Current treatment strategies for inflammatory bowel disease patients at the risk of developing cancer: a comprehensive review

Inflammatory bowel disease (IBD) is a chronic condition that affects the digestive tract and can lead to inflammation and damage to the intestinal lining. IBD patients with cancer encounter difficulties since cancer treatment weakens their immune systems. A multidisciplinary strategy that strikes a balance between the requirement to manage IBD symptoms and the potential effects of treatment on cancer is necessary for effective care of IBD in cancer patients. To reduce inflammation and avoid problems, IBD in cancer patients is often managed by closely monitoring IBD symptoms in conjunction with the necessary medication and surgical intervention. Anti-inflammatory medications, immunomodulators, and biologic therapies may be used for medical care, and surgical options may include resection of the diseased intestine or removal of the entire colon. The current study provides a paradigm for shared decision-making involving the patient, gastroenterologist, and oncologist while considering recent findings on the safety of IBD medicines, cancer, and recurrent cancer risk in individuals with IBD. We hope to summarize the pertinent research in this review and offer useful advice. (AU)

Necessidades de aprendizagem de familiares de crianças e adolescentes em tratamento com quimioterápicos antineoplásicos orais / Necesidades de aprendizaje de los familiares de niños y adolescentes en tratamiento con quimioterapia antineoplástica oral / Learning needs of relatives of children and teenagers under oral antineoplastic chemotherapy treatment

RESUMO Objetivo descrever as necessidades de aprendizagem de familiares de crianças e adolescentes com câncer quanto ao tratamento com quimioterápicos antineoplásicos orais. Método pesquisa qualitativa descritiva desenvolvida em um hospital federal do Rio de Janeiro, Brasil. Os dados foram coletados nos meses de julho a setembro de 2020 a partir de entrevistas semiestruturadas com vinte e três familiares de crianças e adolescentes com câncer em quimioterapia antineoplásica oral. Os dados foram processados no software Interface de R pour Analyses Multidimensionnelles de Textes et de Questionnaires pela Classificação Hierárquica Descendente. Resultados dentre os temas que demandam aprendizagem pelos familiares estão administração oral, armazenamento e manipulação dos quimioterápicos orais, além dos efeitos adversos e emergências que demandam atendimento hospitalar. Conclusão e implicações para a prática no tratamento com quimioterápicos orais, as necessidades de aprendizagem dos familiares de crianças e adolescentes precisam ser problematizadas em práticas educativas dialógicas para, assim, favorecer a segurança, a adesão e a eficácia do tratamento.

RESUMEN Objetivo describir las necesidades de aprendizaje de familiares de niños y adolescentes con cáncer en cuanto al tratamiento con quimioterápicos antineoplásicos orales. Método investigación cualitativa descriptiva desarrollada en un hospital federal de Río de Janeiro, Brasil. Los datos fueron recogidos en los meses de julio a septiembre de 2020 a partir de entrevistas semiestructuradas con veintitrés familiares de niños y adolescentes con cáncer en quimioterapia antineoplásica oral. Los datos fueron procesados en el software Interface de R pour Analyses Multidimensionnelles de Textes et de Questionnaires por la Clasificación Jerárquica Descendente. Resultados entre los temas que demandan aprendizaje por los familiares están administración oral, almacenamiento y manipulación de los quimioterápicos orales, además de los efectos adversos y emergencias que demandan atención hospitalaria. Conclusión e implicaciones para la práctica en el tratamiento con quimioterápicos orales, las necesidades de aprendizaje de los familiares de niños y adolescentes necesitan ser problematizadas en prácticas educativas dialógicas para, así, favorecer la seguridad, la adhesión y la eficacia del tratamiento.

ABSTRACT Objective to describe the learning needs of family members of children and adolescents with cancer regarding treatment with oral antineoplastic chemotherapies. Method a descriptive qualitative research developed in a federal hospital in Rio de Janeiro, Brazil. Data were collected in the months from July to September 2020 from semi-structured interviews with twenty-three family members of children and adolescents with cancer undergoing oral antineoplastic chemotherapy. Data was processed in the software Interface de R pour Analyses Multidimensionnelles de Textes et de Questionnaires by the Descending Hierarchical Classification. Results among the themes that demand learning by the family members are oral administration, storage and handling of oral antineoplastic drugs, as well as adverse effects and emergencies that require hospital care. Conclusion and implications for practice in oral antineoplastic treatment, the learning needs of family members of children and adolescents need to be problematized in dialogic educational practices in order to favor the safety, adherence, and efficacy of the treatment.

Association between polymorphism of NUDT15 gene and hepatotoxicity induced by 6-MP in children with acute lymphoblastic leukemia / 中华医学遗传学杂志

OBJECTIVE@#To investigate the association between single nucleotide polymorphism of NUDT15 gene (SNP rs116855232) and hepatotoxicity in children with acute lymphocytic leukemia (ALL).@*METHODS@#A total of 135 children with ALL in Shandong Province were recruited in this study, and patients were divided into two groups based on the presence of liver injury. Genotypes of each patient were detected using PCR and Sanger sequencing. Clinical data and the average dose of 6-mercaptopurine (6-MP) were collected and analyzed by SPSS 19.0 software.@*RESULTS@#Respectively, 99 patients were found with CC genotype, 32 patients with CT genotype and 4 patients with TT genotype. Compared with ALL patients without hepatotoxicity, there was a difference in genotypes between the two groups in the initial stage of chemotherapy for leukemia (Chi@*CONCLUSION@#The polymorphism of rs116855232 in NUDT15 gene was associated with hepatotoxicity induced by 6-mercaptopurine in children with ALL, and ALL patients with TT genotype should take a lower dose of 6-MP to avoided hepatotoxicity.

Informe diário de evidências COVID-19: busca realizada em 21 de maio de 2020 / COVID-19 daily evidence report: search conducted on May 21, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 21 artigos.

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.

Significance of NUDT15 gene in individualized treatment with 6-mercaptopurine in children with acute lymphoblastic leukemia / 中国当代儿科杂志

As an important drug during maintenance treatment of acute lymphoblastic leukemia (ALL), 6-mercaptopurine (6-MP) has several side effects, including hepatotoxicity and bone marrow suppression. Since its tolerability varies from person to person, 6-MP treatment should be individualized. The deficiency of thiopurine methyltransferase (TPMT) enzyme activity is associated with 6-MP intolerance. There is a lower frequency of mutation in TPMT alleles among Asian patients. Recent studies have shown that in ALL patients with NUDT15 gene mutation, the maximum tolerated dose of 6-MP is lower than the conventional dose. The article reviews the significance of NUDT15 gene in individualized treatment with 6-MP in children with ALL.

Severe recurrent nocturnal hypoglycemia during chemotherapy with 6-mercaptopurine in a child with acute lymphoblastic leukemia

Various endocrine dysfunctions occur during chemotherapy, including hypoglycemia. However, reports of hypoglycemia associated with 6-mercaptopurine (6-MP) are rare. Herein, we report an 8-year-old boy with severe symptomatic hypoglycemia likely due to 6-MP during chemotherapy. He had been diagnosed with acute lymphoblastic leukemia 3 years previously and was in the maintenance chemotherapy period. Treatment included oral dexamethasone, methotrexate, and 6-MP, of which only 6-MP was administered daily. Hypoglycemic symptoms appeared mainly at dawn, and his serum glucose dropped to a minimum of 37 mg/dL. Laboratory findings showed nothing specific other than increased serum cortisol, free fatty acids, ketone, alanine aminotransferase, and aspartate aminotransferase. Under the hypothesis of hypoglycemia due to chemotherapy drugs, we changed the time of 6-MP from evening to morning and recommended him to ingest carbohydrate-rich foods before bedtime. Hypoglycemia improved dramatically, and there was no further episode during the remaining maintenance chemotherapy period. To the best of our knowledge, this is the first report of this type of hypoglycemia occurring in an Asian child including Korean.

APEX1 Polymorphism and Mercaptopurine-Related Early Onset Neutropenia in Pediatric Acute Lymphoblastic Leukemia / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Mercaptopurine (MP) is one of the main chemotherapeutics for acute lymphoblastic leukemia (ALL). To improve treatment outcomes, constant MP dose titration is essential to maintain steady drug exposure, while minimizing myelosuppression. We performed two-stage analyses to identify genetic determinants of MP-related neutropenia in Korean pediatric ALL patients. MATERIALS AND METHODS: Targeted sequencing of 40 patients who exhibited definite MP intolerance was conducted using a novel panel of 211 pharmacogenetic-related genes, and subsequent analysis was performed with 185 patients. RESULTS: Using bioinformatics tools and genetic data, four functionally interesting variants were selected (ABCC4, APEX1, CYP1A1, and CYP4F2). Including four variants, 23 variants in 12 genes potentially linked to MP adverse reactions were selected as final candidates for subsequent analysis in 185 patients. Ultimately, a variant allele in APEX1 rs2307486was found to be strongly associated with MP-induced neutropenia that occurred within 28 days of initiating MP (odds ratio, 3.44; p=0.02). Moreover, the cumulative incidence of MP-related neutropenia was significantly higher in patients with APEX1 rs2307486 variants, as GG genotypes were associated with the highest cumulative incidence (p < 0.01). NUDT15 rs116855232 variants were strongly associated with a higher cumulative incidence of neutropenia (p < 0.01), and a lower median dose of tolerated MP throughout maintenance treatment (p < 0.01). CONCLUSION: We have identified that APEX1 rs2307486 variants conferred an increased risk of MP-related early onset neutropenia. APEX1 and NUDT15 both contribute to cell protection from DNA damage or misincorporation, so alleles that impair the function of either gene may affect MP sensitivities, thereby inducing MP-related neutropenia.

NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated. RESULTS: A total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate-activity group 24.4 vs. normalactivity group 31.1, p < 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p < 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate-activity group 92 days vs. normal-activity group 59 days, p < 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group. CONCLUSION: NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels.

Leucemia linfoblástica aguda infantil: una aproximación genómica / Acute lymphoblastic leukemia: a genomic perspective

Resumen: En paralelo al proyecto de la secuenciación del genoma humano, se han desarrollado varias plataformas tecnológicas que están permitiendo ganar conocimiento sobre la estructura del genoma de las entidades humanas, así como evaluar su utilidad en el abordaje clínico del paciente. En la leucemia linfoblástica aguda (LLA), el cáncer infantil más común, las herramientas genómicas prometen ser útiles para detectar a los pacientes con alto riesgo de recaída, ya sea al diagnóstico o durante el tratamiento (enfermedad mínima residual), además de que permiten identificar los casos en riesgo de presentar reacciones adversas a los tratamientos antineoplásicos y ofrecer una medicina personalizada con esquemas terapéuticos diseñados a la medida del paciente. Un ejemplo claro de esto último es la identificación de polimorfismos de un solo nucleótido (SNPs) en el gen de la tiopurina metil transferasa (TPMT), donde la presencia de dos alelos nulos (homocigotos o heterocigotos compuestos) indica la necesidad de reducir la dosis de la mercaptopurina hasta en un 90% para evitar efectos tóxicos que pueden conducir a la muerte del paciente. En esta revisión se proporciona una visión global de la genómica de la LLA, describiendo algunas estrategias que contribuyen a la identificación de biomarcadores con potencial utilidad en la práctica clínica.

Abstract: In parallel to the human genome sequencing project, several technological platforms have been developed that let us gain insight into the genome structure of human entities, as well as evaluate their usefulness in the clinical approach of the patient. Thus, in acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, genomic tools promise to be useful to detect patients at high risk of relapse, either at diagnosis or during treatment (minimal residual disease), and they also increase the possibility to identify cases at risk of adverse reactions to chemotherapy. Therefore, the physician could offer patient-tailored therapeutic schemes. A clear example of the useful genomic tools is the identification of single nucleotide polymorphisms (SNPs) in the thiopurine methyl transferase (TPMT) gene, where the presence of two null alleles (homozygous or compound heterozygous) indicates the need to reduce the dose of mercaptopurine by up to 90% to avoid toxic effects which could lead to the death of the patient. In this review, we provide an overview of the genomic perspective of ALL, describing some strategies that contribute to the identification of biomarkers with potential clinical application.

Steroid-refractory extensive enteritis complicated by ulcerative colitis successfully treated with adalimumab

Extracolonic involvement of the gastrointestinal tract is extremely uncommon in ulcerative colitis (UC) and rarely found in the upper gastrointestinal tract or in postoperative cases since it typically responds to steroids. Here we report a case of UC complicated by extensive ileal inflammation that was refractory to steroids. A 20-year-old man was diagnosed with UC of typical pancolitis without ileal involvement and started treatment with pH-dependent mesalazine and oral prednisolone. Although his symptoms transiently resolved, the condition flared when the steroid dose was tapered down. Computed tomography revealed marked thickening of the ileal wall, and capsule endoscopy and balloon-assisted enteroscopy found diffuse mucosal inflammation with ulcers in the ileum. On the contrary, the inflammation in the colon and rectum was improving. Since the response to the second steroid course was inadequate, treatment with adalimumab and 6-mercaptopurine was initiated and finally achieved clinical and endoscopic remission. The investigation of small intestinal lesions is necessary in patients with UC whose clinical deterioration cannot be explained by colonic lesions.

Research advances in pharmacogenomics of mercaptopurine / 中国当代儿科杂志

Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. It may cause severe adverse effects such as myelosuppression, which may result in the interruption of treatment or complications including infection or even threaten patients' lives. However, the adverse effects of mercaptopurine show significant racial and individual differences, which reveal the important role of genetic diversity. Recent research advances in pharmacogenomics have gradually revealed the genetic nature of such differences. This article reviews the recent research advances in the pharmacogenomics and individualized application of mercaptopurine.

Effect of Immunomodulators and Biologic Agents on Malignancy in Patients with Inflammatory Bowel Disease / 대한소화기학회지

Immunosuppressive agents and biological agents are widely used for therapy in patients with inflammatory bowel disease (IBD). However, these therapies may be associated with an increased risk of malignancy. There is evidence that exposure of the therapeutic agents such as thiopurine and anti-tumor necrosis factor for IBD is associated with an increased risk of lymphoproliferative disorders, skin cancers, or uterine cervical cancers. This article reviews the malignancies associated with the use of immunosuppressive agents and biological agents in IBD.

NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases

BACKGROUND/AIMS: Recent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA) and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826) remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD). METHODS: One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing. RESULTS: None of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks) and late (≥8 weeks) leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined. CONCLUSIONS: Of the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurine-induced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD.

Thiopurine S-Methyltransferase Polymorphisms in Korean Dermatologic Patients

BACKGROUND: Thiopurine S-methyltransferase (TPMT) is an important enzyme in the metabolism of thiopurines including azathioprine (AZA), 6-mercaptopurine, and 6-thioguanine. TPMT genotyping is widely used for screening of AZA-related toxicity during routine clinical practice in Korea. However, the data of TPMT genotypes and its AZA-related toxicity have not been studied in the field of dermatology. OBJECTIVE: The aim of this study was to evaluate the genetic basis of TPMT polymorphism in Korean dermatologic patients and subsequently to investigate the relationship between mutant TPMT and adverse responses to AZA treatment. METHODS: This study was retrospective, single-center study. One hundred forty-nine Korean dermatologic patients who underwent TPMT screening test were included. Each patient's medical records, the result of TPMT screening test, dose and treatment period of AZA, and side effects, were reviewed. Laboratory tests were assessed at each visit in order to monitor adverse drug reactions. Leukopenia grading was used in accordance with the common terminology criteria for adverse events (CTCAE) ver. 4.03. RESULTS: Behçet's disease was the leading disorder among the patients. The frequency of TPMT mutation was 4.0% (6/149) among the participants in this study. Four of the six patients with genetic alterations were treated with a low-dose AZA regimen, but no AZA-related adverse events were observed. CONCLUSION: Our results suggest that 1) TPMT polymorphisms in Korean dermatologic patients are similar to those previously reported in Asian patients with the most common mutant allele being TPMT*3C and 2) AZA can be used in the patients with these polymorphisms under a careful dosing regimen.

Estudo dos efeitos da co-exposição aos antineoplásicos hidroxiuréia e 6-mercaptopurina sobre o desenvolvimento embriofetal de ratos / [Study of the effects of co-exposure to hydroxyurea and 6- antineoplastic agents mercaptopurine on the embryo-fetal development of rats]

Os antineoplásicos hidroxiureia (HU) e 6-mercaptopurina (6MP) inibem a síntese do DNA. A HU inibe a enzima ribonucleotideo redutase (RR) que converte ribonucleotídeos em desoxirribonucleotídeos, resultando em bloqueio da síntese de DNA. A 6MP é ativada pela via HGPRT que origina nucleotídeos de 6-tioguanina, incorporados erroneamente ao DNA. HU e 6MP são teratógenos potentes em roedores e afetam o desenvolvimento da prole das mães expostas. Estudos indicam que os efeitos da co-administração desses fármacos não são explicados pela mera adição dos efeitos isolados, entretanto, o modo pelo qual eles interagem não está claro.Na primeira parte deste trabalho investigamos as relações dose-efeito embriotóxico da HU e 6-MP; na segunda, analisamos os efeitos das exposições sequenciais ou concomitantes aos dois fármacos sobre o desenvolvimento pré-natal. Avaliamos embrioletalidade, retardo do crescimento e indução de anomalias externas e esqueléticas fetais. Os experimentos envolveram: cruzamento dos animais; tratamento das ratas grávidas (DG11) com HU ou 6-MP; cesariana e retirada do útero (DG21); fixação dos fetos, diafanização e coloração do esqueleto; avaliação dos esqueletos. Na segunda parte deste estudo, selecionamos a dose máxima não teratogênica de HU (250 mg/kg ip) e uma dose embriotóxica de 6MP (24 mg/kg sc) e testamos os efeitos combinados desses fármacos, injetados concomitantemente, ou com intervalos de 2 ou 4 horas, em quatro grupos de ratas grávidas: Não tratadas; Tratadas com HU e veículo; Tratadas com veículo e 6MP; Tratadas com HU e 6MP. Os resultados mostraram que a administração concomitante de HU atenuou vários efeitos da 6MP, como as proporções de fetos mortos e malformados, a redução dos pesos fetal e placentário, e o aumento da incidência de anomalias externas e ósseas...

The cytotoxic chemotherapeutics hydroxyurea (HU) and 6-ercaptopurine (6MP) inhibit DNA synthesis. HU inhibits the enzyme ribonucleotide reductase (RR) which converts ribonucleotides into deoxyribonucleotide leading to blockage of DNA synthesis. 6MP is activated by HGPRT and undergoes kinase reactions forming 6-thioguanine nucleotides which are erroneously incorporated into DNA. HU and 6MP are potent teratogens in rodents and affect the development of the offspring ofexposed mothers. Some studies suggest that responses resulting from the combined administration of these drugs cannot be explained by the sum of individual effects however the way they interact is unclear. In the first part of this work we investigated the dose-embryotoxic response of HU and 6MP; in the second, we analyzed the effects of sequential and concurrent exposure to both drugs on prenatal development. Embryolethality, growth retardation and induction of fetal external and skeletalabnormalities were evaluated. All the experiments included: mating of males and females; treatment of pregnant females (GD11) with HU or 6MP; cesarean section and removal of gravid uterus (GD21); clearing and staining fetuses for skeleton evaluation. In the second part of this study, the maximumnon teratogenic dose of HU (250 mg/kg ip) and a clear embryotoxic dose of 6MP (24 mg/kg sc) were selected to be injected in the dams at intervals of 2 or 4 hours, or concurrently. Four experimental groups of pregnant females were constituted: Untreated; Treated with HU and vehicle; Treated with vehicle and 6MP; Treated with HU and 6MP. Concomitant administration of HU attenuated various effects of 6MP, such as the proportion of dead and malformed fetuses, the reduction of fetal and placental weights and the increase in incidence of external/skeletal abnormalities...

Progress of Research on 6-Thioguanine versus 6-Mercaptopurine in childhood ALL / 中国实验血液学杂志

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children. Despite good remission rate has achieved nowadays, the patients still face a substantial risk of relapse. It has long been recognized that thiopurines are critical components in the treatment for prevention of recurrence in childhood ALL, the 6-mercaptopurine (6-MP) has usually been used in daily long-term maintenance therapy, and 6-thioguanine (6-TG) limited to the reinforcement of therapy. However, there is no optimal regimen for 6-TG or 6-MP. The related research advances on the clinical effectiveness of the two thiopurines are reviewed.

Oral Maintenance Chemotherapy with 6-Mercaptopurine and Methotrexate in Patients with Acute Myeloid Leukemia Ineligible for Transplantation

For decades, maintenance chemotherapy has failed to improve the cure rate or prolong the survival of patients with acute myeloid leukemia (AML), other than those with acute promyelocytic leukemia. Immediately after the first complete remission following consolidation therapy was obtained, oral maintenance chemotherapy (daily 6-mercaptopurine and weekly methotrexate) was given and continued for two years in transplant-ineligible AML patients. Leukemia-free survival (LFS) and overall survival (OS) were studied and compared between these patients and the historical control group who did not receive maintenance therapy. Consecutive 52 transplant-ineligible AML patients were analyzed. Among these patients, 27 received oral maintenance chemotherapy. No significant difference was found in the patients' characteristics between the maintenance and the control groups. The median OS was 43 (95% CI, 19-67) and 19 (95% CI, 8-30) months in the maintenance and the control groups, respectively (P = 0.202). In the multivariate analysis, the presence of maintenance therapy was an independent prognostic factor for better OS (P = 0.021) and LFS (P = 0.024). Clinical benefit from maintenance chemotherapy was remarkable in older patients (> or = 60 yr) (P = 0.035), those with intermediate or unfavorable cytogenetics (P = 0.006), those with initial low blast count in peripheral blood (P = 0.044), and those receiving less than two cycles of consolidation therapy (P = 0.017). Maintenance oral chemotherapy as a post-remission therapy can prolong the survival of patients with AML who are not eligible for transplantation, particularly older patients, those with intermediate or unfavorable cytogenetics, those with initial low blast count, and those receiving less than two cycles of consolidation therapy.

The Risk of Tuberculosis in Korean Patients with Inflammatory Bowel Disease Receiving Tumor Necrosis Factor-alpha Blockers

The aims of this study were to assess the risk of tuberculosis (TB) and the status of latent tuberculosis infection (LTBI) in Korean patients with inflammatory bowel disease (IBD) receiving tumor necrosis factor (TNF)-alpha blockers. We reviewed medical records of 525 Korean IBD patients (365 TNF-alpha blocker naive and 160 TNF-alpha blocker exposed) between January 2001 and December 2013. The crude incidence of TB was significantly higher in IBD patients receiving TNF-alpha blockers compared to TNF-alpha-blocker-naive patients (3.1% vs. 0.3%, P=0.011). The mean incidence of TB per 1,000 patient-years was 1.84 for the overall IBD population, 4.89 for TNF-alpha blocker users, and 0.45 for TNF-alpha-blocker-naive patients. The adjusted risk ratio of TB in IBD patients receiving TNF-alpha blocker was 11.7 (95% confidence interval, 1.36-101.3). Pulmonary TB was prevalent in patients treated with TNF-alpha blockers (80.0%, 4/5). LTBI was diagnosed in 17 (10.6%) patients, and none of the 17 LTBI patients experienced reactivation of TB during treatment with TNF-alpha blockers. Treatment with TNF-alpha blockers significantly increased the risk of TB in IBD patients in Korea. De novo pulmonary TB infection was more prevalent than reactivation of LTBI, suggesting an urgent need for specific recommendations regarding TB monitoring during TNF-alpha blocker therapy.

The Risk of Tuberculosis in Korean Patients with Inflammatory Bowel Disease Receiving Tumor Necrosis Factor-alpha Blockers

The aims of this study were to assess the risk of tuberculosis (TB) and the status of latent tuberculosis infection (LTBI) in Korean patients with inflammatory bowel disease (IBD) receiving tumor necrosis factor (TNF)-alpha blockers. We reviewed medical records of 525 Korean IBD patients (365 TNF-alpha blocker naive and 160 TNF-alpha blocker exposed) between January 2001 and December 2013. The crude incidence of TB was significantly higher in IBD patients receiving TNF-alpha blockers compared to TNF-alpha-blocker-naive patients (3.1% vs. 0.3%, P=0.011). The mean incidence of TB per 1,000 patient-years was 1.84 for the overall IBD population, 4.89 for TNF-alpha blocker users, and 0.45 for TNF-alpha-blocker-naive patients. The adjusted risk ratio of TB in IBD patients receiving TNF-alpha blocker was 11.7 (95% confidence interval, 1.36-101.3). Pulmonary TB was prevalent in patients treated with TNF-alpha blockers (80.0%, 4/5). LTBI was diagnosed in 17 (10.6%) patients, and none of the 17 LTBI patients experienced reactivation of TB during treatment with TNF-alpha blockers. Treatment with TNF-alpha blockers significantly increased the risk of TB in IBD patients in Korea. De novo pulmonary TB infection was more prevalent than reactivation of LTBI, suggesting an urgent need for specific recommendations regarding TB monitoring during TNF-alpha blocker therapy.