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PURPOSE: Renal tumors account for approximately 7% of all childhood cancers. These include Wilms tumor (WT), clear cell sarcoma of the kidney (CCSK), malignant rhabdoid tumor of the kidney (MRTK), renal cell carcinoma (RCC), congenital mesoblastic nephroma (CMN) and other rare tumors. We investigated the epidemiology of pediatric renal tumors in Korea. MATERIALS AND METHODS: From January 2001 to December 2015, data of pediatric patients (0-18 years) newly-diagnosed with renal tumors at 26 hospitals were retrospectively analyzed. RESULTS: Among 439 patients (male, 240), the most common tumor was WT (n=342, 77.9%), followed by RCC (n=36, 8.2%), CCSK (n=24, 5.5%), MRTK (n=16, 3.6%), CMN (n=12, 2.7%), and others (n=9, 2.1%). Median age at diagnosis was 27.1 months (range 0-225.5) and median follow-up duration was 88.5 months (range 0-211.6). Overall, 32 patients died, of whom 17, 11, 1, and 3 died of relapse, progressive disease, second malignant neoplasm, and treatment-related mortality. Five-year overall survival and event free survival were 97.2% and 84.8% in WT, 90.6% and 82.1% in RCC, 81.1% and 63.6% in CCSK, 60.3% and 56.2% in MRTK, and 100% and 91.7% in CMN, respectively (p < 0.001). CONCLUSION: The pediatric renal tumor types in Korea are similar to those previously reported in other countries. WT accounted for a large proportion and survival was excellent. Non-Wilms renal tumors included a variety of tumors and showed inferior outcome, especially MRTK. Further efforts are necessary to optimize the treatment and analyze the genetic characteristics of pediatric renal tumors in Korea.
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Carcinoma de Células Renais , Neoplasias Renais , Nefroma Mesoblástico , Tumor Rabdoide , Sarcoma , Tumor de Wilms , Criança , Humanos , Masculino , Carcinoma de Células Renais/epidemiologia , Estudos Retrospectivos , Recidiva Local de Neoplasia , Neoplasias Renais/terapia , Neoplasias Renais/tratamento farmacológico , Nefroma Mesoblástico/congênito , Nefroma Mesoblástico/metabolismo , Nefroma Mesoblástico/patologia , Tumor Rabdoide/patologia , República da Coreia/epidemiologiaRESUMO
Mitotane is an adrenolytic drug that exhibits therapeutic effects within a narrow target range (14-20 µg/dL). Various complications develop if the upper limit is exceeded. We present the case of a 5-year-old girl with breast development, acne, and pubic hair who was diagnosed with an adrenal mass that was subsequently excised. The pathological finding was adrenocortical carcinoma with a high risk of malignancy, and adjuvant therapy (combined mitotane and radiation therapy) was recommended. Mitotane was initiated at a low dose to allow monitoring of the therapeutic drug level, and high-dose hydrocortisone was also administered. However, the patient exhibited elevated adrenocorticotropic hormone levels and vague symptoms such as general weakness and difficulty concentrating. It was important to determine if these symptoms were signs of the neurological complications that develop when mitotane level is elevated. Encephalopathy progression and pubertal signs appeared 6 months after diagnosis, induced by high mitotane level. The mitotane decreased to subtherapeutic level several months after its discontinuation, at which time endocrinopathy (central hypothyroidism, hypercholesterolemia, and secondary central precocious puberty) developed. The case shows that low-dose mitotane can trigger neurological and endocrinological complications in a pediatric patient, indicating that the drug dose should be individualized with frequent monitoring of the therapeutic level.
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The gold standard for the diagnosis of pyruvate kinase (PK) deficiency, the most frequent red blood cell enzymopathy, is an enzymatic activity assay. However, this assay is rather unreliable in a clinical setting, often leading to misdiagnosis or missed diagnosis. This report presented the cases of two patients diagnosed with PK deficiency using molecular genetic testing, even though conventional laboratory tests, including the PK activity assay, failed to detect any abnormalities. Genetic analysis of the patients and their asymptomatic parents revealed the presence of variants in both alleles of the PKLR gene that were assessed as "likely pathogenic" or "pathogenic" in the form of compound heterozygotes. One of the mutations detected was common in both patients. Our results suggested that genetic testing might be required for the reliable diagnosis of suspected congenital hemolytic anemia cases displaying atypical presentation.
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Anemia Hemolítica Congênita não Esferocítica , Erros Inatos do Metabolismo dos Piruvatos , Anemia Hemolítica Congênita não Esferocítica/diagnóstico , Anemia Hemolítica Congênita não Esferocítica/genética , Eritrócitos , Testes Genéticos , Humanos , Biologia Molecular , Mutação , Piruvato Quinase/deficiência , Piruvato Quinase/genética , Erros Inatos do Metabolismo dos Piruvatos/diagnóstico , Erros Inatos do Metabolismo dos Piruvatos/genéticaRESUMO
This corrects the article on p. e393 in vol. 35, PMID: 33258329.
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BACKGROUND: Hodgkin's lymphoma (HL) constitutes 10%-20% of all malignant lymphomas and has a high cure rate (5-year survival, around 90%). Recently, interest has increased concerning preventing secondary complications (secondary cancer, endocrine disorders) in long-term survivors. We aimed to study the epidemiologic features and therapeutic outcomes of HL in children, adolescents, and young adults in Korea. METHODS: We performed a multicenter, retrospective study of 224 patients aged < 25 years diagnosed with HL at 22 participating institutes in Korea from January 2007 to August 2016. RESULTS: A higher percentage of males was diagnosed at a younger age. Nodular sclerosis histopathological HL subtype was most common, followed by mixed cellularity subtype. Eighty-one (36.2%), 101 (45.1%), and 42 (18.8%) patients were classified into low, intermediate, and high-risk groups, respectively. Doxorubicin, bleomycin, vinblastine, dacarbazine was the most common protocol (n = 102, 45.5%). Event-free survival rate was 86.0% ± 2.4%, while five-year overall survival (OS) rate was 96.1% ± 1.4%: 98.7% ± 1.3%, 97.7% ± 1.6%, and 86.5% ± 5.6% in the low, intermediate, and high-risk groups, respectively (P = 0.021). Five-year OS was worse in patients with B-symptoms, stage IV disease, high-risk, splenic involvement, extra-nodal lymphoma, and elevated lactate dehydrogenase level. In multivariate analysis, B-symptoms and extra-nodal involvement were prognostic factors for poor OS. Late complications of endocrine disorders and secondary malignancy were observed in 17 and 6 patients, respectively. CONCLUSION: This is the first study on the epidemiology and treatment outcomes of HL in children, adolescents, and young adults in Korea. Future prospective studies are indicated to develop therapies that minimize treatment toxicity while maximizing cure rates in children, adolescents, and young adults with HL.
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Antineoplásicos/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adolescente , Antineoplásicos/efeitos adversos , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Criança , Pré-Escolar , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Doenças do Sistema Endócrino/etiologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Lactente , Recém-Nascido , Masculino , República da Coreia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Vimblastina/efeitos adversos , Vimblastina/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: Anemia is associated with high morbidity and mortality in older people. However, the prevalence and characteristics of anemia in older individuals are not fully understood, and national data on these aspects in older Korean adults are lacking. This study aimed to evaluate the prevalence and characteristics of anemia in older adults using data from the Korea National Health and Nutrition Examination Survey (KNHANES), which is a nationwide cross-sectional epidemiological study conducted by the Korean Ministry of Health and Welfare. METHODS: Data from a total of 62,825 participants of the 2007-2016 KNHANES were compiled and analyzed to investigate differences in participant characteristics and potential risk factors for anemia. Differences in clinical characteristics of participants were compared across subgroups using the chi-square test for categorical variables and independent t-test for continuous variables. Univariate and multivariate analyses using logistic regression were performed to identify related clinical factors. RESULTS: The prevalence of anemia was higher in the population aged ≥65 years than in the younger population. Anemia was also more prevalent among females than among males, but this difference was not significant in people aged > 85 years. Being underweight, receiving a social allowance, living alone, and having comorbidities such as hypertension, rheumatoid arthritis, diabetes mellitus (DM), cancer, and chronic renal failure (CRF) were more common among older adults with anemia than among the population without anemia. In univariate and multivariate analyses, older age, female sex, underweight, and presence of comorbidities including rheumatoid arthritis, DM, cancer, and CRF were associated with an increased risk of anemia. CONCLUSIONS: This study revealed that age, female sex, underweight, and the presence of comorbidities such as rheumatoid arthritis, DM, cancer, and CRF were associated with an increased risk of anemia in older Korean adults. Further study on causal relationships between anemia and other variables in the older population is necessary.
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Anemia , Inquéritos Nutricionais , Idoso , Idoso de 80 Anos ou mais , Anemia/diagnóstico , Anemia/epidemiologia , Estudos Transversais , Atenção à Saúde , Feminino , Humanos , Masculino , Prevalência , República da Coreia/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: For children and adolescents with cancer, going back to school is a key milestone in returning to "normal life." PURPOSE: To identify the support vital for a successful transition, we evaluated the parents' needs and the challenges they face when their children return to school. METHODS: This multi-institutional study was conducted by the Korean Society of Pediatric Hematology and Oncology. The written survey comprised 24 questions and was completed by 210 parents without an interviewer. RESULTS: Most parents (165 of 206) reported that their children experienced difficulties with physical status (n=60), peer relationships (n=30), academic performance (n=27), emotional/behavioral issues (n=11), and relationships with teachers (n=4) on reentering school. Parents wanted to be kept informed about and remain involved in their children's school lives and reported good parent-teacher communication (88 of 209, 42.1%). Parents reported that 83.1% and 44.9% of teachers and peers, respectively, displayed an adequate understanding of their children's condition. Most parents (197 of 208) answered that a special program is necessary to facilitate return to school after cancer therapy that offers emotional support (n=85), facilitates social adaptation (n=61), and provides tutoring to accelerate catch up (n=56), and continued health care by hospital outreach and school personnel (n=50). CONCLUSION: In addition to scholastic aptitude-oriented programs, emotional and psychosocial support is necessary for a successful return to school. Pediatric oncologists should actively improve oncology practices to better integrate individualized school plans and educate peers and teachers to improve health literacy to aid them in understanding the needs of children with cancer.
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PURPOSE: Dexrazoxane has been used as an effective cardioprotector against anthracycline cardiotoxicity. This study intended to analyze cardioprotective efficacy and secondary malignancy development, and elucidate risk factors for secondary malignancies in dexrazoxane-treated pediatric patients. MATERIALS AND METHODS: Data was collected from 15 hospitals in Korea. Patients who received any anthracyclines, and completed treatment without stem cell transplantation were included. For efficacy evaluation, the incidence of cardiac events and cardiac event-free survival rates were compared. Data about risk factors of secondary malignancies were collected. RESULTS: Data of total 1,453 cases were analyzed; dexrazoxane with every anthracyclines group (D group, 1,035 patients) and no dexrazoxane group (non-D group, 418 patients). Incidence of the reported cardiac events was not statistically different between two groups; however, the cardiac event-free survival rate of patients with more than 400 mg/m2 of anthracyclines was significantly higher in D group (91.2% vs. 80.1%, p=0.04). The 6-year cumulative incidence of secondary malignancy was not different between both groups after considering follow-up duration difference (non-D, 0.52%±0.37%; D, 0.60%±0.28%; p=0.55). The most influential risk factor for secondary malignancy was the duration of anthracycline administration according to multivariate analysis. CONCLUSION: Dexrazoxane had an efficacy in lowering cardiac event-free survival rates in patients with higher cumulative anthracyclines. As a result of multivariate analysis for assessing risk factors of secondary malignancy, the occurrence of secondary malignancy was not related to dexrazoxane administration.
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Antraciclinas/efeitos adversos , Cardiotônicos/administração & dosagem , Cardiotoxicidade/prevenção & controle , Dexrazoxano/administração & dosagem , Segunda Neoplasia Primária/epidemiologia , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Cardiotônicos/uso terapêutico , Cardiotoxicidade/epidemiologia , Criança , Pré-Escolar , Dexrazoxano/uso terapêutico , Análise Fatorial , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Análise Multivariada , Segunda Neoplasia Primária/etiologia , República da Coreia , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
We compared transplant outcomes between donor types and stem cell sources for childhood acute myeloid leukemia (AML). The medical records of children with AML in the Yeungnam region of Korea from January 2000 to June 2017 were reviewed. In all, 76 children with AML (male-to-female ratio = 46:30) received allogenic hematopoietic stem cell transplantation (allo-HSCT). In total, 29 patients received HSCT from either a matched-related donor or a mismatched-related donor, 32 patients received an unrelated donor, and 15 patients received umbilical cord blood. In term of stem cell sources, bone marrow was used in 15 patients and peripheral blood in 46 patients. For all HSCT cases, the 5-year overall survival (OS) was 73.1% (95% CI: 62.7-83.5) and the 5-year event-free survival (EFS) was 66.1% (95% CI: 54.5-77.7). There was no statistical difference in 5-year OS according to the donor types or stem cell sources (P = .869 and P = .911). There was no statistical difference in 5-year EFS between donor types or stem cell sources (P = .526 and P = .478). For all HSCT cases, the 5-year relapse rate was 16.1% (95% CI: 7.3-24.9) and the 5-year non-relapse mortality (NRM) was 13.3% (95% CI: 5.1-21.5). There was no statistical difference in the 5-year relapse rate according to the donor types or stem cell sources (P = .971 and P = .965). There was no statistical difference in the 5-year NRM between donor types or stem cell sources (P = .461 and P = .470).
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The number of childhood cancer survivors is increasing as survival rates improve. However, complications after treatment have not received much attention, particularly metabolic syndrome. Metabolic syndrome comprises central obesity, dyslipidemia, hypertension, and insulin resistance, and cancer survivors have higher risks of cardiovascular events compared with the general population. The mechanism by which cancer treatment induces metabolic syndrome is unclear. However, its pathophysiology can be categorized based on the cancer treatment type administered. Brain surgery or radiotherapy may induce metabolic syndrome by damaging the hypothalamic-pituitary axis, which may induce pituitary hormone deficiencies. Local therapy administered to particular endocrine organs directly damages the organs and causes hormone deficiencies, which induce obesity and dyslipidemia leading to metabolic syndrome. Chemotherapeutic agents interfere with cell generation and growth, damage the vascular endothelial cells, and increase the cardiovascular risk. Moreover, chemotherapeutic agents induce oxidative stress, which also induces metabolic syndrome. Physical inactivity caused by cancer treatment or the cancer itself, dietary restrictions, and the frequent use of antibiotics may also be risk factors for metabolic syndrome. Since childhood cancer survivors with metabolic syndrome have higher risks of cardiovascular events at an earlier age, early interventions should be considered. The optimal timing of interventions and drug use has not been established, but lifestyle modifications and exercise interventions that begin during cancer treatment might be beneficial and tailored education and interventions that account for individual patients' circumstances are needed. This review evaluates the recent literature that describes metabolic syndrome in cancer survivors, with a focus on its pathophysiology.
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PURPOSE: This study evaluated the effect of first nocturnal ejaculation timing on risk and sexual behaviors of Korean male adolescents. METHODS: We analyzed data from the 10th edition of the Korea Youth Risk Behavior Web-based survey that was conducted with male high school adolescents in grades 10-12. The survey included 17,907 adolescents, and 10,326 responded their experience of first nocturnal ejaculation. Of these, 595 had their first nocturnal ejaculation in ≤grade 4 ("early puberty") and 9,731 had their first nocturnal ejaculation in ≥grade 5 ("normal puberty"). We analyzed differences between these 2 groups in risk and sexual behaviors. RESULTS: Early first nocturnal ejaculation showed a positive association with sexual intercourse (odds ratio [OR], 3.27; 95% confidence interval [CI], 2.56-4.17), sexual debut at elementary school age (OR, 7.45; 95% CI, 5.00-11.10), and having had a sexually transmitted disease (OR, 6.60; 95% CI, 3.94-11.08). After a multiple logistic regression to adjust for socio-demographic variables, early first nocturnal ejaculation was still positively associated with sexual intercourse (OR, 2.73; 95% CI, 2.03-3.69), sexual debut at elementary school age (OR, 5.96; 95% CI, 3.47-10.22), and having had a sexually transmitted disease (OR, 5.17; 95% CI, 2.52-10.20). Early first nocturnal ejaculation was positively associated with alcohol consumption, smoking, and substance use. However, this was not statistically significant after adjusting for several socio-demographic variables. CONCLUSION: There is a positive association between early nocturnal ejaculation and sexual behaviors in male adolescents. Proactive education about sexual behaviors is required for adolescents who reach sexual maturity early.
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BACKGROUND: The "a disintegrin and metalloproteases" (ADAMs) are a multifunctional gene family that contribute to the homeostasis of the extracellular matrix, transduction of specific intracellular signals, organogenesis, inflammation, tissue remodeling, adhesion, and cell migration. ADAM17 is the best-characterized of the "sheddases," and its putative substrates are widespread, including various inflammatory modulators. ADAM10 is the most similar to ADAM17 in terms of protein sequence and the structural properties of their catalytic domains. The objective of this work was to assess the roles of ADAM17 and ADAM10 in nasal polyps (NPs) by measuring their expression. METHODS: The expression of ADAM10 and 17 was investigated in NPs at endonasal sinus surgery (n = 15) and compared with that in inferior turbinate mucosa samples obtained from nonallergic hypertrophic rhinitis patients (n = 15). Tissue samples were analyzed by real-time polymerase chain reaction (PCR), Western blotting, and immunohistochemical staining. RESULTS: The ADAM17 messenger RNA (mRNA) and protein levels were significantly higher in the inferior turbinate than in NPs (p < 0.05). The ADAM10 mRNA and protein levels did not differ significantly between NPs and inferior turbinates (p > 0.05). ADAM10 and ADAM17 were expressed primarily in inflammatory cells, submucosal glandular cells, and lining epithelial cells. CONCLUSION: ADAM17 may contribute to the development of NPs in contrast to ADAM10, based on their expression patterns. It may be important to discover the role of ADAM17 in the development of NP and helpful to examine the specific mechanism of the development of NPs.
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Proteína ADAM10/metabolismo , Proteína ADAM17/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Proteínas de Membrana/metabolismo , Pólipos Nasais/metabolismo , Proteína ADAM10/genética , Proteína ADAM17/genética , Secretases da Proteína Precursora do Amiloide/genética , Humanos , Proteínas de Membrana/genética , Pólipos Nasais/genética , Pólipos Nasais/cirurgia , Seios Paranasais/metabolismo , Seios Paranasais/cirurgia , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: A disintegrin and metalloprotease (ADAM) is a multifunctional gene family that contributes to the homeostasis of the extracellular matrix, transduction of specific intracellular signals, organogenesis, inflammation, tissue remodeling, adhesion, and cell migration. ADAM17 is the best characterized sheddase, with widespread putative substrates, including various inflammatory modulators. ADAM10 is the most similar ADAM to ADAM17 in terms of both protein sequence and the structural properties of their catalytic domains. The objective of this work was to assess the expression of ADAM10 and ADAM17 in allergic rhinitis to gain insight into their respective roles. METHODS: The expression of ADAM10 and ADAM17 was investigated in the nasal mucosa under allergic and nonallergic conditions. Tissue samples were evaluated by reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting, and data were analyzed semiquantitatively with densitometry. RESULTS: The ADAM17 messenger RNA (mRNA) level was significantly (p < 0.001) lower in the allergic nasal mucosa than in the nonallergic nasal mucosa, whereas the ADAM10 mRNA level was significantly (p < 0.001) lower in the nonallergic nasal mucosa. The ADAM17 protein levels were also significantly (p < 0.001) lower in the allergic nasal mucosa, whereas the ADAM10 protein levels were lower in the nonallergic nasal mucosa (p = 0.002). CONCLUSION: Decreased expression of ADAM17 and increased expression of ADAM10 may contribute to the development of allergic rhinitis through unknown pathways. We suggest that understanding the expression profile of ADAM17 and ADAM10 might help to elucidate the mechanism of allergic rhinitis.
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Proteínas ADAM/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Inflamação/imunologia , Proteínas de Membrana/metabolismo , Mucosa Nasal/fisiologia , Rinite Alérgica/imunologia , Proteínas ADAM/genética , Proteína ADAM10 , Proteína ADAM17 , Secretases da Proteína Precursora do Amiloide/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Proteínas de Membrana/genéticaRESUMO
In order to clarify the optimal timing for peripheral blood stem cell (PBSC) collection, PBSC collection records of 323 children who were scheduled to undergo autologous stem cell transplantation from two study periods differing in the timing of PBSC collection were analyzed. In the early study period (March 1998 to August 2007, n=198), PBSC collection was initiated when the peripheral WBC count exceeded 1,000/µL during recovery from chemotherapy. Findings in this study period indicated that initiation of PBSC collection at a higher WBC count might result in a greater CD34(+) cell yield. Therefore, during the late study period (September 2007 to December 2012, n=125), PBSC collection was initiated when the WBC count exceeded 4,000/µL. Results in the late study period validated our conclusion from the early study period. Collection of a higher number of CD34(+) cells was associated with a faster hematologic recovery after transplant in the late study period. Initiation of PBSC collection at WBC count > 4,000/µL was an independent factor for a greater CD34(+) cell yield. In conclusion, PBSC collection at a higher WBC count is associated with a greater CD34(+) cell yield, and consequently a faster hematologic recovery after transplant.
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Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Neoplasias/sangue , Adolescente , Adulto , Antígenos CD34/metabolismo , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Lactente , Contagem de Leucócitos , Masculino , Neoplasias/tratamento farmacológico , Transplante Autólogo , Adulto JovemRESUMO
Patients with hematologic malignancies who relapse after their first hematopoietic stem cell transplantation tend to have poor prognoses. One option for these patients is a second allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there are few reports of second allo-HSCT therapy in children with relapsed hematologic malignancies. Patient outcomes in 27 individuals with acute leukemia who received at least 2 allo-HSCTs at the Samsung Medical Center between May 1997 and September 2010 were analyzed retrospectively. After a median follow-up of 33 months, 11 of 27 patients (40.7%) were alive and in stable remission. The 5-year overall survival rate for all 27 patients was 32.6%. There was no statistically significant difference in the survival rates of patients differing in their sex, the stem cell source, the donor type, or the presence of acute or chronic graft-versus-host disease. Remission before the second allo-HSCT was the only prognostic factor that influenced the survival rates (44.1% vs. 11.1%, P=0.009). Of 16 cases of mortality, 9 mortality cases (56.3%) were associated with relapse and 7 cases (43.7%) were associated with treatment-related mortality. Therefore, a second allo-HSCT offers the chance of stable remission for some patients with acute hematologic malignancies who relapse after their first allo-HSCT.
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Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/cirurgia , Transplante de Células-Tronco Hematopoéticas , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/cirurgia , Adolescente , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do TratamentoRESUMO
To overcome the limitations of allogeneic hematopoietic stem cell transplantation (HSCT), we conducted a study to identify a strategy for enhancing hematopoietic stem cell (HSC) engraftment during HSCT. Co-transplantation experiments with mesenchymal stem cells (MSCs) derived from adult human tissues including bone marrow (BM), adipose tissue (AT), and umbilical cord blood (CB) were conducted. We showed that AT-MSCs and CB-MSCs enhanced the engraftment of HSCs as effectively as BM-MSCs in NOD/SCID mice, suggesting that AT-MSCs and CB-MSCs can be used as alternative stem cell sources for enhancing the engraftment and homing of HSCs. CB-MSCs derived from different donors showed different degrees of efficacy in enhancing the engraftment of HSCs. The most effective CB-MSCs showed higher proliferation rates and secreted more MCP-1, RANTES, EGF, and VEGF. Our results suggest that AT-MSCs and CB-MSCs could be alternative stem cell sources for co-transplantation in HSCT. Furthermore, in terms of MSCs' heterogeneity, characteristics of each population of MSCs are considerable factors for selecting MSCs suitable for co-transplantation with HSC.
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Sobrevivência de Enxerto/fisiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Mesenquimais/fisiologia , Tecido Adiposo/citologia , Tecido Adiposo/fisiologia , Tecido Adiposo/transplante , Animais , Células da Medula Óssea/fisiologia , Proliferação de Células , Células Cultivadas , Sangue Fetal/fisiologia , Sangue Fetal/transplante , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCIDRESUMO
TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] is a promising agent for clinical use since it kills a wide range of tumour cells without affecting normal cells. We provide evidence that pretreatment with etoposide significantly enhanced TRAIL-mediated apoptosis via up-regulation of DR5 (death receptor 5 or TRAIL-R2) expression in the caspase 8 expressing neuroblastoma cell line, SK-N-MC. In addition, sequential treatment with etoposide and TRAIL increased caspases 8, 9 and 3 activation, Mcl-1 cleavage and Bid truncation, which suggests that the ability of etoposide and TRAIL to induce apoptosis is mediated through activation of an intrinsic signalling pathway. Although TRAIL-R2 expression increased in IMR-32 cells in response to etoposide treatment, cell death was not increased by concurrent treatment with TRAIL compared with etoposide alone, because the cells lacked caspase 8 expression. Restoration of caspase 8 expression by exposure to IFNγ (interferon γ) sensitizes IMR-32 cells to TRAIL. Moreover, pretreatment with etoposide increased TRAIL-induced apoptosis in caspase 8 restored IMR-32 cells through activation of a caspase cascade that included caspases 8, 9 and 3. These results indicate that the etoposide-mediated sensitization of neuroblastoma cells to TRAIL is associated with an increase in TRAIL-R2 expression and requires caspase 8 expression. These observations support the potential use of a combination of etoposide and TRAIL in future clinical trials.
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Multiple RBC transfusions inevitably lead to a state of iron overload before and after high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT). Nonetheless, iron status during post-SCT follow-up remains unknown. Therefore, we investigated post-SCT ferritin levels, factors contributing to its sustained levels, and organ functions affected by iron overload in 49 children with high-risk neuroblastoma who underwent tandem HDCT/autoSCT. Although serum ferritin levels gradually decreased during post-SCT follow-up, 47.7% of the patients maintained ferritin levels above 1,000 ng/mL at 1 yr after the second HDCT/autoSCT. These patients had higher serum creatinine (0.62 vs 0.47 mg/mL, P = 0.007) than their counterparts (< 1,000 ng/mL). Post-SCT transfusion amount corresponded to increased ferritin levels at 1 yr after the second HDCT/autoSCT (P < 0.001). A lower CD34(+) cell count was associated with a greater need of RBC transfusion, which in turn led to a higher serum ferritin level at 1 yr after HDCT/autoSCT. The number of CD34(+) cells transplanted was an independent factor for ferritin levels at 1 yr after the second HDCT/autoSCT (P = 0.019). Consequently, CD34(+) cells should be transplanted as many as possible to prevent the sustained iron overload after tandem HDCT/autoSCT and consequent adverse effects.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sobrecarga de Ferro/etiologia , Neuroblastoma/terapia , Transplante de Células-Tronco , Reação Transfusional , Antígenos CD34/metabolismo , Benzoatos/uso terapêutico , Criança , Pré-Escolar , Creatinina/sangue , Deferasirox , Ferritinas/sangue , Seguimentos , Humanos , Lactente , Quelantes de Ferro/uso terapêutico , Neuroblastoma/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco , Transplante Autólogo , Triazóis/uso terapêuticoRESUMO
BACKGROUND: We evaluated whether iron chelation treatment during induction chemotherapy could safely reduce serum iron levels and thereby reduce the frequency of hepatic veno-occlusive disease (VOD) during high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) in children with high-risk solid tumors. PROCEDURE: Children diagnosed with high-risk solid tumors between August 2008 and July 2009 were enrolled. Deferasirox treatment (25 mg/kg/day) was initiated when serum ferritin levels increased to more than 1,000 ng/ml during induction chemotherapy. Patients who were diagnosed with the same disease between April 2005 and June 2007 and treated in the same way without any iron chelation treatment formed the control group. Efficacy and toxicity of deferasirox treatment were compared between the two groups. RESULTS: Eighteen of 20 patients enrolled received deferasirox treatment. Deferasirox treatment was completed as scheduled in 11 (61.1%) of them without dose reduction or discontinuation. The serum ferritin levels prior to HDCT/autoSCT were lower in the deferasirox group than in the control group (median 1,268 ng/ml vs. 1,828 ng/ml, P < 0.001), although there was no difference in the RBC transfusion amount between the two groups. While 7 (17.9%) VODs developed during 39 HDCT/autoSCTs in the control group, there was no VOD during 40 HDCT/autoSCTs in the deferasirox group (P = 0.005). However, renal dysfunction (38.9%) including Fanconi syndrome (16.7%) was a frequently observed adverse effect of deferasirox treatment. CONCLUSIONS: Deferasirox treatment during induction chemotherapy reduces the frequency of VOD during HDCT/autoSCT. The development of renal dysfunction should be closely monitored during deferasirox treatment.
Assuntos
Benzoatos/uso terapêutico , Neoplasias Encefálicas/terapia , Hepatopatia Veno-Oclusiva/prevenção & controle , Quimioterapia de Indução/efeitos adversos , Quelantes de Ferro/uso terapêutico , Neuroblastoma/terapia , Transplante de Células-Tronco/efeitos adversos , Triazóis/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Benzoatos/efeitos adversos , Criança , Pré-Escolar , Deferasirox , Transfusão de Eritrócitos , Síndrome de Fanconi/induzido quimicamente , Feminino , Ferritinas/sangue , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Lactente , Quelantes de Ferro/efeitos adversos , Masculino , Transplante Autólogo , Triazóis/efeitos adversosRESUMO
Umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) enhance the engraftment of human hematopoietic stem cells (HSCs) when they are cotransplanted in animal and human studies. However, the type of MSCs that preferentially facilitate the engraftment and homing of HSCs is largely unknown. The authors categorized UCB-MSCs as the least-effective MSCs (A) or most-effective MSCs (B) at enhancing the engraftment of HSCs, and compared the gene expression profiles of various cytokines and growth factors in the UCB-MSC populations. The most-effective UCB-MSCs (B) secreted higher levels of several factors, including chemokine (C-X-C motif) ligand 12 (CXCL12), regulated upon activation, normal T cells expressed and secreted (RANTES), epithelial growth factor (EGF), and stem cell factor (SCF), which are required for the engraftment and homing of HSCs. By contrast, levels of growth-related oncogene (GRO), insulin-like growth factor-binding protein 1 (IGFBP1), and interleukin-8 (IL-8), which are associated with immune inflammation, were secreted at higher levels in UCB-MSCs (A). In addition, there were no differences between the transcripts of the 2 UCB-MSC populations after interferon-gamma (IFN-γ) stimulation, except for cyclooxygenase (COX)-1. Based on these findings, the authors propose that these chemokines may be useful for modulating these cells in a clinical setting and potentially for enhancing the effectiveness of the engraftment and homing of HSCs.