Various programed death ligand 1 (PD-L1) immunohistochemistry (IHC) assays have been developed and used in clinical trials in association with different drugs. In order to harmonize and make PD-L1 ...testing in non-small-cell lung cancer (NSCLC) widely available, we conducted a multicenter study comparing PD-L1 standardized assays and laboratory-developed tests (LDTs).
IHC with five anti-PD-L1 monoclonal antibodies (28-8, 22C3, E1L3N, SP142 and SP263) was performed concomitantly on 41 NSCLC surgical specimens in 7 centers using Dako Autostainer Link 48 (3 centers), Leica Bond (2 centers) or Ventana BenchMark Ultra (2 centers) platforms. For each matching platform, 22C3, 28-8 and SP263 assays were performed. For nonmatching platforms and other antibodies, LDTs were developed in each center. A total of 35 stainings were performed for each case across different platforms and antibodies. PD-L1 staining was assessed in tumor cells and immune cells by seven trained thoracic pathologists. For statistical analysis, 1%, 50% and 1%, 5%, 10% expression thresholds were used for tumor cells and immune cells, respectively.
28-8, 22C3 and SP263 assays were highly concordant for tumor cells staining across the five Dako or Ventana platforms. Among 27 LDTs developed in 7 centers on Dako, Ventana and Leica platforms, 14 (51.8%) demonstrated similar concordance when compared with reference assays for tumor cell staining. Clone SP263 achieved the highest concordance rate across all platforms. Lower concordance was observed for immune cells staining when using a four categories scale.
28-8, 22C3 and SP263 assays had close analytical performance for tumor cell staining across seven centers. Some LDTs on Dako, Ventana and Leica platforms achieved similar concordance, but caution is warranted for their validation. These LDTs will be further validated in order to provide recommendations for the use of assays and LDT for PD-L1 testing in NSCLC.
•ICI-induced HP remains controversial because of a lack of consensual definition.•HP definitions are very heterogeneous in terms of incidence rate and clinical impact.•Agreement between HP ...definitions is heterogenous and globally poor.•The presence of liver metastasis is associated with HP.
The advent of immune checkpoint inhibitors (ICI) has been a breakthrough in the care of patients with non-small-cell lung cancers (NSCLC). However, physicians are now facing a previously unidentified clinical situation called hyperprogression (HP), which presents as a fast and unexpected increase in tumor burden. HP’s existence and specificity to ICIs remains controversial because a widely acknowledged definition is currently lacking. Meanwhile, management remains elusive.
Medical records from all consecutive NSCLC patients who were treated with ICI from 2015 to 2018 were retrospectively analyzed. The HP incidence rate was calculated according to five definitions (tumor growth rate TGRratio, ΔTGR, tumor growth kinetic TGK, RECIST, and time to treatment failure TTF), and the agreement between such definitions was determined. The HP impact on overall survival (OS) was then assessed. The association between HP (defined using the TGRratio definition) and clinical and biological variables was also assessed. Clinical HP management and its impact on outcomes were described.
We identified 169 consecutive ICI-treated patients, with potential HP accounting for 11.3 %, 5.7 %, 17.0 %, 9.6 %, and 31.7 % patients, according to TGRratio, ΔTGR, TGK, RECIST, and TTF definitions. Agreement between the different HP definitions was highly heterogeneous (range 29 %–77 %) and globally poor. HP was associated with shorter OS, compared to standard RECIST progressive disease, but this difference only reached statistical significance when using the TTF definition. TGRratio-based HP was significantly associated with hepatic metastases. In TGRratio-based HP patients, neither resuming chemotherapy nor corticosteroids use was associated with statistically significant impact on overall survival.
We found fairly heterogeneous HP rates using different definitions. TTF was the only definition leading to significantly worsened OS. Further studies are needed to provide consensus recommendations for the assessment, definition, and management of HP, whose existence is likely real.
Results from a prototype TES detector for the Ricochet experiment Augier, C.; Baulieu, G.; Belov, V. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
12/2023, Letnik:
1057
Journal Article
Recenzirano
Odprti dostop
Coherent elastic neutrino-nucleus scattering (CEνNS) offers valuable sensitivity to physics beyond the Standard Model. The Ricochet experiment will use cryogenic solid-state detectors to perform a ...precision measurement of the CEνNS spectrum induced by the high neutrino flux from the Institut Laue-Langevin nuclear reactor. The experiment will employ an array of detectors, each with a mass of ∼30 g and a targeted energy threshold of 50 eV. Nine of these detectors (the “Q-Array”) will be based on a novel Transition-Edge Sensor (TES) readout style, in which the TES devices are thermally coupled to the absorber using a gold wire bond. We present initial characterization of a Q-Array-style detector using a 1 gram silicon absorber, obtaining a baseline root-mean-square resolution of less than 40 eV.
Malignant pleural mesothelioma (MPM) is a very aggressive tumor with no known curative treatment. Better knowledge of the molecular mechanisms of mesothelial carcinogenesis is required to develop new ...therapeutic strategies. MPM, like all cancer cells, needs to maintain telomere length to prevent senescence. Previous studies suggested that the telomere lengthening mechanism in MPM is based mainly on telomerase activity. For this reason, we focused on the key catalytic enzyme, TERT (telomerase reverse transcriptase), by analyzing its gene expression in MPM and by studying the mechanism underlying its upregulation. We used our large collection of MPM composed of 61 MPM in culture and 71 frozen MPM tumor samples. Evaluation of TERT mRNA expression by quantitative RT-PCR showed overexpression in MPM in culture compared with normal mesothelial cells, and in MPM tumor samples compared with normal pleura. We identified a 'hot spot' of mutations in the TERT gene core promoter in both MPM in culture and in MPM tumor samples with an overall frequency of 15%. Furthermore, data clearly identified mutation in the TERT promoter as a mechanism of TERT mRNA upregulation in MPM. In contrast, gene copy number amplification was not associated with TERT overexpression. Then, we analyzed the clinicopathological, etiological and genetic characteristics of MPM with mutations in the TERT promoter. TERT promoter mutations were more frequent in MPM with sarcomatoid histologic subtype (P<0.01), and they were frequently associated with CDKN2A gene inactivation (P=0.03). In conclusion, a subgroup of MPM presents TERT promoter mutations, which lead to TERT mRNA upregulation. This is the first recurrent gain-of-function oncogenic mutations identified in MPM.
High Impedance TES Bolometers for EDELWEISS Marnieros, S.; Armengaud, E.; Arnaud, Q. ...
Journal of low temperature physics,
06/2023, Letnik:
211, Številka:
5-6
Journal Article
Recenzirano
The EDELWEISS collaboration aims for direct detection of light dark matter using germanium cryogenic detectors with low threshold phonon sensor technologies and efficient charge readout designs. We ...describe here the development of Ge bolometers equipped with high impedance thermistors based on a Nb
x
Si
1−x
TES alloy. High aspect ratio spiral designs allow the TES impedance to match with JFET or HEMT front-end amplifiers. We detail the behavior of the superconducting transition properties of these sensors and the detector optimization in terms of sensitivity to a-thermal phonons. We report preliminary results of a 200 g Ge detector that was calibrated using
71
Ge activation by neutrons at the LSM underground laboratory.
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