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  Clinical aspects of leukemia, a brief literature review
08/05/2016

MARCONI MARTINS JOSE
MG - BELO HORIZONTE
Leukemia erythroid Acute is a form of the hematopoietic system neoplasia presentation is classified as a form of acute myelogenous leukemia There are several types of leukemias are two major types which are acute leukemias responsible for variable th

Área(s) de Atuação que o Presente Artigo trata
Biologia
Saúde
Análises Clínicas


1.        INTRODUCTION:

Acute erythroid leukemia is a malignancy form of presentation of the hematopoietic system in which there is involvement of immature cells of the erythroid compartment (Valli et al. 2002). According to the Group of French-American-British Studies (Group FAB) (Bennett et al. 1976) and the World Health Organization (WHO) (Jaffe et al. 2001), which is based on the Clinical Advisory Committee Meeting, held in Airlie House, Virginia, November 1997 (. Harris et al 2000), acute erythroid leukemia is classified as a form of acute myelogenous leukemia (AML M6) and subdivided into two forms of clinicopathological presentation: LMA M6A, most often described in humans ( Valli 2007a), and AML M6B, more commonly reported in animals, especially in mice (D'Andrea & Ney 2000 Moreau-Gachelin 2006) and cats (Jain et al., 1991, Valli 2007a, b), and rarely in dogs (Anderson & Johnson 1962 Groulade & Guillon 1967 Liu & Carb 1968 Tolle et al. 1977), cattle (Watanabe et al. 1998), chimpanzees (McClure et al., 1974) and rats (Groulade & Guillon 1967 Bird & Huggins 1971). The first, also known as erythroleukemia, bilinhagem consists of a neoplasm, involving myeloblasts, and erythroblasts (Bennett et al., 1976, Jain et al., 1991, Harris et al., 2000). The second, also called mielose eritrêmica (Bennett et al., 1976, Valli 2007a, b) pure erythroid leukemia (Harris et al., 2000, Jaffe et al. 2001), erythroleukemia predominantly erythroid (Jaffe et al., 2001), AML M6Er (Jain et al. 1991) and acute eritremia (Jarrett & MacKey 1974), is a disorder that affects only the erythroid lineage (Bennett et al., 1976, Jain et al. 1991).

The acute lymphoblastic leukemia (ALL) has a low cure rates in poor countries, which did not occur in developed countries. This disparity is justified due to the high number of children who abandon treatment for lack of financial, cultural and structural conditions; Apart from toxicity of treatment. While some hospitals focus their treatment programs to improve the quality of life for the survivors. Childhood leukemia is a rare disease; its incidence is estimated at three to four new cases per 100,000 children under 15 years old.

There are several types of leukemias are two major types that are responsible for the acute leukaemias variable that produces the type of leukemia that can be treated with chemotherapy that are lymphoblastic leukemias and acute myeloblastic leukemia Acute. There is one more type of leukemia that can be used to treat medullary transplantation that has two variables lymphoblastic leukemia Chronic and Chronic Leukemias Mieloplásticas. Try to it through this study found such a theoretical hypothesis.

This paper aims to conceptualize leukemia and identify which type of leukemia should be adopted chemotherapy, radiotherapy or marrow transplantation, and describe the types of leukemias; present main parameters of leukemias; laboratory and identify the best approach for the treatment of leukemia parameters.

 

2.        METHODOLOGY:

To carry out this work was carried out literature review in Brazilian and foreign journals in Portuguese and English being translated into Portuguese, national books used in medical academies from 2000 to 2015. We opted for the search in SciELO platform (Scientific Electronic Library online) portal of CAPES, and national books, LICACS platform (health Library). We attempted to collect the data and scientific articles. After this collection, he selected those that best fit the job profile and then carried out the compilation of information and the construction of the text.

 

3.        REFERENCIAL TEÓRICO:

Leukemias are cancers of the blood cells and these can affect the entire bone marrow, to the point of preventing the production of normal blood cells (bone marrow failure), leading to bleeding frames of variables, infection and anemia. Leukemias are divided into acute and chronic.

The group of acute myeloblastic leukemias are divided into lymphoblastic and, with that differentiation is done in the source cell from each group. Generally acute leukemias have a very rapidly evolving, requiring early diagnosis and prompt treatment. Despite being a rare type of cancer, acute leukemia has a high death rate in people eat the age of 35 years. The incidence of leukemia is similar around the world, and among the acute leukemias, the myeloblastic has a slight predominance of lymphocytic. They are more prevalent in men, with the largest number of cases in Caucasians. The age of the patients greatly differ between two groups, and acute lymphocytic leukemia (ALL) very common to 10 years of age and acute myeloid leukemia (AML) very common on average 65 years old. The treatment for the two groups are also very different. Furthermore acute myelogenous leukemia have a poorer prognosis than chronic.

Leukemia is a cancer that affects the white blood cells produced by the bone marrow. It is a disease that is characterized by abnormal accumulation of leukocytes in the bone marrow, hindering or preventing the production of red cells, white cells and platelets. These abnormal cells, called leukemic cells or cancer cells can invade other organs such as liver, spleen, lymph nodes, kidneys and brain. Leukemia is classified according to the type of leukocyte that affect, and are therefore called lymphocytic leukemia, acute lymphoblastic or lymphocytic when it reaches the lymphocytes; and myeloid leukemia, when it reaches the myelocytes. Moreover, it can present itself in two forms, acute and chronic. In the acute form, the cells are immature, do not play their role as they should and reproduce rapidly; while the chronic form, the cells are mature, and can keep some of its functions, and reproduce slowly.


 

The Acute Lymphoblastic Leukemia is most common in children but may affect people over the age of 65 years, while the acute myelogenous leukemia is more common in adults. Chronic lymphocytic leukemia usually affects adults over the age of 55 years and rarely occurs in children, and chronic myelogenous leukemia mainly affects adults.

 

Damage to the bone marrow resulting in lack of blood platelets which are important for the coagulation process. This means people with leukemia may bleed excessively. The leukocytes, which are involved in fighting pathogens, may be suppressed or no function, putting the patient at risk of infections.

Since erythrocyte deficiency causes anemia, which may cause shortness of breath and fatigue. There may be pain in the bones or joints because of the extent of cancer in those areas. Headache and vomiting may indicate that the cancer has spread to the central nervous system. In some types of leukemia can be enlarged lymph nodes. All of these symptoms can also be attributed to other diseases. For the diagnosis you need to do tests that are physical examination (changes of the lymph nodes, spleen and liver) and laboratory analysis.

The tests used for diagnostic purposes are: CBC, coagulation test routine chemical tests (electrolytes, creatinine, etc.) and blood smears of bone marrow and in some instances, the bone marrow biopsy. More advanced studies such as phenotyping, cytogenetics and molecular biology are indicated. With regard to risk factors previously quoted chemotherapy, radiotherapy and the treatment itself of LLA. Add to these well-defined factors such as exposure to ionizing radiation and benzene, in addition to smoking. A viruses (HTLV 1) has been identified as a cause of leukemia / lymphoma. Epstein-Barr virus has also been associated with certain types of leukemia. It should be remembered that the syndromes also increase the risk such as Down, Fanconi anemia and ataxia-telangiectasia.

In laboratory tests it is possible to realize: a) Large increase in white blood cell count, or decreased thereof; b) low levels of platelets and hemoglobin, and c) in patients already diagnosed with acute lymphoblastic leukemia, these tests can help detect liver or kidney problems caused by leukemia cells or side effects of certain chemotherapy drugs.

Investigations are conducted as follows:

 

·                     Biopsy: check for cancer cells. A biopsy is the only sure way to know if the tumor cells are in bone marrow.
            There are two ways to get bone marrow:

 

a)    bone marrow aspiration - performed to tell if the leukemia is responding to treatment;

b) Biopsy bone marrow - note the size, shape and other characteristics of white blood cells in the samples classifying them in específicos.importante types is whether the cells look mature (similar to normal blood cells) or immature (without features of Sangui cells normal -neas). The most immature cells are called lymphoblasts. determining the percentage of cells in bone marrow are blast cells. A diagnosis of acute lymphocytic leukemia requires geralmen you that at least 20% to 30% of the cells in the bone marrow are blast cells. Under normal circumstances, the blasts are never more than 5% of bone marrow cells. However, they are sometimes required other laboratory tests to make a definitive diagnosis.

·                    Cytogenetics: Analysis of the harvested cell chromosomes from peripheral blood samples, bone marrow or lymph nodes. Is the application of dyestuffs to biochemical blood cells and bone marrow, in order to show its composition without appreciably modifying the morphology. The cytochemical stains help in the diagnosis of leukemias and other haematological malignancies.

·                    Flow cytometry and immunohistochemical - Flow cytometry is done with a whip-apa that can make individual measurements of thousands of cells, an accurate count is es sential for the disease treatment efficiency. This technique is often used to examine cells from bone marrow, lymph nodes and blood samples for diagnosing leukemias. They are analyzed by means of monoclonal antibodies labeled with fluorescent substances.

·                    Cytogenetics - In this test, the chromosomes of the leukemic cells are analyzed pa-ra detect any abnormality. In some cases of leukemia cells present cro-mossômicas changes visible under the microscope. Most chromosomal abnormalities in adults with acute lymphoblastic read-cemia is the type of translocation. The information about the translocation type can be useful in predicting the therapeutic response of a patient.

·                    Fluorescent In Situ Hybridization (FISH) - This is another type of test that evaluates the chromosomes using fluorescent dyes that only bind to specific parts of s-cific chromosomes. The FISH test detects most chromosome abnormalities (translocations), visible to the mi-croscópio in cytogenetic tests, as well as minor changes not seen in cytogenetic tests.

·                    Chain Reaction Polymerase (PCR) - This is an examination of very sensi-level DNA, which allows find small chromosomes, not visible under the microscope, even when few leukemic cells are present in the sample. As the FISH assay is used to diagnose specific genetic changes. In acute lymphoblastic leukemia, it is often used to diagnose the gene produced by the Philadelphia chromosome.

·           Lumbar puncture: Analysis of the cerebrospinal fluid.

·           Chest X-ray: X-rays are important to evaluate indirectly the pul-Mões and heart.

 

There is often a delay in diagnosis of ALL, because the first symptoms are usually vague, unspecific or silent; Additionally, there may be a previous history of respiratory or exanthematous viral infection that has not solved completely. However, its rapid progression, some are diagnosed earlier. With evolution, the clinical signs and symptoms reflect the bone marrow failure in providing hematopoiesis due to replacement of normal hematopoietic elements by leukemic cells (blasts), resulting in anemia, neutropenia and thrombocytopenia (Cornacchioni, 2004). Usually these are the signs that lead physicians to request laboratory diagnostic tests. The extramedullary involvement may occur mainly in the central nervous system, testis, liver, kidney, spleen, ovaries and eyes. predilection sites in the relapse of acute lymphoblastic leukemia are the CNS and testicles. Leukemia, when it affects the CNS, have the diagnosis established by the meeting of blasts in the cerebrospinal fluid. Already testicular involvement is mainly revealed by painless enlargement, unilateral or bilateral (CRIST, 2002).

The LLA is further classified according to morphological, immunological, molecular cytogenetic and genetic of leukemic cells (CHRIST, 2002). Clinical forms of the LLcTA characterized into four subtypes: acute leukemic, lymphoma, Chronic and smoldering (oligo-symptomatically). In addition to these well-defined subtypes of clinical and laboratory criteria, there is a borderline state between asymptomatic individuals LLcTA, which is termed as pre-stage LLcTA. This asymptomatic phase there is the presence of atypical circulating lymphocytes may spontaneously disappear and the condition is defined by the monoclonality of the proviral insertion of HTLV-I on CD4 + T lymphocytes (Smith, 2002).

Thus, the diagnosis is suggested by the presence of blast cells in the peripheral blood smear, but is confirmed by morphology (FAB classification - proposed by British American Franco group) of cytochemical reactions, cytogenetics and immunophenotyping of bone marrow blasts peripheral blood or bone.

The morphologic classification (FAB) subdivides the lymphoblasts in L1 (85% of cases), L2 (14%) and L3 (1%), but what does not define the lineage and maturation stage the realization of immunophenotyping and cytogenetics is critical to the complementary diagnosis. Cytogenetic abnormalities are important for the response to the treatment and prognosis of the disease, whereas hyperploid blasts have favorable prognoses and translocations t (9; 22), t (4; 11) and t (1; 19) are associated with a poor prognosis. The immunophenotyping reactions assess cellular antigens expressed on leukemic blasts by flow cytometry; allow the classification, the determination of lines and lymphoid differentiation stages and still enable differentiation between the lymphoid lineage and myeloid and phenotypes aberrant useful in monitoring treatment (minimal residual disease) (SILVA, 2004)

Some clinical and laboratory characteristics of patients with LLA have prognostic value, so are stratified at diagnosis subgroups with favorable and unfavorable outcomes, guiding treatment. The initial white blood cell count is the most significant factor on the prognosis unfavorably evolving those cases with WBC> 50,000 / mm3. Children under the age of 18 months or greater than ten years also have worse prognosis. Because of the ease in the evaluation, the WBC count and age at diagnosis became reliable basis for risk stratification for patients with ALL. Regarding chromosomal characteristics, there is a better prognosis conditioned by hyperdiploidy. Moreover, certain chromosomal translocations are associated with high rates of early virological failure and relapse such as: T (8.14) T (4.11) T (4.19) t (11,22) (Cornacchioni , 2004).Some clinical and laboratory characteristics of patients with LLA have prognostic value, so are stratified at diagnosis subgroups with favorable and unfavorable outcomes, guiding treatment. The initial white blood cell count is the most significant factor on the prognosis unfavorably evolving those cases with WBC> 50,000 / mm3. Children under the age of 18 months or greater than ten years also have worse prognosis. Because of the ease in the evaluation, the WBC count and age at diagnosis became reliable basis for risk stratification for patients with ALL. Regarding chromosomal characteristics, there is a better prognosis conditioned by hyperdiploidy. Moreover, certain chromosomal translocations are associated with high rates of early virological failure and relapse such as: T (8.14) T (4.11) T (4.19) t (11,22) (Cornacchioni , 2004).

Remember the cases of leukemia that occur secondarily, ie, have a well-defined cause that promoted these being the minority. In most cases there is no well-defined cause for the disease. In cases of secondary leukemia, we can highlight, as risk factors, previous treatment of Hodgkin's disease, and use of some chemotherapeutic treatment of own LLA. The clinical presentation of these tumors are non-specific, but the clinical history and findings on physical examination, the diagnosis is made most often. The patient usually presents with a complaint of weakness for about 1 to 3 months, small weight loss, fever, bone and abdominal pain, shortness of breath and more importantly, bleeding and training easily bruising. Physical examination may be noted the presence of signs of bleeding (hematoma and petechiae) and consistent pallor with anemia and bleeding. Increasing the size of the liver, spleen and lymph nodes are unusual findings in acute leukemia. Already laboratory tests show a decrease in platelets and red cells. The white blood cells may vary widely in amount.

Chronic leukemias also have myelogenous and lymphocytic form. Chronic lymphocytic leukemia (CLL) is the most common leukemias. Despite all the advances in knowledge about the disease and the form of treatment currently most advanced, there has been no change in patient survival. Chronic lymphocytic leukemia usually presents itself in patients aged over 60 years, which is why often aggressive chemotherapy is not used, thus achieving near-cure rates of zero. Another reason that the treatment to be made of palliative treatment is the characteristic of the disease that often does not require therapeutic intervention, living the patient about 20 years without major problems.

It is important to differentiate the patient that need not need treatment. This decision is based on results of blood tests and physical examination of the patient (disease staging). The diagnosis is performed basically in the same manner as in acute leukemias; what draws attention is that the involvement of the spleen, liver and lymph nodes is more common in chronic leukemia. Other forms of leukemias should be considered as pro-lymphocytic leukemia, chronic lymphocytic leukemia and T-cell hairy cell leukemia. It remains to comment on chronic myelogenous leukemia, o¬nde is a gradual replacement of bone marrow cells by mature myeloid cells, which are insensitive to cell proliferation control, which may progress to severe anemia, decreased platelets and involvement of virtually all organs body (blast crisis).

According to literature, the results are promising more studies need to delve into the matter and improve treatment. Examinations are many however is no need for knowledge of the clinical staff to better serve the choice and speed the results and know which exam request. The medical knowledge help on the tests to be ordered, its application and the results you get are essential for effective treatment. Do not just order tests that where not known the results or your application. Many tests are invasive and cause suffering to the patient and should be evaluated prior to your request. The treatments are good most need first of patient adherence to treatment because of its high cost and the effectiveness of treatment is indexed to its continuity. There are simple tests such as blood count as there is also the more complex and more expensive as the biomolecular need of resources for their implementation and often own resources given that health plans do not cover.

 

4.        TREATMENT

Except for cases of transplant indication, the treatment of CML remains a challenge.
INCA guides that applies to the treatment of CML the second scheme:

· Alopurinol in the daily dose of 300mg - VO (adult) and 300 mg / m2 in children up to 40kg, and with abundant moisture.

· Leucoferese during pregnancy to avoid the use of chemotherapy and signs and symptoms of leukostases - for example, priapism - to a rapid reduction in tumor volume.

· hematologic Control with Hidroxiuréia

Adult: Start 2g / day - VO and keep 1-2g / day. Initial doses of 3 to 4 g / day can be used for short periods in patients with very high white blood cell count. The maintenance dose is adjusted as leucocytes, and should be discontinued if the leukocyte count is below 2,500 / mm3 and platelet count, 100.000 / mm3 turning the maintenance dose when ontagens tend to normal.

Child: the child under 30kg, the hydroxyurea is prescribed at a dose of 50mg / kg / day; and that over 30kg, 2g / m2 / day. In both cases, the maintenance dose of 10-30mg / kg / day, except for the interruption of taking the number of leukocytes is below 2,500 / mm3 and platelet count, 100.000 / mm3, turning the dose when maintenance tend to normal counts.

typing test for HLA-DR related donor research (patient aged less than 55 years) or unrelated (patients aged less than 50 years).

• allogeneic bone marrow transplantation (related or unrelated): for patients in chronic or accelerated phase under the age of 55 years (related) or up to 50 years of age (not related).

Alpha-Interferon - with gradual dose increases to reach 5,000,000 U / m2 / day - SC. If no Grade 3 or 4 toxicity as measurable criteria of the National Cancer Institute (NCI), international use, associating cytarabine 10 - 20mg / m2 / day - SC (maximum daily dose 40 mg) for 10 days each month.· Mesilato de Imatinibe - Doentes com mais de 18 anos.

It is suggested by INCA Paracetamol to prevent or control the side effects of Alpha-Interferon is prescribed according to the weight and age of the child. Not exceed 2.6g per day. Or, in the case of an adult at a dose of 750mg - VO 3 to 4 times daily. Do not exceed 4 g / day. According INCA both the use of interferon-alpha as in imatinib mesylate, the occurrence of intolerance (grade 3 toxicity and 4) indicates the temporary withholding drug in use, giving it the return it with a lower dose of the than previously used.

In case of toxicity of imatinib mesylate, the daily dose can be minimized 300mg, since below this dose not exhibit a therapeutic effect. If the degree of toxicity impose a temporary suspension of the drug, it can, overcome the toxic effect, restart it with the minimum daily dose (300mg) and gradually increase it until the daily dose that the patient tolerates, the limit of their recommended daily dose. If this lower dose or maximum tolerable dose fall short of the minimum effective therapeutic dose, definitely should be discontinued which is the two drugs mentioned.

 To control and know the clinical evolution of the patient should be done according to the INCA tests at every stage - weekly until stabilization of hematological indices: physical examination, complete blood count, platelet count, lactate dehydrogenase, uric acid, urea, creatinine and liver function tests.

 

• LMC em FC - blood count of 1/1 month and myelogram 6/6 months or suspected postremission relapse with cytogenetic examination (including percentage of cells with the Philadelphia chromosome).

• LMC em FA - blood count of 1/1 month and myelogram 3/3 months or suspected postremission relapse with cytogenetic examination (including percentage of cells with the Philadelphia chromosome).

LMC em FB - Weekly blood count to hematologic remission; then monthly. Myelogram 3/3 months or suspected postremission relapse with cytogenetic examination (including percentage of cells with the Philadelphia chromosome), remains hematologic remission.

Hematologic Response corresponds to 50% of the initial white blood cell count, maintained for at least two weeks. The Hematologic Complete Response occurs when the white blood cell count is below 10,000 / mm3, no pro-myelocytes or myeloblasts, less the 5% of myelocytes or metamyelocytes and platelet around 450,000 / mm3 maintained for at least four weeks.

Already Cytogenetic Response may be absent (> 90% cells positive Ph chromosome), lower (35% to 90% Ph chromosome positive cells); Part (5% to 34% Ph chromosome-positive cells); Complete (0% of cells positive with Ph chromosome) is greater than the sum of complete plus partial, i.e., <35% positive cells with Ph chromosome.

INCA alert that must be modified treatment when the following circumstances occur:

• Grade 3 toxicity and 4 of NCI - suspension Criterion both alpha interferon and Imatinib Mesylate.

• No complete hematologic response within three months, the duration of the use of interferon-alpha or imatinib mesylate.

• Complete cytogenetic response Absence or greater after at least 12 months of use of Alpha-Interferon (CML chronic phase).

• hematologic progression without changing phase CML, in the course of the use of Alpha-Interferon or Imatinib Mesylate.

• cytogenetic progression without changing phase CML, in the course of the use of Alpha-Interferon.

• CML phases of progression with or without hematologic relapse, the duration of use of Alpha-Interferon.

• CML phases of progression with hematologic relapse, the duration of the use of imatinib mesylate.

All processing to flee the above in their norms, according to the INCA, is considered experimental and irregular.

 

5.        CONSIDERATION FINAL

Some publications have shown that research in oncology field is growing. It can be seen that there is progress every day and dissemination of results and experiences internationally is increasingly common. The examinations and techniques in the diagnosis are becoming more accurate day precise which reduces the cost of treatment, agility and patient survival and quality. The work of this information is descriptive analysis of what is published at the time periodicals and INCA guidelines. Although leukemia is a laboratory diagnosis cancer, it is necessary to the doctor a good field of semiotics and semiotics for a quick physical diagnosis and early treatment as soon as possible for patient recovery or improvement in quality of life and quickly identify any signal poisoning treatment for proper fit. It was noted in articles the existence of large toxic effect of drugs used and suggested by INCA which makes aggressive and heavy treatment. This literature review attempted to gather knowledge from several authors to assist in future research.

 

6.        ACKNOWLEDGMENTS:

First а God qυе qυе allowed all this to happen ао long dе my life, nãо е only in recent years as a university, mаs that еm оs all times is the biggest qυе master one can know. My thanks friends Tec pathology 1º Sgt Evandro de Souza Nascimento, 3º Sgt Ronaldo Antônio da Silva, 1º Sgt Pathology Tec. Magno Eduardo Ferreira, 1º Sgt Pharmacy Tec. Samia Alessandra Aleixo Abbot, 1º Sgt  pathology Tec. Adriano Gonçalves dos Reis, Sub Ten biologist Claudine José da Silva, 1º Sgt Edson Ferreira dos Santos and all the friends of the PMMG Pharmaceutical Center who believed in me when Carlos Maj Eduardo Fernandes and 1º Ten Cristiano Marcio de Paula my bosses direct and fellow dе work pelа qυе friendship made dа of my specialization in Laboratory Medicine е qυе will continue present еm my life cоm sure. The UNA this university, sеυ faculty, direction е qυе administration oportunizaram а window qυе today glimpse υm upper horizon riddled pеlа acendrada confidence nо merit е ethics here today especially to Ms. Gustavo Oliveira Gonçalves. Mainly supporting me in difficult time I spent with the death of my father showing me that besides professionals have inexorable human qualities. And thank especially my fiancee Rosilene Ferreira de Souza who was always on my side in the most difficult hours of my life that always motivated me in the fight and to overcome every obstacle life.

 

7.        BIBLIOGRAFIA:

·                TOCHETTO, Camila; SOUZA, Tatiana M.; Barros, CLAUDIO S.L.; FIGHERA,  Rafael A. Aspectos epidemiológicos, clínicos, hematológicos e anatomopatológicos da leucemia eritroide aguda (LMA M6) em gatos. Pesq. Vet. Bras. V. 31, n.7:610-619, julho 2011

·                VERAS, Geni Lourdes de Resende Ramos; ARAGÃO, Vânia Maria de Farias; DOS SANTOS , Alcione Miranda. Leucemia linfoblástica aguda em São Luís. Aspectos clínicos e terapêuticos. RBM Jul 12 V 69 N 7

·                KA AS, Imbert P; MOREIRA C, Niang A; BAUJAT G, Seye MM; GUYON P. Epidemiology and prognosis of childhood cancers in Dakar, Senegal. Med Trop (Mars); v. 63:p.521-526, 2003.

·                SILVA DB, Pires MMS; NASSAR SM. Câncer pediátrico: análise de um registro hospitalar. J Pediatr; v.78, n.5: p.409-514, 2002.

·                SHOCHAT SJ et al. Childhood Cancer: patterns of protocol participation in a national survey. CA Cancer Journal for Clinicians; v.51, n.2:p.119-130, 2001.

·                CORNACCHIONI ALB; CRISTÓFANI LM, Almeida MTA; MALUF Júnior PT, ODONE Filho V. Recidivas extramedulares em leucemia linfocítica aguda: impacto da quimioterapia e definição de um grupo particularmente favorável. Pediatria; v.26: p.27-33, 2004.

·                CRIST, WM; SMITHSON WA. As leucemias. In: Behrman RE, Kliegman RM, Jenson HB. Nelson Tratado de Pediatria. 16ª ed. Ed. Guanabara Koogan; p.1519-1522. 2002.

·                SILVA YZ et al. Expressão dos marcadores mieloides e prognóstico das leucemias linfoides agudas. Pediatria; v.26:p.97-103, 2004.

·                SILVA, Fernanda Azevedo; MEIS, Ernesto, DOBBIN,Jane de Almeida; OLIVEIRA, Maria do Socorro Pombo de; Leucemia-linfoma de células T do adulto no Brasil: epidemiologia, tratamento e aspectos controversos. Revista Brasileira de Cancerologia, v.48, n.4, p585-595, 2002.

·                ROLDÁN, María Teresa Milanés; BUCHILLÓN, Rafael Losada; RAMÍREZ, Porfirio Hernández; LLANES, Olga M. Agramonte; MONZÓN, Edelis Rosell. Aspectos clínicos y epidemiológicos de la leucemia mieloide aguda en el anciano. Rev Cubana Hematol Inmunol Hemoter;v.18, n.1:p.25-33, 2002.

Condutas do INCA Leucemia mielóide crônica. Leucemia Mielóide Crônica. Revista Brasileira de Ca


MARCONI MARTINS JOSE
MG - BELO HORIZONTE

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