The Role of Non-Coding RNAs in Epigenetic Dysregulation in Glioblastoma Development.

Glioblastoma (GBM) is a primary brain tumor arising from glial cells. The tumor is highly aggressive, the reason for which it has become the deadliest brain tumor type with the poorest prognosis. Like other cancers, it compromises molecular alteration on genetic and epigenetic levels. Epigenetics refers to changes in gene expression or cellular phenotype without the occurrence of any genetic mutations or DNA sequence alterations in the driver tumor-related genes. These epigenetic changes are reversible, making them convenient targets in cancer therapy. Therefore, we aim to review critical epigenetic dysregulation processes in glioblastoma. We will highlight the significant affected tumor-related pathways and their outcomes, such as regulation of cell cycle progression, cell growth, apoptosis, angiogenesis, cell invasiveness, immune evasion, or acquirement of drug resistance. Examples of molecular changes induced by epigenetic modifications, such as DNA epigenetic alterations, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) regulation, are highlighted. As understanding the role of epigenetic regulators and underlying molecular mechanisms in the overall pro-tumorigenic landscape of glioblastoma is essential, this literature study will provide valuable insights for establishing the prognostic or diagnostic value of various non-coding transcripts, including miRNAs.

The Glioblastoma CircularRNAome.

Glioblastoma remains one of the most aggressive cancers of the brain, warranting new methods for early diagnosis and more efficient treatment options. Circular RNAs (circRNAs) are rather new entities with increased stability compared to their linear counterparts that interact with proteins and act as microRNA sponges, among other functions. Herein, we provide a critical overview of the recently described glioblastoma-related circRNAs in the literature, focusing on their roles on glioblastoma cancer cell proliferation, survival, migration, invasion and metastasis, metabolic reprogramming, and therapeutic resistance. The main roles of circRNAs in regulating cancer processes are due to their regulatory roles in essential oncogenic pathways, including MAPK, PI3K/AKT/mTOR, and Wnt, which are influenced by various circRNAs. The present work pictures the wide implication of circRNAs in glioblastoma, thus highlighting their potential as future biomarkers and therapeutic targets/agents.

Abberant Immunohistochemical Expression of OCT3/4 and EMT Related Markers, Vimentin and E-cadherin, is Correlated with Adverse Histopathological Features in Colorectal Adenocarcinoma.

Background: Although clinical management for colorectal cancer has been markedly improved, it is faced with a growing incidence among the young and among those in developing nations. Furthermore, diagnosis occurs mostly in advanced stages, when the therapeutic resources are limited. Therefore we need new biomarkers for diagnostics and therapeutic targets. The key event that leads to invasion and metastasis is the epithelial to mesenchymal transition (EMT), which can be studied with IHC markers. We aimed to corelate the expression of EMT related markers (Vimentin and E-cadherin) and a stem cell marker (OCT 3/4) with the clinicopathological parameters of the tumors. Material and Methods: Surgical resection specimens from 30 treatment-naive colon cancer patients, hospitalized from 2018 to 2021 were assessed. Immunohistochemical tests were performed to investigate the expression of EMT related markers and OCT 3/4 in tumor cells. Results: Vimentin, OCT3/4 positivity and loss of E-cadherin were significantly associated with tumor grade, tumor budding, invasive tumor front, and lymph node metastasis. Conclusions: Vimentin, E-cadherin and OCT 3/4 might serve as a panel of biomarkers that can aid in the prognostication of patients, with the added potential of being oncotargets.

PD-L1 Expression in Esophageal and Gastroesophageal Junction Carcinoma, Correlation with the Immune Infiltrate - Preliminary Study.

Background: Although traditional management for esophageal and esogastric cancer has been improved, survival at 5 years is still low, and immunotherapy could be a way to improve it. In addition to the predictive value of the response to immunotherapy, PD-L1 also has a known prognostic value. We aimed to evaluate the immunohistochemical expression of PD-L1, CD8+ T-cell, and CD4/CD25+ T-cell (Tregs) infiltration and their relationship in esophageal and gastroesophageal junction carcinoma. Material and Methods: Endoscopic biopsies were analyzed in 14 patients with esophageal cancer or esogastric junction, before starting the neoadjuvant treatment, hospitalized from the period 2019- to 2021 in the St. Mary's Clinical Hospital, Bucharest. Immunohistochemical tests were performed to investigate the expression of lymphocyte intratumoral infiltrate markers. Results: Of the 14 cases, 13 (93%) were male, and 1 (7%) were female. Histological, 4 cases were adenocarcinomas, and 10 cases were squamous cell carcinomas. 10 cases showed epithelial PD-L1 positivity (78%). Using a quantitative evaluation of PD-L1 we obtained a statistical correlation between the median values of this marker with the expression of CD8. There was obtained a statistical correlation between PD-L1 positivity and low expression of CD4 or CD4+/CD25 T cells. Conclusions: PD-L1 is expressed in tumors with higher CD8+ T cell densities and lower CD4/CD25 positive cells (Tregs), indicating that the good prognosis of PD-L1-positive tumors could be due to the inhibition of CD4 / CD25-positive cells (Tregs) rather than the stimulation of CD8-positive T cells, by an adaptive immune resistance mechanism.

Peculiar encounter of sarcoidosis and solid pseudopapillary tumor of the pancreas.

Objective: Current literature indicates a connection between sarcoidosis and malignancy, prompting advanced screening in uncertain cases. Solid pseudopapillary tumors (SPT) of the pancreas are rare entities that can be confirmed by adding imaging results to immunohistochemistry staining. The aim of this article is to describe a rare association of sarcoidosis and SPT.Materials and methods: Case report.Results: A young female patient with no prior medical history presents with shortness of breath and fatigue. The diagnosis of pulmonary and hepatic sarcoidosis is placed upon laboratory and radiographic changes. Intermittent abdominal pain prompts an MRI that shows the presence of a tumoral mass in the tail of the pancreas. Surgical resection of the mass is performed and histological examination indicates a SPT, subsequently confirmed by immunohistochemistry.Conclusion: This is the third reported case of concomitant sarcoidosis and solid pseudopapillary tumor of the pancreas.

Epithelial-Mesenchymal Transition Gene Signature Related to Prognostic in Colon Adenocarcinoma.

Colon adenocarcinoma (COAD) remains an important cause of cancer-related mortality worldwide. Epithelial-mesenchymal transition (EMT) is a key mechanism, promoting not only the invasive or metastatic phenotype but also resistance to therapy. Using bioinformatics approaches, we studied the alteration on EMT related genes and its implication on COAD prognostic based on public datasets. For the EMT mechanisms, two overexpressed genes were identified (NOX4 and IGF2BP3), as well as five downregulated genes (BMP5, DACT3, EEF1A2, GCNT2 and SFRP1) that were related to prognosis in COAD. A qRT-PCR validation step was conducted in a COAD patient cohort comprising of 29 tumor tissues and 29 normal adjacent tissues, endorsing the expression level for BMP5, as well as for two of the miRNAs targeting key EMT related genes, revealing upregulation of miR-27a-5p and miR-146a-5p. The EMT signature can be used to develop a panel of biomarkers for recurrence prediction in COAD patients, which may contribute to the improvement of risk stratification for the patients.

A clinical case of recurrent episcleritis as the initial manifestation of granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) is a type of small-sized blood vessel vasculitis that predominantly affects the upper airways, lungs and kidneys and associates with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Nevertheless, any organ of the body can be affected by GPA, including the eye. Occasionally, ocular involvement can be the initial manifestation, thus representing an essential clue for the physician in the early diagnosis of the disease. We present the case of a 53-year-old woman in whom recurrent episcleritis was the first sign of a multisystem disease. All further investigations led to the final diagnosis of GPA. The remission induction therapy chosen by the rheumatologist consisted of intravenous cyclophosphamide (CP) and methylprednisolone pulse-therapy, followed by oral glucocorticoids (GC). Based on the favorable clinical and paraclinical evolution, induction therapy was replaced by remission maintenance therapy. Azathioprine (AZA) was initiated and oral GC were continued, with dose tapering. Complete remission of episcleritis was observed. Abbreviations: GPA = granulomatosis with polyangiitis, EGPA = eosinophilic granulomatosis with polyangiitis, MPA = Microscopic polyangiitis, ANCA = Anti-neutrophil cytoplasmic antibodies, c-ANCA = ANCA to proteinase-3, p-ANCA = ANCA to myeloperoxidase, ELISAs = antigen-specific enzyme-linked immunosorbent assays, ENT = ear, nose, throat, CP = cyclophosphamide, NSAIDs = nonsteroidal anti-inflammatory drugs, AZA = azathioprine, GC = glucocorticoids.

A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer.

The mitogen-activated protein kinase (MAPK) pathway is an important bridge in the switch from extracellular signals to intracellular responses. Alterations of signaling cascades are found in various diseases, including cancer, as a result of genetic and epigenetic changes. Numerous studies focused on both the homeostatic and the pathologic conduct of MAPK signaling; however, there is still much to be deciphered in terms of regulation and action models in both preclinical and clinical research. MAPK has implications in the response to cancer therapy, particularly the activation of the compensatory pathways in response to experimental MAPK inhibition. The present paper discusses new insights into MAPK as a complex cell signaling pathway with roles in the sustenance of cellular normal conduit, response to cancer therapy, and activation of compensatory pathways. Unfortunately, most MAPK inhibitors trigger resistance due to the activation of compensatory feed-back loops in tumor cells and tumor microenvironment components. Therefore, novel combinatorial therapies have to be implemented for cancer management in order to restrict the possibility of alternative pathway activation, as a perspective for developing novel therapies based on integration in translational studies.

The prognostic role of Skp2 and the tumor suppressor protein p27 in colorectal cancer.

PURPOSE: This study aimed at exploring the role of Skp2, p27 and Cks1 expression as prognostic factors for colorectal cancer (CRC) patients, and to identify a correlation between their expression and the cell proliferation marker Ki67. METHODS: We conducted a retrospective study on 130 patients with CRC treated with surgery and adjuvant treatment at the Oncology Institute Cluj-Napoca between 2006- 2010. The Skp2, p27, Cks1 and Ki67 immunoexpression was grouped from 1 to 4, according to percents of tumor cells with nuclear reactivity. Their correlation with overall survival (OS), recurrence free survival (RFS) and with the classical histopathological prognostic factors were analyzed. All patients had 5-year follow-up. RESULTS: The majority of patients had locally advanced TNM stages II and III. More than a half of the tumors had low immunoexpression of Skp2 and Cks1, and high and moderate p27 and Ki67 expression. Skp2 overexpression negatively influenced the p27 (p=0.002). Both OS and RFS were significantly higher in patients with moderate and high expression of p27 (p=0.005). Skp2 and Cks1 overexpression negatively influenced OS and RFS. Skp2 overexpression positively correlated with TNM stage (p<0.001), node capsular invasion (p=0.002) and lymphovascular invasion (p=0.042). Ki67 expression did not correlate with Skp2 (p=0.88), Cks1 (p=0.67) and p27 (p=0.40), neither with OS (p=0.841) and RFS (p=0.84). CONCLUSIONS: The most important prognostic factor was the Skp2 overexpression. It was the only protein we studied that correlated with the other well-known prognostic factors in CRC. The expression of Ki67 did not bring any novel prognostic information regarding CRC.

The importance of a multidisciplinary team in rectal cancer management.

INTRODUCTION: The aim of this study was to evaluate the impact of the interval between surgery and adjuvant treatments regarding the overall survival and recurrence-free survival in patients from a developing country. For stages II and III rectal cancer, international guidelines recommend neoadjuvant chemoradiotherapy (CRT) regardless of the tumor location. In the developing countries there is a shortage of radiotherapy centers, specialists, which lead to long waiting lists for radiotherapy. These problems might lead to protocol deviations. METHODS: We conducted a retrospective study on 161 patients with rectal cancer treated with surgery, postoperative CRT and with or without chemotherapy for a total of 6 months, at The Oncology Institute Cluj-Napoca between 2006-2010. All patients had 5 years of follow-up. RESULTS: A total of 161 patients were enrolled in this study. The majority of patients were locally advanced stages (89.44%). The well known prognostic factors, such as TNM stage, performance status, CEA serum level, perineural, vascular and lymphatic invasion, and node capsular effraction had a statistically significant influence on overall survival. In 21.12% of patients the first adjuvant treatment was started in the first 4 weeks after surgery. Only 13.04% of patients started the concomitant CRT within the limit of 6 weeks after surgery. Concerning the time between surgery and CRT, we did not observe a statistically significantly difference in OS if the radiotherapy started after the first 6 weeks (p=0.701). The OS rate for locally advanced rectal cancer patients was 69.44%. CONCLUSIONS: In rectal cancer, the importance of the first therapeutic act is crucial. Following international guidelines provides a survival advantage and a better quality of life. In case of adjuvant treatment, it is recommended to start this treatment as soon as the local infrastructure allows it.