and seize opportunities, based on tourist so that the region becomes competitive in the market of tourist destinations, customizing and expanding the base of tourists through the best use of their natural charms, history and culture. The main results show that Paraty lacks infrastructure improvements to develop local tourism, ranging from the basic sanitation to the best training and qualification of workforce. Moreover, the entire existing structure still can not be effectively considered an LPA, in spite of a network organization of small and medium enterprises focused on sustainable tourism development in the municipality. What becomes clear in terms of networking, is an informal LPA, where nonexistent leadership and inner confidence.

A variant acute promyelocytic leukemia with t(11;17) (q23;q12); ZBTB16-RARA showing typical morphology of classical acute promyelocytic leukemia / 대한혈액학회지

A subgroup of acute leukemia with morphology resembling acute promyelocytic leukemia (APL) shows variant translocations involving RARA and has a different morphology from that of classical APL. The variant APL with t(11;17)(q23;q12); ZBTB16-RARA subgroup has been reported to have leukemic cells with regular nuclei, many granules, absence of Auer rods, an increased number of Pelgeroid neutrophils, strong myeloperoxidase (MPO) activity, and all-trans-retinoic-acid (ATRA) resistance. Here, we report a case of variant APL with t(11;17)(q23;q12); ZBTB16-RARA showing typical morphological features of classical APL, including numerous Auer rods and faggot cells. The leukemic cells expressed CD13, CD33, CD117, human leukocyte antigen (HLA)-DR, and cytoplasmic-MPO on the immunophenotyping study. The diagnosis was confirmed by cytogenetic and molecular studies. To distinguish variant APL cases from classical APL cases, regardless of whether morphologically the findings are consistent with those of classical APL, combining morphologic, immunophenotypic, cytogenetic, and molecular studies before chemotherapy is very important.

Long-term survival in a patient with acute promyelocytic leukemia with isolated meningeal relapse / 대한혈액학회지

The meningeal involvement is rare in acute promyelocytic leukemia. We experienced a 39-year-old woman who achieved complete remission with all-trans retinoic acid, idarubicin and cytarabine therapy. Several months later, she complained of non-specific headache. Her complete blood cell count was normal, but magnetic resonance image of brain revealed focal meningeal enhancement and cerebrospinal fluid showed leukemic promyelocytes and PML/RARA rearrangement. Bone marrow study showed hematologic, cytogenetic and molecular remission. She was treated with intrathecal and systemic chemotherapy and whole brain radiotherapy. The patient has survived for 68 months since the last systemic chemotherapy.

PML-RARalpha gene detection method optimization for quantitative PCR

Hybrid gene PML-RARα is the molecular target found in most cases of acute promyelocytic leukemia (APL) and has been used for diagnosis and minimal residual disease studies. The standard molecular technique employed is qualitative reverse transcriptase-polymerase chain reaction (RT-PCR), but with the emergence of real time PCR (Q-PCR), PML-RARα gene detection approaches have been described allowing transcript detection, with the methodological advantage of eliminating post-PCR processing. However, current protocols report the use of expensive fluorescent labeled probes, limiting its routine application in the laboratory. The objective of this study was to optimize PML-RARalpha gene detection method for Q-PCR, using SYBR® Green fluorescent dye. The analysis was performed with NB4 cellular lineage cDNA. Thermal cycling protocols, cDNA synthesis with random or specific primer and different MgCl2 and amplification primers concentrations were tested. Results show that amplification improved in the following conditions: 2 mM MgCl2, 10 pmol primers and cDNA synthesized with specific primer. There were no significant differences using annealing temperature (58ºC/30 s) followed by extension (72ºC/30 s) or annealing associated with extension as a single step (60ºC/45 s). This paper demonstrates the optimization of PML-RARα gene detection for Q-PCR studies using a technique considered sensitive and less expensive for routine use in the laboratory.

O gene híbrido PML-RARα é o marcador molecular presente na maioria dos casos de leucemia aguda promielocítica (LAP), sendo útil ao diagnóstico e ao estudo da doença residual mínima. A técnica molecular empregada como rotina laboratorial é a reação em cadeia da polimerase com transcrição reversa (RT-PCR) qualitativa, porém com o surgimento da PCR em tempo real (Q-PCR), foram descritas abordagens de detecção do gene PML-RARalfa possibilitando a quantificação de transcritos, com a vantagem metodológica da eliminação do processamento pós-PCR. No entanto, os protocolos relatam o uso de sondas fluorescentes de custo elevado para a rotina clínica, limitando sua aplicação. Este estudo teve como objetivo otimizar o método de detecção do gene PML-RARα para Q-PCR, utilizando como sistema de marcação fluorescente o intercalante SYBR® Green. A análise foi realizada com cDNA da linhagem celular NB4, tendo sido testados protocolos de termociclagem, síntese de cDNA com primer randômico ou específico e diferentes concentrações de MgCl2 e primers para amplificação. Os resultados mostraram amplificação mais eficiente nas seguintes condições: 2 mM MgCl2, 10 pmol de primers e cDNA sintetizado com primer específico. Não houve diferença na utilização de etapas para anelamento (58ºC/30 s) seguido de extensão (72ºC/30 s) ou etapa única de anelamento associado à extensão (60ºC/45 s). Esses resultados demonstram a otimização da detecção do gene PML-RARα para Q-PCR através de um método considerado sensível e de baixo custo para a rotina laboratorial.

Real-Time PCR analysis of af4 and dek genes expression in acute promyelocytic leukemiat (15;17)patients

Among several newly identified oncogenes, dek and af4 are attractive targets for researchers interested with leukemia. In this study quantitative Real-Time RT-PCR technique was used to define alterations in expression of dek and af4 genes associated with acute promyelocytic leukaemia (APL) t (15; 17). RNA samples obtained from bone marrow aspirates of fourteen APL patients, cDNA portions were labelled with Syber Green 1 dye and LightCycler analysis have been performed. Expression changes in patients were found not significant in comparison to healthy donors for af4 (P=0.192) and dek (P= 0.0895). We suggest that af4 gene may have a role in leukomogenesis restricted to lymphoblastic lineage; also further studies must carry on with a larger series of patients in order to understand the relationship between the dek gene and APL. Our study was the first attempt for analysing dek and af4 genes in APL t (15; 17) patients by quantitative Real-Time RT-PCR. This rapid and sensitive method could be used to screen these genes in different types of leukaemia.

Influence of Antiphospholipid Antibodies on IVF-ET Outcome in Women Referred for IVF-ET / 대한산부인과학회잡지

OBJECTIVE: The present study was designed to investigate if antiphospholipid antibodies (aPL) could affect the pregnancy outcome in women undergoing in vitro fertilization and embryo transfer (IVF-ET). MATERIALS AND METHODS: From January 1997 to June 2001, 9 women with aPL who underwent IVF- ET were studied. Forty-five women without aPL who underwent IVF-ET served as control. Anticardiolipin antibody (aCL) IgG, IgM, lupus anticoagulant (LA) were assayed with use of standardized enzyme linked immunosorbent assays (ELISA) and dilute Russell's viper venom time (dRVVT) test. Long protocol of gonadotropin-releasing hormone agonist (GnRH-a) was used for controlled ovarian hyperstimulation (COH) in all patients. Statistical analysis was performed using Student's t-test, Fisher's exact test, and x2 test as appropriate. Statistical significance was defined as p<0.05. RESULTS: There were no significant differences between the study and control groups in patient characteristics such as age, infertility duration, hormonal profile, cause of infertility and number of previous IVF attempts. There were also no significant differences between two groups with respect to clinical response to COH and IVF results such as number of retrieved oocytes, fertilization rate, number of embryos frozen and number of embryos transferred. The clinical pregnancy rate per cycle seemed to be higher in the study group than in the control group (25.0% vs 14.9%), however, the difference was not statistically significant. Miscarriage rate per clinical pregnancy was significantly higher in the study group at 67.0% (4/6) compared with 29.4% (5/17) in the control group. Delivery rate per clinical pregnancy was significantly lower in the study group at 16.7% (1/6) compared with 58.8% (5/17) in the control group. CONCLUSION: Women with aPL undergoing IVF-ET may have similar IVF outcome compared with women without aPL, except miscarriage rate per clinical pregnancy.

Simulated experiment in vitro of APL specialized by arsenic trioxide acid infiltrating into the human lung / 中国实用内科杂志

Objective To explore the molecular pathological mechanism and treatment of retinoic acid syndrome(RAS).Methods SDF-1? of health adult lung was measured by RT-PCR,CXCR4 on the cell membrane of APL specialized by arsenic trioxide(APL/ATO)were tested by FCM,and we used the rotary cell culture system(RCCS)to build the model of simulated experiment in vitro of APL/ATO infiltrating into the human lung;observe if Dex,Ara-C and DNR can influence the ability of APL/ATO in adhesion,transplantation and infiltration.Results The APL/ATO could evidently infiltrate into human lung,mean fluorescence intensity(MFI)of CXCR4 on the cell membrane of APL/ATO was 28.77?1.05,which was much higher than the unspecialized APL(9.20?4.14).Contrast to control cells,Dex could dramatically restrain the ability of APL/ATO in adhesion and transference [(29.91?2.70)% vs(48.20?5.00)%,30.01?5.01 vs 60.10?3.02],while Ara-C and DNR could distinctly depress the ability of APL/ATO in adhesion,transplantation and infiltration[(30.10?3.00)%﹑(32.20?2.20)% vs(48.20?5.00)%;28.01?5.00,24.02?4.01 vs 60.10?3.02;18.20?3.56,16.01?3.25 vs 46.01?4.05].Conclusion High expression of CXCR4 on APL/ATO and SDF-1?in the lung may be one of the molecular mechanism of the lung infiltration and RAS;DEX、Ara-C and DNR can restrain the ability of APL/ATO in adhesion,transplantation and infiltration.

A Case of Relapsed Acute Promyleocytic Leukemia Induced Remission with Arsenic Trioxide(As2O3)

Acute promyelocytic leukemia(APL) is a unique entity in the spectrum of acute myelogenous leukemia. It has several characteristic features, including distinctive morphology, chromosomal translocation, t(15:17), disseminated intravascular coagulation and effect on retinoic acid. Retinoic acid which is a derivative of vitamin A induces differentation of APL cells in vitro and in vivo, but its cessation induces relapse of APL. Arsenic trioxide(AszOz) can induce clinical remission in patients with APL, including those who have relapsed after retinonic acid treatment. We report a case of a 9-year-old male with APL who had relapsed after cessation of retinoic acid treatment. The patient successfully achieved remission following treatment with AsO. Arsenic trioxide treatment would be an effective and relatively safe drug in childhood APL patients refractory to retinoic acid.

Anticancer Effect of Arsenic Trioxide in Acute Promyelocytic Leukemia

PURPOSE: Acute promyelocytic leukemia (APL or AML, M3) represents an unique model for cancer research in terms of biological and clinical features. Since 1988, it has been widely confirmed that all-trans retinoic acid (ATRA) can induce complete clinical remission in over 85% of APL patients by a differentiation process, with PML-RARalpha protein possibly being the direct target of ATRA. However, ATRA treatment has two clinical limitations, namely, retinoic acid syndrome and retinoic resistance. Recently, it has been shown that arsenic trioxide used in some traditional Chinese remedy is very effective in retinoic resistant APL treatment. We tried to observe arsenic effect on cell lines and APL patient cells. MEHTODS: We investigated arsenic trioxide-induced apoptosis on APL, HL60, K562, KPH1 cell lines through MTT assay, DNA fragmentation assay and morphologic features. RESULTS: In MTT assay, cell survival rate decreased as the concentration of arsenic trioxide increased. In DNA fragmentation assay with HL60 cell line, DNA fragmentation was more frequent in high concentrations of arsenic trioxide than in low concentrations. During arsenic trioxide treatment, the morphologic change in bone marrow cells of APL patient, included nuclear differentiation and dark cytoplasmic granule during arsenic trioxide treatment. Serum arsenic reached peak level at 4hr after injection. We experienced a case of a 9-year-old male with APL who had relapsed after cessation of retinoic acid treatment. The patient successfully achieved remission following arsenic trioxide treatment without bone marrow depression and exacerbating bleeding diathesis. CONCLUSION: Arsenic trioxide can be used effectively to treat APL patients by inducing apoptosis and partial differentiation in tumor cells. The precise cellular and molecular mechanisms of its therapeutic effects remain to be determined.

Treatment of Acute Promyelocytic Leukemia (APL) by a Combination of All-Trans Retinoic Acid (ATRA) and Chemotherapy / 대한혈액학회지

BACKGROUND: All-trans-retinoic acid (ATRA) induces complete remission (CR) in the great majority of patients with PML/RAR -positive acute promyelocytic leukemia (APL). However, it is associated with a rapid rise in leukocytes in one third to half the patients, with potentially fatal "ATRA syndrome". Furthermore, most of the patients relapse with maintenance therapy using ATRA alone or low-dose chemotherapy. In this study, we have analyzed the outcome for APL patients who were treated with ATRA alone or combined with low-dose chemotherapy followed by postremission chemotherapy in Chonnam University Hospital from April 1993 to December 1997. METHODS: Sixteen patients with newly diagnosed APL were eligible to analysis. Patients received 45mg/m2 ATRA until CR occurred. If initial WBC were above 5,000/microliter, low-dose chemotherapy was concomitantly given, and if during the ATRA therapy WBC were above 5,000/microliter by day 5 or 10,000/microliter by day 10, or 15,000/microliter by day 15, low-dose chemotherapy was added. Four polychemotherapy cycles or allogeneic bone marrow transplantation were given as postremission therapy. RESULTS: Median age was 34 years (range, 17 to 67). Of 16 APL patients, 15 (93.8%) achieved CR and 1 (6.2%) died of intracerebral hemorrhage. After a median follow-up of 11.5 months (range, 0 to 47), the Kaplan-Meier estimated overall survival (OS) rate was 87.1 +/- 8.6% at 3 year, the event-free survival (EFS) rate was 87.1 +/- 8.6%, 58.0 +/- 24.4% and 29.0 +/- 23.9% at 1 year, 2 year and 3 year, and the disease-free survival (DFS) rate was 92.9 +/- 6.9%, 69.6 +/- 20.7% and 46.4 +/- 23.5% at 1 year, 2 year and 3 year, respectively. CONCLUSION: The present study suggests that ATRA with or without low-dose chemotherapy followed by postremission chemotherapy is a well-tolerated and effective regimen that is shown to improve the CR rate, reduce a early mortality rate and considerably prolong the overall survival in patients with newly diagnosed APL.