An analysis pipeline for understanding 6-thioguanine effects on a mouse tumour genome.

Mouse tumour models are extensively used as a pre-clinical research tool in the field of oncology, playing an important role in anticancer drugs discovery. Accordingly, in cancer genomics research, the demand for next-generation sequencing (NGS) is increasing, and consequently, the need for data analysis pipelines is likewise growing. Most NGS data analysis solutions to date do not support mouse data or require highly specific configuration for their use. Here, we present a genome analysis pipeline for mouse tumour NGS data including the whole-genome sequence (WGS) data analysis flow for somatic variant discovery, and the RNA-seq data flow for differential expression, functional analysis and neoantigen prediction. The pipeline is based on standards and best practices and integrates mouse genome references and annotations. In a recent study, the pipeline was applied to demonstrate the efficacy of low dose 6-thioguanine (6TG) treatment on low-mutation melanoma in a pre-clinical mouse model. Here, we further this study and describe in detail the pipeline and the results obtained in terms of tumour mutational burden (TMB) and number of predicted neoantigens, and correlate these with 6TG effects on tumour volume. Our pipeline was expanded to include a neoantigen analysis, resulting in neopeptide prediction and MHC class I antigen presentation evaluation. We observed that the number of predicted neoepitopes were more accurate indicators of tumour immune control than TMB. In conclusion, this study demonstrates the usability of the proposed pipeline, and suggests it could be an essential robust genome analysis platform for future mouse genomic analysis.

Case Report: Azathioprine: An Old and Wronged Immunosuppressant.

Mycophenolate rapidly substituted azathioprine (AZA) in transplant immunosuppression regimens since the 1990s, when early clinical trials indicated better outcomes, although opposite results were also observed. However, none of these trials used the well-established optimization methods for AZA dosing, namely, thiopurine methyltransferase pharmacogenetics combined with monitoring of the thiopurine metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). Resistance to optimize AZA therapy remains today in transplant therapy, despite the fact that thiopurine metabolite testing is being used by other medical disciplines with evident improvement in clinical results. In a previous analysis, we found that active 6-TGN metabolites were not detectable in about 30% of kidney transplant patients under continuous use of apparently adequate azathioprine dosage, which demonstrates the need to monitor these metabolites for therapeutic optimization. Two of four case studies presented here exemplifies this fact. On the other hand, some patients have toxic 6-TGN levels with a theoretically appropriate dose, as seen in the other two case studies in this presentation, constituting one more important reason to monitor the AZA dose administered by its metabolites. This analysis is not intended to prove the superiority of one immunosuppressant over another, but to draw attention to a fact: there are thousands of patients around the world receiving an inadequate dose of azathioprine and, therefore, with inappropriate immunosuppression. This report is also intended to draw attention, to clinicians using thiopurines, that allopurinol co-therapy with AZA is a useful therapeutic pathway for those patients who do not adequately form active thioguanine metabolites.

Ultrafast Excited-State Decay Mechanisms of 6-Thioguanine Followed by Sub-20 fs UV Transient Absorption Spectroscopy.

Understanding the primary steps following UV photoexcitation in sulphur-substituted DNA bases (thiobases) is fundamental for developing new phototherapeutic drugs. However, the investigation of the excited-state dynamics in sub-100 fs time scales has been elusive until now due to technical challenges. Here, we track the ultrafast decay mechanisms that lead to the electron trapping in the triplet manifold for 6-thioguanine in an aqueous solution, using broadband transient absorption spectroscopy with a sub-20 fs temporal resolution. We obtain experimental evidence of the fast internal conversion from the S2(ππ*) to the S1(nπ*) states, which takes place in about 80 fs and demonstrates that the S1(nπ*) state acts as a doorway to the triplet population in 522 fs. Our results are supported by MS-CASPT2 calculations, predicting a planar S2(ππ*) pseudo-minimum in agreement with the stimulated emission signal observed in the experiment.

Partição de Comprimidos Antineoplásicos Utilizados no Tratamento de Leucemias Agudas em Crianças e Adolescentes / Splitting of Antineoplastic Tablets Used in Acute Leukemias Treatment in Children and Adolescents / Partición de Comprimidos Antineoplásicos Empleados en el Tratamiento de Leucemias Agudas en Niños y Adolescentes

Introdução: A manipulação de antineoplásicos para ajuste de dose, como partição de comprimidos, é comum no tratamento de leucemias agudas de crianças e adolescentes. Objetivo: Identificar a frequência e descrever a prática da partição domiciliar de comprimidos antineoplásicos utilizados no tratamento oral de crianças e adolescentes com leucemias agudas na fase de manutenção. Método: Trata-se de um estudo transversal descritivo, realizado em um hospital pertencente à rede de saúde pública do Distrito Federal com assistência especializada em pediatria. Foram incluídos no estudo crianças e adolescentes entre 1 e 18 anos, diagnosticados com leucemias agudas e em fase de manutenção do tratamento no período de estudo. Foi aplicado um questionário semiestruturado ao responsável principal pela administração dos medicamentos quimioterápicos via oral, podendo ser o cuidador ou a própria criança/adolescente. Foram coletadas variáveis sociodemográficas dos pacientes e cuidadores e variáveis sobre a prática de partição de medicamentos antineoplásicos no domicílio. Resultados: Todos os 48 entrevistados no período do estudo relataram ter partido comprimidos antineoplásicos ao longo do tratamento de leucemias agudas, sendo estes mercaptopurina (n=45 [93,75%]) e tioguanina (n=3 [6,25%]). Conclusão: A partição de comprimidos antineoplásicos foi uma prática unânime em virtude da necessidade referida de ajuste de dose individual para o tratamento de leucemias agudas de crianças e adolescentes, considerando a indisponibilidade de formulações adequadas. Os resultados reforçam a necessidade de a partição ser uniformizada e realizada de maneira a minimizar os riscos e a garantir a segurança para as crianças e adolescentes e seus cuidadores.

Introduction: Antineoplastic drug manipulation for dose adjustment, such as tablet splitting, is standard in acute leukemia treatment for children and adolescents. Objective: To identify the frequency and describe the practice of household splitting of antineoplastic tablet for oral treatment of children and adolescents with acute leukemias in the maintenance phase. Method: Cross-sectional descriptive study performed in a public health system hospital from Distrito Federal (Brazil) with specialized pediatric assistance. Children and teenagers between 1 and 18 years old, diagnosed with acute leukemia and in treatment maintenance phase during the study period were included. A semi-structured questionnaire was applied to the main responsible for administering oral chemotherapy drugs, which could be the caregiver or the child/adolescent themselves. Sociodemographic variables of patients and caregivers and variables on the practice of splitting antineoplastic drugs at home were collected. Results: All 48 interviewees in the study period reported having split antineoplastic tablets during the treatment for acute leukemias, such as mercaptopurine (n = 45 [93.75%]) and thioguanine (n = 3 [6.25%]). Conclusion: The splitting of antineoplastic tablets was a unanimous practice due to the reported need to adjust the individual dose for acute leukemia treatment in children and adolescents, considering the unavailability of adequate formulations. The results reinforce the need for splitting to be standardized and performed in a way that minimizes risks and ensures safety for patients and their caregivers

Introducción: La manipulación de fármacos antineoplásicos para el ajuste de dosis, como las particiones de comprimidos, es frecuente en el tratamiento de las leucemias agudas en niños y jóvenes. Objetivo: Identificar la frecuencia y describir la práctica de la división domiciliaria de medicamentos antineoplásicos utilizados en el tratamiento oral de niños y adolescentes con leucemias agudas en la fase de mantenimiento. Método: Se trata de un estudio transversal descriptivo realizado en un hospital de la red de salud pública del Distrito Federal (Brasil) con asistencia especializada en pediatría. El estudio incluyó a niños y jóvenes de entre 1 y 18 años de edad diagnosticados con leucemia aguda y en fase de mantenimiento del tratamiento en el período del estudio. Se aplicó un cuestionario semiestructurado a la persona principal responsable de la administración de fármacos quimioterapéuticos por vía oral, que puede ser el cuidador o el propio niño/joven. Fueron colectadas variables sociodemográficas de los pacientes y cuidadores y variables sobre la práctica de la división de los medicamentos antineoplásicos en domicílios. Resultados: Los 48 entrevistados en el período de estudio informaron haber roto las pastillas antineoplásicas durante el tratamiento de la leucemia aguda, siendo éstas mercaptopurina (n=45 [93,75%]) y tioguanina (n=3 [6,25%]). Conclusión: La partición de comprimidos antineoplásicos fue una práctica unánime debido a la necesidad mencionada de ajustar la dosis individual para el tratamiento de las leucemias agudas de niños y adolescentes, considerando la falta de formulaciones apropiadas. Los resultados refuerzan la necesidad de estandarizar y realizar la partición para minimizar los riesgos y garantizar la seguridad de los niños, jóvenes y sus cuidadores.

Outcomes in Pediatric Autoimmune Hepatitis and Significance of Azathioprine Metabolites.

OBJECTIVES: Autoimmune hepatitis (AIH) is a common pediatric liver disease and long-term remission is usually maintained with azathioprine (AZA). There is no consensus on the target range for AZA active metabolite 6-thioguanine (6-TGN) levels in pediatric AIH. The aim of the present study was to characterize the outcomes of pediatric patients with AIH and determine correlations between AZA dosing or 6-TGN metabolite levels and biochemical remission. METHODS: A retrospective chart review was performed and data on presentation, laboratories including AZA metabolite levels, medication use, and outcomes were collected. RESULTS: Between 2002 and 2013, 66 children with AIH were identified (mean age at diagnosis 9.6 ±â€Š5.1 years) with a mean follow-up period of 2.9 ±â€Š3.2 years. Common presenting symptoms included jaundice, fatigue, and abdominal pain. The majority of subjects received steroids for induction and AZA for maintenance of remission. Seventy-nine percent achieved biochemical remission (mean time to remission 6.2 ±â€Š9.2 months), 14% were in the induction phase of therapy, 6% required liver transplantation, and 18% were weaned off immunosuppression and remained in remission. 6-TGN levels ranging from 50 to 250 pmol/8 × 10 red blood cell count were associated with biochemical remission (alanine aminotransferase levels of ≤50 U/L). CONCLUSIONS: The vast majority of children with AIH maintain a sustained remission with AZA monotherapy. Biochemical remission was maintained with 6-TGN levels much lower than that recommended for inflammatory bowel disease. These findings suggest that patients should be maintained at the lowest AZA dose possible that is associated with biochemical remission.

Improving the outcomes of elderly patients with acute myeloid leukemia in a Brazilian University Hospital.

OBJECTIVE: To evaluate the outcomes of acute myeloid leukemia patients who were older than 60 years of age at the time of diagnosis following the implementation of a treatment algorithm based on age, performance status, and cytogenetic results. METHODS: We retrospectively compared the results of 31 elderly acute myeloid leukemia patients (median age of 74 years) who were treated according to the new algorithm. RESULTS: Fifteen patients with a good performance status and no unfavorable karyotypes were treated with either intensive cytotoxic chemotherapy (<70 years, nine cases) or adapted etoposide, 6-thioguanine and idarubicine (>70 years, six cases); 16 cases with a poor performance status or unfavorable cytogenetics received supportive care only. Six patients achieved a complete remission and two achieved a partial remission after chemotherapy. There were three toxic deaths during induction, two in the adapted etoposide, 6-thioguanine and idarubicine group and one in the intensive cytotoxic chemotherapy group. The overall median survival time was 2.96 months, 1.3 months in the supportive care group, and 4.6 months in the treatment group. CONCLUSIONS: Our results illustrate the importance of treatment guidelines adapted to local resources in an attempt to improve the survival of elderly acute myeloid leukemia patients in developing countries.

Improving the outcomes of elderly patients with acute myeloid leukemia in a Brazilian University Hospital

OBJECTIVE: To evaluate the outcomes of acute myeloid leukemia patients who were older than 60 years of age at the time of diagnosis following the implementation of a treatment algorithm based on age, performance status, and cytogenetic results. METHODS: We retrospectively compared the results of 31 elderly acute myeloid leukemia patients (median age of 74 years) who were treated according to the new algorithm. RESULTS: Fifteen patients with a good performance status and no unfavorable karyotypes were treated with either intensive cytotoxic chemotherapy (<70 years, nine cases) or adapted etoposide, 6-thioguanine and idarubicine (>70 years, six cases); 16 cases with a poor performance status or unfavorable cytogenetics received supportive care only. Six patients achieved a complete remission and two achieved a partial remission after chemotherapy. There were three toxic deaths during induction, two in the adapted etoposide, 6-thioguanine and idarubicine group and one in the intensive cytotoxic chemotherapy group. The overall median survival time was 2.96 months, 1.3 months in the supportive care group, and 4.6 months in the treatment group. CONCLUSIONS: Our results illustrate the importance of treatment guidelines adapted to local resources in an attempt to improve the survival of elderly acute myeloid leukemia patients in developing countries.

Monitoração terapêutica da azatioprina: uma revisão: [revisão] / Therapeutic drug monitoring of azathioprine: a review: [review]

Os nucleotídeos de tioguanina (6-TGN), metabólitos ativos da azatioprina (AZA) e da 6-mercaptopurina (6-MP), atuam como antagonistas das purinas, inibindo as sínteses de DNA, RNA e a protéica, e induzindo à citotoxicidade/imunossupressão. A enzima geneticamente determinada, tiopurina metiltransferase (TPMT), está envolvida no metabolismo desses agentes e, hipoteticamente, determina a resposta clínica às tiopurinas. A baixa atividade dessa enzima diminui a metilação das tiopurinas, resultando em potencial sobredose, enquanto altos níveis de TPMT levam à superprodução do metabólito tóxico 6-metilmercaptopurina (6-MMP) e à não-efetividade terapêutica da AZA e da 6-MP. Várias mutações no gene da TPMT têm sido identificadas e correlacionadas com fenótipos de baixa atividade. Neste artigo, também se discute a monitoração terapêutica desses fármacos por meio da medida dos níveis de 6-TGN intra-eritrocitários, os quais se correlacionam com imunossupressão e mielotoxicidade. Já a 6-MMP está diretamente relacionada com hepatotoxicidade. Esses ensaios estão associados ao uso de doses adequadas dessa droga, resultando num melhor controle da doença e menor uso de corticosteróides.

Thioguanine nucleotides (6-TGN), active metabolites of azathioprine (AZA) and 6-mercaptopurine (6-MP), act as purine antagonists, inhibiting DNA, RNA, and protein synthesis and inducing cytotoxicity and immunosuppression. The genetically determined thiopurine methyltransferase enzyme (TPMT) is involved in the metabolism of these agents and, theoretically, determines the clinical response to thiopurines. Low activity of this enzyme decreases the methylation of thiopurines, what results in potential overdosing, whereas high TPMT status leads to overproduction of toxic metabolite 6-methilmercaptopurine (6-MMP) and ineffectiveness of AZA and 6-MP. Several mutations in the TPMT gene have been identified and correlated with low activity phenotypes. In this study, we also discuss the therapeutic monitoring of these drugs by means of red blood cell 6-TGN levels, which correlate with immunosuppression and mielotoxicity. 6-MMP is directly connected with hepatotoxicity. These metabolites assays are associated with the use of appropriate doses of this drug, what results in a better control of the disease and a decreased use of corticosteroids.

An improved HPLC method for the quantitation of 6-mercaptopurine and its metabolites in red blood cells

A procedure is described for the rapid determination of the intra-erythrocyte concentration of 6-mercaptopurine (6-MP) and its metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). Erythrocytes (8 x 10(8) cells) in 350 æl Hanks solution containing 7.5 mg dithiothreitol were treated with 50 æl 70 percent perchloric acid. The precipitate was removed by centrifugation (13,000 g) and the supernatant hydrolyzed at 100§C for 45 min. After cooling, 100 æl was analyzed directly by HPLC using a Radialpack Resolve C18 column eluted with methanol-water (7.5:92.5, v/v) containing 100 mM triethylamine. 6-TG, 6-MP and the hydrolysis product of 6-MMP, 4-amino-5-(methylthio)carbonyl imidazole, were monitored at 342, 322 and 303 nm using a Shimadzu SPD-M10A diode array UV detector. The analytes eluted at 5.3, 6.0 and 10.2 min, respectively. The calibration curves were linear (rý > 0.998), and the analytical recoveries were 73.2 percent for 6-TG, 119.1 percent for 6-MP and 97.4 percent for 6-MMP. The intra- and inter-assay variations were highest for 6-MP (9.6 and 14.3 percent, respectively). The lowest detectable concentrations were 3, 3 and 25 pmol/8 x 10(8) erythrocytes for 6-TG, 6-MP and 6-MMP, respectively. The quantification limits (coefficients of variation <15 percent) were 8, 10 and 70 pmol/8 x 10(8) erythrocytes for 6-TG, 6-MP and 6-MMP, respectively. The method was applied to the analysis of 183 samples from 36 children under chemotherapy for acute lymphoblastic leukemia. The concentrations of the metabolites in the red cells of the patients ranged from 0 to 1934 pmol/8 x 10(8) erythrocytes for 6-TGN, and from 0 to 105.8 and 0 to 45.9 nmol/8 x 10(8) erythrocytes for 6-MP and 6-MMP, respectively. The procedure gave results that were in agreement with those obtained with other methods designed to detect cases of non-compliance with treatment, including patient interviews and medical evaluation, among others, demonstrating its applicability to monitoring the treatment of leukemic children.

An improved HPLC method for the quantitation of 6-mercaptopurine and its metabolites in red blood cells.

A procedure is described for the rapid determination of the intra-erythrocyte concentration of 6-mercaptopurine (6-MP) and its metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). Erythrocytes (8 x 10(8) cells) in 350 microl Hanks solution containing 7.5 mg dithiothreitol were treated with 50 microl 70% perchloric acid. The precipitate was removed by centrifugation (13,000 g) and the supernatant hydrolyzed at 100 degrees C for 45 min. After cooling, 100 microl was analyzed directly by HPLC using a Radialpack Resolve C18 column eluted with methanol-water (7.5:92.5, v/v) containing 100 mM triethylamine. 6-TG, 6-MP and the hydrolysis product of 6-MMP, 4-amino-5-(methylthio)carbonyl imidazole, were monitored at 342, 322 and 303 nm using a Shimadzu SPD-M10A diode array UV detector. The analytes eluted at 5.3, 6.0 and 10.2 min, respectively. The calibration curves were linear (r(2) > 0.998), and the analytical recoveries were 73.2% for 6-TG, 119.1% for 6-MP and 97.4% for 6-MMP. The intra- and inter-assay variations were highest for 6-MP (9.6 and 14.3%, respectively). The lowest detectable concentrations were 3, 3 and 25 pmol/8 x 10(8) erythrocytes for 6-TG, 6-MP and 6-MMP, respectively. The quantification limits (coefficients of variation <15%) were 8, 10 and 70 pmol/8 x 10(8) erythrocytes for 6-TG, 6-MP and 6-MMP, respectively. The method was applied to the analysis of 183 samples from 36 children under chemotherapy for acute lymphoblastic leukemia. The concentrations of the metabolites in the red cells of the patients ranged from 0 to 1934 pmol/8 x 10(8) erythrocytes for 6-TGN, and from 0 to 105.8 and 0 to 45.9 nmol/8 x 10(8) erythrocytes for 6-MP and 6-MMP, respectively. The procedure gave results that were in agreement with those obtained with other methods designed to detect cases of non-compliance with treatment, including patient interviews and medical evaluation, among others, demonstrating its applicability to monitoring the treatment of leukemic children.

[Survival evaluation of children with acute lymphoblastic leukemia treated with Berlin-Frankfurt-Munich trial]. / Avaliação da sobrevida de crianças com leucemia linfocítica aguda tratadas com o protocolo Berlim-Frankfurt-Munique.

OBJECTIVE: To determine the survival rate of children with acute lymphoblastic leukemia treated in Hospital São Lucas - Pontifícia Universidade Católica - Rio Grande do Sul during the past 10 years. To evaluate well known prognostic factors and to compare results of BFM 90 and 95 trials. METHODS: Mixed cohort study of 0 to 15-years-old children treated with BFM 90 and 95 trials during the past 10 years at Hospital São Lucas - Pontifícia Universidade Católica - Rio Grande do Sul. Data were obtained from medical records. The occurrence of death was described by Kaplan-Meier survival curves. The overall effect of the prognostic factors was evaluated using the Cox's multivariate model. RESULTS: Sixty three patients, whose mean age (+/- standard-deviation) was 6.3 +/- 4.2 years, were included. Thirty five patients (55.6%) were female. The estimated probability of relapse free survival at 5 years (+/- standard-error) was 50.8 +/- 7.2% for all patients, with 77.7 +/- 9.9% in the standard risk group, 41.3 +/- 15.4% in the intermediate risk group, and 39.3 +/- 13.7% in high risk group. CONCLUSION: The estimated probability of relapse free survival was below the results in developed countries. However the standard risk group obtained better prognostic but the small number of the cases doesn't allow permanent conclusions.

Teniposide plus cytarabine as intensification therapy and in continuation therapy for advanced nonlymphoblastic lymphomas of childhood.

PURPOSE AND METHODS: Thirty-nine consecutive children (age, 2 to 11 years) with nonlymphoblastic (NL) lymphomas were treated uniformly with chemotherapy based on the LNH-II-85 protocol. The protocol consisted of a remission-induction phase that lasted 30 days and started with cyclophosphamide (CTX) 1.2 g/m2 on day 1, followed by vincristine (VCR) 1.5 mg/m2 on days 3, 10, 17, and 24, daunomycin (DAUNO) 60 mg/m2 on days 12 and 13, and prednisone 40 mg/m2/d for 30 days. If a complete remission was achieved, an intensification regimen was given that consisted of eight courses of teniposide (VM-26) 165 mg/m2 plus cytarabine (ARA-C) 300 mg/m2 every 4 days according to bone marrow tolerance. A continuation phase was subsequently started, with alternating courses of thioguanine (6-TG) 300 mg/m2/d for 4 days plus CTX 1.2 g/m2 on day 5; hydroxyurea 2.5 g/m2/d for 4 days plus DAUNO 45 mg/m2 on day 5; VCR 1.5 mg/m2 plus methotrexate (MTX) 120 mg/m2 (24 hours apart); mercaptopurine (6-MP) 500 mg/m2/d for 4 days plus MTX 40 mg/m2; and VM-26 plus ARA-C for 3 courses (4 days apart), by the end of 48 weeks. CNS prophylaxis consisted of intrathecal administration of MTX, ARA-C, and dexamethasone according to age, administered three times during remission induction and every 6 weeks afterwards. RESULTS: By the end of the analysis in July 1991, 38 of 39 patients had attained a complete remission and 36 were event-free survivors. Two failures that occurred after completion of therapy were second malignancies (acute lymphocytic leukemia and acute nonlymphocytic leukemia). CONCLUSION: These results are significantly better than those obtained with less intensive former regimens performed in our institution before the availability of VM-26. The favorable impact of an intense consolidation phase with VM-26 is remarkably exemplified by three additional patients not included in this study whose families withdrew them from therapy after the intensification phase, all three of whom have been in remission.

The effect of time after treatment, treatment schedule and animal age on the frequency of 6-thioguanine-resistant T-lymphocytes induced in Fischer 344 rats by N-ethyl-N-nitrosourea.

The persistence of 6-thioguanine-resistant (TGr) T-lymphocytes was investigated in Fischer 344 rats treated with N-ethyl-N-nitrosourea (ENU) using two schedules. Male rats, aged 3 months, were given i.p. injections containing a total of 0, 50 or 100 mg ENU/kg either as a single treatment (single-dose group) or divided among 10 weekly treatments (split-dose group). At 1, 3, 5, 10, 20, 30 and 50 weeks after the single-dose treatment, and 10, 20, 30 and 50 weeks after beginning the split-dose regimen, animals were assayed for the frequency of TGr spleen lymphocytes. ENU produced significant dose- and time-dependent responses in the single- and the split-dose treatment groups. Although a few of the 50 mg/kg split-dose treatments were significantly higher than the comparative single-dose groups, the number of TGr lymphocytes produced by the two dosing regimens were generally similar. The frequency of TGr cells for control animals increased with the age of the animals. The mode of ENU administration did not greatly influence the percent cloning efficiency (%CE) of the non-selection cultures, although the %CE declined in animals over 10 months of age. To investigate the relationship between the frequency of TGr cells and the age of the animals at the time of ENU administration, additional rats aged 17 months were treated with a single dose of ENU and at 1, 5 and 10 weeks following exposure, the frequencies of TGr cells were determined from the isolated lymphocytes. No difference in mutagen sensitivity between rats treated at 3 months of age and those treated at 17 months of age was detected at the time points evaluated. The data demonstrate the persistence of ENU-induced TGr T-lymphocytes in the rat and suggest that the dose and possibly the treatment schedule, but not the age of the animal at the time of treatment, affect the response.

[Bone marrow transplantation in Mexico. Report of the 1st successful case in acute myeloblastic leukemia. Grupo de Trasplante Medular Oseo del INNSZ]. / Trasplante de médula ósea en México. Informe del primer caso exitoso en leucemia aguda mieloblástica. Grupo de Trasplante Medular Oseo del INNSZ.

The first case of allogeneic bone marrow transplantation in acute myelogenous leukemia (AML) done in Mexico is reported. The patient was a 26 year old Mexican woman who in October 1987 was diagnosed of having AML of the M2 subtype. After three cycles of the TADOP regimen (6-thioguanine, cytosine-arabinoside, doxorubicin, vincristine & prednisone), the patient entered complete remission. Unfortunately, after a seven month period of remission she suffered a relapse which was refractory to a new chemotherapy cycle. On 9/14/88 an allogeneic BMT from her HLA identical brother was performed. The conditioning regimen consisted of busulfan and cyclophosphamide. Prophylaxis for GVHD consisted of cyclosporine and methylprednisolone. The posttransplantation course was satisfactory, reaching > 500 neutrophils x 10(9)/L on day 14 and > 50,000 platelets x 10(9)/L without support on day 23 posttransplant. The patient developed fever of unknown etiology, which was satisfactorily resolved with ceftazidime, vancomycin and metronidazole. She also presented a grade II oral and esophageal mucositis. As a late complication, on day 90 posttransplant, she developed a bilateral pneumonia which was resolved with sulfamethoxazole-trimethoprim administration. Up to the time of this report (40 months posttransplant) the patient is completely asymptomatic, is under no immunosuppression, and shows no evidence of graft versus host disease or recurrent leukemia.

Comparación de dos esquemas de quimioterapia en la leucemia aguda mieloblástica del adulto: resultados del grupo cooperativo / Non-ablative combined chemotherapy in adults with acute myelogenous leukemia: the INNSZ cooperative group

En este estudio retrospectivo se analizan los resultados del tratamiento de 76 pacientes adultos con leucemia aguda mieloblástica (LAM); 43 fueron tratados con el esquema quimioterápico 7 + 3 (arabinósido de citosina durante siete días continuos y una antraciclina durante tres días), y 33 fueron tratados con el esquema TADOP (thioguanina, arabinósido de citosina, doxorrubicina, vincristina y prednisona). Los resultados fueron los siguientes: el número de ciclos para lograr la RC entre el esquema 7 + 3 y el TADOP mostró diferencias estadisticamente significativas: 1 versus 5 (p < 0.001). La remisión completa se logró en el 60 por ciento de los pacientes tratados con 7 + 3 y en el 48 por ciento de los pacientes con TADOP (p NS); la mediana de duración de la RC fue de 21 y 10 meses respectivamente (p < 0.05); la mielotoxicidad fatal se observó en el 30 por ciento y 42 por ciento respectivamente (p NS); la causa de muerte durante la inducción fue hemorragia en 53 por ciento y 57 por ciento para cada grupo respectivamente (p NS); la supervivencia total a un año fue de 50 por ciento y 54 por ciento (p NS), a los 36 meses de 22 por ciento y 15 por ciento (p NS) y la supervivencia libre de enfermedad a un año, 46 por ciento y 45 por ciento respectivamente (p NS). Se subclasificaron estos grupos en pacientes quienes recibieron tratamientos mielosupresores intensos (7 + 3) y fueron apoyados con transfusiones plaquetarias suficientes y obtenidas por citaféresis; los que recibieron 7 + 3 y se apoyaron con plaquetas obtenidas a partir de centrifugación y los que recibieron TADOP cuyo apoyo fue en todos los casos con plaquetas obtenidas por centrifugación; la supervivencia total a un año mostró diferencias significativas: 75 por ciento, 22 por ciento, y 54 por ciento, respectivamente (p < 0.01). La cantidad promedio de plaquetas transfundidas por pacientes fue de 24.4, 13.3 y 7.0 respectivamente (p < 0.01). Con estos datos podemos concluir que un esquema como el TADOP puede ser de utilidad cuando no se cuenta con un apoyo transfusional adecuado; sin embargo, la mejor opción terapéutica en pacientes con leucemia aguda mieloblástica es la administración de quimioterapia mielosupresora agresiva con apoyo transfusional óptimo por la técnica de citaféresis, por lo que consideramos que los pacientes con LAM deben tratarse preferentemente en sitios que cuentan con una infraestructura de apoyo transfusional adecuada

[Comparison of 2 chemotherapy protocols in adult acute myeloblastic leukemia. Results of the Instituto Nacional de la Nutrición Salvador Zubirán cooperative group]. / Comparación de dos esquemas de quimioterapia en la leucemia aguda mieloblástica del adulto. Resultados del grupo cooperativo INNSZ.

Up to now, the best treatment for patients with acute myelogenous leukemia (AML) is the induction of bone marrow hypoplasia by ablative combined chemotherapy; the prototype of these schedules is the so-called 7 + 3 (seven days of continuous infusion of cytarabine and three days of one-hour infusion of any anthracycline); these schedules require the support of both platelet transfusions and antibiotics. Other non-ablative schedules have also been tried in the treatment of such patients. Here we analyze the results of the treatment of 76 adult patients with AML; 43 were treated with the classical 7 + 3 schedule, whereas 33 were treated with a combination of chemotherapy used in non-ablative doses (TADOP: thioguanine, arabinosyl-citosine, doxorrubicin, vincristine and prednisone). The results were as follows, respectively, for 7 + 3 and TADOP: complete remission (CR) was achieved in 60 and 48% of patients (p NS); the number of cycles to achieve CR had a median of 1 and 5 months (p less than 0.001); the median duration of the CR was 21 and 10 months (p less than 0.05); fatal myelotoxicity was 30 and 42% (p NS), one-year disease free survival (DFS) was 45 and 46% (p NS) and three-year survival was 22% and 15% (p NS). Additionally, patients treated with 7 + 3 were divided into two groups according to the type of platelet transfusion support; those supported with apheresis equipment and those with centrifugation-derived platelets.(ABSTRACT TRUNCATED AT 250 WORDS)