Background
A phase 1 study was conducted to determine the maximum tolerated dose of bendamustine when given in combination with clofarabine, etoposide, and dexamethasone daily for 5 days in children ...and adolescents with relapsed or refractory hematologic malignancies.
Methods
Patients younger than 22 years with second or greater relapsed or refractory acute leukemia or lymphoma after 2 or more prior regimens were eligible. With the rolling 6 design, participants received escalating doses of bendamustine (30, 40, or 60 mg/m2/d) in combination with clofarabine (40 mg/m2), etoposide (100 mg/m2), and dexamethasone (8 mg/m2) daily for 5 days. Optional pharmacokinetic studies were performed in cycle 1 on day 1 and day 5.
Results
Sixteen patients were enrolled. Six patients were treated at the dose level of 30 mg/m2/d, 6 were treated at the dose level of 40 mg/m2/d, and 4 were treated at the dose level of 60 mg/m2/d. The dose‐limiting toxicity was prolonged myelosuppression. The combination was otherwise well tolerated. The recommended dose of bendamustine in this combination was 30 mg/m2/d for 5 days. Ten responses were observed after 1 cycle: 6 complete remissions, 1 durable minimal residual disease–negative complete remission without platelet recovery in a patient with early T‐cell precursor leukemia, and 3 partial remissions. Six patients proceeded to transplantation. The event‐free survival rate was 40.6% (95% confidence interval CI, 17.5%‐63.7%) at 1 year and 33.9% (95% CI, 11.9%‐55.9%) at 3 years.
Conclusions
Bendamustine is well tolerated in combination with clofarabine, etoposide, and dexamethasone. The combination administered over 5 days is effective for multiple relapsed and refractory hematologic malignancies. This trial is registered with ClinicalTrials.gov (NCT01900509).
Lay Summary
Improvements to the existing chemotherapy regimen are still needed for patients who relapse after targeted therapies and immunotherapies and for those who are not eligible for or have no access to such therapies.
A regimen combining cyclophosphamide, clofarabine, and etoposide has been used in relapsed and refractory pediatric patients with hematologic malignancies.
This study shows that substituting bendamustine for cyclophosphamide in combination with clofarabine and etoposide is safe and effective.
Bendamustine can safely be administered daily over 5 days in combination with clofarabine, etoposide, and dexamethasone. Minimal residual disease–negative complete remissions are achieved in 70% of pediatric patients with relapsed or refractory B‐cell acute lymphoblastic leukemia.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Distance based multi-response permutation procedures are discussed in the context of analyzing the spatial relationship of short-grass prairie plant species. Under certain conditions, multiresponse ...permutation procedures may provide useful information on how the spatial relationship of multi-species populations change over large geographical area. This method is illustrated using mapped data of short-grass prairie plants typical of the eastern plains of Colorado. The use of permutation procedure for randomized block experiments indicated that the dominant species tend to be segregated on the four plots used in this study. The large value associated with the measure of agreement suggested a similar structure of the spatial distribution and association of individual species on the plots. Further analysis revealed that all but one of the dominant species occurred in clusters of varying size and density. The ability to study the spatial relationship among species on independent plots provides a valuable tool in studying the spatial dynamics of diverse populations.
The history of research in Serengeti shows that with every decade different problems have appeared. These problems have been addressed by researchers with a view to providing information to be used ...by the Park managers. The earliest problems related to the lack of basic information on how the ecosystem worked – where did the migration go? What limited populations? Later decades produced problems related to the impact of increasing human populations on the habitats and animal numbers, and also how the Protected Area affects surrounding peoples – how was fire changing the savanna? How was poaching changing ungulate populations? How were animals damaging crops? Recent problems are focused on the impacts of development – how does a road across northern Serengeti affect the migration? How would offtake of water from the Mara River affect migrant species? Research has provided the relevant information and in most cases successful management decisions have been taken. Tanzania as a whole has also benefited from this research. We show how it is directly relevant to the major national concerns of economics, health, social welfare, ecosystem services and conservation.
Summary statistics of mean z-scores for height-for-age and weight-for-age reveal that the entire population of GSE is stunted (due to chronic under-nutrition) and underweight (which could be a sign ...of long or short-term malnutrition). When compared to the mean z-scores for all of rural mainland Tanzania, we see that these health problems are not unique to the GSE. In fact, only 15% of GSE villages sampled had mean z-scores (for both height-for-age and weight-for-age) that were below the mean z-scores for all of rural mainland Tanzania. Such a finding suggests that conservation agendas alone are not the cause of malnutrition in the GSE but poor nutrition is more a sign of the ongoing political and economic struggle of all rural Tanzanians. To further understand these patterns of heterogeneity in human health across the GSE, more research is needed to uncover the ultimate drivers of malnutrition and poor health.
Summary of over 45 years of data on small mammal diversity and abundance collected in the greater Serengeti ecosystem, quantifying the diversity of small mammals by habitat type and increasing the ...known number of species recorded in the system to a minimum of 37. Fluctuations were recorded in rodent abundance from 1968 to 2010 and demonstrated for the first time that ‘outbreaks’ in rodent abundance occur in natural ecosystems in Africa, not just in agricultural systems. Short-season rainfall is a major driver of rodent outbreaks and in turn small mammals play a vital role in the food web of the greater Serengeti ecosystem because several species of predators show a strong response to rodent abundance. In addition to the linkages between rainfall, primary productivity, small mammals and predators described in this chapter, there is increasing evidence that small mammals play a wide range of subtle and indirect roles in the function of savanna ecosystems.
Improvement in existing chemotherapy regimen is still needed for patients who relapse following targeted therapies and immunotherapies, and in those who are not eligible, or have no access to such ...therapies. A regimen combining cyclophosphamide, clofarabine, and etoposide has been used in relapsed and refractory pediatric patients with hematologic malignancies. In this study we show that substituting bendamustine for cyclophosphamide in combination with clofarabine and etoposide is safe and effective.
Bendamustine can safely be administered daily over five days in combination with clofarabine, etoposide, and dexamethasone. MRD-negative complete remissions were achieved in 70% of pediatric patients with relapsed or refractory B-ALL.
Full text
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We describe an original, short, and convenient chemical synthesis of enantiopure (S)-4,5-dihydroxy-2,3-pentanedione (DPD), starting from commercial methyl ...(S)-(-)-2,2-dimethyl-1,3-dioxolane-4-carboxylate. DPD is the precursor of autoinducer (AI)-2, the proposed signal for bacterial interspecies communication. AI-2 is synthesized by many bacterial species in three enzymatic steps. The last step, a LuxS-catalyzed reaction, leads to the formation of DPD, which spontaneously cyclizes into AI-2. AI-2-like activity of the synthesized molecule was ascertained by the Vibrio harveyi bioassay. To further validate the biological activity of synthetic DPD and to explore its potential in studying DPD (AI-2)-mediated signaling, a Salmonella typhimurium luxS mutant was constructed. Expression of the AI-2 regulated lsr operon can be rescued in this luxS mutant by addition of synthetic DPD or genetic complementation. Biofilm formation by S. typhimurium has been reported to be defective in a luxS mutant, and this was confirmed in this study to test DPD for chemical complementation. However, biofilm formation of the luxS mutant cannot be restored by addition of DPD. In contrast, introduction of luxS under control of its own promoter complemented biofilm formation. Further results demonstrated that biofilm formation of the luxS mutant cannot be restored with luxS under control of the strong nptII promoter. This indicates that altering the intrinsic promoter activity of luxS affects Salmonella biofilm formation. Conclusively, we synthesized biologically active DPD. Using this chemical compound in combination with genetic approaches opens new avenues in studying AI-2-mediated signaling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This chapter describes the abiotic (e.g., soils, climate, landscape) and biotic (e.g., plant, animal) patterns of heterogeneity in the Serengeti, and identifies processes that contribute to their ...generation and maintenance. It describes patterns of heterogeneity in terms of the nature of their measurement—whether qualitative or quantitative—and the extent to which they included a spatial component. Furthermore, it identifies how humans have impacted natural patterns of heterogeneity across the Serengeti ecosystem within the last century. Because abiotic and biotic sources of heterogeneity can interact in complex ways and can produce unpredictable results, the chapter concludes by discussing three examples of heterogeneity generated and maintained by complex interactions between abiotic and biotic sources.
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