We studied the prognostic value of minimal disseminated disease (MDD) and anti-ALK immune response in children with NPM-ALK-positive anaplastic-large cell lymphoma (ALCL) and evaluated their ...potential for risk stratification. NPM-ALK transcripts were analyzed by RT-PCR in bone marrow/peripheral blood of 128 ALCL patients at diagnosis, whereas ALK antibody titers in plasma were assessed using an immunocytochemical approach. MDD was positive in 59% of patients and 96% showed an anti-ALK response. Using MDD and antibody titer results, patients could be divided into three biological risk groups (bRG) with different prognosis: high risk (bHR): MDD-positive and antibody titer ≤ 1/750, 26/128 (20%); low risk (bLR): MDD negative and antibody titer >1/750, 40/128 (31%); intermediate risk (bIR): all remaining patients, 62/128 (48%). Progression-free survival was 28% (s.e., 9%), 68% (s.e., 6%) and 93% (s.e., 4%) for bHR, bIR and bLR, respectively (P<0.0001). Survival was 71% (s.e., 9%), 83% (s.e., 5%) and 98% (s.e., 2%) for bHR, bIR and bLR (P=0.02). Only bHR and histology other than common type were predictive of higher risk of failure (hazard ratio 4.9 and 2.7, respectively) in multivariate analysis. Stratification of ALCL patients based on MDD and anti-ALK titer should be considered in future ALCL trials to optimize treatment.
•A supercritical state based quantitative on-orbit filling method is presented.•Determine refill moment via thermal response of liquid-vapor accumulator.•Guide fluid replenishment via pressure ...difference and time based empirical model.•Measure filled quantity via density variation of supercritical fluid.
The ability of resupplying fluid is vital to many aerospace applications for the sake of lifetime prolongation and performance maintenance, especially for deep-space explorations. Compared to conventional on-orbit filling technologies with the emphasis on efficiency maximization, fluid replenishment for two-phase cooling systems in space requires an accurate control of the transferred quantity constrained by its working principle. Under microgravity, weighing is impractical, and due to the dependent relationship between the saturated temperature and the saturated pressure, mass cannot be deduced from measurements of the two thermal properties, making the filled quantity determination challenging in space. For this reason, this article presents a novel quantitative on-orbit filling method for two-phase systems, through which the transferred mass is obtained from the density variation of the supercritical fluid in the supply vessel. Via heating the fluid to supercritical, a homogeneous state independent from gravity is achieved, and therefore the fluid density can be deducted from the temperature and the pressure. The filling process is driven by pressure difference and precisely regulated by solenoid valves and a flow restrictor situated in the transfer line, constituting two fundamental components. To direct the filling, an empirical model aiming to predict the transferred mass is established in terms of the pressure difference and transfer time. Based on that, a fill/refill architecture is deployed to transfer a quantitative amount of coolant to a delicate pumped CO2 two-phase thermal control system, the Upgraded Tracker Thermal Pump System in the Alpha Magnetic Spectrometer-02 on the International Space Station, which was designed and constructed to replace the current Tracker cooling system in 2019. Results of the test conducted in a thermal-vacuum chamber showed that the density-variation approach in the upgraded two-phase system achieved a filling accuracy better than 7%, and the empirical model showed consistency with the approach within 5%. Moreover, a criterion to assess when the two-phase cooling system needs a coolant refill was proposed according to the investigation of a two-phase fluid accumulator of the system under thermal regulation, in which the heat transfer is strongly affected by liquid-vapor distribution. Given the above, the proposed method contributes to the on-orbit filling for two-phase systems with more precise control over the transferred quantity. It also delivers valuable insights to the operational status evaluation of two-phase systems for future space missions.
Between 2007 and 2013, 13 children diagnosed with primary mediastinal large B‐cell lymphoma (PMLBL) were treated according to a modified version of AIEOP (Associazione Italiana Ematologia Oncologia ...Pediatrica) LNH‐97 protocol based on high‐dose methotrexate, anthracyclines, and addition of anti‐CD20. Ten patients achieved a continuous complete remission with front‐line therapy. The overall 5‐year survival was 91.7%, and event‐free survival was 83.9%, with only one patient dying of progressive disease. Despite the few cases, these results demonstrate that this therapy, which includes anti‐CD20, given in a multicenter setting, is feasible with acceptable toxicity in children with PMLBL.
Anaplastic large cell lymphoma (ALCL) harbors the reciprocal chromosomal translocation t(2;5)(p23;q35) in approximately 80% of the cases. The genes involved are nucleophosmin (NPM) and anaplastic ...lymphoma kinase (ALK) and the resulting chimeric NPM-ALK protein is thought to play a key role in the pathogenesis of t(2;5) positive ALCL. Few data on bone marrow (BM) involvement in ALCL have been published and they mostly rely on morphological examination of BM smears. We studied 52 ALCL for NPM-ALK expression by RT-PCR: 47/52 biopsies were positive. In 41 of the 47 cases we obtained the BM at diagnosis and investigated the prevalence of minimal BM infiltration by RT-PCR and real-time PCR. Minimal disseminated disease was positive in 25/41 patients (61%), of whom six had morphologically infiltrated BM. Survival analysis demonstrated a 5-year progression-free survival of 41 +/- 11% for patients with molecularly positive BM vs 100% for patients with negative BM (P = 0.001). These results suggest that minimal BM involvement at diagnosis is a common event in pediatric ALCL and that minimal BM disease monitoring could identify patients at risk of relapse.
Understanding the mechanisms that control stress-induced apoptosis is critical to explain how tumours respond to treatment, as cancer cells frequently escape drug toxicity by regulating stress ...response through heat shock protein (HSP) expression. The overexpression of Hsp72, in particular, results in increased incidence of cell transformation, and correlates with poor prognosis in a wide range of cancers. We have shown that Hsp72 assists folding of oncogenic NPM-ALK kinase in anaplastic large-cell lymphomas (ALCLs), but its role in the maintenance of the malignant phenotype remains uncertain. Therefore, we assessed Hsp72 expression in ALCLs, investigating more in detail the mechanisms that regulate its status and activity. We found that Hsp72 is unique among the HSPs involved in tumourigenesis to be overexpressed in ALK(+) tumours and cell lines and to be induced by stress. Different from other HSPs, Hsp72 prevents cell injury, Bax activation and death by apoptosis in ALK(+) cells, acting both upstream and downstream of mitochondria. Conversely, Hsp72 is underexpressed in ALK(-) ALCL cells, and it is unable to protect cells from apoptosis under stress. Moreover, when Hsp72 expression is reduced following NPM-ALK inhibition, lymphoma cells undergo apoptosis, demonstrating the importance of Hsp72 in regulating ALCL stress response and drug sensitivity.
Abstract Commonly used in structural applications since the ’90s, composite materials represent a valid alternative to metallic solutions. An intense research activity accompanied the spread of this ...technology to the point that, nowadays, a large variety of modeling techniques and tools are at the designers’ disposal. Although the literature on this topic is vast, detailed, and thorough, the need for new, faster, and more efficient design tools and methodologies remains. In this context, this work covers the development of an Open-Source computational laminate analysis toolbox, its structure, and its validation. The objective of the research was the creation of a simple and accessible mean for the calculation of laminates’ stresses in complex structural components with a reduced computational cost. To this end, the authors implemented the basics of micro, meso, and micromechanics in a Python-based toolbox and then performed a validation campaign against the results of an FE analysis. The work resulted in an input-generation/output-analysis instrument to be used by designers alongside the FEA.
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