Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Significant unmet need remains for patients with relapsed/refractory FL after ≥3 lines of prior therapy. While recent ...advancements have likely improved the survival of patients with FL, most patients will eventually relapse. The treatment of patients with FL after multiple relapses or those with refractory disease has historically led to lower overall response rates (ORR) and shorter progression-free survival (PFS) with each subsequent line of therapy. New treatments with high ORR and durable PFS are needed in this setting, particularly in patients that progress within 2 years of first line chemoimmunotherapy (POD24) and/or those refractory chemoimmunotherapy. Chimeric antigen receptor T-cell therapies targeting the B-cell antigen CD-19 have shown to be an efficacious treatment option for both heavily pretreated patients and/or patients with refractory FL, resulting in a high ORR and durable remissions.
Mercury (Hg) has been listed as a global high priority pollutant by many
international organizations due to its mobility and persistence in the
environments and high toxicity to organisms. This ...research was conducted
with the aims to determine: (i) total Hg content (THg) and its spatial
distribution in sediments of river Tisa along the river course, (ii)
possible sources of THg and (iii) degree of THg pollution in sediments from
the river Tisa through different criteria. Total Hg in the sediments ranged
from 0.07 to 0.49 mg kg-1, with mean ? S.D. value of 0.26 ? 0.10 mg kg-1.
The highest mean value of THg (0.30 mg kg-1) was found in the lower stream,
while the lowest (0.13 mg kg-1) was found in the tributary. According to
Principal Component Analyses (PCA) strong positive loading of metals in all
parts of the river Tisa is mainly controlled from the same sources. These
sources are related to anthropogenic activities based on calculated
Enrichment Factor (EF) values. Total Hg are higher than background value.
According to the Republic of Serbia official standard, THg values of river
Tisa sediments were within the range of maximum permissible values.
Compared with National Oceanic and Atmospheric Administration (NOAA)
guideline, 80.49% of sediment samples indicated that THg in the river Tisa
sediments represented minimal and possible risk towards the living
organisms. Integrating the results of pollution assessment, it could be
concluded that THg in river Tisa sediments in Serbia demonstrates
considerable contamination according to Geoaccumulation Index (Igeo), and Contaminant Factor (CF), and high pollution risk according to Potential Environmental Risk Index (PERI).
TISA adoption represents a key challenge in the field of global liberalization of trade in services not only from the perspective of developed countries, the main actors in the field, but also for ...the emerging countries, which are developing a service economy. In this context, our research proposes a qualitative analysis on TISA impact on the legal services and we will illustrate our assumptions with a case study related to the perspective of its application in Romania. Taking into consideration the main analyses from the literature in the field, the present article will highlight, through a SWOT analysis the main opportunities, but also the most important challenges for the legal services sector in the current global environment.
The object of this article is to preliminary present the rescue archaeological excavations prior to the construction of the Arad-Timişoara Highway, conducted in 2010 on-site B_06. The investigated ...area is located on the Arad-Seceani highway section, in the km 15+490-15+780 stretch. The field research concluded the site was a large settlement lying both on the highway route as well as to its west and east. The archaeological investigations carried out within the area of site B0_6 and the perimeter limits of the highway route identified and comprehensively examined 132 stratigraphic units, of which three are Sarmatian inhumations. Of the total researched features, 106 were discovered in the northern half of the investigated area, while the three graves, together with another feature, lay midway through the project area. The inhumations lay isolate from the 106 features from the northern side of the investigated area, but also from the 22 located southward as well. The 106 features belong to a Dacian settlement broadly dated to the 2nd – early 3rd century AD, while the graves date to late 2nd – first decades of the 3rd century AD, the features discovered in the southern half of the investigated area belonging to another chronological and cultural level (the 4th – 5th century AD).
To determine longitudinal changes in angle configuration in the eyes of primary angle-closure suspects (PACS) treated by laser peripheral iridotomy (LPI) and in untreated fellow eyes.
Longitudinal ...cohort study.
Primary angle-closure suspects aged 50 to 70 years were enrolled in a randomized, controlled clinical trial.
Each participant was treated by LPI in 1 randomly selected eye, with the fellow eye serving as a control. Angle width was assessed in a masked fashion using gonioscopy and anterior segment optical coherence tomography (AS-OCT) before and at 2 weeks, 6 months, and 18 months after LPI.
Angle width in degrees was calculated from Shaffer grades assessed under static gonioscopy. Angle configuration was also evaluated using angle opening distance (AOD250, AOD500, AOD750), trabecular-iris space area (TISA500, TISA750), and angle recess area (ARA) measured in AS-OCT images.
No significant difference was found in baseline measures of angle configuration between treated and untreated eyes. At 2 weeks after LPI, the drainage angle on gonioscopy widened from a mean of 13.5° at baseline to a mean of 25.7° in treated eyes, which was also confirmed by significant increases in all AS-OCT angle width measures (P<0.001 for all variables). Between 2 weeks and 18 months after LPI, a significant decrease in angle width was observed over time in treated eyes (P<0.001 for all variables), although the change over the first 5.5 months was not statistically significant for angle width measured under gonioscopy (P = 0.18), AOD250 (P = 0.167) and ARA (P = 0.83). In untreated eyes, angle width consistently decreased across all follow-up visits after LPI, with a more rapid longitudinal decrease compared with treated eyes (P values for all variables ≤0.003). The annual rate of change in angle width was equivalent to 1.2°/year (95% confidence interval CI, 0.8-1.6) in treated eyes and 1.6°/year (95% CI, 1.3-2.0) in untreated eyes (P<0.001).
Angle width of treated eyes increased markedly after LPI, remained stable for 6 months, and then decreased significantly by 18 months after LPI. Untreated eyes experienced a more consistent and rapid decrease in angle width over the same time period.
Tisagenlecleucel (tisa-cel) is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed/refractory large B-cell lymphoma. Outcomes of patients with ...out-of-commercial specification (OOS) CAR T products are not well characterized. We therefore assessed 37 adult patients who underwent leukapheresis for tisa-cel therapy in a single center. In nine (24%) patients, manufactured tisa-cel was considered OOS. Three of them (33%) received tisa-cel after institutional review board approval; 2/9 (22%) did not receive tisa-cel due to disease progression; and 4/9 (44%) received academic point-of-care (POC) CAR T-cell as salvage therapy, at a median of 35 days following OOS notification. Three of those four patients achieved a complete response. In univariate analysis, risk factors for OOS were ≥ 4 prior therapies or previous bendamustine exposure. In conclusion, we report high OOS incidence of 24% in real-life setting. Forty-four percent of those patients received POC CAR T-cell as salvage therapy.
Variability or stability might have an impact on treatment success and toxicity of CD19 CAR T-cells. We conducted a prospective observational study of 12 patients treated with Tisagenlecleucel for ...CD19
B-cell malignancies. Using a 31-color spectral flow cytometry panel, we analyzed differentiation stages and exhaustion markers of CAR T-cell subsets prior to CAR T-cell infusion and longitudinally during 6 months of follow-up. The majority of activation markers on CAR T-cells showed stable expression patterns over time and were not associated with response to therapy or toxicity. Unsupervised cluster analysis revealed an immune signature of CAR T-cell products associated with the development of immune cell-associated neurotoxicity syndrome. Warranting validation in an independent patient cohort, in-depth phenotyping of CAR T-cell products as well as longitudinal monitoring post cell transfer might become a valuable tool to increase efficacy and safety of CAR T-cell therapy.
Abstract
Background
Genetically engineered chimeric antigen receptor (CAR) T lymphocytes are promising therapeutic tools for cancer. Four CAR T cell drugs, including tisagenlecleucel (tisa-cel) and ...axicabtagene-ciloleucel (axi-cel), all targeting CD19, are currently approved for treating B cell malignancies. Flow cytometry (FC) remains the standard for monitoring CAR T cells using a recombinant biotinylated target protein. Nevertheless, there is a need for additional tools, and the challenge is to develop an easy, relevant, highly sensitive, reproducible, and inexpensive detection method. Molecular tools can meet this need to specifically monitor long-term persistent CAR T cells.
Methods
Based on 2 experimental CAR T cell constructs, IL-1RAP and CS1, we designed 2 quantitative digital droplet (ddPCR) PCR assays. By targeting the 4.1BB/CD3z (28BBz) or 28/CD3z (28z) junction area, we demonstrated that PCR assays can be applied to approved CD19 CAR T drugs. Both 28z and 28BBz ddPCR assays allow determination of the average vector copy number (VCN) per cell. We confirmed that the VCN is dependent on the multiplicity of infection and verified that the VCN of our experimental or GMP-like IL-1RAP CAR T cells met the requirement (< 5 VCN/cell) for delivery to the clinical department, similar to approved axi-cel or tisa-cel drugs.
Results
28BBz and 28z ddPCR assays applied to 2 tumoral (acute myeloid leukemia (AML) or multiple myeloma (MM) xenograft humanized NSG mouse models allowed us to quantify the early expansion (up to day 30) of CAR T cells after injection. Interestingly, following initial expansion, when circulating CAR T cells were challenged with the tumor, we noted a second expansion phase. Investigation of the bone marrow, spleen and lung showed that CAR T cells disseminated more within these tissues in mice previously injected with leukemic cell lines. Finally, circulating CAR T cell ddPCR monitoring of R/R acute lymphoid leukemia or diffuse large B cell lymphoma (n = 10 for tisa-cel and n = 7 for axi-cel) patients treated with both approved CAR T cells allowed detection of early expansion, which was highly correlated with FC, as well as long-term persistence (up to 450 days), while FC failed to detect these events.
Conclusion
Overall, we designed and validated 2 ddPCR assays allowing routine or preclinical monitoring of early- and long-term circulating approved or experimental CAR T cells, including our own IL-1RAP CAR T cells, which will be evaluated in an upcoming phase I clinical trial.
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