Data on outcomes of allogeneic transplantation in children with Down syndrome and acute myelogenous leukemia (DS-AML) are scarce and conflicting. Early reports stress treatment-related mortality as the main barrier; a recent case series points to post-transplant relapse.
Design and methods
We reviewed outcome data for 28 patients with DS-AML reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2000 and 2009 and performed a first matched-pair analysis of 21 patients with DS-AML and 80 non-DS AML controls.
The median age at transplantation for DS-AML was 3 years and almost half of the cohort was in second remission. The 3-year probability of overall survival was only 19%. In multivariate analysis, adjusting for interval from diagnosis to transplantation, risks of relapse (HR 2.84, p<0.001; 62% vs. 37%) and transplant-related mortality (HR 2.52, p=0.04; 24% vs. 15%) were significantly higher for DS-AML compared to non-DS AML. Overall mortality risk (HR 2.86, p<0.001; 21% vs. 52%) was significantly higher for DS-AML.
Both transplant-related mortality and relapse contribute to higher mortality. Excess mortality in DS-AML patients can only effectively be addressed through an international multi-center effort to pilot strategies aimed at lowering both transplant-related mortality and relapse risks.
hematopoietic stem cell transplantation; Down syndrome; trisomy 21; AML; ALL; relapse; pediatric
While the role of auto-HCT is well established in neuroblastoma, the role of allo-HCT is controversial. The CIBMTR conducted a retrospective review of 143 allo-HCT for NBL reported in 1990-2007. Patients were categorized into two different groups: those who had not (Group 1) and had (Group 2) undergone a prior auto HCT (n=46 and 97, respectively). One-year and five-year overall survival (OS) were 59% and 29% for Group 1 and 50% and 7% for Group 2. Amongst donor types, disease free survival (DFS) and OS were significantly lower for unrelated transplants at 1 and 3 years but not 5 years post-HCT. Patients in complete response (CR) or very good partial response (VGPR) at transplant had lower relapse rates and better DFS and OS, compared to those not in CR or VGPR. Our analysis indicates that allo-HCT can cure some neuroblastoma patients, with lower relapse rates and improved survival in patients without a history of prior auto-HCT as compared to those patients who had previously undergone auto-HCT. Although the data do not address why either strategy was chosen for patients, allo-HCT after a prior auto-HCT appears to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.
neuroblastoma; allogeneic HCT; autologous HCT; CIBMTR
Preformed anti-HLA antibodies (AHA) are known to be associated with delayed engraftment and reduced overall survival after adult hematopoietic stem cell transplantation. However, limited data is available in pediatric patients. In this study, we explored the role of AHA on clinical outcomes in 70 pediatric patients who received a single unit of HLA mismatch cord blood for hematologic malignancies, immunodeficiencies or metabolic diseases. The presence of AHA was detected in 44% (31/70) of the patients. Preformed class I AHA was associated with an increased occurrence of grade 1–4 acute graft-versus host disease (p<0.05). The presence of anti- major-histocompatibility-complex class I–related chain A antigens (MICA) antibodies was significantly associated with a reduced platelet recovery after transplantation (p<0.05). AHA of class II with the strength of antibody titer measured as the mean fluorescence intensity above 2000 was associated with reduced event-free survival (p<0.05). A reduction of high titer of AHA and anti-MICA antibodies might have to be considered before cord blood transplantation in pediatric patients for better outcomes.
Sepsisis a clinical syndrome characterized by a multi-system response to a microbial pathogenic insult consisting of a mosaic of interconnected biochemical, cellular, and organ-organ interaction networks. A central thread that connects these responses is inflammation, which, while attempting to defend the body and prevent further harm, causes further damage through the feed-forward, pro-inflammatory effects of damage-associated molecular pattern molecules. In this review, we address the epidemiology and current definitions of sepsis, and focus specifically on the biological cascades that comprise the inflammatory response to sepsis. We suggest that attempts to improve clinical outcomes by targeting specific components of this network have been unsuccessful due to the lack of an integrative, predictive, and individualized systems-based approach to define the time-varying, multi-dimensional state of the patient. We highlight the translational impact of computational modeling and other complex systems approaches as applied to sepsis, including in silico clinical trials, patient-specific models, and complexity-based assessments of physiology.
Sepsis; Inflammatory Response; Physiologic Variability; Mathematical Model
Acute inflammation leads to organ failure by engaging catastrophic feedback loops in which stressed tissue evokes an inflammatory response and, in turn, inflammation damages tissue. Manifestations of this maladaptive inflammatory response include cardio-respiratory dysfunction that may be reflected in reduced heart rate and ventilatory pattern variabilities. We have developed signal-processing algorithms that quantify non-linear deterministic characteristics of variability in biologic signals. Now, coalescing under the aegis of the NIH Computational Biology Program and the Society for Complexity in Acute Illness, two research teams performed iterative experiments and computational modeling on inflammation and cardio-pulmonary dysfunction in sepsis as well as on neural control of respiration and ventilatory pattern variability. These teams, with additional collaborators, have recently formed a multi-institutional, interdisciplinary consortium, whose goal is to delineate the fundamental interrelationship between the inflammatory response and physiologic variability. Multi-scale mathematical modeling and complementary physiological experiments will provide insight into autonomic neural mechanisms that may modulate the inflammatory response to sepsis and simultaneously reduce heart rate and ventilatory pattern variabilities associated with sepsis. This approach integrates computational models of neural control of breathing and cardio-respiratory coupling with models that combine inflammation, cardiovascular function, and heart rate variability. The resulting integrated model will provide mechanistic explanations for the phenomena of respiratory sinus-arrhythmia and cardio-ventilatory coupling observed under normal conditions, and the loss of these properties during sepsis. This approach holds the potential of modeling cross-scale physiological interactions to improve both basic knowledge and clinical management of acute inflammatory diseases such as sepsis and trauma.
mathematical model; inflammation; physiologic variability; heart rate variability; neural control
During the cardiac cycle, the heart normally produces repeatable physiological sounds. However, under pathologic conditions, such as with heart valve stenosis or a ventricular septal defect, blood flow turbulence leads to the production of additional sounds, called murmurs. Murmurs are random in nature, while the underlying heart sounds are not (being deterministic).
We show that a new analytical technique, which we call Digital Subtraction Phonocardiography (DSP), can be used to separate the random murmur component of the phonocardiogram from the underlying deterministic heart sounds.
We digitally recorded the phonocardiogram from the anterior chest wall in 60 infants and adults using a high-speed USB interface and the program Gold Wave http://www.goldwave.com. The recordings included individuals with cardiac structural disease as well as recordings from normal individuals and from individuals with innocent heart murmurs. Digital Subtraction Analysis of the signal was performed using a custom computer program called Murmurgram. In essence, this program subtracts the recorded sound from two adjacent cardiac cycles to produce a difference signal, herein called a "murmurgram". Other software used included Spectrogram (Version 16), GoldWave (Version 5.55) as well as custom MATLAB code.
Our preliminary data is presented as a series of eight cases. These cases show how advanced signal processing techniques can be used to separate heart sounds from murmurs. Note that these results are preliminary in that normal ranges for obtained test results have not yet been established.
Cardiac murmurs can be separated from underlying deterministic heart sounds using DSP. DSP has the potential to become a reliable and economical new diagnostic approach to screening for structural heart disease. However, DSP must be further evaluated in a large series of patients with well-characterized pathology to determine its clinical potential.
Digital subtraction; phonocardiography; MATLAB; Murmurgram
Children undergoing stem cell transplant (SCT) experience high levels of somatic distress and mood disturbance. This trial evaluated the efficacy of complementary therapies (massage, humor therapy, relaxation/imagery) for reducing distress associated with pediatric SCT.
Across 4 sites, 178 pediatric patients scheduled to undergo SCT were randomized to a child-targeted intervention involving massage and humor therapy (HPI-C), the identical child intervention plus a parent intervention involving massage and relaxation/imagery (HPI-CP) or standard care (SC). Randomization was stratified by site, age, and type of transplant. The interventions began at admission and continued through SCT week +3. Primary outcomes included patient and parent reports of somatic distress and mood disturbance obtained weekly from admission through week +6 using the BASES scales. Secondary outcomes included length of hospitalization, time to engraftment, and usage of narcotic analgesic and antiemetic medications.
A mixed model approach was used to assess longitudinal trends of patient and parent-report outcomes and test differences between groups on these measures. Significant changes across time were observed on all patient and parent-report outcomes. However, no significant differences between treatment arms were found on the primary outcomes. Similarly, no signficant between group differences were noted on any of the medical variables as secondary outcomes.
Results of this multi-site trial failed to document significant benefits of complementary interventions in the pediatric SCT setting.
stem cell transplant; children; complementary therapy; massage; symptoms
Although cardiac auscultation remains important to detect abnormal sounds and murmurs indicative of cardiac pathology, the application of electronic methods remains seldom used in everyday clinical practice. In this report we provide preliminary data showing how the phonocardiogram can be analyzed using color spectrographic techniques and discuss how such information may be of future value for noninvasive cardiac monitoring.
We digitally recorded the phonocardiogram using a high-speed USB interface and the program Gold Wave http://www.goldwave.com in 55 infants and adults with cardiac structural disease as well as from normal individuals and individuals with innocent murmurs. Color spectrographic analysis of the signal was performed using Spectrogram (Version 16) as a well as custom MATLAB code.
Our preliminary data is presented as a series of seven cases.
We expect the application of spectrographic techniques to phonocardiography to grow substantially as ongoing research demonstrates its utility in various clinical settings. Our evaluation of a simple, low-cost phonocardiographic recording and analysis system to assist in determining the characteristic features of heart murmurs shows promise in helping distinguish innocent systolic murmurs from pathological murmurs in children and is expected to useful in other clinical settings as well.
To determine the response, toxicity, and survival for children with progressive or recurrent medulloblastoma and germinoma using a single myeloablative course of chemotherapy supported by autologous hematopoietic stem cells.
Patients and Methods
Subjects were in second remission or had minimal residual disease at the time of study entry. The conditioning regimen consisted of cyclophosphamide 6,000 mg/m2 plus melphalan 180 mg/m2.
Twenty nine evaluable pediatric patients were accrued. The most frequent major toxicities were myelosuppression, infections, and stomatitis, but no toxic deaths were recorded. Best responses were: CR=6, CCR=13, PR=6, SD=2, and PD=2. There were 6 medulloblastoma and 3 germinoma survivors with a median follow-up of 7.5 years (range= 2.8–10). Two germinoma survivors received radiotherapy after autografting for presumptive progressive disease.
Myeloablative chemotherapy consisting of cyclophosphamide and melphalan was tolerable in the relapsed brain tumor setting with 19/29 cases achieving CR or CCR status and 9/29 becoming long term survivors.
medulloblastoma; germinoma; chemotherapy; autograft
The mechanistic role of the yeast kinase CDC5, in allowing cells to adapt to the presence of irreparable DNA damage and continue to divide, is revealed.
The Saccharomyces cerevisiae polo-like kinase Cdc5 promotes adaptation to the DNA damage checkpoint, in addition to its numerous roles in mitotic progression. The process of adaptation occurs when cells are presented with persistent or irreparable DNA damage and escape the cell-cycle arrest imposed by the DNA damage checkpoint. However, the precise mechanism of adaptation remains unknown. We report here that CDC5 is dose-dependent for adaptation and that its overexpression promotes faster adaptation, indicating that high levels of Cdc5 modulate the ability of the checkpoint to inhibit the downstream cell-cycle machinery. To pinpoint the step in the checkpoint pathway at which Cdc5 acts, we overexpressed CDC5 from the GAL1 promoter in damaged cells and examined key steps in checkpoint activation individually. Cdc5 overproduction appeared to have little effect on the early steps leading to Rad53 activation. The checkpoint sensors, Ddc1 (a member of the 9-1-1 complex) and Ddc2 (a member of the Ddc2/Mec1 complex), properly localized to damage sites. Mec1 appeared to be active, since the Rad9 adaptor retained its Mec1 phosphorylation. Moreover, the damage-induced interaction between phosphorylated Rad9 and Rad53 remained intact. In contrast, Rad53 hyperphosphorylation was significantly reduced, consistent with the observation that cell-cycle arrest is lost during adaptation. Thus, we conclude Cdc5 acts to attenuate the DNA damage checkpoint through loss of Rad53 hyperphosphorylation to allow cells to adapt to DNA damage. Polo-like kinase homologs have been shown to inhibit the ability of Claspin to facilitate the activation of downstream checkpoint kinases, suggesting that this function is conserved in vertebrates.
Cellular surveillance mechanisms, termed checkpoints, have evolved to recognize the presence of DNA damage, halt cell division, and promote repair. The purpose of these checkpoints is to prevent the next generation of cells from inheriting a damaged genome. However, after futile attempts at repair over several hours of growth arrest, yeast cells eventually adapt and continue with cell division despite the presence of persistent DNA lesions. This process of adaptation employs CDC5, a kinase that also has essential roles in promoting cell division in the absence of DNA damage. We found that increasing levels of Cdc5 promote adaptation by suppressing the hyperphosphorylation of the checkpoint kinase Rad53, which in turn suppresses the DNA damage checkpoint and relieves cell division arrest. Intriguingly, overexpression of PLK1, the human homolog of CDC5, has been reported in various tumor types and has been linked to poor prognosis. Therefore, understanding the mechanism of adaptation in yeast may provide valuable insight into the role of PLK1 overexpression in tumor progression. Two related papers, published in PLoS Biology (van Vugt et al., doi:10.1371/journal.pbio.1000287) and PLoS Genetics (Donnianni et al., doi:10.1371/journal.pgen.1000763), similarly investigate the phenomenon of checkpoint adaptation.
Bone marrow aspiration (BMA) and bone marrow trephine biopsy are important procedures for the diagnosis of hematological malignancies and nonmalignant diseases in children. During BMA, bone marrow particles are obtained for analysis including microscopic morphologic evaluations and differential counts. During a trephine biopsy, a core of bone marrow is obtained and processed for the evaluation of marrow cellularity and to rule out marrow involvement by solid tumours, lymphomas or other processes. These invasive procedures should only be performed by a trained individual following a standard operating technique. There are no clear published guidelines in the paediatric literature. Hence, the purpose of the present article is to provide guidelines for the performance of BMAs and bone marrow trephine biopsies in children that will be useful for both general paediatricians and paediatric hematologists and oncologists.
Aspiration; Bone marrow; Children; Guidelines
In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.
Patients requiring prolonged acute mechanical ventilation (PAMV) represent one-third of those who need mechanical ventilation, but they utilize two-thirds of hospital resources devoted to mechanical ventilation. Measures are needed to optimize the efficiency of care in this population. Both duration of intensive care unit stay and mechanical ventilation are associated with anemia and increased rates of packed red blood cell (pRBC) transfusion. We hypothesized that transfusions among patients receiving PAMV are common and associated with worsened clinical and economic outcomes.
A retrospective analysis of a large integrated claims database covering a 5-year period (January 2000 to December 2005) was conducted in adult patients receiving PAMV (mechanical ventilation for ≥ 96 hours). The incidence of pRBC transfusions was examined as the main exposure variable, and hospital mortality served as the primary outome, with hospital length of stay and costs being secondary outcomes.
The study cohort included 4,344 hospitalized patients receiving PAMV (55% male, mean age 61.5 ± 16.4 years). Although hemoglobin level upon admission was above 10 g/dl in 75% of patients, 67% (n = 2,912) received at least one transfusion, with a mean of 9.1 ± 12.0 units of pRBCs transfused per patient over the course of hospitalization. In regression models adjusting for confounders, exposure to pRBCs was associated with a 21% increase in the risk for hospital death (95% confidence interval [CI] = 1.00 to 1.48), and marginal increases in length of stay (6.3 days, 95% CI = 5.1 to 7.6) and cost ($48,972, 95% CI = $45,581 to $52,478).
Patients receiving PAMV are at high likelihood of being transfused with multiple units of blood at relatively high hemoglobin levels. Transfusions independently contribute to increased risk for hospital death, length of stay, and costs. Reducing exposure of PAMV patients to blood may represent an attractive target for efforts to improve quality and efficiency of health care delivery in this population.
Biological systems have evolved complex regulatory mechanisms, even in situations where much simpler designs seem to be sufficient for generating nominal functionality. Using module-based analysis coupled with rigorous mathematical comparisons, we propose that in analogy to control engineering architectures, the complexity of cellular systems and the presence of hierarchical modular structures can be attributed to the necessity of achieving robustness. We employ the Escherichia coli heat shock response system, a strongly conserved cellular mechanism, as an example to explore the design principles of such modular architectures. In the heat shock response system, the sigma-factor σ32 is a central regulator that integrates multiple feedforward and feedback modules. Each of these modules provides a different type of robustness with its inherent tradeoffs in terms of transient response and efficiency. We demonstrate how the overall architecture of the system balances such tradeoffs. An extensive mathematical exploration nevertheless points to the existence of an array of alternative strategies for the existing heat shock response that could exhibit similar behavior. We therefore deduce that the evolutionary constraints facing the system might have steered its architecture toward one of many robustly functional solutions.
Biological systems maintain phenotypic stability in the face of various perturbations arising from environmental changes, stochastic fluctuations, and genetic variations. This robustness, which seems to be an inherent property of such systems, is still poorly understood at the molecular level. At the same time, systems approaches that were used with great success in the study and design of complex engineered systems provide a unique opportunity for investigating the basic tenants of robustness in cellular mechanisms. This is motivated by the fact that at the system level, biology and engineering seem to have a large number of common features despite their extremely different physical implementations. The heat shock response is one such robust cellular system, which interestingly achieves its seemingly simple objective of refolding or eliminating heat-denatured proteins through a complicated set of interactions. In analogy to engineering control architectures, the complex regulation strategies seem to be a specifically designed solution to generate robustness against different types of perturbations.
Summary: MathSBML is a Mathematica package designed for manipulating Systems Biology Markup Language (SBML) models. It converts SBML models into Mathematica data structures and provides a platform for manipulating and evaluating these models. Once a model is read by MathSBML, it is fully compatible with standard Mathematica functions such as NDSolve (a differential-algebraic equations solver). MathSBML also provides an application programming interface for viewing, manipulating, running numerical simulations; exporting SBML models; and converting SBML models in to other formats, such as XPP, HTML and FORTRAN. By accessing the full breadth of Mathematica functionality, MathSBML is fully extensible to SBML models of any size or complexity.
Availability: Open Source (LGPL) at http://www.sbml.org and http://www.sf.net/projects/sbml.
A married woman under my care underwent successful bone marrow
transplantation as part of treatment for a malignancy. She wishes to start a
family. What are her chances? Are there risks?
Success in becoming pregnant after stem cell transplantation depends on such
factors as cumulative doses of chemotherapy and radiation and mother’s age
at time of transplant. There is increased risk of prematurity, low birth
weight, and spontaneous abortion. Pregnancy should be managed as high
Incubation in vitro of viable Leishmania enriettii with antibodies from infected or immune guinea pigs and a fluorescein-labeled antiguinea pig Ig conjugate induced aggregation of surface antigens to form a "cap" over the anterior pole of the amastigote and over both the anterior and posterior poles of the promastigote form of the parasite. Cap formation occurred only with optimum quantities of guinea pig antibodies and was inhibited by low temperature and the metabolic inhibitors, sodium azide and iodoacetamide. The aggregated antigens were rapidly lost from the surface of the parasite but reappeared after 3 h of incubation at 23°C. This phenomenon of ligand-induced membrane antigen movement is apparently similar to that described in mammalian cells, and may represent the first stage of the interaction between host antibodies and the surface membrane of protozoal parasites.
The resistance to destruction of spores of Bacillus subtilis var. niger hermetically sealed in various polymeric films and exposed to ethylene oxide with and without relative humidity was determined. The effect of desiccation was also determined. The order of increased resistance to sterilization with regard to type of polymeric film was found to be: polyethylene equal to polyvinyl chloride, less than nylon, less than cellophane/polyethylene laminate, less than phenoxy, less than mylar/polyethylene laminate. Desiccated spores sealed in various polymeric films were much more resistant to ethylene oxide sterilization than nondesiccated spores. Relative humidity was an important factor in ethylene oxide sterilization with spores not sealed in polymeric films. However, with spores hermetically sealed in polyethylene, added relative humidity was an insignificant factor in the sterilization process.
The interactions of networks of transcription factors and signaling molecules can be understood, in part, through concepts from control theory and engineering.
Although ethylene oxide is a reliable sterilizer, the process may be limited by diffusion. Thus, situations may exist where microorganisms are protected from the sterilizing gas. It is possible that the exterior of a substance may be sterilized, whereas the interior is not. We investigated three general types of materials in which this limitation of diffusion could occur: the bore of glass and plastic tubing, the center of cotton balls, and plastic adhesive film/paper backing interface. These materials were contaminated as close to their geometric center as possible with Bacillus subtilis var. niger spores occluded in crystals of sodium chloride. After exposure of the contaminated materials (except aluminum foil) to ethylene oxide, thioglycolate broth (a standard sterility-test medium) indicated sterility, whereas Trypticase Soy Broth indicated nonsterility. It is likewise possible that aerobic microorganisms, surviving in or on material after exposure to dry heat or steam sterilization processes, would not be recovered by thioglycollate broth. Entrapped aerobic organisms will probably not grow out in the low oxygen tension zone of an anaerobic medium such as thioglycollate broth. It is recommended than an aerobic medium such as Trypticase Soy Broth be used concurrently with thioglycolate broth for sterility testing.
The resistance to destruction of spores of Bacillus subtilis var. niger occluded in crystals of calcium carbonate and exposed to ethylene oxide and moist and dry heat was determined and compared with the destruction of unoccluded spores. Occluded spores could not be inactivated with ethylene oxide. Resistance to inactivation was approximately 900 and 9 times higher for occluded than for unoccluded spores subjected to moist and dry heat, respectively, at 121 C. The protective effect may be due either to the unavailability of oxygen for destruction by oxidation or to inhibition of the loss of essential cell constituents by vaporization. Evidence also implicates the crystal structure as a thermal conductivity barrier. Occluded spores retained viability over a 3-year period compared with unoccluded spores which decreased over 90% during this period. Occluded spores in insoluble materials are seldom encountered in the technology of sterilization, but could be the most critical factor in the sterilization of interplanetary vehicles. Entrapped spores in insoluble materials are usually difficult to detect, and are very stable as well as extremely resistant to destruction by heat and ethylene oxide.
Sudden development of pain in the head followed by evidences of meningeal irritation, with or without motor or sensory symptoms or signs, is almost pathognomonic of subarachnoid hemorrhage. The final diagnosis rests upon the demonstration of blood in the cerebrospinal fluid. If the hemorrhage is massive, or from an aneurysm of an unprotected arterial trunk, the patient may die in a comparatively short time. If the bleeding is less abundant and from an aneurysm which is protected by adjacent structures the patient may survive. Angiography should probably be done early in most cases. If neurological signs or the results of angiography indicate that the aneurysm is in such a location that surgical treatment is feasible it should probably be undertaken. If medical treatment is to be carried out the patient should have protracted rest, frequent spinal drainage so long as the cerebrospinal fluid contains blood or is under materially increased pressure, sedatives and analgesics, and passive movements of the neck and limbs to forestall limitation of motion of joints.