Search

Since the description of primary mediastinal large B-cell lymphoma (PMBL) as a distinct entity from diffuse large B-cell lymphomas (DLBCL), numerous studies have made it possible to improve their definition. Despite this, this differential diagnosis can be challenging in daily practice. However, in some centers, PMBL may be treated according to a particular regimen, distinct from those used in DLBCL, emphasizing the importance of accurate identification at diagnosis. This study aimed to describe the histological and molecular characteristics of PMBL to improve the accuracy of their diagnosis. Forty-nine cases of PMBL were retrospectively retrieved. The mean age at diagnosis was 39 years (21-83), with a sex ratio of 0.88. All cases presented a fibrous background with diffuse growth of intermediate to large cells with an eosinophil (26/49, 53%) or retracted cytoplasm (23/49, 47%). "Hodgkin-like" cells were observed in 65% of cases (32/49, 65%). The phenotype was: BCL6+ (47/49, 96%), MUM1+ (40/49, 82%), CD30+ (43/49, 88%), and CD23+ (37/49, 75%). Genomic DNAs were tested by next generation sequencing of 33 cases using a custom design panel. Pathogenic variants were found in all cases. The most frequent mutations were: SOCS1 (30/33, 91%), TNFAIP3 (18/33, 54.5%), ITPKB (17/33, 51.5%), GNA13 (16/33, 48.5%), CD58 (12/33, 36.4%), B2M (12/33; 36.4%), STAT6 (11/33, 33.3%) as well as ARID1A (10/33, 30.3%), XPO1 (9/33, 27.3%), CIITA (8/33, 24%), and NFKBIE (8/33, 24%). The present study describes a PMBL cohort on morphological, immunohistochemical, and molecular levels to provide pathologists with daily routine tools. These data also reinforce interest in an integrated histomolecular diagnosis to allow a precision diagnosis as early as possible.

The molecular profiling of circulating tumor DNA (ctDNA) is a helpful tool not only in cancer treatment, but also in the early detection of relapse. However, the clinical interpretation of a ctDNA negative result remains challenging. The characterization of circulating nucleosomes (carrying cell-free DNA) and associated epigenetic modifications (playing a key role in the tumorigenesis of different cancers) may provide useful information for patient management, by supporting the contributive value of ctDNA molecular profiling. Significantly elevated concentrations of H3K27Me3 nucleosomes were found in plasmas at the diagnosis, and during the follow-up, of NSCLC patients, compared to healthy donors ( p -value < 0.0001). By combining the H3K27Me3 level and the ctDNA molecular profile, we found that 25.5% of the patients had H3K27Me3 levels above the cut off, and no somatic alteration was detected at diagnosis. This strongly supports the presence of non-mutated ctDNA in the corresponding plasma. During the patient follow-up, a high H3K27Me3-nucleosome level was found in 15.1% of the sample, despite no somatic mutations being detected, allowing the identification of disease progression from 43.1% to 58.2% over molecular profiling alone. Measuring H3K27Me3-nucleosome levels in combination with ctDNA molecular profiling may improve confidence in the negative molecular result for cfDNA in lung cancer at diagnosis, and may also be a promising biomarker for molecular residual disease (MRD) monitoring, during and/or after treatment.

Pseudomyxoma peritonei (PMP) is ideally treated by cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), leading to significant morbidity. Beyond the histologic grade, the prognosis lies in the completeness of cytoreduction (CC-score of 0/1 vs. 2/3) and the severe complication rate. The mucinous nature of the peritoneal implants sometimes induces liver and/or spleen scalloping on imaging. The predictive value of scalloping was assessed regarding resectability, grade, survival and severe morbidity. This monocentric, retrospective analysis compared CC-0/1 with CC-2/3 groups regarding liver and spleen scalloping parameters, assessed on pre-operative computed tomography (CT) scan, reviewed for the study. In addition, prognostic factors of severe complications and recurrence-free and overall survivals were explored in the CC-0/1 population. Overall, 129 patients were included (109 CC-0/1, 20 CC-2/3), with 58 (45%) exhibiting scalloping. All patients with splenic scalloping also had a liver one. Scalloping was more frequent (75% vs. 39%), with greater median maximal depth (21 vs. 11 mm) and higher PCI (32 vs. 14) in the CC-2/3 population, but was not predictive of either grade or survival. In CC-0/1 patients, survivals and postoperative complications were not affected by scalloping parameters. Scalloping appeared as a marker of advanced PMP, but was not predictive of grade, severe complications, or long-term outcomes.

Patient-Derived Xenografts (PDXs) in the Chorioallantoic Membrane (CAM) are a representative model for studying human tumors. Circulating Tumor Cells (CTCs) are involved in cancer dissemination and treatment resistance mechanisms. To facilitate research and deep analysis of these few cells, significant efforts were made to expand them. We evaluated here whether the isolation of fresh CTCs from patients with metastatic cancers could provide a reliable tumor model after a CAM xenograft. We enrolled 35 patients, with breast, prostate, or lung metastatic cancers. We performed microfluidic-based CTC enrichment. After 48-72 h of culture, the CTCs were engrafted onto the CAM of embryonated chicken eggs at day 9 of embryonic development (EDD9). The tumors were resected 9 days after engraftment and histopathological, immunochemical, and genomic analyses were performed. We obtained in ovo tumors for 61% of the patients. Dedifferentiated small tumors with spindle-shaped cells were observed. The epithelial-to-mesenchymal transition of CTCs could explain this phenotype. Beyond the feasibility of NGS in this model, we have highlighted a genomic concordance between the in ovo tumor and the original patient's tumor for constitutional polymorphism and somatic alteration in one patient. Alu DNA sequences were detected in the chicken embryo's distant organs, supporting the idea of dedifferentiated cells with aggressive behavior. To our knowledge, we performed the first chicken CAM CTC-derived xenografts with NGS analysis and evidence of CTC dissemination in the chicken embryo.

Background: New predictive biomarkers are needed to accurately predict metastasis-free survival (MFS) and cancer-specific survival (CSS) in localized prostate cancer (PC). Keratin-7 (KRT7) overexpression has been associated with poor prognosis in several cancers and is described as a novel prostate progenitor marker in the mouse prostate., Methods: KRT7 expression was evaluated in prostatic cell lines and in human tissue by immunohistochemistry (IHC, on advanced PC, n = 91) and immunofluorescence (IF, on localized PC, n = 285). The KRT7 mean fluorescence intensity (MFI) was quantified in different compartments by digital analysis and correlated to clinical endpoints in the localized PC cohort., Results: KRT7 is expressed in prostatic cell lines and found in the basal and supra-basal compartment from healthy prostatic glands and benign peri-tumoral glands from localized PC. The KRT7 staining is lost in luminal cells from localized tumors and found as an aberrant sporadic staining (2.2%) in advanced PC. In the localized PC cohort, high KRT7 MFI above the 80th percentile in the basal compartment was significantly and independently correlated with MFS and CSS, and with hypertrophic basal cell phenotype., Conclusion: High KRT7 expression in benign glands is an independent biomarker of MFS and CSS, and its expression is lost in tumoral cells. These results require further validation on larger cohorts.

The development of the resistance to platinum salts is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Among the reasons underlying this resistance is the enrichment of cancer stem cells (CSCs) populations. Several studies have reported the involvement of calcium channels in chemoresistance. The Orai3 channel is overexpressed and constitutes a predictive marker of metastasis in NSCLC tumors. Here, we investigated its role in CSCs populations induced by Cisplatin (CDDP) in two NSCLC cell lines. We found that CDDP treatment increased Orai3 expression, but not Orai1 or STIM1 expression, as well as an enhancement of CSCs markers. Moreover, Orai3 silencing or the reduction of extracellular calcium concentration sensitized the cells to CDDP and led to a reduction in the expression of Nanog and SOX-2. Orai3 contributed to SOCE (Store-operated Calcium entry) in both CDDP-treated and CD133 + subpopulation cells that overexpress Nanog and SOX-2. Interestingly, the ectopic overexpression of Orai3, in the two NSCLC cell lines, lead to an increase of SOCE and expression of CSCs markers. Furthermore, CD133 + cells were unable to overexpress neither Nanog nor SOX-2 when incubated with PI3K inhibitor. Finally, Orai3 silencing reduced Akt phosphorylation. Our work reveals a link between Orai3, CSCs and resistance to CDDP in NSCLC cells.