The paper describes a newly proposed combination of the two existing Duval Pentagons method utilized for the identification of mineral oil-insulated transformers. The aim of the combination is to ...facilitate automatic fault identification through computer programs, and at the same time, apply the full capability of both original Pentagons, now reduced to a single geometry. The thorough classification of a given fault (say, of the electrical or thermal kind), employing individual Pentagons 1 and 2, as originally defined, involves a complex geometrical problem that requires the build-up of a convoluted geometry (a regular Pentagon whose axes represent each of five possible combustible gases) to be constructed using computer language code and programming, followed by the logical localization of the geometrical centroid of an irregular pentagon, formed by the partial contribution of individual combustibles, inside two similar structures (Pentagons 1 and 2) that, nonetheless, have different classification zones and boundaries, as more thoroughly explained and exemplified in the main body of this article. The proposed combined approach results in a lower number of total fault zones (10 in the combined Pentagons against 14 when considering Pentagons 1 and 2 separately, although zones PD, S, D1 and D2 are common to both Pentagons 1 and 2), and therefore eliminates the need to solve for two separate Pentagons.
The aim and contribution of this paper is to identify with Duval Pentagon 2 the stray gassing (SG) patterns of inhibited and uninhibited mineral oils in transformers in service and in the ...well-established laboratory SG tests of CIGRE and ASTM, so that SG in transformers can be easily distinguished from the other types of faults occurring in them. The SG test of IEC 60296-2020 is inadequate or much less effective for that purpose.
Several high voltage condenser type OIP (oil impregnated paper) bushings used in the electrical industry are filled with dodecylbenzene, because of its ability to absorb hydrogen formed by corona ...partial discharges in the thick paper insulation of these pieces of equipment. Some of them form large quantities of ethane, raising the concern of overheating faults in their paper insulation, which may be risky for their safe operation in service. The article presents dissolved gas analysis results of oil samples taken from the bushings with high ethane formation, together with results of laboratory tests of stray gassing of dodecylbenzene performed according to CIGRE procedure. By using Duval Pentagon 2 it is possible to compare patterns in the laboratory and in bushings and evaluate the temperature range of possible defects. Stray gassing/overheating of dodecylbenzene in bushings within the stray gassing temperature range and whatever the possible other causes, is not a concern for their safe operation according to observations published by CIGRE.
Patients with acute leukemia refractory to induction or reinduction chemotherapy have poor prognoses if they do not undergo hematopoietic stem-cell transplantation (HSCT). However, HSCT when a ...patient is not in complete remission (CR) is of uncertain benefit. We hypothesized that pretransplantation variables may define subgroups that have a better prognosis.
Overall, 2,255 patients who underwent transplantation for acute leukemia in relapse or with primary induction failure after myeloablative conditioning regimen between 1995 and 2004 were reported to the Center for International Blood and Marrow Transplant Research. The median follow-up of survivors was 61 months. We performed multivariate analysis of pretransplantation variables and developed a predictive scoring system for survival.
The 3-year overall survival (OS) rates were 19% for acute myeloid leukemia (AML) and 16% for acute lymphoblastic leukemia (ALL). For AML, five adverse pretransplantation variables significantly influenced survival: first CR duration less than 6 months, circulating blasts, donor other than HLA-identical sibling, Karnofsky or Lansky score less than 90, and poor-risk cytogenetics. For ALL, survival was worse with the following: first refractory or second or greater relapse, > or = 25% marrow blasts, cytomegalovirus-seropositive donor, and age of 10 years or older. Patients with AML who had a predictive score of 0 had 42% OS at 3 years, whereas OS was 6% for a score > or = 3. Patients with ALL who had a score of 0 or 1 had 46% 3-year OS but only 10% OS rate for a score > or = 3.
Pretransplantation variables delineate subgroups with different outcomes. HSCT during relapse can achieve long-term survival in selected patients with acute leukemia.
To compare two perspective taking strategies on (i) clinicians' ability to accurately identify negative thoughts and feelings of parents of children with cancer, and (ii) clinician distress.
...Sixty-three hematology-oncology professionals and nursing students watched a video featuring parents of children with cancer. Participants were randomly assigned to one of two groups. In the imagine-self group, they were instructed to imagine the feelings and life consequences which they would experience if they were in the parents' position. In the imagine-other group, they were instructed to imagine the feelings and life consequences experienced by the parents. Parent-clinician agreement on thoughts/feelings was evaluated (standard stimulus paradigm). Clinician distress was also assessed.
The intervention was effective in manipulating perspective type. The groups did not significantly differ on parent-clinician agreement. Concentrating on personal feelings (imagine-self strategy) did predict lower agreement when controlling for trait empathy. Clinician distress was higher in the imagine-self group.
Although the link between perspective type and detection of distress remains unclear, the results suggest that clinicians who highly focus on their own feelings tend to be less accurate on parental distress and experience more distress themselves.
This research could potentially improve communication training and burnout prevention.
Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan ...exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve AUC) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT.
In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUC
), non-compartmental analysis (AUC from 0 to infinity AUC
and to the next dose AUC
), and by individual centres using various approaches (AUC
). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease GvHD); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses.
790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4-10·7). The median busulfan AUC
was 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC
(r
=0·74), but the latter correlated poorly with AUC
(r
=0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2-73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1-82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg × h/L compared with 66·1% (60·9-71·4) in the 235 patients at the low historical target of 58-86 mg × h/L and 49·5% (29·2-66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio HR 0·57, 95% CI 0·39-0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12-2·57; p=0·013) and transplantation-related mortality (2·99, 1·82-4·92; p<0·0001) were significantly higher in the high AUC group (>101 mg × h/L) than in the low AUC group (<78 mg × h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg × h/L vs ≥78 mg × h/L, HR 1·30, 95% CI 0·73-2·33; p=0·37).
Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78-101 mg × h/L using a new validated pharmacokinetic model for all indications.
Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco.
Abstract
Neuroblastoma, the most common type of pediatric extracranial solid tumor, causes 10% of childhood cancer deaths. Despite intensive multimodal treatment, the outcomes of high-risk ...neuroblastoma remain poor. We urgently need to develop new therapies with safe long-term toxicity profiles for rapid testing in clinical trials. Drug repurposing is a promising approach to meet these needs. Here, we investigated disulfiram, a safe and successful chronic alcoholism treatment with known anticancer and epigenetic effects. Disulfiram efficiently induced cell cycle arrest and decreased the viability of six human neuroblastoma cell lines at half-maximal inhibitory concentrations up to 20 times lower than its peak clinical plasma level in patients treated for chronic alcoholism. Disulfiram shifted neuroblastoma transcriptome, decreasing MYCN levels and activating neuronal differentiation. Consistently, disulfiram significantly reduced the protein level of lysine acetyltransferase 2A (KAT2A), drastically reducing acetylation of its target residues on histone H3. To investigate disulfiram’s anticancer effects in an in vivo model of high-risk neuroblastoma, we developed a disulfiram-loaded emulsion to deliver the highly liposoluble drug. Treatment with the emulsion significantly delayed neuroblastoma progression in mice. These results identify KAT2A as a novel target of disulfiram, which directly impacts neuroblastoma epigenetics and is a promising candidate for repurposing to treat pediatric neuroblastoma.
Unrelated umbilical cord blood transplantation (UCBT) is an alternative to provide transplants in children with acute leukemia or myelodysplastic syndrome who lack a related donor. Intravenous ...Busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used, with more predictable bioavailability and better outcomes comparing to oral Bu. There is still an important variation in Bu pharmacokinetic between patients that is associated with an increased risk of toxicity and graft failure. The objective of the study was to analyze the impact of first-dose pharmacokinetic adapted myeloablative conditioning regimen of intravenous Bu on the different outcomes after transplantation. Data of 36 children who underwent allogeneic HSCT with Bu plus a second alkylating agent at Sainte Justine Hospital in Montreal, Canada, between December 2000 and April 2012 were analyzed. For children with high risk myeloid malignancies receiving an UCBT, first dose Bu pharmacokinetic seems to be a significant prognostic factor, influencing neutrophil (100% vs 67.9%) and platelet recovery (95.5% vs 70.5%), non-relapse mortality (0% vs 18.6%), EFS (64% vs 28.6%) and OS (81.3% vs 37.5%) for a first-dose steady-state concentration (Css) <600ng/mL vs >600ng/mL, respectively. These data reinforce the importance of Busulfan therapeutic drug monitoring-guided dosing in pediatric HSCT patients, particularly in the context of UCBT.
High-risk neuroblastoma (NB) remains a major therapeutic challenge despite the recent advent of disialoganglioside (GD2)-antibody treatment combined with interleukin (IL)-2 and granulocyte ...monocyte-colony stimulating factor (GM-CSF). Indeed, more than one third of the patients still die from this disease. Here, we developed a novel approach to improve the current anti-GD2 immunotherapy based on NK cell stimulation using toll-like receptor (TLR)-activated plasmacytoid dendritic cells (pDCs). We demonstrated that this strategy led to the efficient killing of NB cells. When the expression of GD2 was heterogeneous on NB cells, the combination of pDC-mediated NK-cell activation and anti-GD2 treatment significantly increased the cytotoxicity of NK cells against NB cells. Activation by pDCs led to a unique NK-cell phenotype characterized by increased surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), with increased expression of CD69 on CD56dim cytotoxic cells, and strong interferon-γ production. Additionally, NB-cell killing was mediated by the TRAIL death-receptor pathway, as well as by the release of cytolytic granules via the DNAX accessory molecule 1 pathway. NK-cell activation and lytic activity against NB was independent of cell contact, depended upon type I IFN produced by TLR-9-activated pDCs, but was not reproduced by IFN-α stimulation alone. Collectively, these results highlighted the therapeutic potential of activated pDCs for patients with high-risk NB.
Posttransplant leukemia detection before overt relapse is key to the success of immunotherapeutic interventions, as they are more efficient when leukemia burden is low. However, optimal schedule and ...monitoring methods are not well defined. We report the intensive bone marrow monitoring of minimal residual disease (MRD) using flow cytometry (FC) and nested reverse transcription polymerase chain reaction (RT-PCR) whenever a fusion transcript allowed it and chimerism by PCR at 11 timepoints in the first 2 years after transplant. Seventy-one transplants were performed in 59 consecutive children, for acute myeloid (n = 38), lymphoid (n = 31), or mixed-phenotype (n = 2) leukemia. MRD was monitored in 62 cases using FC (n = 58) and/or RT-PCR (n = 35). Sixty-seven percent of leukemia recurrences were detected before overt relapse, with a detection rate of 89% by RT-PCR and 40% by FC alone. Increased mixed chimerism was never the first evidence of recurrence. Two patients monitored by RT-PCR relapsed without previous MRD detection, one after missed scheduled evaluation and the other 4.7 years post transplant. Among the 22 cases with MRD detection without overt relapse, 19 received therapeutic interventions. Eight (42%) never relapsed. In conclusion, intensive marrow monitoring by RT-PCR effectively allows for early detection of posttransplant leukemia recurrence.
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