Identification of Metabolomic Markers in Frozen or Formalin-Fixed and Paraffin-Embedded Samples of Diffuse Glioma from Adults.

The aim of this study was to identify metabolomic signatures associated with the gliomagenesis pathway (IDH-mutant or IDH-wt) and tumor grade of diffuse gliomas (DGs) according to the 2021 WHO classification on frozen samples and to evaluate the diagnostic performances of these signatures in tumor samples that are formalin-fixed and paraffin-embedded (FFPE). An untargeted metabolomic study was performed using liquid chromatography/mass spectrometry on a cohort of 213 DG samples. Logistic regression with LASSO penalization was used on the frozen samples to build classification models in order to identify IDH-mutant vs. IDH-wildtype DG and high-grade vs low-grade DG samples. 2-Hydroxyglutarate (2HG) was a metabolite of interest to predict IDH mutational status and aminoadipic acid (AAA) and guanidinoacetic acid (GAA) were significantly associated with grade. The diagnostic performances of the models were 82.6% AUC, 70.6% sensitivity and 80.4% specificity for 2HG to predict IDH status and 84.7% AUC, 78.1% sensitivity and 73.4% specificity for AAA and GAA to predict grade from FFPE samples. Thus, this study showed that AAA and GAA are two novel metabolites of interest in DG and that metabolomic data can be useful in the classification of DG, both in frozen and FFPE samples.

Immunosuppressive Tumor Microenvironment Status and Histological Grading of Endometrial Carcinoma.

The recent successes of new cancer immunotherapy approaches have led to investigate their relevance in the context of the Endometrial Carcinoma (EC). These therapies, that take the tumor-induced immunosuppressive microenvironment into account, target the tumor immune escape, in particular the inhibitory receptors involved in the regulation of the effector T cells' activity (immune checkpoints). The aim of this study was to identify, in ECs, differences in intergrades immune status that could contribute to the differences in tumor aggressiveness, and could also be used as theranostic tools. The immune status of tumors was assessed by quantitative real-time PCR. We analyzed the expression of specific genes associated to specific leukocytes subpopulations and the expression of reporting genes associated with the tumor escape/resistance. This study highlights significant differences in the EC intergrades immune status especially the tumor-infiltrating cell types and their activation status as well as in the molecular factors produced by the environment. The immune microenvironment of grade 1 ECs hints at a robust tumoricidal milieu while that of higher grades is more evocative of a tolerogenic milieu. This genes-based immunological monitoring of tumors that easily highlights significant intergrade differences relating to the density, composition and functional state of the leukocyte infiltrate, could give solid arguments for choosing the best therapeutic options, especially those targeting immune checkpoints. Moreover it could enable an easy adaptation of individual treatment approaches for each patient.

Using 22C3 Anti-PD-L1 Antibody Concentrate on Biopsy and Cytology Samples from Non-small Cell Lung Cancer Patients.

Pembrolizumab monotherapy has been approved for the first- and second-line treatment of patients with PD-L1-expressing advanced non-small cell lung cancer (NSCLC). Testing for PD-L1 expression with the PD-L1 immunohistochemistry (IHC) 22C3 companion diagnostic assay, which gives a tumor proportion score (TPS), has been validated on tumor tissue. We developed an optimized laboratory-developed test (LDT) that uses the 22C3 antibody (Ab) concentrate on a widely available IHC autostainer for biopsy and cytology specimens. The PD-L1 TPS was evaluated with 120 paired whole-tumor tissue sections and biopsy samples and with 70 paired biopsy and cytology samples (bronchial washes, n = 40; pleural effusions, n = 30). The 22C3 Ab concentrate-based LDT showed a high concordance rate between biopsy (~100%) and cytology (~95%) specimens when compared to PD-L1 IHC expression determined using the PD-L1 IHC 22C3 companion assay at both TPS cut points (≥1%, ≥50%). The optimized LDT presented here, using the 22C3 Ab concentrate to determine the PD-L1 expression in both tumor tissue and in cytology specimens, will expand the ability of laboratories worldwide to assess the eligibility of patients with NSCLC for treatment with pembrolizumab monotherapy in a reliable and reproducible manner.

Comprehensive study of three novel cases of TFEB-amplified renal cell carcinoma and review of the literature: Evidence for a specific entity with poor outcome.

The first case of TFEB-amplified renal cell carcinoma was published in 2014. Since then, 29 additional cases have been described. The prognostic and therapeutic implications of this rare entity remain to be determined. We describe here the clinical, histological, and genetic features of three novel cases, and the first complete literature review. Four tumors were examined from three patients selected from the large collection of genetically characterized renal tumors in our institution. The pathological and immunohistochemical features were centrally reviewed by a uropathologist. Quantitative and structural genomic abnormalities were analyzed using comparative genomic hybridization, fluorescence in situ hybridization, and next generation sequencing. The three cases showed high-level amplification but no translocation of TFEB. Histologically, two tumors showed a papillary or pseudopapillary architecture. They did not show similarities with renal cell carcinoma harboring translocation of TFEB. The tumors were locally advanced high-grade lesions. They exhibited a metastatic course, which was rapidly leading to death in one patient. A second patient developed metastatic disease that did not respond to four lines of targeted treatments. The third patient had a protracted history of pulmonary and cardiac metastases. Complete clinical and biological data were examined and compared to those of the reported cases. Within the classification of renal tumors, TFEB-amplified renal cell carcinoma may constitute a novel entity characterized histologically by high-grade, papillary or pseudopapillary architecture, and necrotic remodeling and clinically by a poor outcome. Its pathogenesis has to be further characterized to develop appropriate targeted therapy.