The Role of mTOR in B Cell Lymphoid Malignancies: Biologic and Therapeutic Aspects.

Non-Hodgkin lymphoma's (NHL) incidence is rising over time, and B cell lymphomas comprise the majority of lymphomas. The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue 1 (Akt)/mammalian target of the rapamycin (mTOR) signaling pathway plays a critical role in a variety of cellular processes, such as cell proliferation and survival. Its role in lymphomagenesis is confirmed in many different types of B cell lymphomas. This review is mainly focused on the PI3K/v-akt/mTOR pathway-related oncogenic mechanisms in B cell NHLs with an emphasis on common B cell lymphoma types [diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)]. Furthermore, it summarizes the literature regarding the clinical applications of the mTOR inhibitors temsirolimus and everolimus in B cell NHLs, which have been tested in a range of clinical trials enrolling patients with B cell malignancies, either as monotherapy or in combination with other agents or regimens.

Glioma Cells Expressing High Levels of ALDH5A1 Exhibit Enhanced Migration Transcriptional Signature in Patient Tumors.

Accumulating data shows that altered metabolic activity contributes to glioma development. Recently, modulation of SSADH (succinic semialdehyde dehydrogenase) expression, implicated in the catabolism of GABA neurotransmitter, was shown to impact glioma cell properties, such as proliferation, self-renewal and tumorigenicity. The purpose of this study was to investigate the clinical significance of SSADH expression in human gliomas. Using public single-cell RNA-sequencing data from glioma surgical resections, we initially grouped cancer cells according to ALDH5A1 (Aldehyde dehydrogenase 5 family member A1) expression, which encodes SSADH. Gene ontology enrichment analysis of genes differentially expressed between cancer cells expressing high or low levels of ALDH5A1, highlighted enrichment in genes implicated in cell morphogenesis and motility. In glioblastoma cell lines, ALDH5A1 knockdown inhibited cell proliferation, induced apoptosis and reduced their migratory potential. This was accompanied by a reduction in the mRNA levels of the adherens junction molecule ADAM-15 and deregulation in the expression of EMT biomarkers, with increased CDH1 and decreased vimentin mRNA levels. Evaluation of SSADH expression in a cohort of 95 gliomas using immunohistochemistry showed that SSADH expression was significantly elevated in cancer tissues compared to normal brain tissues, without any significant correlation with clinicopathological characteristics. In summary, our data show that SSADH is upregulated in glioma tissues irrespective of the histological grade and its expression sustains glioma cell motility.

Laying the groundwork for the Biobank of Rare Malignant Neoplasms at the service of the Hellenic Network of Precision Medicine on Cancer.

Biobanks constitute an integral part of precision medicine. They provide a repository of biospecimens that may be used to elucidate the pathophysiology, support diagnoses, and guide the treatment of diseases. The pilot biobank of rare malignant neoplasms has been established in the context of the Hellenic Network of Precision Medicine on Cancer and aims to enhance future clinical and/or research studies in Greece by collecting, processing, and storing rare malignant neoplasm samples with associated data. The biobank currently comprises 553 samples; 384 samples of hematopoietic and lymphoid tissue malignancies, 72 samples of pediatric brain tumors and 97 samples of malignant skin neoplasms. In this article, sample collections and their individual significance in clinical research are described in detail along with computational methods developed specifically for this project. A concise review of the Greek biobanking landscape is also delineated, in addition to recommended technologies, methodologies and protocols that were integrated during the creation of the biobank. This project is expected to re­enforce current clinical and research studies, introduce advances in clinical and genetic research and potentially aid in future targeted drug discovery. It is our belief that the future of medical research is entwined with accessible, effective, and ethical biobanking and that our project will facilitate research planning in the '­omic' era by contributing high­quality samples along with their associated data.

MTOR/4EBP1 signaling and MMR status in colorectal cancer: New correlations and arising perspectives.

This is the first study aiming to investigate mTOR signaling and its relation to mismatch repair status (MMR status) in colorectal cancer (CRC). MMR status and the phosphorylated proteins, pmTOR and p4EBP1, have been immunohistochemically analyzed in 108 formalin-fixed, paraffin-embedded CRC specimens. The correlations between them and with clinicopathological data, MAPK pathway (KRAS, NRAS, BRAF) as well as their impact on patients' overall survival have been statistically analyzed. Our results indicated that positive pmTOR expression was significantly associated with KRAS mutations (p = 0.004). From multivariate survival analysis, only p4EBP1 expression emerged as independent adverse prognostic factor for overall survival (HR, 3.322; 95%CI, 1.110-9.945; p = 0.032). Furthermore, MMR deficient carcinomas tend to express low p4EBP1 protein levels (p = 0.002). A survival analysis stratified by MMR status and p4EBP1 expression, showed that MMR proficient tumours with high p4EBP1 expression had the worst overall survival compared with the other examined subgroups (p = 0.019). In conclusion, MAPK and PI3k/Akt pathways seem to be simultaneously overactivated in CRC. P4EBP1 could be used as a prognostic biomarker. By further analyzing the significant association between MMR status and p4EBP1 expression, we suggest that MMR deficient tumours could represent a subpopulation most likely to derive treatment benefit from mTOR inhibition.

Dissecting the Role of Circular RNAs in Sarcomas with Emphasis on Osteosarcomas.

Circular RNAs (circRNAs) are single-stranded RNAs generated from exons back-splicing from a single pre-mRNA, forming covalently closed loop structures which lack 5'-3'-polarity or polyadenylated tail. Ongoing research depicts that circRNAs play a pivotal role in tumorigenesis, tumor progression, metastatic potential and chemoresistance by regulating transcription, microRNA (miRNA) sponging, RNA-binding protein interactions, alternative splicing and to a lesser degree, protein coding. Sarcomas are rare malignant tumors stemming from mesenchymal cells. Due to their clinically insidious onset, they often present at advanced stage and their treatment may require aggressive chemotherapeutic or surgical options. This review is mainly focused on the regulatory functions of circRNAs on osteosarcoma progression and their potential role as biomarkers, an area which has prompted lately extensive research. The attributed oncogenic role of circRNAs on other mesenchymal tumors such as Kaposi Sarcoma (KS), Rhabdomyosarcoma (RMS) or Gastrointestinal Stromal Tumors (GISTs) is also described. The involvement of circRNAs on sarcoma oncogenesis and relevant emerging diagnostic, prognostic and therapeutic applications are expected to gain more research interest in the future.

Timing and impact of a deep response in the outcome of patients with systemic light chain (AL) amyloidosis.

A rapid and deep haematologic response is fundamental in order to improve outcomes of patients with AL amyloidosis. We evaluated the impact of timing and depth of haematologic response at early time points (at 1 and 3 months from the start of therapy) in 227 consecutive previously untreated AL patients, who received bortezomib-based primary therapy. After 1 month of therapy, 30.5% had ≥VGPR, 28% PR and 36% no response (NR), with 11% having iFLC <20 mg/L and 15% dFLC <10 mg/L. Deep haematologic response at 1 month (either ≥VGPR or iFLC <20 mg/L or dFLC <10 mg/L), was associated with a high organ response rate. The survival of patients with ≥VGPR was significantly better than those with PR and NR at 1-month landmark (p < .001) but this benefit was mainly driven by those with iFLC <20 mg/L. The depth of haematologic response at 1 month was significant across all Mayo stages. At 3 months, 46% of the patients had not significantly improved the depth of their response but even patients that improved their response from an iFLC ≥20 mg/L at 1 month to iFLC <20 mg/L at 3 months still had inferior outcome to those with an early deep response. Thus, in patients with AL amyloidosis, a very rapid and deep response is crucial, especially for those at high risk, targeting very low FLC levels within the first month of therapy.

Association between PD-L1 expression and driver gene mutations in non-small cell lung cancer patients: correlation with clinical data.

Lung cancer is the leading cause of cancer death worldwide. Recently, promising therapies have emerged based on PD-1/PD-L1 immune checkpoint inhibitors, which have been approved even as frontline treatment for patients with non-small cell lung cancer (NSCLC). We examined the association between PD-L1 expression and clinicopathological parameters as well as overall survival in 220 NSCLC patients. PD-L1 expression was estimated by immunohistochemistry using 22C3 PharmDx Dako assay and was defined as high, if TPS was ≥ 50%, low, if TPS was 1%-49%, and absent, if TPS was < 1%. EGFR mutations were detected by COBAS while KRAS and BRAF mutations by pyrosequencing. ROS1 and ALK rearrangements were estimated by immunohistochemistry with positive cases being confirmed by CISH and FISH, respectively. Data analysis was performed using SPSS v25.0. PD-L1 expression was positively correlated with KRAS mutations. Anti-PD-1 therapy (pembrolizumab) prolonged overall survival compared to any other treatment. This effect was more pronounced in KRAS-mutated cases compared to KRAS wild-type ones. Patients with positive PD-L1 expression - high or low - who had been treated with pembrolizumab, showed significant survival benefit compared to positive or negative PD-L1 expressors who did not receive immunotherapy. In multivariate analysis, PD-L1 status, stage and pembrolizumab treatment were independent variables for overall survival. PD-L1 expression (TPS ≥ 1%) by itself emerged as a poor prognostic factor, while treatment with pembrolizumab prolonged overall survival. KRAS mutations may affect tumour microenvironment and patient's response to immunotherapy. Immune checkpoint inhibitors could represent an alternative therapeutic option particularly for KRAS-mutated NSCLC patients. Further investigation into this notion is warranted in order to validate this observation.