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Purpose: MALT lymphoma is thought to have a genetic component. Genetic studies in the greek population are rare and genetic determinants remain to be established. The current study aimed to seek correlations between genetic polymorphisms and risk of MALT lymphoma in the Greek population. Patients and Methods: 83 MALT lymphoma patients and 60 age-matched healthy outpatients were recruited. SNPs in TNFa, LTA and CTLA-4 genes and IL1RN-VNTR and GSTT1 and GSTTM1 null polymorphisms were genotyped using published PCR/PCR-RFLP methods, while two novel PCR-RFLP methods were developed for IL-22 rs7314777 and TCF19 rs7750641 SNPs. Part of the results was validated by DNA-sequencing. Statistical analysis was performed using SPSS and the SNPstats bioinformatic tool. Results: The mean age of the patients and controls were 55.9 and 56.2 years respectively. The majority of patients (63) suffered gastric marzinal zone lymphoma (GMZL) and 71.1% were stage I at diagnosis. A statistically significant association was noted for the CTLA-4 49A/ G G variant (OR:2.56,p: 0.006) and the TCF19 rs7750641 SNP T variant (OR: 3.86, p:0.023). Conclusions: Our study confirmed a role for CTLA-4 49A/G and TCF19 rs7750641 SNPs in the Greek population. Additional studies could help confirm these associations and possibly link them to prognosis or response to treatment parameters. © 2021 Elsevier Masson SAS

Silencing of tumour-suppressor genes through promoter methylation is frequently observed in carcinogenesis. In this study, we determined the methylation status of RASSF1A, MGMT, APC, AXIN2 and DACT1 genes in 73 cases of non-small cell lung cancer. Methylation-sensitive high-resolution melting analysis (MS-HRM) was used to analyse the promoter methylation, which was further validated with Bisulfite pyrosequencing or Sanger sequencing. Promoter methylation of RASSF1A and APC was frequently found (56% and 49% of cases, respectively), while methylation of MGMT, AXIN2, DACT1 was observed in 30%, 19% and 16%, respectively. Concurrent gene methylation of at least two genes was observed in 55% of the examined cases, with a total of 89% of samples displaying methylation in one or more of the investigated genes. Further analysis of concurrent methylation revealed a positive correlation between AXIN2-DACT1 and an inverse correlation of APC-MGMT. Associations of methylated genes and clinicopathological features were emerged. In more detail, APC promoter methylation was correlated with smoking status (p= 0.020) and non-metastatic cases (p= 0.003). Moreover, MGMT methylation was preferentially found in TTF1-negative cases (p= 0.049). Interestingly, correlation occurred between AXIN2/DACT1 methylation and smoking status (p= 0.009) as well as tumour grade (p= 0.013), as none of these genes was methylated in the majority of smokers and one of the genes was methylated in high-grade tumours. We conclude that aberrant promoter methylation was observed in our cohort while concurrent methylation patterns were also determined. APC, MGMT and AXIN2/DACT1 methylation are potentially of clinical importance regarding prognosis and histological subtyping of NSCLC. © 2022 Elsevier GmbH

Primary mediastinal large B- cell lymphoma (PMLBCL) is a mature aggressive B-cell lymphoma which affects mainly young and middle-aged women. The majority of patients present with bulky mediastinal lymphadenopathy. Extranodal involvement is a rare phenomenon at disease presentation. Herein, we describe a case of a young female with PMLBCL presenting with symptomatic, bulky ovarian involvement. The 23-year old patient presented at the Emergency Department with abdominal pain. The chest X-ray film revealed a mediastinal mass and CT scan revealed a large pelvic mass, possibly involving the ovaries. Due to the development of signs of acute abdomen, she was urgently transferred to the operation room where surgical resection of the right ovary and the adjacent mass was performed. The histological examination of the resected material revealed proliferation of PMLBCL cells. This is the first report in the scientific literature describing symptomatic ovarian mass as the initial mode of presentation of PMLBCL. © 2022 The Authors

Craniosynostosis is the premature fusion of skull sutures and has a severe pathological impact on childrens’ life. Mechanical forces are capable of triggering biological responses in bone cells and regulate osteoblastogenesis in cranial sutures, leading to premature closure. The mechanosensitive proteins polycystin-1 (PC1) and polycystin-2 (PC2) have been documented to play an important role in craniofacial proliferation and development. Herein, we investigated the contribution of PC1 to the pathogenesis of non-syndromic craniosynostosis and the associated molecular mechanisms. Protein expression of PC1 and PC2 was detected in bone fragments derived from craniosynostosis patients via immunohistochemistry. To explore the modulatory role of PC1 in primary cranial suture cells, we further abrogated the function of PC1 extracellular mechanosensing domain using a specific anti-PC1 IgPKD1 antibody. Effect of IgPKD1 treatment was evaluated with cell proliferation and migration assays. Activation of PI3K/AKT/mTOR pathway components was further detected via Western blot in primary cranial suture cells following IgPKD1 treatment. PC1 and PC2 are expressed in human tissues of craniosynostosis. PC1 functional inhibition resulted in elevated proliferation and migration of primary cranial suture cells. PC1 inhibition also induced activation of AKT, exhibiting elevated phospho (p)-AKT (Ser473) levels, but not 4EBP1 or p70S6K activation. Our findings indicate that PC1 may act as a mechanosensing molecule in cranial sutures by modulating osteoblastic cell proliferation and migration through the PC1/AKT/mTORC2 cascade with a potential impact on the development of non-syndromic craniosynostosis. © 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Uveal melanomas (UMs) comprise the most common primary intraocular malignancies in adults, with the eye representing the second most common site for melanoma, following the skin. Prognosis remains poor, with approximately half of the cases presenting with metastatic disease at the time of diagnosis. Erythropoietin-producing human hepatocellular receptors (EPHs) comprise the largest known family of tyrosine receptors, in which, along with their ligands, ephrins, play an important role in a plethora of processes in human physiology, and are implicated in key steps of carcinogenesis. In the present study, EPHA2, EPHA4, and EPHA6 immunohistochemical expressions were investigated in UM tissues and further correlated to a multitude of clinicopathological parameters, including disease stage and patients’ overall survival (OS). High levels of EPHA2 expression were significantly associated with increased tumor vertical thickness (p = 0.03) and the presence of intrascleral involvement (p = 0.05), whereas high EPHA6 nuclear expression was associated with older age at diagnosis (p = 0.03) and absence of retinal detachment (p = 0.05). In a multivariate survival analysis, increased EPHA4 expression was associated with shortened OS along with the presence of metastasis (p < 0.001) and monosomy 3 (p = 0.02). In a separate model, the concurrent overexpression of at least two of the investigated EPHs (HR = 14.7, p = 0.03) also proved to be an independent poor prognostic factor. In conclusion, our results implicate these specific members of the EPHA group as potential biomarkers for disease prognosis as well as possible targets for the development of novel therapeutic interventions. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Case: We present a case of a 35-year-old-man with a giant sclerosing epithelioid fibrosarcoma (SEF) of the thigh. The patient presented with a history of a painful thigh mass. Plain radiographs revealed a soft-tissue mass with extensive calcifications, whereas on magnetic resonance imaging, a lobulated mass between the adductors and the posterior muscles of the thigh was noted. A wide en block resection was undertaken, and the histopathology confirmed the diagnosis of SEF. Postoperative radiation therapy was followed. The patient had no signs of recurrence at the 4-year follow-up. Conclusion: The clinicopathological, imaging characteristics, and treatment options of this rare soft-tissue tumor are discussed. COPYRIGHT © 2021 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED.

Cardiac tumors range from benign to high grade malignancies. The incidence of cardiac involvement either by primary, or secondary tumors during autopsy is reported to be extremely low. Extranodal NK/T-cell lymphoma (ENKTL), nasal type is an unusual type of lymphoma. The skin is the second most common site of involvement after the respiratory tract. We present a case of a 63-year-old male, who was recently diagnosed with ENKTL, nasal type, who received chemotherapy, and died without any evident cause. The corpse was referred for routine medicolegal examination. Macroscopical determination of the cause of death was not feasible and subsequent histopathological examination revealed heart infiltration by ENKTL that was found in vivo in cutaneous lesions. Similar infiltrations existed in the pancreatic tissue. To the best of our knowledge, myocardial infiltration of ENKTL, inducing severe myocardial lesions that eventually caused death, is rare, with limited cases reported in the literature. © 2021.

Glioblastoma (GBM) is the most common primary brain tumor in adults, and the most lethal form of glioma, characterized by variable histopathology, aggressiveness and poor clinical outcome and prognosis. GBMs constitute a challenge for oncologists because of their molecular heterogeneity, extensive invasion, and tendency to relapse. Glioma cells demonstrate a variety of deregulated genomic pathways and extensive interplay with epigenetic alterations. Epigenetic modifications have emerged as essential players in GBM research, with biomarker potential for tumor classification and prognosis and for drug targeting. Histone posttranslational modifications (PTMs) are crucial regulators of chromatin architecture and gene expression, playing a pivotal role in malignant transformation, tumor development and progression. Alteration in the expression of genes coding for lysine and arginine methyltransferases (G9a, SUV39H1 and SETDB1) and acetyltransferases and deacetylases (KAT6A, SIRT2, SIRT7, HDAC4, 6, 9) contribute to GBM pathogenesis. In addition, proteins of the sumoylation pathway are upregulated in GBM cell lines, including E1 (SAE1), E2 (Ubc9) components, and a SUMO-specific protease (SENP1). Preclinical and clinical studies are currently in progress targeting epigenetic enzymes in gliomas, including a new generation of histone deacetylase (HDAC), protein arginine methyltransferase (PRMT) and bromodomain (BRD) inhibitors. Herein, we provide an update on recent advances in glioma epigenetic research, focusing on the role of histone modifications and the use of epigenetic therapy as a valid treatment option for glioblastoma. © 2020 Elsevier Inc.

Alterations in global histone methylation regulate gene expression and participate in cancer onset and progression. The profile of histone methylation marks in pediatric astrocytomas is currently understudied with limited data on their distribution among grades. The global expression patterns of repressive histone marks H3K9me3, H3K27me3, and H4K20me3 and active H3K4me3 and H3K36me3 along with their writers SUV39H1, SETDB1, EZH2, MLL2, and SETD2 were investigated in 46 pediatric astrocytomas and normal brain tissues. Associations between histone marks and modifying enzymes with clinicopathological characteristics and disease-specific survival were studied along with their functional impact in proliferation and migration of pediatric astrocytoma cell lines using selective inhibitors in vitro. Upregulation of histone methyltransferase gene expression and deregulation of histone code were detected in astrocytomas compared to normal brain tissues, with higher levels of SUV39H1, SETDB1, and SETD2 as well as H4K20me3 and H3K4me3 histone marks. Pilocytic astrocytomas exhibited lower MLL2 levels compared to diffusely infiltrating tumors indicating a differential pattern of epigenetic regulator expression between the two types of astrocytic neoplasms. Moreover, higher H3K9me3, H3K36me3, and SETDB1 expression was detected in grade IIΙ/IV compared to grade II astrocytomas. In univariate analysis, elevated H3K9me3 and MLL2 and diminished SUV39H1 expression adversely affected survival. Upon multivariate survival analysis, only SUV39H1 expression was revealed as an independent prognostic factor of adverse significance. Treatment of pediatric astrocytoma cell lines with SUV39H1 inhibitor reduced proliferation and cell migration. Our data implicate H3K9me3 and SUV39H1 in the pathobiology of pediatric astrocytomas, with SUV39H1 yielding prognostic information independent of other clinicopathologic variables. © 2021, The American Society for Experimental NeuroTherapeutics, Inc.