Granulation of Silicon Nitride Powders by Spray Drying: A Review.

Spray drying is a widely used method of converting liquid material (aqueous or organic solutions, emulsions and suspensions) into a dry powder. Good flowability, narrow size distribution, and controllable morphology are inherent in powders produced by spray drying. This review considers the granulation factors that influence the final properties of the silicon nitride dried powders. The first group includes the types of atomizers, manifolds, and drying chamber configurations. The process parameters fall into the second group and include the following: inlet temperature, atomizing air flow, feed flow rate, drying gas flow rate, outlet temperature, and drying time. Finally, the last group, feedstock parameters, includes many factors such as feed surface tension, feed viscosity, solvent type, solid particle concentration, and additives. Given the large number of factors affecting morphology, particle size and moisture, optimizing the spray drying process is usually achieved by the "trial and error" approach. Nevertheless, some factors such as the effect of a solvent, dispersant, binder, and sintering additives considered in the literature that affect the Si3N4 granulation process were reviewed in the work. By summarizing the data available on silicon nitride powder production, the authors attempt to tackle the problem of its emerging demand in science and industry.

The Influence of Surface Texturing of Ceramic and Superhard Cutting Tools on the Machining Process-A Review.

Machining is an indispensable manufacturing process for a wide range of engineering materials, such as metals, ceramics, and composite materials, in which the tool wear is a serious problem, which affects not only the costs and productivity but also the quality of the machined components. Thus, the modification of the cutting tool surface by application of textures on their surfaces is proposed as a very promising method for improving tool life. Surface texturing is a relatively new surface engineering technology, where microscale or nanoscale surface textures are generated on the cutting tool through a variety of techniques in order to improve tribological properties of cutting tool surfaces by reducing the coefficient of friction and increasing wear resistance. In this paper, the studies carried out to date on the texturing of ceramic and superhard cutting tools have been reviewed. Furthermore, the most common methods for creating textures on the surfaces of different materials have been summarized. Moreover, the parameters that are generally used in surface texturing, which should be indicated in all future studies of textured cutting tools in order to have a better understanding of its effects in the cutting process, are described. In addition, this paper proposes a way in which to classify the texture surfaces used in the cutting tools according to their geometric parameters. This paper highlights the effect of ceramic and superhard textured cutting tools in improving the machining performance of difficult-to-cut materials, such as coefficient of friction, tool wear, cutting forces, cutting temperature, and machined workpiece roughness. Finally, a conclusion of the analyzed papers is given.

Grading of neurological toxicity in patients treated with tisagenlecleucel in the JULIET trial.

Chimeric antigen receptor-T (CAR-T) cell therapy achieves durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), but may be associated with neurological toxicity (NT). We retrospectively assessed differences and concordance among 3 available grading scales (the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 [CTCAE], modified CAR-T Related Encephalopathy Syndrome [mCRES], and American Society for Transplantation and Cellular Therapy [ASTCT] scales) applied to the same set of NT data from the JULIET (A Phase 2, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory DLBCL) trial. Individual patient-level NT data from the phase 2, single-group, global, pivotal JULIET trial (NCT02445248) were retrospectively and independently graded, using CTCAE, ASTCT, and mCRES, by 4 medical experts with experience managing patients with 3 different CD19-targeted CAR constructs. According to the US Food and Drug Administration definition of NT using CTCAE, 62 of 106 patients infused with tisagenlecleucel had NT as of September 2017. Among 111 patients infused with tisagenlecleucel (as of December 2017), the 4 experts identified 50 patients (45%) who had any-grade NT per CTCAE, 19 (17%) per mCRES, and 19 (17%) per ASTCT. Reevaluation according to the mCRES/ASTCT criteria downgraded 31 events deemed NT by CTCAE to grade 0. This is the first study to retrospectively apply CTCAE, mCRES, and ASTCT criteria to the same patient data set. We conclude that CTCAE v4.03 was not designed for, and is suboptimal for, grading CAR-T cell therapy-associated NT. The CRES and ASTCT scales, which measure immune effector cell-associated neurotoxicity syndrome, offer more accurate assessments of NT after CAR-T cell therapy.

Grading and management of cytokine release syndrome in patients treated with tisagenlecleucel in the JULIET trial.

Chimeric antigen receptor T-cell (CAR-T) therapy yields durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Cytokine release syndrome (CRS) is a CAR-T therapy-related adverse event. To date, clinical trials of different CAR-T products have not been aligned on CRS grading scales and management algorithms. We assessed concordance between the Penn, Lee, and American Society for Transplantation and Cellular Therapy (ASTCT) grading systems by retrospectively regrading CRS events in the JULIET (A Phase 2, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory DLBCL) trial. Four medical experts with experience treating patients with 3 different CAR-T products independently regraded individual patient-level CRS events from the phase 2, global, pivotal JULIET trial (#NCT02445248). As of 8 December 2017, a total of 111 patients with r/r DLBCL underwent infusion with tisagenlecleucel. Sixty-four patients had CRS events graded per the Penn scale; on retrospective review, 63 and 61 patients had CRS events regraded per the Lee and ASTCT criteria, respectively. The Lee scale yielded concordance for 39, lower grade for 20, and higher grade for 5 events compared with the Penn scale. The ASTCT criteria provided concordance for 37, lower grade for 23, and higher grade for 4 events compared with the Penn scale. Sixteen (14%) of 111 patients in the JULIET trial received tocilizumab, all for severe events (Penn grade 3/4 CRS). This study is the first to assess concordance between 3 CRS grading scales using the same patient data set and to compare tocilizumab use according to the Lee scale in the JULIET trial and the ZUMA-1 (Long-Term Safety and Activity of Axicabtagene Ciloleucel in Refractory Large B-Cell Lymphoma) trial. This analysis describes key differences between grading scales and may inform CRS management practices.

Cross-sectional physician survey on the use of minimal residual disease testing in the management of pediatric and adult patients with acute lymphoblastic leukemia.

OBJECTIVES: Minimal residual disease (MRD) is a strong prognostic factor in acute lymphoblastic leukemia (ALL), which progresses quickly and is fatal within months if untreated. This study explored use of MRD testing in adult and pediatric B-cell ALL patients, and academic versus community settings. METHODS: A survey was administered to US-based hematologists/oncologists currently managing ≥5 B-cell ALL patients and using MRD tests. Descriptive analyses (frequencies and percentages) and Pearson's chi square testing assessed any differences in various characteristics. RESULTS: 150 adult treaters (treating physicians: 100 community, 50 academic) and 30 pediatric treaters participated. Use of MRD testing was higher among pediatric treaters (93% of patients) than adult treaters (73% of patients) (p < 0.05), and higher among adult treaters at academic centers than in community settings (84% and 67% of patients, respectively; p < 0.01). MRD testing is part of a standard protocol for 93% of pediatric treaters versus 53% of adult treaters. Pediatric treaters most commonly administer an MRD test during/after induction or upon relapse. No consensus on timing among adult treaters was noted. DISCUSSION: MRD testing is an important tool in the prediction of relapse in ALL. Resolving barriers could improve detection of molecular relapse in patients with ALL, particularly among adults and in community settings. CONCLUSION: MRD testing is fairly common in treatment of ALL, but some barriers still exist in access.

Industry's Giant Leap Into Cellular Therapy: Catalyzing Chimeric Antigen Receptor T Cell (CAR-T) Immunotherapy.

PURPOSE OF REVIEW: We describe the significant technological leap from bench to bedside that was achieved through a strong academic-industry collaboration between dedicated clinicians and researchers at the University of Pennsylvania, the Children's Hospital of Philadelphia, and Novartis to commercialize the chimeric antigen receptor T cell (CAR-T) therapy tisagenlecleucel (CTL019; Kymriah®; Novartis Pharma AG, Basel, Switzerland). RECENT FINDINGS: Tisagenlecleucel was the first CAR-T therapy and the first gene therapy to receive US Food and Drug Administration approval in 2017, with an initial indication for pediatric and young adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia, followed by approval in May 2018 for a second indication in adult patients with r/r diffuse large B cell lymphoma. Subsequent approvals in the European Union, Switzerland, and Canada soon followed. The tisagenlecleucel success story represents the development and commercialization of a first-of-its-kind personalized cellular therapy with a manufacturing process that supports commercial production and ongoing global clinical trials in a growing number of countries.

Tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma patients without measurable disease at infusion.

Tisagenlecleucel demonstrated high rates of durable responses in adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. Most patients (92%) received bridging therapies to control disease after study entry and before tisagenlecleucel infusion. Here, we examine the efficacy and safety of tisagenlecleucel in the subset of 7 patients who achieved complete response (CR) after bridging therapy and before tisagenlecleucel infusion. Tisagenlecleucel rapidly expanded in all 7 patients, and the transgene levels were measurable for up to 2 years after infusion. After infusion, all 7 patients were still in CR at the month 3 evaluation, and 5 of 7 patients remained progression-free >12 months. Adverse events were similar to the overall JULIET population. Cytokine release syndrome (CRS) was reported in 4 of 7 patients (grade 2 = 2 and grade 3 = 2 using the Penn grading scale), and 1 patient experienced grade 1 neurotoxicity. No patient required tocilizumab or steroids for CRS management. These data provide preliminary evidence of tisagenlecleucel efficacy in patients with r/r DLBCL without detectable disease after bridging or salvage therapies and warrant further investigation of tisagenlecleucel as consolidative therapy in future trials. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

Economic Burden of Veno-occlusive Disease in Patients With B-cell Acute Lymphoblastic Leukemia in the United States.

PURPOSE: The goal of this study was to evaluate the incidence, inpatient mortality, and economic burden of hepatic veno-occlusive disease (VOD) in adults with B-cell acute lymphoblastic leukemia (ALL) in the United States. METHODS: Using MarketScan Commercial Claims and Encounters Database and Medicare Supplemental and Coordination of Benefits Database, data for patients with B-cell ALL from April 1, 2009, to October 31, 2016, were extracted by using diagnosis codes. VOD was identified based on clinical criteria and expert opinions. Patients with VOD were followed up from diagnosis of VOD until the earliest occurrence of inpatient death, end of continuous enrollment, end of study period, or for a maximum of 100days. The incidence of VOD and VOD-associated inpatient mortality were calculated. VOD-related health care costs based on paid adjudicated claims were calculated. FINDINGS: Of the 2571 adults with B-cell ALL, the overall incidence of VOD was low at 3.4% (88 of 2571). Of these patients with VOD, 52% (46 of 88) experienced multiorgan failure and were identified as having severe VOD. VOD was only identified in patients having undergone hematopoietic stem cell transplantation (5.4% [88 of 1624]). The inpatient mortality rate of those with any VOD over the 100-day postindex period was 26.1%, and the inpatient mortality was even higher for patients with severe VOD (37.0%). Total mean (SD) medical costs per patient during the 100 days' post-VOD diagnosis were $55,975 ($160,335); mean (SD) costs per patient were ∼4-fold higher for severe ($86,953 [$206,906]) versus nonsevere ($22,047 [$72,847]) VOD. IMPLICATIONS: Clinical criteria were used to identify VOD events and thus VOD might be underdiagnosed. The mortality of VOD also might be underestimated because only inpatient deaths are captured in the data. The incidence and mortality of VOD could also be underestimated because we focused on adult patients who might receive reduced-intensity treatment. The economic burden of VOD may be underestimated because the Healthcare Common Procedure Coding System code specific for defibrotide was not available, and thus the cost for defibrotide might not be included. Finally, as the study population consisted of patients with commercial or Medicare supplemental insurance, results may not be generalizable to all patients with VOD in the United States. Although VOD occurred infrequently in adults with B-cell ALL, it was associated with high inpatient mortality and substantial costs. Patients with severe VOD were associated with highest mortality and highest costs. Given the clinical and economic burden associated with VOD, it is important that patients at high risk for VOD be identified and treated to minimize this risk.

Basic fibroblast growth factor suppresses p53 activation in the neoplastic cells of a proportion of patients with chronic lymphocytic leukaemia.

p53 is the most frequently inactivated gene in human cancers, reflecting its pivotal role in maintaining genomic integrity. The present study was conducted to explore the possibility that tumour cells with no intrinsic defects of the p53 pathway might nevertheless acquire p53 dysfunction through extrinsic suppression of the pathway by microenvironmental factors. Neoplastic cells from patients with chronic lymphocytic leukaemia (CLL) were cultured in the presence or absence of basic fibroblast growth factor (bFGF) and exposed to ionizing radiation (IR) to induce p53 accumulation. bFGF is greatly increased in the plasma of CLL patients and can suppress p53 activation in some experimental models. IR induced a marked increase in p53 levels in 28 samples from 24 patients. bFGF inhibited IR-induced p53 accumulation to some extent in most of these samples and by more than 50% in seven samples from seven patients. Suppression of p53 activation by bFGF was frequently but not always accompanied by upregulation of the p53-inhibitory protein MDM2 and/or phosphorylation of MDM2 at serine 166, and was associated with impaired transcriptional activation of the p53 target gene p21. These observations provide the first demonstration in human cancer cells that the p53 pathway can be suppressed by factors in the tumour-cell microenvironment.

Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study.

BACKGROUND: Developing inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information. METHODS: We built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs) or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population - patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A) post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1) or random-effects (Case 2 and Case 3) logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical significant inhibitor (10/100, 5/100 [high rates], and 1/86 [the Food and Drug Administration mandated cutoff rate in PTPs]) were calculated. The effect of discounting prior information or scaling up the study data was evaluated. RESULTS: Results based on noninformative priors were similar to the classical approach. Using priors from PTPs lowered the point estimate and narrowed the 95% credible intervals (Case 1: from 1.3 [0.5, 2.7] to 0.8 [0.5, 1.1]; Case 2: from 1.9 [0.6, 6.0] to 0.8 [0.5, 1.1]; Case 3: 2.3 [0.5, 6.8] to 0.7 [0.5, 1.1]). All probabilities of satisfying a threshold of 1/86 were above 0.65. Increasing the number of patients by two and ten times substantially narrowed the credible intervals for the single cohort study (1.4 [0.7, 2.3] and 1.4 [1.1, 1.8], respectively). Increasing the number of studies by two and ten times for the multiple study scenarios (Case 2: 1.9 [0.6, 4.0] and 1.9 [1.5, 2.6]; Case 3: 2.4 [0.9, 5.0] and 2.6 [1.9, 3.5], respectively) had a similar effect. CONCLUSION: Bayesian approach as a robust, transparent, and reproducible analytic method can be efficiently used to estimate the inhibitor rate of hemophilia A in complex clinical settings.

Global Post-Authorization Safety Surveillance Study: real-world data on prophylaxis and on-demand treatment using FEIBA (an activated prothrombin complex concentrate).

This prospective, Post-Authorization Safety Surveillance (PASS) study was carried out in patients with hemophilia A or B and inhibitors treated with FEIBA for 1 year to collect real-world data on safety and effectiveness of FEIBA. The study followed a cohort design and did not make stipulations on treatment or observation schedule, as it was designed to observe routine medical practices based on physicians' treatment decisions, including whether patients received on-demand or prophylaxis with FEIBA. The attending physician maintained documentation, including medical records, laboratory reports, adverse event reports, and so on and a subject diary was used. Eighty-one patients were treated with FEIBA at 40 sites in 10 countries over a 4-year period. Sixty-nine patients (85.2%) had hemophilia A, two had (2.5%) hemophilia B, and ten (12.3%) had acquired hemophilia A. At baseline 45 patients (55.6%) were prescribed prophylaxis and 36 (44.6%) on-demand treatment. This study was novel in following safety and effectiveness in 'real world' on-demand and prophylactic use of FEIBA, and was able to collect data in these rare patients under routine clinical practice.

Evaluation of safety and effectiveness of factor VIII treatment in haemophilia A patients with low titre inhibitors or a personal history of inhibitor. Patient Data Meta-analysis of rAFH-PFM Post-Authorization Safety Studies.

There is no prospective evidence on inhibitor recurrence among haemophilia A patients with low titre inhibitors or history of inhibitors, and whether or how therapeutic choices affect the risk of recurrence. The aims of this study were to synthesise safety data in patients with moderate-severe haemophilia A and with low titre inhibitors or inhibitor history enrolled in the rAHF PFM (ADVATE) - Post-Authorization Safety Studies (ADVATE-PASS) international programme. The study was conducted in clinics participating to the ADVATE PASS programme. The patient population consisted of patients entering the studies with low titre (≤ 5 BU) inhibitors or a positive personal history of inhibitors. Patients on Immune Tolerance Induction at study entry were excluded. Primary outcome was new or recurrent inhibitor titre > 5 BU. Secondary outcomes were any increase of inhibitor titre not reaching 5 BU; any unexplained change in treatment regimen. Primary analysis was done by two-stage random effects meta-analysis. Secondary analysis was done by a hierarchical Bayesian random effects logistic model. A total of 219 patients from seven studies were included. Of these 214 (97.7 %) patients had been previously treated for more than 50 exposure days. Two hundred ten patients had positive history for inhibitors, nine a baseline measurable titre. No patient presented a primary outcome event (95 % confidence interval [CI] 0-1.6 %). Six patients with previous history developed a low titre recurrence (overall rate 2.2, 95 %CI 0-4.8 %). When any increase of inhibitor titre or any treatment change was accounted for, overall 3.7 % (95 % CI 0 %-8.0 %) of patients experienced the outcome. In conclusion, the observed rate of events does not support the definition of this population as at high risk for inhibitor development.

Light propagation in chiral media with large pitch.

Light propagation in uniaxial chiral media with large pitch is studied. In these systems there are forbidden zones for extraordinary beams, which lead to effective reflection on zone boundaries and to wave damping inside the forbidden zone. We analyze the vicinities of the turning points and the transition of an extraordinary wave through the forbidden zone. Narrow forbidden zones with merging turning points are studied in detail. The transition through the forbidden zone is studied experimentally in nematic liquid crystal doped with a chiral addition. There is a good agreement between experimental results and theoretical calculations.

Crossed source-detector geometry for a novel spray diagnostic: Monte Carlo simulation and analytical results.

Sprays and other industrially relevant turbid media can be quantitatively characterized by light scattering. However, current optical diagnostic techniques generate errors in the intermediate scattering regime where the average number of light scattering is too great for the single scattering to be assumed, but too few for the diffusion approximation to be applied. Within this transitional single-to-multiple scattering regime, we consider a novel crossed source-detector geometry that allows the intensity of single scattering to be measured separately from the higher scattering orders. We verify Monte Carlo calculations that include the imperfections of the experiment against analytical results. We show quantitatively the influence of the detector numerical aperture and the angle between the source and the detector on the relative intensity of the scattering orders in the intermediate single-to-multiple scattering regime. Monte Carlo and analytical calculations of double light-scattering intensity are made with small particles that exhibit isotropic scattering. The agreement between Monte Carlo and analytical techniques validates use of the Monte Carlo approach in the intermediate scattering regime. Monte Carlo calculations are then performed for typical parameters of sprays and aerosols with anisotropic (Mie) scattering in the intermediate single-to-multiple scattering regime.