RESUMO
Objectives: Primary graft failure (pGF) after hematopoietic stem-cell transplant is associated with considerable morbidity and mortality. The incidence in haplo-HSCT has been reported to be between 0% and 30%. In 2018, we identified a pGF incidence of 35% in our pediatric haplo-HSCT recipients with hematologic malignancies, which motivated us to enact changes to the conditioning regimen.Methods: We performed a single-center prospective, pre-post study of consecutive patients under 16 years with hematologic malignancies, from January 2015 to December 2022 who received a haplo-HSCT. Twenty-six pediatric patients received a haplo-HSCT before September 2018 (G1) and 36 patients after (G2). The main conditioning regimen for G1 was myeloablative with Flu/Cy/Bu, and for G2 the main regimen was reduced intensity Flu/Cy/Mel/TBI2.Results: Nine patients (35%) in G1 had primary graft failure, while in G2 there were no patients with pGF. The median follow-up for G1 was 15.9 months, and for G2 was 24.8 months, with an estimated overall survival at 12 months of 63% (95% CI 47-76) versus 85% (95% CI 73-93), and at 24 months of 47% (95% CI 31-64) versus 70% (95% CI 54-82) respectively (p = .007).Conclusion: After September 2018 conditioning regimen modifications were implemented with the objective of reducing primary failure, consisting mainly of switching from busulfan to melphalan as the alkylating agent of choice, and adding, when clinically possible TBI. Primary failure has been significantly reduced in our institution since then.
Assuntos
Neoplasias Hematológicas , Melfalan , Humanos , Criança , Estudos Prospectivos , Transplante Haploidêntico , BussulfanoRESUMO
An essential step in the success of germ cell transplantation is the preparation of the recipient's testicular environment to increase the availability of stem cell niches. However, most methods for this purpose in birds face serious limitations such as partial germ cell depletion, high toxicity and mortality, or the need to use expensive technologies. Here, we validated a simple and practical technique of transferring quail testicular cells into chicken testes depleted of endogenous spermatozoa by fractioned chemotherapy (20 mg/kg/week busulfan for 5 weeks). This protocol resulted in a very low mortality of the treated day-old chicks and, despite maintenance of androgenic activity, sperm production was decreased by 84.3% at 25 weeks of age. NANOG immunostaining revealed that very few to no germ cells were present following treatment with 20 and 40 mg/kg, respectively. RT-qPCR data also showed that c-MYC and NANOG expression declined in these treatments, but GRFα1 and BID expressions remained unaltered among groups. After xenotransplantation, quail germ cells were immunodetected in chicken testes using a species-specific antibody (QCPN), and quail ovalbumin DNA was found in seminal samples collected from chicken recipients. Together, these data confirm that fractionated administration of busulfan in hatchlings is a practical, effective, and safe protocol to prepare recipient male birds capable of supporting xenogeneic spermatogenesis.
Assuntos
Espermatogônias , Testículo , Masculino , Animais , Bussulfano , Galinhas , Transplante Heterólogo , Sêmen , Espermatogênese , CodornizRESUMO
BACKGROUND AND OBJECTIVES: Allogeneic stem cell transplantation (Allo-SCT) in elderly patients is a growing practice. We aimed to determine the graft-versus-host disease (GVHD) relapse-free survival (GRFS) in patients ≥65 years who underwent Allo-SCT in two countries from Latin America. PATIENTS AND METHODS: We performed a retrospective analysis of patients ≥65 years who underwent Allo-SCT in Argentina and Brazil from 2007 to 2019. RESULTS: Ninety-eight patients were evaluated, with primary diagnoses of acute myeloid leukemia and myelodysplastic syndrome; 30% of patients had a hematopoietic cell transplant-comorbidity index (HCT-CI) score ≥3 and 49% were in complete remission. Donor types included matched sibling (n = 41), matched unrelated (n = 31), and haploidentical (HID; n = 26) donors. The conditioning regimen was myeloablative in 28 patients (14 busulfan pharmacokinetically [PK]-guided) and reduced-intensity in 70 patients. The two-year non-relapse mortality (NRM) was 29%, with a higher NRM in melphalan-based compared to other conditionings (51% vs. 33%, p = 0.02). The two-year relapse rate was 24%, with a reduction in PK-guided busulfan (0% vs. 28%, p = 0.03). The two-year overall survival (OS) and GRFS was 52% and 38%, respectively, with a significant reduction in GRFS in HCT-CI ≥3 (27% vs. others 42%, p = 0.02) and donors ≥40 years (29% vs. <40 years 55%, p = 0.02). These variables remained significantly associated with GRFS after multivariate analysis. CONCLUSION: In this cohort of elderly patients from Argentina and Brazil undergoing Allo-SCT, donor age and comorbidities significantly influenced GRFS. The role of the conditioning regimen in this population deserves further investigation.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Idoso , Bussulfano , Estudos Retrospectivos , América Latina , Recidiva , Condicionamento Pré-TransplanteRESUMO
OBJECTIVE: The aim of this study was to analyze and identify documented infections and possible risk factors for Clostridioides difficile infections in children with cancer. METHODS: This is a retrospective case-control study, carried out in a pediatric cancer hospital, covering the years 2016-2019. Matching was performed by age and underlying disease, and for each case, the number of controls varied from 1 to 3. Logistic regression models were used to assess risk factors. RESULTS: We analyzed 63 cases of documented infection by C. difficile and 125 controls. Diarrhea was present in all cases, accompanied by fever higher than 38°C in 52.4% of the patients. Mortality was similar among cases (n=4; 6.3%) and controls (n=6; 4.8%; p=0.7). In all, 71% of patients in the case group and 53% in the control group received broad-spectrum antibiotics prior to the infection. For previous use of vancomycin, the Odds Ratio for C. difficile infection was 5.4 (95% confidence interval [95%CI] 2.3-12.5); for meropenem, 4.41 (95%CI 2.1-9.2); and for cefepime, 2.6 (95%CI 1.3-5.1). For the antineoplastic agents, the Odds Ratio for carboplatin was 2.7 (95%CI 1.2-6.2), melphalan 9.04 (95%CI 1.9-42.3), busulfan 16.7 (95%CI 2.1-134.9), and asparaginase 8.97 (95%CI 1.9-42.9). CONCLUSIONS: C. difficile symptomatic infection in children with cancer was associated with previous hospitalization and the use of common antibiotics in cancer patients, such as vancomycin, meropenem, and cefepime, in the last 3 months. Chemotherapy drugs, such as carboplatin, melphalan, busulfan, and asparaginase, were also risk factors.
Assuntos
Clostridioides difficile , Infecções por Clostridium , Infecção Hospitalar , Neoplasias , Humanos , Criança , Estudos de Casos e Controles , Estudos Retrospectivos , Vancomicina , Cefepima/uso terapêutico , Meropeném , Bussulfano/uso terapêutico , Melfalan/uso terapêutico , Asparaginase/uso terapêutico , Institutos de Câncer , Carboplatina/uso terapêutico , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/induzido quimicamente , Infecção Hospitalar/tratamento farmacológico , Antibacterianos/uso terapêutico , Infecções por Clostridium/epidemiologia , Infecções por Clostridium/induzido quimicamente , Infecções por Clostridium/tratamento farmacológico , Neoplasias/complicações , Fatores de RiscoRESUMO
OBJECTIVE: Male infertility secondary to exposure to gonadotoxic agents during reproductive age is a concerning issue. The aim of this experimental study was to determine the effect of Loboob on sperm parameters. METHODS: 55 healthy rats were selected, weighted and divided into five groups consisting of 11 rats each. The control group received no medication. Rats in Treatment Group 1 received 10mg/kg Busulfan and rats in Treatment Groups 2, 3, and 4 received 35,70 and 140 mg/kg Loboob respectively in addition to 10mg/kg Busulfan. Finally, the sperm parameters and weights of the rats were compared using the Kolmogorov-Smirnov, non-parametric Kruskal-Wallis, and Dunn-Bonferroni tests. RESULTS: All sperm parameters and weights were significantly decreased among rats receiving Busulfan. All dosages of Loboob were effective to enhance the motility of slow spermatozoa, while only in the rats given 70 and 140 mg/kg of Loboob saw improvements in progressively motile sperm percentages (0.024 and 0.01, respectively). Loboob at a dosage of 140mg/kg improved sperm viability. It did not improve normal morphology sperm or decrease immotile sperm counts. Loboob did not affect mean rat weight. CONCLUSIONS: Loboob offered a dose-dependent protective effect on several sperm parameters in rats with busulfan-induced subfertility.
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Infertilidade Masculina , Motilidade dos Espermatozoides , Humanos , Masculino , Ratos , Animais , Contagem de Espermatozoides , Bussulfano/toxicidade , Sêmen , Espermatozoides , Infertilidade Masculina/induzido quimicamente , Infertilidade Masculina/tratamento farmacológicoRESUMO
Abstract Testicular damage is one of the most hazardous effects of chemotherapy as it is frequently associated with oligozoospermia and azoospermia. This study aimed at evaluating the protective effect of melatonin in a rat model of busulfan-induced testicular injury. Rats were divided into four groups: control, melatonin, busulfan, busulfan plus melatonin. After 15 days, the semen was collected from the epididymis and testes were assessed. Sperm removed from cauda epididymis and analyzed for sperm count and viability. Testis tissues were also removed, fixed in formalin and were embedded in paraffin. Sections of testis tissue were stained with hematoxylin-eosin for histological examination and prepared for TUNEL (Terminal deoxynucleotide transferase dUTP Nick End Labeling) assay to detect apoptosis and PCNA (proliferating cell nuclear antigenassay) to detect proliferation cells. Serum and testes supernatants were separated to detect testosteron level and oxidative stress parameters. In histological examination, degenerative changes in seminiferous tubules were observed in the experimental groups. In biochemical examination, the total oxidant status (TOS) levels in Busulfan group were significantly higher than in the control group while the total antioxidant status (TAS) levels of all the groups were similar. In conclusion, the beneficial properties of melatonin treatment by its potent anti-oxidants may reduce adverse effects of chemotherapy in the reproductive system in a rodent system.
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Animais , Masculino , Ratos , Espermatogênese/efeitos dos fármacos , Bussulfano/agonistas , Melatonina/efeitos adversos , Testículo/anormalidadesRESUMO
OBJECTIVE: Busulfan is one of the most common chemotherapeutic drugs and has the ability to induce apoptosis in testicular germ cells, which leads to infertility. In this study, the effects of ozone therapy and melatonin were evaluated on testicular disorders induced by busulfan. METHODS: In this study, we divided 24 male mice into four groups: control group, groups treated with busulfan, busulfan/melatonin, and busulfan/ozone. At the end of a 35-day period, blood samples were taken from the mice and their testosterone levels were measured. Both of the mice's testes were removed and weighed, afterwards, each one of them was used for evaluation of morphology by Johnson's score, as well as for measuring the diameter and thickness of seminiferous tubules. The other testis was homogenized for measuring Malondialdehyde (MDA) and antioxidant status using Catalase (CAT), Super Oxide Dismutase (SOD), and Total Antioxidant Capacity (TAC) levels. Epididymis spermatozoa were also used to evaluate motility, morphology, and sperm count. RESULTS: Busulfan significantly reduced the testis quality (weight, sperm parameters, testosterone, CAT, SOD, and TAC levels) and increased MDA and destruction of seminiferous tubules compared to the control group. Ozone and melatonin treatments significantly increased testis quality, sperm parameters, MDA, and antioxidant status, but they did not affect the TAC level. CONCLUSIONS: This study showed that similar to melatonin, ozone can reduce the effect of busulfan toxicity on mice testis. However, further studies are needed to understand the precise mechanism of ozone function on testis.
Assuntos
Melatonina , Ozônio , Animais , Bussulfano/metabolismo , Bussulfano/toxicidade , Masculino , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Estresse Oxidativo , Ozônio/metabolismo , Ozônio/toxicidade , Espermatozoides , Testículo/metabolismoRESUMO
Busulfan is given in the conditioning regimens preceding hematopoietic stem cell transplantation (HSCT), and plasma levels can be monitored. A targeted, individualized systemic exposure (SE) dose can be achieved by calculating the area under the plasma concentration versus time curve (AUC). The objective of this study was to determine a cutoff value for safety for the AUC for busulfan plasma levels in patients undergoing HSCT. A total of 149 consecutive HSCT patients were studied. After an oral test dose of busulfan, we set target doses of 4000, 5000, or 6000 µMol⸱min/day, and analyzed the AUC of oral or intravenous Bu. These patients were compared with 53 historical control subjects who had received myeloablative conditioning regimen without busulfan pharmacokinetic monitoring. Using a test dose and the administration route had no impact on the sinusoidal obstructive syndrome (SOS) incidence, transplant-related mortality or 1-year overall survival. However, patients receiving busulfan at doses set up at AUC > 5000 had an increased risk to develop SOS after HSCT (hazard ratio 3.39, p = 0.034, 95% CI 1.09-10.52). Adjusting the busulfan dose according to SE levels target dose during conditioning is associated with lower rates of oral severe mucositis and SOS. A cutoff of 5000 µMol⸱min is safe and does not impair survival.
Assuntos
Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Hepatopatia Veno-Oclusiva/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Administração Intravenosa , Administração Oral , Adolescente , Área Sob a Curva , Bussulfano/farmacocinética , Criança , Pré-Escolar , Ensaios Clínicos Controlados como Assunto , Suscetibilidade a Doenças , Feminino , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/epidemiologia , Hepatopatia Veno-Oclusiva/mortalidade , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Prognóstico , Condicionamento Pré-Transplante/métodos , Adulto JovemRESUMO
Busulfan is a bifunctional alkylating agent used for myeloablative conditioning and in the treatment of chronic myeloid leukemia due to its ability to cause DNA damage. However, in rodent experiments, busulfan presented a potential teratogenic and cytotoxic effect. Studies have evaluated the effects of busulfan on fetuses after administration in pregnancy or directly on pups during the lactation period. There are no studies on the effects of busulfan administration during pregnancy on offspring development after birth. We investigated the effects of busulfan on somatic and reflex development and encephalic morphology in young rats after exposure in pregnancy. The pregnant rats were exposed to busulfan (10 mg/kg, intraperitoneal) during the early developmental stage (days 12-14 of the gestational period). After birth, we evaluated the somatic growth, maturation of physical features and reflex-ontogeny during the lactation period. We also assessed the effects of busulfan on encephalic weight and cortical morphometry at 28 days of postnatal life. As a result, busulfan-induced pathological changes included: microcephaly, evaluated by the reduction of cranial axes, delay in reflex maturation and physical features, as well as a decrease in the morphometric parameters of somatosensory and motor cortex. Thus, these results suggest that the administration of a DNA alkylating agent, such as busulfan, during the gestational period can cause damage to the central nervous system in the pups throughout their postnatal development.