Course Of Intensification Research Articles

Assessment of Outcomes of Consolidation Therapy By Number of Cycles of Blinatumomab Received in Newly Diagnosed Measurable Residual Disease Negative Patients with B-Lineage Acute Lymphoblastic Leukemia: In the ECOG-ACRIN E1910 Randomized Phase III National Clinical Trials Network Trial

Introduction: ECOG ACRIN E1910 is a randomized phase III trial that showed that adults with newly diagnosed BCR::ABL1 negative acute lymphoblastic leukemia (ALL) who become MRD negative (<0.01%) after induction chemo who receive blinatumomab with conventional chemotherapy (chemo) have improved survival compared with those who received chemo only (Litzow et al, Blood (2022) 140: Supplement 2, LBA-1). However, not all pts were able to receive all four planned cycles of blinatumomab in consolidation. In this report we assessed outcomes of pts in the blinatumomab arm of the trial who received all 4 cycles of blinatumomab compared to those who received 1-2 cycles. Methods: Patient between the ages of 30 and 70 with newly diagnosed BCR::ABL1 negative B-lineage ALL were enrolled and initially received 2.5 months of combination induction chemo utilizing a BFM-like regimen adapted from the E2993/UKALLXII clinical trial, with pegaspargase (after induction only for patients >=55 years of age) and addition of rituximab for CD20 positive patients. After remission induction (step 1) pts in morphologic complete remission (CR/CRi) received an intensification course of high dose methotrexate with pegaspargase for CNS prophylaxis (step 2). At the conclusion of step 2, remission and MRD status were determined centrally by 6-color flow cytometry with MRD negativity defined as <0.01%. In the primary analysis subset, MRD negative patients were randomized to receive an additional 4cycles of consolidation chemo or 2 cycles of blinatumomab at 28 mcg/day (flat dose) for 28 days each cycle followed by 3 cycles of consolidation chemo, another 4-week cycle of blinatumomab (3rd cycle of blinatumomab) followed by an additional cycle of chemo and then a 4th cycle of blinatumomab (step 3). Following completion of consolidation chemo +/- blinatumomab, pts were given 2.5 years of POMP maintenance therapy timed from the start of the intensification cycle (step 4). Estimates of OS were calculated using the Kaplan-Meier method. Comparison of OS between treatment arms were conducted using the stratified log-rank test and Cox proportional-hazards model with age, CD20 status, rituximab use, and whether pts intend to receive HSCT or not as stratification factors. As the number of cycles needed to optimize outcome has not been studied, an unplanned landmark analysis was used to compare OS of pts in the blinatumomab arm who received all 4 cycles o those who received 1-2 cycles. Time 0 was chosen as 9 months post step 3 randomization (the time that patients were supposed to complete 4 cycles of blina). Four pts who received blinatumomab but died within 9 months post step 3 randomization were therefore excluded from this analysis. Results: The study was activated on December 17, 2013 and closed to enrollment on October 15, 2019. 772 pts were screened for the trial and 488 were enrolled on step 1 induction therapy. The median age of the pts was 51 years (range 30-70). 224 MRD negative pts were randomized, 112 pts to each arm. In the blinatumomab arm 12 pts received 1 cycle (11%), 32 pts received 2 cycles (29%), 4 pts received 3 cycles (4%) and 63 pts received 4 cycles (57%). The OS of pts who received 1-2 cycles of blinatumomab was compared to control (Figure 1) The difference was not significant (hazard ratio 0.62, 95% CI 0.28 to 1.34, p=0.22). Fig 2 compares the survival of those who received 1-2 cycles to those who received 4 cycles ( (HR: 0.39, 95% CI 0.12 to 1.16, p=0.076). Conclusion: The addition of blinatumomab to consolidation chemotherapy resulted in a significantly better overall survival compared to chemotherapy alone in pts with newly diagnosed B-lineage ALL who were MRD negative after intensification. This represents a new standard of care for pts aged 30-70 years with BCR::ABL1 negative ALL. The optimal dose and number of cycles is however unknown. In this unplanned subgroup analysis we demonstrate that a survival benefit can only be confirmed in patients who receive the intended 4 cycles of blinatumomab during consolidation. Further studies will be needed to determine if fewer cycles can provide a similar benefit.

The policy of the administration of the US President Richard M. Nixon on PRC (March-July 1969)

The article investigates the formation of the foreign policy course of US President Richard M. Nixon on China in March-July 1969. The practical implementation of pre-election initiatives by the administration of the President Richard M. Nixon in the Chinese direction in March-July 1969 was studied. There were analyzed reasons, course and consequences of intensification of Washington's foreign policy strategy towards Beijing during the during investigated period. The role of various groups in the American establishment in the process of forming the foreign policy course of the new administration towards China in March-July 1969 is outlined. It is described the specific US foreign policy actions towards communist China at the beginning of Richard M. Nixon presidential period. Despite the presence in the political, academic and social circles of the United States of certain attitudes in favor of the recognition of the People's Republic of China as the political reality of international life, the question of the legal recognition of China in the second half of the 1960’s constantly moved to the background. The victory of Richard М. Nixon in the presidential election in 1968 was accompanied by a series of changes in the system of geopolitical and military priorities of the United States. The new administration’s more realistic approach to China was due primarily to the fact that Beijing, which renounced its alliances and claimed the role of a «third force», was a strong player in the international arena. Moreover, the policy of Kennedy–Johnson did not justify itself, as China has intensified its foreign policy, established relations with many countries, including the US allies. At the beginning of the presidency of Richard М. Nixon in March-July 1969, his administration was managed to quickly develop and begin to implement a holistic concept of «new policy» for China. His Chinese policy was inextricably linked to the US foreign policy in Asia and reflected the clash of American and Chinese interests in the region. At the same time, the representatives of the American establishment have a clear idea of how they could influence Soviet-Chinese relations in order to deepen the rift between the USSR and China, and what concrete benefits they could derive from this. A number of objective and subjective factors not prevented the administration of the 37th President of the United States, Richard М. Nixon, radically changing Washington’s Chinese policy. Communist China continued to be recognized as a powerful factor in the US-Soviet dialogue. In spite of this, in the late 60’s of the twentieth century the objective preconditions began to evolve gradually, which promoted to the normalization of US-China relations in the future, and allowed to resolve most of the controversial issues that ultimately led to the international recognition of the People’s Republic of China by the United States of America.

The Foreign Policy of US President James E. Carter on the Peoples Republic of China, 1980-1981

The article researches the US foreign policy towards the PRC during the presidency of James E. Carter in 1980–1981. The practical implementation of pre-election initiatives by the administration of the President James E. Carter in the Chinese direction in 1980–1981 was studied. There were analysed reasons, course and consequences of intensification of Washington's foreign policy strategy towards Beijing during the investigated period. The role of various groups in the American establishment in the process of forming the foreign policy course of the new administration towards China in 1980–1981 is outlined. It is described the specific US foreign policy actions towards communist China of James E. Carter presidential period.

Improved Outcome with a Pediatric-Inspired Regimen for Philadelphia-Negative Acute Lymphoblastic Leukemia in the Elderly

Background: Approximately 30% of adult acute lymphoblastic leukemia (ALL) occurs after the age of 60. The improvements observed in the past decade in adults with pediatric-inspired regimen do not translate in this population with increase treatment related toxicity and early deaths. The European Working Group for Adult ALL (EWALL) backbone, adapted for elderly patients, reported a poor 3 year overall survival (3y-OS) of about 24% due to high relapse rates. Our center report the outcome of a regimen designed to improve the outcome of the EWALL backbone taking advantage of the favorable results of pediatric-inspired protocols in younger adults and retrospectively compared it to an historical cohort.Methods: Since 2012, patients > 60 y-old with Ph-neg ALL were treated in our center according to the EWALL first induction backbone. Patients achieving complete response (CR) were eligible to receive a pediatric-inspired consolidation phase designed for younger patients. After two consolidations courses, patients received late intensification phase followed by a third consolidation course. Monthly maintenance course was then started for CR patients. CNS prophylaxis included intrathecal injections and cranial irradiation. Consolidations included 9 cycles alternating cytarabine (8000mg/m2) intermediate-dose methotrexate (1500mg/m2) and cyclophosphamide (1000mg/m2) plus VP-16 (150mg/m2). Patients aged more than 70 years received reduced doses of chemotherapy during consolidation. Treatments are detailed in the table. We retrospectively compared the outcomes with those observed in patients > 60 y-old treated according to the EWALL induction and consolidation backbone (Goekbuget et al. 2008) in our center between 2007 and 2011.Results: Twenty-four patients were included in the study. Median age was 67 [IQR: 64-71]. Nineteen patients (79%) had B-phenotype ALL. Four (13%) patients had adverse cytogenetics, three (13%) had hyperleukocytosis, none had CNS involvement. Twenty nine percent of patients had a Charlson Comorbidity Index > 1. Twenty-one patients were included in the historical cohort treated according to the EWALL backbone from 2007 to 2011. Main baseline characteristics were well balanced between the two study cohorts. Complete remission (CR) rate was 81% in the experimental cohort versus 79% in the historical cohort. The induction deaths were 4% in the experimental cohort versus 14% in the historical cohort. All patients in CR (19) in the experimental group were eligible to intensive consolidations and late intensification. Two of these patients were unable to reach maintenance phase (1 deterioration of general status and 1 relapse) and 1 patients omitted late intensification because of renal failure. During late intensification, the median duration with neutrophils < 0.5 X 109/L was 8 days [IQR: 4-14]. Six patients (32%) developed an infection during consolidation courses and 3 patients during late intensification course. Major toxicities during pediatric-inspired consolidation courses included infections (9 patients, including three with bacteremia, two with pyelonephritis and one with pneumonia), grade 3-4 liver toxicity (6), acute kidney failure (3) and hyperglycemia requiring insulin (1). Eighty-one percent of patients eligible to late intensification received over 80% of the scheduled dose of L-ASP. No death was observed during consolidations or late intensification. The median follow up times were 2,6 years and 8,2 years for the experimental cohort and the historical cohort, respectively. The experimental regimen translated into a significantly longer two years disease-free survival (57% [IC95% 31-76] vs 29% [IC95% 11-51] p=0.007 by log-rank test) and a longer two years overall survival than the historical cohort (54% [CI95% 30-73] vs 24% [CI95% 12-47] p=0.01 by log-rank test). The OS and DFS of the experimental and historical cohorts are show in the figure.Conclusion: Results presented here strongly suggest that an intensified pediatric-inspired protocol after an age-adapted induction course might yield significantly better results than former protocols in older adults with Ph-negative ALL. The intensity of this consolidation treatment was tolerable, and the low rate of relapse is promising in this population with an unmet medical need. [Display omitted] DisclosuresForcade:Neovii: Other: Travel grant.

Методичний підхід до обґрунтування оптимальних техніко-економічних характеристик виробництва біодизеля з мікроводоростей

Global experience shows that one of the important directions in overcoming the external energy dependence and mitigating its negative consequences for the country is the intensification of the use of its own resource base. Such a measure for Ukraine can be production of analogues of petroleum motor fuel from biological raw materials, namely biodiesel and biobenzine. A significant obstacle in the course of intensification of the use of the existing resource base is the lack of a scientifically based vision of the inland development of technologies for the cultivation and conversion of energy biofeedstock into motor fuel. The article is aimed at developing a methodical approach (based on the provisions of economic theory) to the gradual substantiation of optimal technical and economic characteristics of production for the cultivation and processing of microalgae to biodiesel under the conditions of existing climatic restrictions. The developed methodical approach includes the substantiation of the following: choice of raw materials, choice of method and technology of cultivation, characteristics of cultivation technology, and directly the technical and economic characteristics of production. According to the developed methodical approach, it is proved that microalgae is considered as the energy raw material of the future, while the types of microalgae of the genus Chlorella, and above all the species Chlorella vulgaris, meet the requirements of industrial cultivation the most. The more acceptable for use in the climate of Ukraine method of microalgae cultivation is cultivation in photobioreactors (PBR). The technical and economic indicators of the industrial complex for the cultivation and processing of microalgae in biodiesel indicate the expediency of practical application of the developed methodical approach. The gradual substantiation of the choice of raw materials, the method and technology of cultivation of microalgae when applying the traditional conversion of the biomass allowed to ensure the optimality of technical and economic characteristics of biodiesel production in the climatic conditions of Ukraine.

Formation of the foreign policy course of US president J.F. Kennedy on the Peoples Republic of China (january-october 1961)

The article investigates the formation of the foreign policy course of US President John F. Kennedy on China in January-October 1961. There were characterized the election statements of the US presidential candidate from the Democratic Party J.F. Kennedy on China. The practical implementation of pre-election initiatives by the administration of the President John F. Kennedy in the Chinese direction in January-October 1961 was studied. There were analyzed reasons, course and consequences of intensification of Washington’s foreign policy strategy towards Beijing during the during investigated period. The role of various groups in the American establishment in the process of forming the foreign policy course of the new administration towards China in January-October 1961 is outlined. It is described the specific US foreign policy actions towards communist China at the beginning of J.F. Kennedy presidential period. The victory of J.F. Kennedy in the presidential election in 1960 was accompanied by a series of changes in the system of geopolitical and military priorities of the United States. The new administration’s more realistic approach to China was due primarily to the fact that Beijing, which renounced its alliances and claimed the role of a “third force”, was a weak player in the international arena and therefore minor, insignificant deviations from traditional policies of “containment and isolation” seemed acceptable. Moreover, the policy of “isolation” did not justify itself, as China has intensified its foreign policy, established relations with many countries, including the US allies. Gradually, the number of states that supported China’s demands for a seat in the UN grew, which created a real prospect for broad recognition of communist China. At the beginning of the presidency of J.F. Kennedy in January-October 1961, his administration was unable to quickly develop and begin to implement a holistic concept of “new frontiers” for China. His Chinese policy was inextricably linked to the US foreign policy in Asia and reflected the clash of American and Chinese interests in the region. At the same time, the representatives of the American establishment did not have a clear idea of how they could influence Soviet-Chinese relations in order to deepen the rift between the USSR and China, and what concrete benefits they could derive from this. This was due to a number of reasons. First of all, when he was elected, the administration of J.F. Kennedy joined the more important events at that time in terms of the US military and political interests than the policy towards China (European problems, issues of Atlantic unity, the Berlin crisis). Secondly, Washington still viewed communist China as a state that threatened American interests in Asia and was eager to expand its influence and strengthen its military power. An important influence on the formation of the foreign policy course of the administration J.F. Kennedy also had at the beginning of his presidency the fact that, having won the election with a minimal advantage, he did not risk starting a major change in Chinese policy and abandoning the policy of “containment”. In such way, the 35th President of the United States tried, at first, to show that he respected public opinion within the country, which was negative about communist China. Secondly, by demonstrating his propensity for the heredity of politics, he hoped to strengthen his vulnerable foreign policy position. That is why J.F. Kennedy, who did not rule out the possibility of changing China’s US policy, saw in his own practical actions toward China at the time no reason to abandon the doctrine of “containment”. Particularly, the idea of “containment” of China was the basis of a number of decisions of the John F. Kennedy administration, which eventually led to the escalation of American military intervention in Indochina.

Comparison of Hyper-CVAD Plus Ofatumumab to Hyper-CVAD Plus Rituximab in Patients with Newly Diagnosed Philadelphia Chromosome-Negative CD20-Positive B-Cell Acute Lymphoblastic Leukemia: A Propensity Score Analysis

Comparison of Hyper-CVAD Plus Ofatumumab to Hyper-CVAD Plus Rituximab in Patients with Newly Diagnosed Philadelphia Chromosome-Negative CD20-Positive B-Cell Acute Lymphoblastic Leukemia: A Propensity Score Analysis

Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia: a single-arm, phase 2 trial

The addition of rituximab to intensive chemotherapy improves outcomes in patients with B-cell acute lymphoblastic leukaemia. Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small extracellular loop of CD20 and has greater in vitro complement-mediated cytotoxicity than rituximab. In this study, we assessed the activity and safety of ofatumumab in combination with chemotherapy in patients with Philadelphia chromosome (Ph)-negative CD20-positive B-cell acute lymphoblastic leukaemia. This was a single-arm, phase 2 trial done at the MD Anderson Cancer Center (Houston, TX, USA). Patients with newly diagnosed, Ph-negative B-cell acute lymphoblastic leukaemia or lymphoblastic lymphoma with CD20 expression of at least 1% were eligible. Patients were treated with up to eight courses of the hyper-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) on courses 1, 3, 5, and 7 alternating with high-dose methotrexate and cytarabine on courses 2, 4, 6, and 8. Ofatumumab was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of eight doses. The first dose of ofatumumab was 300 mg intravenously and all subsequent doses were 2000 mg intravenously. Patients received 30 courses of maintenance therapy with 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP), with four intensification courses (high-dose methotrexate plus L-asparaginase and hyper-CVAD plus ofatumumab on courses 6-7 and 18-19). The primary endpoints were event-free survival, overall response, and overall survival. All enrolled patients were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, NCT01363128. Between Aug 26, 2011, and May 18, 2017, 69 patients (67 patients had B-cell acute lymphoblastic leukaemia and two had B-cell lymphoblastic lymphoma; median age 41 years [IQR 32-50]) were enrolled and treated, including 33 (48%) aged between 18 and 39 years. Nine (27%) of 33 patients had Ph-like acute lymphoblastic leukaemia. With a median follow-up of 44 months (26-53), 4-year event-free survival was 59% (95% CI 48-73); 69% (54-87) in adolescents and young adults aged 18-39 years. 4-year overall survival was 68% (58-81); 74% (60-91) in adolescents and young adults. The overall response rate was 98% (64 of 65 patients). The most common non-haematological grade 3 or 4 adverse events were infections (35 [54%] of 65 patients during induction and 53 [78%] of 68 patients during consolidation). Ten (14%) of 69 patients died in complete remission from sepsis (two [3%]), cardiac arrest (one [1%]), therapy-related acute myeloid leukaemia (two [3%]), and haematopoietic stem-cell transplantation complications (five [7%]). None of these deaths were considered related to ofatumumab treatment by the study investigators. The combination of hyper-CVAD plus ofatumumab is safe and active in adults with Ph-negative CD20-positive B-cell acute lymphoblastic leukaemia. Modifications of this regimen with the addition of novel monoclonal and bispecific antibody constructs targeting CD19 and CD22 might further improve outcomes and allow reduction in the intensity and duration of chemotherapy. Novartis.

Impact of Small Scale Irrigation Development on Farmers’ Livelihood Improvement in Ethiopia: A Review

This review aims to illustrate the impact of small scale irrigations on farmers’ livelihood improvement in Ethiopia. It discusses the Ethiopian small scale irrigation development, categories and it impact on farmers’ livelihood improvement. The Ethiopian government has made a huge investment to develop small-scale irrigation schemes, and plans to enhance the recent level of irrigation infrastructure three fold by the end of 2020 to solve the household food insecurity problem of smallholder.Small scale irrigation is prioritized as one of the best alternatives for sustainable livelihood improvement, transformation growth and rural poverty alleviation in the country .It has multi-dimensional impacts on the living development of the rural people. It benefits smallholders in the course of crop diversification and intensification, employment opportunities, livestock production, credit services and increasing household incomes. Therefore, this review is important for understanding what was done in the past and what is going on now in improving farmers’ livelihood through small scale irrigation development in Ethiopia. Keywords: Small scale irrigation, Livelihood improvement, Ethiopia DOI : 10.7176/JRDM/62-02 Publication date: January 31 st 2020

Differential role of dose and environment in initiating and intensifying neurotoxicity caused by MDMA in rats

BackgroundMDMA causes serotonin (5-HT) syndrome immediately after administration and serotonergic injury in a few days or weeks. However, a serotonin syndrome is not always followed by serotonergic injury, indicating different mechanisms responsible for two adverse effects. The goal of present study was to determine causes for two adverse events and further test that dose and environment have a differential role in initiating and intensifying MDMA neurotoxicity.MethodsInitiation and intensification were examined by comparing neurotoxic effects of a high-dose (10 mg/kg × 3 at 2 h intervals) with a low-dose (2 mg/kg × 3) under controlled-environmental conditions. Initiation of a serotonin syndrome was estimated by measuring extracellular 5-HT, body-core temperature, electroencephalogram and MDMA concentrations in the cerebrospinal fluid, while intensification determined in rats examined under modified environment. Initiation and intensification of the serotonergic injury were assessed in rats by measuring tissue 5-HT content, SERT density and functional integrity of serotonergic retrograde transportation.ResultsBoth low- and high-dose could cause increases in extracellular 5-HT to elicit a serotonin syndrome at the same intensity. Modification of environmental conditions, which had no impact on MDMA-elicited increases in 5-HT levels, markedly intensified the syndrome intensity. Although either dose would cause the severe syndrome under modified environments, only the high-dose that resulted in high MDMA concentrations in the brain could cause serotonergic injury.ConclusionOur results reveal that extracellular 5-HT is the cause of a syndrome and activity of postsynaptic receptors critical for the course of syndrome intensification. Although the high-dose has the potential to initiate serotonergic injury due to high MDMA concentrations present in the brain, whether an injury is observed depends upon the drug environment via the levels of reactive oxygen species generated. This suggests that brain MDMA concentration is the determinant in the injury initiation while reactive oxygen species generation associated with the injury intensification. It is concluded that the two adverse events utilize distinctly different mediating molecules during the toxic initiation and intensification.

Combined experimental and computational investigations of a device for respiratory organs protection at low air temperatures

Investigation of the Arctic region is a crucial task and comprises various geopolitical, economical, technological and ecological activities at a global scale. In the course of intensification of the geopolitical struggle for resources usage, the Arctic region has now brought under new scrutiny. The known development strategies for the Arctic zone of the Russian Federation are based on the usage of advanced technologies. They are aimed at the creation of supply systems for emergency-rescue and other urgent works at specific severe conditions and critically important objects, including oil and gas production, power and communal facilities. These tasks might be accomplished using modern heat-protective devices, which provide effective and sustainable usage of human energy resources. Among the vast variety of individual safety gear for workers, there are some devices which are highly-efficient at extremely low-temperature conditions. These devices are based on thermal energy regeneration process of the exhaled air. Air temperature under the mask is increased driven by the heat of expired air and heating of incoming cold air while passing through the regenerative heat exchange unit. This heat-exchange unit was previously heated during expiration. This paper presents a survey concerning the following themes: a review of scientific researches, concerning tools for human respiratory organs protection at low air temperatures, patent documents and commercially-viable technical devices used for this purpose, as well as mathematical models of regenerative heat exchange. The devices and methods were compared, their advantages and disadvantages were revealed. It was stated that the most effective heat-exchange device is not that made of tissue material, but that is a solid-state composite construction of an irregular shape with internal channels for air transport. The presented thermal mask cap is designed so that vertically oriented channel rows do not connect with each other. The developed mathematical model is based on Newton-Richmann law. This model includes equations with efficiency coefficients for regenerative cap material at accumulation and regeneration heat stages. For various external air temperatures, we have calculated temperature oscillations between regenerative heat exchange unit input and output. These values were plotted together with the experimental temperature values and compared. Mathematical model adequacy and energy efficiency coefficients for thermal masks were determined. An engineering technique for device efficiency determination was proposed. The conducted combined experimental and computational investigations allowed us to carry out the efficiency analysis of the existing heat-protective masks which are based on thermal energy regeneration process of the exhaled air for inhaled air heating. The numerical values for the efficiency coefficients were obtained, and we made some conclusions concerning further device improvements on behalf of the Arctic region development.

Образовательные практики в концептуальном поле социологии

&lt;p&gt;В статье анализируется феномен образовательных практик в современном образовательном пространстве. Образовательные практики рассматриваются в контексте модернизации российской системы образования. Особое внимание при этом уделяется информатизации образовательного процесса, которая способствует формированию новых видов образовательных практик. &lt;/p&gt;&lt;p&gt;Анализ проблемы образовательных практик осуществляется сквозь призму социологии повседневности и социологии образования, которые позволяют более детально изучить особенности феномена образовательных практик.&lt;/p&gt;&lt;p&gt;Образовательные практики трактуются как совокупность опривыченных действий, навыков, сконструированных в условиях приобретения и усвоения определенных знаний, включающих в себя также типизированные способы поиска и отбора новой информации с помощью различных средств и ресурсов и типизированные способы взаимодействия с другими участниками учебного процесса. Образовательные практики отражают некие привычки учиться определенным образом, сформированные в ситуации решения познавательно-исследовательских задач. Они актуализируются в процессе интенсификации познавательного интереса и активности индивида. В рамках данного подхода появляется возможность зафиксировать и изучить спектр образовательных практик, распространенных в современном образовательном пространстве, с указанием особенностей их объективных и субъективных параметров. &lt;/p&gt;

Role of the Dinaric Karst (western Balkans) in shaping the phylogeographic structure of the threatened crayfish Austropotamobius torrentium

Summary1. This study examines phylogeography and phylogeny of the threatened stone crayfish, Austropotamobius torrentium, in order to elucidate the role of the Dinaric Karst geology in shaping the evolutionary history and genetic diversity of aquatic fauna in the western Balkans. Mitochondrial 16S rRNA and COI genes were partially sequenced from 188 and 159 crayfish, respectively, sampled from 70 localities. Phylogenetic relationships were reconstructed using four methods of phylogenetic inference. Divergence times between phylogroups were estimated in a Bayesian framework, and their demographic history was examined using neutrality tests and mismatch distribution analysis.2. Seven geographically localised phylogroups separated by pronounced genetic gaps were found. Five of them have a distribution range within the northern‐central Dinaric (NCD) region, while the remaining two include populations from the southern Balkans (SB) and central and south‐eastern Europe (CSE). The oldest divergence event separated two NCD lineages from the rest of populations in the Late Miocene or Early Pliocene. Divergences amongst the five NCD phylogroups and SB + CSE occurred in the Pliocene. The most recent split separated SB and CSE phylogroups during the Late Pliocene. For both genes, uncorrected pairwise divergences between most of the phylogroups (4.1–8.7% for COI and 1.6–4.8% for 16S rRNA) were of the same range as, or higher than, some of the interspecific distances previously reported for the genus Austropotamobius.3. Geographically isolated and deeply divergent cryptic monophyletic phylogroups within A. torrentium in the NCD region arose in the course of intensification of Neotectonic movements during the Pliocene and the beginning of the Pleistocene and the development of karstification that has heavily fragmented the palaeohydrography of the area. The results confirm a gradual north–south expansion of stone crayfish during the pre‐Pleistocene that preceded the rapid northward post‐glacial re/colonisation of central Europe (CSE phylogroup) through the Danube drainage.4. Austropotamobius torrentium comprises morphologically cryptic but molecularly distinct taxa. Considering the relatively small geographical areas they inhabit, the NCD phylogroups of stone crayfish should be given the highest conservation priority.

Cost-analysis of treatment of childhood acute lymphoblastic leukemia with asparaginase preparations: the impact of expensive chemotherapy

Asparaginase is an expensive drug, but important in childhood acute lymphoblastic leukemia. In order to compare costs of PEGasparaginase, Erwinia asparaginase and native E. coli asparaginase, we performed a cost-analysis in the Dutch Childhood Oncology Group ALL-10 medium-risk group intensification protocol. Treatment costs were calculated based on patient level data of 84 subjects, and were related to the occurrence of allergy to PEGasparaginase. Simultaneously, decision tree and sensitivity analyses were conducted. The total costs of the intensification course of 30 weeks were $57,893 in patients without PEGasparaginase allergy (n=64). The costs were significantly higher ($113,558) in case of allergy (n=20) necessitating a switch to Erwinia asparaginase. Simulated scenarios (decision tree analysis) using native E. coli asparaginase in intensification showed that the costs of PEGasparaginase were equal to those of native E. coli asparaginase. Also after sensitivity analyses, the costs for PEGasparaginase were equal to those of native E. coli asparaginase. Intensification treatment with native E. coli asparaginase, followed by a switch to PEGasparaginase, and subsequently to Erwinia asparaginase in case of allergy had similar overall costs compared to the treatment with PEGasparaginase as the first-line drug (followed by Erwinia asparaginase in the case of allergy). PEGasparaginase is preferred over native E. coli asparaginase, because it is administered less frequently, with less day care visits. PEGasparaginase is less immunogenic than native E. coli asparaginase and is not more expensive. Asparaginase costs are mainly determined by the percentage of patients who are allergic and require a switch to Erwinia asparaginase.

Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial

Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification. Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1-25 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119. Of 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42-72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5%, 92·8-98·2; unadjusted odds ratio 1·00, 95% CI 0·43-2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI -5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3-8·9) given one delayed intensification and six (2·4%, 0·2-4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0-2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one (<1%) treatment-related death, and 74 episodes of grade 3 or 4 toxic effects in 45 patients (17%). Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy. Medical Research Council and Leukaemia and Lymphoma Research.

Combined Treatment Strategy and Outcome of High Risk Neuroblastoma: Experience of the Children’s Cancer Hospital-Egypt

Background: Neuroblastoma (NB) is remarkable for its wide spectrum of clinical behavior and biological characteristics in relation to outcome. The use of aggressive therapy, including autologous hematopoietic stem cell transplantation (HSCT) and the addition of isoretionin (cis-Retinoic Acid/cis-RA), has increased survival rates of patients with advanced disease. Methods: Pediatric 271 newly diagnosed high risk NB patients were prospectively enrolled into the study. Patients received neoadjuvant chemotherapy of alternating cycles: [cyclophosphamide, doxorubicin, vincristine (CAdO)] and [etoposide, carboplatin]. Intensification courses of “ICE” (ifosfamide, carboplatin, and etoposide) regimen were administered to patients with bone marrow (BM) residual infiltration. Whenever safely feasible, complete surgical resection or debulking of the primary tumor was attempted for patients achieving partial response. Eligible patients underwent HSCT, while radiation therapy to the primary and metastatic sites, as well as maintenance with cis-RA was given for 6 months. Results: The median age of our patients was 2.8 years with male to female ratio of 1.65:1. At 4 years, the overall and event free survivals were 33.7% and 23.3% for the entire group under study, with significantly higher rates (42.7% and 35.6%, respectively) for HSCT patients (n = 94; p 0.001). The outcome was also significantly correlated with response to induction therapy, pathological subtype, as well as other variables. Conclusion: Myeloablative therapy followed by stem cell rescue is regarded as the most important goal of high risk NB treatment to improve survival till present. Each of consolidation HSCT, post induction disease status, as well as international neuroblastoma pathology classification (INPC) subtype was an independent predictive variable of survival. A collaborative effort with an emphasis on biologic characteristics of aggressive disease and tailored therapy needs to be strengthened to further our understanding of this disease.

Absence of Chromosomal Abnormalities Corresponds to Better Survival in Adult Ph-Negative ACUTE Lymphoblastic Leukemia – Results of the Russian ACUTE Lymphoblastic Leukemia (RALL) Study Group.

AbstractAbstract 2572Adult ALL regardless recent advantages in adolescents and young adults is still considered to be a therapeutical problem. So called “a pediatric-like approach” applied in adult ALL is reported to be more reasonable even in the older adults (up to 55 y).RALL has initiated a prospective multicenter trial for adult Ph-neg ALL based on: 1) evaluation of b/m blast clearance after 7 days of Prednisolone (PRD) prephase and its substitution by Dexamethasone (DEXA) if b/m blast count was >25%; 2) continuous 2,5 years treatment schedule with prolonged L-asparaginase (Σ=590.000 IU); 3) evaluation of the impact of the late intensification (2 courses of HD of methotrexate and ARA-C) on MRD clearance. The study is registered on the ClinicalTrials.gov public site; NCT01193933.From Nov, 2008, till June, 2012, 24 centers enrolled 173 pts: median age 28 y (15–55), 71f/101m, 112 (64,7%) = B-lin, 54 (31,2%) = T-lin, 1 pt -undifferentiated AL (0,6%), 6 - uknown phenotype (3,5%), median LDH=848 ME (72–13061), median L=13,5 (0,6–556*109/l). Cytogenetics was evaluable in 58,3% of pts (n=101) and 46,5% of them (n=47) had normal karyotype (NK). Initial risk group was evaluated in 154 pts among whom 46 patients (29,9%) were in the standard risk (SR) group (WBC <30 for B-Lin, <100 for T-Lin, EGIL BII-III, T-III; LDH < 2N, No late CR, t(4;11)-negative), 109 (60,1%) - in the high risk (HR) group (WBC >30 for B-Lin, >100 for T-Lin, EGIL BI, T-I-II-IV; LDH > 2N, No late CR, t(4;11)-positive). 19/173 pts (11%) were not qualified. The analysis was performed in June, 2012. +8 day b/m blast count was reported in 149 pts and b/m blasts less than 25% were detected in 36,2% of pts. The portion of PRD non-responders was statistically different in SR and HR groups: 24/45 (53,3%) and 68/101 (67,3%) (p=0,01), confirming the initial risk groups identification.Induction results were obtained in 150 pts, and CR rate was identical in both risk groups (SR=86,9%; HR=84,1%) with total 12 induction deaths (8,0%) and 6 resistant leukemias (4,0%). With a median follow-up of 12 mo (1–36 mo) death in CR was reported in 9/132 (6,8%) pts. OS at 36 mo was 58,6%, DFS-68,3%.MRD analysis for clonal IgH and TCR rearrangements was carried out in 25 pts. And as in our previous studies (ASH 2006, abstr 2294) the clearance was slow with only 41,6% pts negative for MRD at day +133 (4mo) of the protocol. Two late intensification courses (day +157 = 5 mo) increased MRD negativity only up to 50%. Such slow MRD clearance did not correspond to higher relapse rate so far.Age, WBC, immunophenotype, LDH, risk group, +8 day b/m blast count, time to CR, time without treatment (<>8days), L-asparaginase cessation did not influence survival. OS and DFS differed in pts with NK vs all other abnormalities: 87,4% vs 57,9% (p=0,002) and 88,9% vs 66,5%, respectively (p=0,02).So, our data demonstrated that ALL-2009 protocol provided 58% 3-years overall survival and 68,3% DFS. In adult Ph-neg ALL normal karyotype predicts better survival. The MRD clearance is very slow while on this protocol. Disclosures:No relevant conflicts of interest to declare.

Cost-Effectiveness of Treatment of Childhood Acute Lymphoblastic Leukemia with Pegasparaginase and Erwinia Asparaginase: The Impact of Expensive Chemotherapy

Abstract 4227Asparaginase is an expensive drug, but important in childhood acute lymphoblastic leukemia (ALL). Due to increasing costs of treatment of childhood ALL more insight in costs of asparaginase preparations is desired. In order to compare pharmacoeconomic aspects of PEGasparaginase, Erwinia asparaginase and native E.coli asparaginase, we performed a cost-effectiveness analysis in Dutch Childhood Oncology Group (DCOG) ALL-10 medium risk group (MRG) intensification protocol.Between April 2005 and October 2009, MRG patients were included in this multi-center study. Treatment costs were calculated based on patient level data of 84 subjects (33 female), and were related to allergy to asparaginase. We have used 3 treatment scenarios for asparaginase of which 2 scenarios were hypothetical: PEGasparaginase as first line preparation and Erwinia asparaginase as second line used as scenario 1 (similar to the actual ALL-10 treatment schedule); native E.coli asparaginase as first line preparation and Erwinia asparaginase as second line used as hypothetical scenario 2; or native E.coli asparaginase as first line preparation, PEGasparaginase as second line and Erwinia asparaginase as third line preparation used as hypothetical scenario 3. Medical technology assessments techniques were used for this cost-effectiveness analysis. Decision tree analysis was used to compare costs of PEGasparaginase or Erwinia asparaginase to native E.coli asparaginase, while taking into account the incidence of allergy to asparaginase and the different associated costs. Sensitivity analyses (one-way and two-way) were conducted to account for uncertainty in the used prices and calculated costs.The total costs of the ALL-10 MRG intensification course of 30 weeks were $71,147 per patient. Subgroup analysis revealed that the costs were $57,893 in patients without PEGasparaginase allergy (N=64). The costs were significantly higher ($113,558) in case of PEGasparaginase allergy (N=20) necessitating a switch to Erwinia asparaginase. The total costs were also calculated based on two weeks of asparaginase exposure; in case of PEGasparaginase the costs were $ 1,930 and for Erwinia asparaginase $ 3,785 per two weeks of treatment.Decision tree analysis showed that the treatment costs were $ 70,402 when using native E.coli asparaginase as first line preparation in intensification (scenario 3) and $ 71,809 when using PEGasparaginase as first line preparation (scenario 1). Treatment costs using native E.coli asparaginase as first line followed by Erwinia asparaginase as second line (scenario 2) the costs would be significantly higher ($ 103,474). One-way sensitivity analysis showed that the subgroup with allergy to native E.coli asparaginase (scenario 2) had the largest range in treatment costs. When treatment costs were calculated with the new European price of Erwinia asparaginase (the price has been doubled in March 2011), both treatments with PEGasparaginase as first line preparation (scenario 1) or native E.coli asparaginase as first line preparation (scenario 3) would be less expensive ($ 100,199 or $ 103,089, respectively) compared to the native E.coli asparaginase scenario 2 ($ 190,284). Two-way sensitivity analysis revealed that treatment with PEGasparaginase (scenario 1) is less expensive than treatment with native E.coli asparaginase (scenarios 2) for allergy probabilities of PEGasparaginase ranging from zero to 0.8 with a fixed allergy rate of 0.65 (Veerman et al. (Lancet Oncol. 2009)). This also holds true if a fixed allergy rate for native E.coli asparaginase of 0.4 is used, which is frequently found in studies using less native E.coli asparaginase in intensification after native E.coli asparaginase in induction (Nachman et al. (JCO 1997) and Willer et al. (Blood 2011)).In conclusion, treatment with native E.coli asparaginase, followed by a switch to PEGasparaginase, and subsequently to Erwinia asparaginase in case of allergy carried similar overall costs compared to the treatment with PEGasparaginase as first line drug (followed by Erwinia asparaginase in case of allergy). However, PEGasparaginase is preferred, because it is administered less frequently, with less outpatient care visits and is less immunogenic compared to native E.coli asparaginase. The costs with PEGasparaginase are much lower compared to Erwinia asparaginase. Disclosures:No relevant conflicts of interest to declare.

Spatial genetic structure and low diversity of the rare arable plant Bupleurum rotundifolium L. indicate fragmentation in Central Europe

Many threatened plant species have genetic structures indicating effects of fragmentation, and in Central Europe arable plants are among the most threatened taxa. Although this threat has developed only recently in the course of agricultural intensification, their annual life form makes arable plants relatively sensitive to increasing fragmentation and decreasing population sizes. One of Central Europe's rarest arable plant species is Bupleurum rotundifolium (Apiaceae). To analyze the genetic structure and diversity of this species we sampled 27 populations of B. rotundifolium in Central Europe, and assessed genetic structure by amplified fragment length polymorphism (AFLP) fingerprinting.Ordination, clustering and also Bayesian analysis suggested that most of the populations of the Eastern part of Germany formed one cluster, and most of the Western German populations as well as populations from outside Germany built another group. The two clusters accounted for 24% of differences in genetic structure of B. rotundifolium populations, while there was relatively strong differentiation among (41% variance) and within populations of a given group (35% variance). The overall ϕST-value was very high (0.65) and there was evidence for isolation-by-distance. Values of genetic diversity were very low for B. rotundifolium. The proportion of polymorphic loci per population varied between 9.4% and 38.7%, with those from eastern Germany being significantly less diverse (mean 19.1% vs. 25.5%).

Model of electric discharge formation in the lower atmosphere over a seismic region

The altitude distribution of seismic-related direct current (DC) electric field in the Earth–ionosphere layer is computed. This field is generated by the conductivity current flowing in closed atmosphere–ionosphere electric circuit at the preparatory stage of an earthquake. The source of the current is electromotive force caused by upward convective transport and gravitational sedimentation of charged aerosols injected into the atmosphere by soil gases in the course of intensification of seismic processes. It is shown from the solution of a self-consistent set of non-linear equations that pre-earthquake DC electric field enhancement in the atmosphere can reach breakdown value at the altitudes 1–10 km and initiate numerous chaotic electrical discharges in this region. The generation theory of very high-frequency electromagnetic radiation by such discharges is developed. The calculated spectrum and other characteristics of the radiation are in a good agreement with experimental data on radio emission at the frequencies of ∼41 and ∼53 MHz that have been observed on several stations of Crete Island in connection with impending earthquakes.