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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.

To obtain insight into the ontogeny of mantle cell lymphoma (MCL), we assessed 206 patients from a morphological, immunohistochemical, and immunogenetic perspective. Our series included nodal ( n = 151), extranodal ( n = 28), and primary splenic ( n = 27) MCL cases. Skewing of the immunoglobulin heavy variable (IGHV) gene repertoire was noted, with only four IGHV genes accounting for 46% of cases and approximately 70% of cases (107/154) bearing an imprint of somatic hypermutation (SHM) ranging from minimal to pronounced. Interestingly, a distinctive immunophenotypic and immunogenetic profile was identified for primary splenic MCL, which was enriched for DBA.44-positive cases ( P P = 0.02) compared to nodal or extranodal cases, alluding to distinct immunopathogenetic and antigen selection processes. Expression of CD27 (considered a marker of activated B cells) was generally dissociated from SHM and was more prevalent in cases with no or minimal/borderline SHM. These findings support the idea that antigen drive is relevant for most MCL cases, although the specific antigens and the precise location of affinity maturation remain to be elucidated. Moreover, they raise the intriguing hypothesis of multiple cellular origins for MCL.

We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBε, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (

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

Background Primary cardiac lymphomas (PCL) represent extremely rare cardiac tumors which are accompanied by poor prognosis, unless they are timely diagnosed and treated. Case presentation Herein we present a 28-year-old, immunocompetent man who presented to our hospital due to progressively worsening symptoms and signs of superior vena cava syndrome. Multi-modality imaging demonstrated a large intracardiac tumor, which was proven, by biopsy, to be a PCL. The patient received targeted chemotherapy which led to total remission of his disease, with no relapse over a 15-month follow-up period. Conclusions Although PCLs are rare, they should always be kept in mind in the differential diagnosis of cardiac tumors. Timely diagnosis of PCLs and appropriate chemotherapy, alone or in combination with radiotherapy, seems to provide the best results.

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.

Clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ) is a recently described entity characterized by the presence of clonal B cells in the blood and/or bone marrow (BM) with morphologic and immunophenotypic features consistent with marginal zone derivation in otherwise healthy individuals. CBL-MZ is commonly associated with paraproteinemia, usually immunoglobulin M (IgM), raising diagnostic difficulties from Waldenstrom macroglobulinemia (WM). The aim of the present study was to determine the presence of MYD-88 L265P mutation in a well-characterized series of CBL-MZ to identify cases that may in fact represent WM. Fifty-three CBL-MZ cases were retrospectively evaluated. MYD-88 L265P mutation was determined by allele-specific polymerase chain reaction in blood and/or BM mononuclear cells. Almost half of the CBL-MZ cases (49%) were associated with paraproteinemia mainly of the IgM type (65%). MYD-88 L265P mutation was identified in 10 cases (19%). These cases may truly represent WM, whereas 43 cases (81%) are still classified as CBL-MZ. Mutated cases were all associated with paraproteinemia compared with 37% of the nonmutated ones (P

To identify prognostic molecular profiles in patients with mRCC treated with sunitinib, we performed immunohistochemical analysis for VEGF and PI3K/Akt/mTOR pathway components.The immunohistochemical expression of VEGF, p85α, p110γ, PTEN, p-Akt, p-mTOR, p-4E-BP1 and p-p70S6K was studied in 79 patients with mRCC who received first-line treatment with sunitinib. Expression was correlated with clinicopathological features and survival.VEGF was highly expressed (median H-Score 150), while positivity for the markers of the PI3K/Akt/mTOR pathway was: p85α 43/66 (65 %), p110γ41/60 (68 %), PTEN 32/64 (50 %), p-Akt57/63 (90 %), p-mTOR48/64 (75 %), p-4E-BP1 58/64 (90 %) and p-p70S6K 60/65 (92 %). No single immunohistochemical marker was found to have prognostic significance. Instead, the combination of increased p-mTOR and low VEGF expression was adversely correlated with overall survival (OS) (3.2 vs. 16.9 months, P = 0.001).Immunohistochemistry for VEGF and p-mTOR proteins may discriminate patients refractory to first-line sunitinib with poor prognosis. Prospective validation of our findings is needed.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with considerable heterogeneity reflected in the 2008 World Health Organization classification. In recent years, genome-wide assessment of genetic and epigenetic alterations has shed light upon distinct molecular subsets linked to dysregulation of specific genes or pathways. Besides fostering our knowledge regarding the molecular complexity of DLBCL types, these studies have unraveled previously unappreciated genetic lesions, which may be exploited for prognostic and therapeutic purposes. Following the last World Health Organization classification, we have witnessed the emergence of new variants of specific DLBCL entities, such as CD30 DLBCL, human immunodeficiency virus-related and age-related variants of plasmablastic lymphoma, and EBV DLBCL arising in young patients. In this review, we will present an update on the clinical, pathologic, and molecular features of DLBCL incorporating recently gained information with respect to their pathobiology and prognosis. We will emphasize the distinctive features of newly described or emerging variants and highlight advances in our understanding of entities presenting a diagnostic challenge, such as T-cell/histiocyte-rich large B-cell lmphoma and unclassifiable large B-cell lymphomas. Furthermore, we will discuss recent advances in the genomic characterization of DLBCL, as they may relate to prognostication and tailored therapeutic intervention. The information presented in this review derives from English language publications appearing in PubMed throughout December 2015. For a complete outline of this paper, please visit: http://links.lww.com/PAP/A12.

Background: Dietary glycotoxins and androgen excess have been independently associated with a negative influence on the kidney. There are no data concerning the additive effects of these two factors on the kidney function and structure, in females. The present study aims to investigate the effect of dietary glycotoxins and androgen excess on the kidneys of an androgenized female rat model. Methods: The study involved 80 female Wistar rats divided into 3 groups. The animals from group A were androgenized at 4 weeks of age (n = 30), rats of group B were androgenized at 12–20 weeks of age (n = 20) and group C consisted of non-androgenized animals (n = 30). All groups were further randomly assigned, either to a high-Advanced Glycation End product diet (HA diet) or low-AGE diet (LA diet), for 3 months. Results: The rats fed with HA diet had significantly higher serum creatinine levels (p ⩽ 0.0002), when compared with those fed with LA diet. The androgenized group fed with HA diet exhibited higher levels of serum AGE (p = 0.0005), creatinine levels (p

Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoproliferative disorder characterized by blood and bone marrow (BM) involvement associated with splenomegaly, while lymphadenopathy ...

Endothelial dysfunction involves deregulation of the key extracellular matrix (ECM) enzyme lysyl oxidase (LOX) and the vasoconstrictor protein, endothelin-1 (ET-1), whose gene expression can be modulated by the transcriptional activators nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1). Advanced glycation end products (AGEs) present an aggravating factor of endothelial dysfunction which upon engagement to their receptor RAGE induce upregulation of mitogen-activated protein kinases (MAPKs), leading to NF-κB and AP-1 potentiation. We hypothesized that AGEs could induce NF-κΒ- and AP-1-dependent regulation of LOX and ET-1 expression via the AGE/RAGE/MAPK signaling axis. Western blot, real-time qRT-PCR, FACS analysis and electrophoretic mobility-shift assays were employed in human aortic endothelial cells (HAECs) following treatment with AGE-bovine serum albumin (AGE-BSA) to investigate the signaling pathway towards this hypothesis. Furthermore, immunohistochemical analysis of AGEs, RAGE, LOX and ET-1 expression was conducted in aortic endothelium of a rat experimental model exposed to high- or low-AGE content diet. HAECs exposed to AGE-BSA for various time points exhibited upregulation of LOX and ET-1 mRNA levels in a dose- and time-dependent manner. Exposure of HAECs to AGE-BSA also showed specific elevation of phospho(p)-ERK1/2 and p-JNK levels in a dose- and time-dependent fashion. AGE administration significantly increased NF-κΒ- and AP-1-binding activity to both LOX and ET-1 cognate promoter regions. Moreover, LOX and ET-1 overexpression in rat aortic endothelium upon high-AGE content diet confirmed the functional interrelation of these molecules. Our findings demonstrate that AGEs trigger NF-κΒ- and AP-1-mediated upregulation of LOX and ET-1 via the AGE/RAGE/MAPK signaling cascade in human endothelial cells, thus contributing to distorted endothelial homeostasis by impairing endothelial barrier function, altering ECM biomechanical properties and cell proliferation.

Considering the specific anatomic features of the foot, below-knee amputation is the treatment of choice for foot malignancies. However, advances in imaging modalities, adjuvant therapies, and improved surgical techniques have made foot salvage surgery increasingly possible. The calcaneus is an unusual location for malignant tumors, and there is limited information about foot salvage. Currently, 3-dimensional printed implants may successfully address reconstruction challenges after tumor resection. The authors present 2 patients with Ewing's sarcoma of the calcaneus who underwent total calcaneus resection and reconstruction using a custom-made 3-dimensional printed implant. [ Orthopedics . 2019; 42(2):e282–e287.]

Significant progress in the molecular pathology of melanocytic tumors have revealed that benign neoplasms, so-called nevi, are initiated by gain-of-function mutations in one of several primary oncogenes, such as BRAF in acquired melanocytic nevi, NRAS in congenital nevi or GNAQ/GNA11 in blue nevi, with consequent MAPK and PI3K/AKT/mTOR activation. Secondary genetic alterations overcome tumor suppressive mechanisms and allow the progression to intermediate lesions characterized by TERT-p mutation or to invasive melanomas displaying disruption of tumor suppressor genes. Currently, melanoma is molecularly regarded as four different diseases, namely BRAF, NRAS, NF1 and the "triple wild type" subtypes, which are associated with particular clinicopathological features. Melanocytic Spitzoid lesions include benign Spitz nevus, atypical Spitz tumor (AST) and Spitzoid melanoma. This is a challenging diagnostic group, particularly with regard to the distinction between AST and Spitzoid melanoma on clinical and histological grounds. Molecular analysis has identified the presence of HRAS mutation, BAP1 loss (often accompanying by BRAF mutations) or several kinase fusions in distinct categories of Spitz tumors. These aberrations account for the rapid growth characteristic of Spitz nevi. Subsequent growth is halted by various tumor suppressive mechanisms abrogation of which allow the development of AST, now better classified as low-grade melanocytic tumor. Although at present ancillary genetic techniques have not been very helpful in the prediction of biological behavior of AST, they have defined distinct tumor subsets differing with regard to biology and histology. Finally, we discuss how novel molecular markers may assist the differential diagnosis of melanoma, particularly from malignant peripheral nerve sheath tumor (MPNST). It is anticipated that the significant progress in the field of molecular pathology regarding the various types of melanocytic tumors, will eventually contribute to a more accurate histologic categorization, prediction of biologic behavior and personalized treatment.

Background/aim Adenocarcinoma is one of the most common malignant tumors of the small intestine complicating Crohn's disease. However, the coexistence of both conditions with diverticulosis of small bowel in young age makes this coincidence rare and clinical diagnosis very difficult. Case report We report a case of a woman admitted to our Department with acute abdominal pain and fever. The surgical and histological investigation, revealed a rare coexistence that has never been mentioned in the published medical literature. Conclusion Ileal diverticulosis is not frequent and often asymptomatic as well as adenocarcinoma of the small bowel. In this case, those diseases along with Crohn's disease led the patient to acute symptoms.

Breast cancer coexisting with lymphoma is a rare condition with various diagnostic and therapeutic implications. In this report, we describe the case of a 55-year-old Caucasian woman who presented with simultaneous ductal carcinoma in situ of the right breast, and follicular lymphoma involving an inguinal lymph node and the left breast. The patient underwent local excision and radiotherapy for the ductal carcinoma in situ, while a watch and wait strategy was adopted for the lymphoma. Two years later, the patient presented with multifocal ductal carcinoma of the left breast and reappearance of the lymphoma in the left axillary lymph nodes. She underwent bilateral mastectomy, left sentinel node biopsy, and chemotherapy. Synchronous follicular lymphoma and bilateral metachronous breast carcinoma has not been described previously. Diagnosis is based on tissue histology after excision or a needle biopsy. Treatment for these two diseases is distinct, and a multidisciplinary approach should be adopted.

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine carcinoma of the skin. MCC should be included in the diagnosis of a rapidly growing infiltrating mass and histology as well as laboratory investigations such as Merkel cell polyoma virus (MCPyV) detection are valuable in its diagnosis. We present an unusual case of giant MCC-positive MCPyV in a Greek woman located on the lower leg. Our patient is very unusual in terms of her extensive MCC and her rapid and complete response to radiotherapy.

Background The tumor protein p53 (TP53) gene may be inactivated through 17p13 deletion, somatic mutations, or both. In chronic lymphocytic leukemia (CLL) although 17p13 deletion is correlated with poor prognosis, the role of sole TP53 mutations remains controversial. Materials and methods We carried out a mutation analysis of TP53 gene in 72 patients with CLL. Results Seventy-one (98.6%) patients carried the polymorphic site c.215C>G, p.Pro72Arg, but its presence was not correlated with overall survival (OS). Moreover, 19 (26.4%) patients carried a mutation of TP53. Among the eight detected mutations, to our knowledge, one (c.587G>A) has never been reported in the past. There was a correlation of the mutation burden with the stage of the disease (p=0.022), but not with OS. None of the detected mutations was individually correlated with OS. Conclusion The clinical significance of TP53 mutations is still a matter of debate and larger studies and meta-analyses are required to reach an unequivocal conclusion.

Helicobacter pylori (H. pylori) is a Gram negative bacterium that colonizes the stomach of almost half human population. It has evolved to escape immune surveillance, establishes lifelong inflammation, predisposing to genomic instability and DNA damage, notably Double Strand Breaks (DSBs). The epithelial host cell responds by activation of DNA Damage Repair (DDR) machinery that seems to be compromised by the infection. It is therefore now accepted that genetic damage is a major mechanism operating in cases of H. pylori induced carcinogenesis. Here we review the data on the molecular pathways involved in DNA damage and DDR activation during H. pylori infection.

The polycystins PC1 and PC2 are emerging as major players in mechanotransduction, a process that influences all steps of the invasion/metastasis cascade. We hypothesized that PC1 and PC2 facilitate cancer aggressiveness. Immunoblotting, RT-PCR, semi-quantitative and quantitative real-time PCR and FACS analyses were employed to investigate the effect of polycystin overexpression in colorectal cancer (CRC) cells. The impact of PC1 inhibition on cancer-cell proliferation was evaluated through an MTT assay. In vitro data were analyzed by Student's t-test. HT29 human xenografts were treated with anti-PC1 (extracellular domain) inhibitory antibody and analyzed via immunohistochemistry to determine the in vivo role of PC1 in CRC. Clinical significance was assessed by examining PC1 and PC2 protein expression in CRC patients (immunohistochemistry). In vivo and clinical data were analyzed by non-parametric tests, Kaplan-Meier curves, log-rank test and Cox model. All statistical tests were two-sided. PC1 overexpression promotes epithelial-to-mesenchymal transition (EMT) in HCT116 cells, while PC2 overexpression results in upregulation of the mTOR pathway in SW480 cells. PC1 inhibition causes reduced cell proliferation in CRC cells inducing tumor necrosis and suppressing EMT in HT29 tumor xenografts. In clinical study, PC1 and PC2 overexpression associates with adverse pathological parameters, including invasiveness and mucinous carcinomas. Moreover, PC1 overexpression appears as an independent prognostic factor of reduced recurrence-free survival (HR = 1.016, p = 0.03) and lowers overall survival probability, while aberrant PC2 expression predicts poor overall survival (p = 0.0468). These results support, for the first time, a direct link between mechanosensing polycystins (PC1 and PC2) and CRC progression.

Extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT) is an indolent lymphoma arising in extranodal sites. Several infectious agents and autoimmune disorders have been implicated in its pathogenesis. The stomach represents the most common and best-studied organ involved by MALT lymphoma and its development is strongly associated with Helicobacter pylori (Hp) infection. MALT lymphomas are characterized by an indolent clinical course and excellent survival in most cases, independently of the treatment delivered. Recent progress in the knowledge of the etiology and the cellular and molecular pathological events related to MALT lymphomas allowed us to improve our clinical understanding of this disease entity and to better define treatment strategies.

Obesity represents a route to broad physiological dysfunction affecting major organs including male urogenital system. Hyperglycemia, hyperlipidemia, and oxidative stress associated with obesity augment the formation of reactive metabolic by-products, namely advanced glycation end products (AGEs), leading to increased tissue deposition and damage. The exogenous intake and the endogenous accumulation of AGEs contribute to metabolic and reproductive abnormalities in both women and men. The present study assessed the effects of a diet high in saturated fatty acids (SAFA) on the lipid and metabolic profile (AGE levels, oxidative stress) as well as pathogenic (AGE, receptor for AGEs [RAGE] expression, apoptosis) and morphometric parameters of male reproductive system in vivo. Effects of switching to a diet rich in monounsaturated fatty acids (MUFA) or equal in the proportion MUFA to SAFA were further investigated. SAFA-fed animals were characterized by increased serum lipid concentrations ( p

A number of studies have looked into the pathophysiological role of angiogenesis in CLL, but the results have often been inconsistent. We aimed to gain direct insight into the angiogenic process in lymph nodes involved by CLL, focusing on proangiogenic cytokines and microvessel morphometry. The tissue levels of VEGF, Th-2 cytokines IL-6 and IL-8, IL-8 receptor CXCR2, and tyrosine p-STAT-3/SOCS-3 axis modulating cytokine expression were evaluated immunohistochemically in 62 CLL/SLL cases. Microvascular characteristics were evaluated by image analysis. Results were analyzed with regard to clinicopathological characteristics. Proliferation centers (PCs) were less well vascularised compared to non-PC areas. IL-8 and CXCR2 expression was distinctly uncommon as opposed to IL-6, VEGF and SOCS-3, which were detected in the vast majority of cases. The latter two molecule expressions were more pronounced in the PCs in∼40% of the cases. p-STAT-3 immunoreactivity was recorded in 66.67% of the cases with a predilection for PCs. Microvessel morphometry was unrelated to proangiogenic cytokines, p-STAT-3, SOCS-3, or survival. Microvascular caliber and VEGF expression were higher in Binet stage A, whereasIL-6 expression was higher in stage C. VEGF and p-STAT-3 exerted a favorable effect on progression, which remained significant in multivariate analysis, thereby constituting potential outcome predictors in CLL patients.

BACKGROUND Pediatric brain tumors are characterized by altered epigenetic profiles and deregulated chromatin remodelling that affects gene expression. Histone lysine methylation has emerged as important chromatin function regulator, with potential role in glioma formation. Τhis study investigates the expression of histone lysine methyltransferases (SETDB1, SUV39H1, EZH2, MLL2, SETD2) and their corresponding methylation marks (H3K9me3, H3K27me3, H3K4me2/3, H3K36me3) in pediatric astrocytomas. MATERIAL AND METHODS Thirty-four (34) archival pediatric astrocytomas [27 low grade (I/II) and 7 high grade (III/IV) tumors; 21 males, 13 females; 1–15 years old] and 5 postmortem normal brain samples were studied. Methyltransferases expression and histone marks were detected by immunohistochemistry as H-score (intensity multiplied with cell percentage, 0–300) and validated by western blot. RESULTS Elevated nuclear SETD2 and SETDB1 staining was observed in all astrocytomas (median H-score:165 and 110, respectively). SETDB1 and SETD2 expression levels were positively associated (p=0.004), being higher in high grade compared to lower grade tumors (p=0.001, p=0.027, respectively). Furthermore, SETDB1 staining was significantly increased in male children (p=0.051) and negatively associated with patients age (p=0.028). A moderate nuclear and cytoplasmic staining was obtained for MLL2 at low grade (median H-score:84) compared to high grade tumors (median H-score:144). In accordance, lower SUV39H1 nuclear and cytoplasmic expression was detected in low grade tissues (median H score:85) compared to high grade (median H-score:160). EZH2 presented no significant nuclear expression. Increased nuclear staining of H3K9me3 and H4K20me3 repressive marks was observed in astrocytomas (median H-score:297 and 270, respectively), being positively associated (p=0.02). Elevated nuclear staining of H3K4me3 active mark (median H-score:210) was detected in astrocytomas, being significantly higher in high grade tumors (p=0.025) and in male children (p=0.036). CONCLUSION SETDB1, SETD2, SUV39H1 and MLL2 may play a significant role in modulating gene expression in pediatric astrocytomas. Increased presence of H3K9me3, H4K20me3 and H3K4me3 histone marks signifies their possible participation in gliomagenesis. Larger cohort studies need to elucidate the functional significance and underlying molecular mechanisms of these chromatin-modifying enzymes and respective histone changes in pediatric astrocytomas.

Extranodal marginal zone lymphoma (ENMZL) of mucosa-associated lymphoid tissue (MALT)-type are classified as indolent lymphomas based on their histopathological features and clinical course [1,2]. ...

Angiogenesis leads to new blood vessel formation and is implicated in both physiological and pathological situations. The vascular endothelial growth factor (VEGF) family is the major mediator of this process. The aim of our study was to evaluate the expression of VEGF-A, vascular endothelial growth factor receptor-1 (VEGFR-1) and VEGFR-2 and their correlation with clinicopathological parameters and prognosis in patients with classical Hodgkin lymphoma (cHL), since the role of angiogenesis in this tumor still remains unclear. The immunohistochemical expression of VEGF-A, VEGFR-1 and VEGFR-2 was examined in 194 patients with cHL. The neoplastic Hodgkin Reed-Sternberg (HRS) cells expressed VEGF-A, VEGFR-1 and VEGFR-2 in 90.3%, 97.2% and 94.1% of cases, respectively. Only the expression of VEGFR-2 was positively correlated with serum albumin levels ≥ 4 g/dL. No correlation with patient outcome was observed. All three molecules were statistically correlated with ramifications of blood vessels. Summarizing, our results are not sufficient to consider VEGF-A and/or VEGF receptors as prognosticators in cHL.

The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is upregulated in a number of human cancers, including non-small cell lung cancer (NSCLC). Its potential role in NSCLC progression provides an attractive target for anticancer therapy. The expression of phosphorylated mTOR (p-mTOR), phosphorylated AKT (p-AKT), p85α and p110γ subunits of PI3K, phosphorylated p70S6K (p-p70S6K), phosphatase and tensin homolog (PTEN) and phosphorylated 4E-BP1 (p‑4E‑BP1) was examined by immunohistochemistry in 102 NSCLC specimens. The results were correlated with clinicopathological features. We also examined 61 of our cases for the presence of PIK3CA, AKT1, PTEN and K-RAS mutations. A common PIK3CA mutation was detected at exon 9 in 2 samples (p.E545K), whereas another sample displayed a rare mutation (p.D1018N). Furthermore, 10 out of 54 cases (18.5%) had a K-RAS mutation at codon 12, 5 had a PTEN mutation (exons 7 and 8) and 1 case had an AKT1 mutation (p.E17K). PTEN mutations were associated with nodal metastases. The expression of p-mTOR positively correlated with that of p-AKT and p-p70S6K and was higher in adenocarcinomas along with nuclear p110γPI3K expression, whereas p-4E-BP1 expression was higher in squamous cell carcinomas. We also established a positive association between p85αPI3K or p110γPI3K and cytoplasmic p-AKT and its downstream effectors. An inverse correlation was noted between p-4E-BP1 immunoexpression and tumour status and nuclear p-AKT expression as regards tumour stage. Univariate survival analysis demonstrated that p-4E-BP1 expression, either alone or in combination with cytoplasmic p-AKT expression had an adverse prognostic significance in adenocarcinomas. The combination of p-4E‑BP1 and cytoplasmic p-AKT expression remained significant in the multivariate analysis as a function of their interaction with histological type. Our data demonstrate the significance of p‑4E‑BP1 immunoexpression as a molecular marker of prognostic value in adenocarcinomas, particularly when combined with p-AKT.

International audience; Background: Sox11 is a transcription factor expressed in foetal and neoplastic brain tissue, including gliomas. It has been shown to suppress the tumourigenicity of glioma stem cells in vivo, thereby being hypothesised to function as a tumour suppressor. Methods: We investigated the expression of Sox11 in 132 diffuse astrocytomas in relation to the regulator cell marker nestin, c-Met and IDH1-R132H, which have shown to be differentially expressed among the molecular subgroups of malignant gliomas, as well as to an inducer of astrocytic differentiation, that is, signal transducer and activator of transcription (p-STAT-3), clinicopathological features and survival. Results: Sox11 immunoreactivity was identified in all tumours irrespective of grade, but being correlated with p-STAT-3. Three out of seven cases showed partial Sox11 promoter methylation. In >50% of our cases neoplastic cells coexpressed Sox11 and nestin, a finding further confirmed in primary glioblastoma cell cultures. Furthermore, nestin, c-Met and IDH1-R132H expression differed among grade categories. Cluster analysis identified four groups of patients according to c-Met, nestin and IDH1-R132H expression. The c-Met/nestin high-expressor group displayed a higher Sox11 expression. Sox11 expression was an indicator of favourable prognosis in glioblastomas, which remained in multivariate analysis and validated in an independent set of 72 cases. The c-Met/nestin high-expressor group was marginally with shorter survival in univariate analysis. Conclusions: We highlight the importance of Sox11 expression as a favourable prognosticator in glioblastomas. c-Met/nestin/IDH1-R132H expression phenotypes recapitulate the molecular subgroups of malignant glioma.

Summary Aims To investigate the expression of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin (OPG) in bladder urothelial carcinomas (UCs) and assess possible interrelations with other regulators of TRAIL induced apoptosis (p65/NF-κB, p-ERK1/2, p-AKT) and FGFR3, as well as to elucidate their potential involvement in bladder tumourigenesis and determine their potential prognostic utility. Methods Paraffin embedded transurethral resection tissue from 128 patients with UC was immunostained for TRAIL and OPGaswellasfor p65/NF-κB, p-ERK1/2, p-AKTand FGFR3. Results TRAIL and OPG were coexpressed in 96.6% of cases and positively interrelated. OPG expression was significantly different among histological grades, being higher in low-grade UCs and was inversely correlated with the presence of lymphovascular invasion (LVI). TRAIL also displayed an inverse relationship with histological grade, T-category and LVI. Both OPG and TRAIL expression were positively correlated with FGFR3 expression, the former relationship being marginal. Moreover, increased TRAIL expression was marginally correlated with lower NF-kB/p65 nuclear expression. Increased OPG expression adversely affected survival both in univariate and multivariate analysis. Conclusions OPG and TRAIL are frequently expressed and coexpressed in UCs, supporting the involvement of OPG in the resistance to TRAIL-driven apoptosis. Inhibition of NF-κB activation may also play a similar role, although less important. OPG emerged as an independent prognostic marker of adverse significance.

Background. Treatment of splenic marginal zone lymphoma (SMZL) patients is not standardized. Recent data suggest that rituximab is highly effective and could be considered as initial therapy. Aim. To assess the efficacy of rituximab monotherapy in a large series of patients with SMZL and compare these results with splenectomy results. Methods. The studied population included 85 patients. Fifty-eight received rituximab at a dose of 375 mg/m2 per week for 6 weeks as induction followed by maintenance at the same dose every 2 months for 1–2 years, whereas 27 patients were treated using splenectomy only. Results. The overall response rate to rituximab 2 months after the end of induction was 95% (complete response [CR], 45%; unconfirmed CR, 26%; partial response, 24%). The median times to hematologic and clinical response were 2 weeks and 3 weeks, respectively. Forty-three of 55 patients already completed the maintenance phase: 28 sustained their initial response, 14 improved their response, and one progressed. Eighty-five percent of splenectomized patients responded, and two were treated with rituximab as consolidation after splenectomy and achieved a CR. The 5-year overall and progression-free survival (PFS) rates for rituximab-treated and splenectomized patients were 92% and 77% (p = .09) and 73% and 58% (p = .06), respectively. Furthermore, maintenance therapy with rituximab resulted in a longer duration of response (at 5 years, PFS was 84% for patients receiving maintenance and 36% for patients without maintenance, p Conclusions. Rituximab is a very effective and well-tolerated therapy and may be substituted for splenectomy as the first-line treatment of choice for patients with SMZL.

Dissemination of lymphomas in serous effusions is quite common. Cytology aims to contribute in the clinical management of haematologic patients, providing an accurate and rapid diagnosis. Ancillary techniques such as immunocytochemistry and flow cytometry are essential to classify the lymphoma entity. Comprehensive awareness of the clinical picture and previous histologic documentation are essential for a lymphomatous effusion diagnosis. We report an unusual case of monomorphic epitheliotropic intestinal T-cell lymphoma, formerly known as enteropathy associated T-cell lymphoma (EATL) type II, spreading in the pleural cavity. Cell morphology and immunohistochemistry of the pleural fluid were consistent with the histology of a jejunal tumor previously excised. Flow cytometry data were consistent, though not pathognomonic for the disease. Serous effusions with evidence of lymphoma involvement should be thoroughly examined with cytology and adjuvant techniques to provide diagnosis for proper therapeutic strategies.

Hypereosinophilic syndrome is a rare entity that can develop secondary to overproduction of eosinophilopoietic cytokines or as idiopathic disease. Cardiac involvement, which occurs often, is divided into 3 stages, the latter of which is nonreversible and leads to severe heart failure. Early detection and treatment of the syndrome is essential. For this reason, genetic testing for the FIP1L1-PDGFRA fusion gene has recently been added to the diagnostic algorithm. Patients with this mutation are at increased risk for the development of cardiac involvement and typically respond to treatment with the tyrosine kinase inhibitor imatinib mesylate.

Castleman's disease (CD), also known as giant or angiofolicular lymphoid hyperplasia or lymphoid hamartoma, is a group of atypical lymphoproliferative disorders that share common lymph node histological features and may be localized either to a single lymph node (unicentric) or occur systemically (multicentric).Herein, we present a rare case of a of 75-year-old female patient who was referred to our department and after a thorough work-up, underwent splenectomy with synchronous resection of an accessory spleen, splenic artery lymph nodes, and splenic hilar lymph nodes due to splenic involvement in a multicentric CD.The pathology of the specimens led to the conclusion that it was a case of polycentric HHV-8-positive CD, affecting the spleen, the accessory spleen, and the lymph nodes.Incidence of this rare condition is believed to be approximately 0.001-0.05%. CD has been linked to the human immunodeficiency virus (HIV), human herpes virus 8 (HHV-8), and is associated with malignancies. The pathogenesis mechanism is considered to be a dysregulation and hypersecretion of cytokines, either idiopathic or secondary to a viral infection, with the latter considered the most frequent. Solid organ involvement is very rare as is splenic involvement.

Helicobacter pylori (H. pylori) is a Gram negative bacterium that colonizes the stomach of almost half human population. It has evolved to escape immune surveillance, establishes lifelong inflammation, predisposing to genomic instability and DNA damage, notably double strand breaks. The epithelial host cell responds by activation of DNA damage repair (DDR) machinery that seems to be compromised by the infection. It is therefore now accepted that genetic damage is a major mechanism operating in cases of H. pylori induced carcinogenesis. Here, we review the data on the molecular pathways involved in DNA damage and DDR activation during H. pylori infection.

Clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ) is a recently described entity characterized by the presence of clonal B cells in the blood and/or bone marrow (BM) with morphologic and immunophenotypic features consistent with marginal zone derivation in otherwise healthy individuals. CBL-MZ is commonly associated with paraproteinemia, usually immunoglobulin M (IgM), raising diagnostic difficulties from Waldenstrom macroglobulinemia (WM). The aim of the present study was to determine the presence of MYD-88 L265P mutation in a well-characterized series of CBL-MZ to identify cases that may in fact represent WM. Fifty-three CBL-MZ cases were retrospectively evaluated. MYD-88 L265P mutation was determined by allele-specific polymerase chain reaction in blood and/or BM mononuclear cells. Almost half of the CBL-MZ cases (49%) were associated with paraproteinemia mainly of the IgM type (65%). MYD-88 L265P mutation was identified in 10 cases (19%). These cases may truly represent WM, whereas 43 cases (81%) are still classified as CBL-MZ. Mutated cases were all associated with paraproteinemia compared with 37% of the nonmutated ones (P .0001). In addition, mutated cases displayed more frequently CD38 and CD25 positivity (P = .002 and P = .005, respectively). Moreover, cases without paraproteinemia presented more frequently with lymphocytosis, irrespective of the presence of the MYD-88 mutation (P = .02). The present study demonstrates that MYD-88 L265P mutation may represent the only sensitive marker for the differentiation of CBL-MZ from probable WM. However, further studies are warranted to better define the biological significance of MYD-88 L265P mutation and to clarify whether the presence of the mutation establishes WM diagnosis or that it can also be present in borderline cases associated with paraproteinemia.

European Americans are often treated as a homogeneous group, but in fact form a structured population due to historical immigration of diverse source populations. Discerning the ancestry of European Americans genotyped in association studies is important in order to prevent false-positive or false-negative associations due to population stratification and to identify genetic variants whose contribution to disease risk differs across European ancestries. Here, we investigate empirical patterns of population structure in European Americans, analyzing 4,198 samples from four genome-wide association studies to show that components roughly corresponding to northwest European, southeast European, and Ashkenazi Jewish ancestry are the main sources of European American population structure. Building on this insight, we constructed a panel of 300 validated markers that are highly informative for distinguishing these ancestries. We demonstrate that this panel of markers can be used to correct for stratification in association studies that do not generate dense genotype data. © 2008 Price et al.

Testicular torsion/detorsion causes severe tissue damage due to ischemia/reperfusion injury. The present study investigated the protective effect of erythropoietin and sildenafil against ischemia/reperfusion injury following unilateral testicular torsion/detorsion in adult rats. A total of 28 adult male rats were included, and were divided into the following groups: Group A (n=5), sham operated; groups B (n=5), C (n=5), D (n=5) and E (n=8), undergoing right testis torsion and detorsion after 90 min. Group B received no drug treatment. Rats in the groups C and D received low-dose (1,000 IU/kg) or high-dose (3,000 IU/kg) erythropoietin, while those in group E received sildenafil (0.7 mg/kg), through intraperitoneal injection after 60 min of torsion. The right testis was extracted 24 h after detorsion, and the tissue was subjected to histopathological examination and immunohistochemical assessment of cleaved caspase-3 expression. Histological alterations and the quality of spermatogenesis were scored according to the Cosentino and the Johnsen scoring systems, respectively. The results demonstrated normal testicular architecture in group A, while the other groups showed ischemic cellular damages, with the worst scores observed in group B. Groups D and E presented better scores compared with group C. Regarding the quality of spermatogenesis, the best scores were observed in group A, and the worst in group B. Groups C, D and E presented similar results, which were improved in comparison to group B, however, not compared to group A. Furthermore, cleaved caspase-3 levels were lower in groups A, D and E, with equal results observed. Group C had higher levels of cleaved caspase-3 compared with these groups, but lower than group B, which presented the highest cleaved caspase-3 levels. In conclusion, erythropoietin and sildenafil protect testis from ischemia/reperfusion injury by decreasing cellular damage and attenuating apoptosis.

Background Advanced glycation end products (AGEs) and their receptor RAGE emerge as important pathogenic contributors in colorectal carcinogenesis. However, their relationship to the detoxification enzyme Glyoxalase (GLO)-I and Adiponectin receptors (AdipoR1, AdipoR2) in colorectal carcinoma (CRC) is currently understudied. In the present study, we investigated the expression levels of the above molecules in CRC compared to adjacent non-tumoral tissue and their potential correlation with clinicopathological characteristics and patients’ survival. Methods We analyzed the immunohistochemical expression of AGE, RAGE, GLO-1, AdipoR1 and AdipoR2 in 133 primary CRC cases, focusing on GLO-I. The tumour MSI status was further assessed in mucinous carcinomas. Western immunoblotting was employed for validation of immunohistochemical data in normal and tumoral tissues as well in three CRC cell lines. An independent set of 55 patients was also used to validate the results of univariate survival analysis regarding GLO-I. Results CRC tissue showed higher intensity of both AGE and RAGE expression compared with normal colonic mucosa which was negative for GLO-I in most cases (78 %). Western immunoblotting confirmed AGE, RAGE and GLO-I overexpression in tumoral tissue. GLO-I expression was directly related to RAGE and inversely related to AGE immunolabeling. There was a trend towards higher expression of all markers (except for RAGE) in the subgroup of mucinous carcinomas which, although of borderline significance, seemed to be more prominent for AdipoR1 and AGE. Additionally, AGE, AdipoR1 and Adipo R2 expression was related to tumor grade, whereas GLO-1 and AdipoR1 to T-category. In survival analysis, AdipoR2 and GLO-I overexpression predicted shortened survival in the entire cohort and in early stage cases, an effect which for GLO-I was reproduced in the validation cohort. Moreover, GLO-I emerged as an independent prognosticator of adverse significance in the patients’ cohort. Conclusions We herein provide novel evidence regarding the possible interactions between the components of AGE-RAGE axis, GLO-I and adiponectin receptors in CRC. AGE and AdipoR1 are possibly involved in colorectal carcinogenesis, whereas AdipoR2 and GLO-I emerged as novel independent prognostic biomarkers of adverse significance for patients with early disease stage. Further studies are warranted to extend our observations and investigate their potential therapeutic significance.

Background: The therapeutic properties of cannabinoids are well-known since ancient years. Growing evidence exist on endocannabinoid system (ECS) modulation related with human tumorigenesis. Objective: Taking into account the substantial role of ECS on immune cell regulation, the present review is aimed to summarize the emerging evidence concerning cannabinoid receptor (CBR) expression and cannabinoid ligand effects on haematological malignancies. Conclusions: Most of cannabinoid actions, mainly CB2R-mediated against haematopoietic malignant cells, seem promising, as inhibition of cell proliferation and apoptosis and paraptosis induction have been documented. Cannabinoid ligands appear to activate rudimentary pathways for cell survival, such as ERK, JNK, p38 MAPK, and to induce caspase synthesis, in vitro. Such data are strongly recommended to be confirmed by in vivo experiments with emphasis on cannabinoid ligands’ bioavailability and phytocannabinoid psychotropic properties. The preliminary antitumoral ECS effects and their relative lack of important side effects render ECS a promising therapeutic target for the treatment of haematological malignancies.

Here, we summarise the results after carrying out a large survey regarding the assessment of vascular alterations, both vessel changes and vascular lesions in an inter-laboratory setting. In total, 32 neuropathologists from 22 centres, most being members of BrainNet Europe (BNE), participated by filling out a questionnaire with emphasis on assessment of common vascular alterations seen in the brains of aged subjects. A certain level of harmonisation has been reached among BNE members regarding sectioning of the brain, harvesting of brain tissue for histology and staining used when compared to the survey carried out in 2006 by Pantoni and colleagues. The most significant variability was seen regarding the assessment of severity and of clinical significance of vascular alterations. Two strategies have recently been recommended regarding the assessment of vascular alterations in aged and demented subjects. The National Institute on Aging - Alzheimer's Association (NIA-AA) recommends the assessment of hippocampal sclerosis, vascular brain injury and microvascular lesions in 12 regions. Although this strategy will be easy to follow, the recommendations do not inform how the load of observed alterations should be assessed and when the observed lesions are of significance. Deramecourt and his colleagues recommend an assessment and semiquantitative grading of various pathologies in 4 brain regions. This strategy yielded a total score of 0 to 20 as an estimate of pathology load. It is, however, not clear which score is considered to be of clinical significance. Furthermore, in several BNE trials the semiquantitative assessment has yielded poor agreement rates; an observation that might negatively influence the strategy proposed by Deramecourt and his colleagues. In line with NIA-AA, a dichotomised approach of easily recognisable lesions in a standardised set of brain regions harvested for neuropathological assessment and applying reproducible sampling and staining strategies is recommended by BNE. However, a simple strategy regarding assessment of load of alteration is urgently needed to yield reproducible, and at the same time, comparable results between centres.

What's known on the subject? and What does the study add? A few published studies investigating single or various PI3K/AKT/mTOR signalling components have produced inconsistent results. Moreover, PI3K regulatory subunit p85a and activated p70S6K expression levels have not been previously examined in urothelial carcinoma (UC). The present study addresses simultaneously all key members of PI3K/AKT/mTOR signalling cascade supporting a differential implication of PI3K/AKT/mTOR pathway components in urothelial tumorigenesis. Furthermore, we propose p-4E-BP1 as a potential prognostic marker in UC, which might assist the selection of patients more likely to benefit from chemotherapy regimens based on PI3K/AKT/mTOR pathway inhibition. Finally, the present study indicates PIK3CA/AKT1 mutational status as a potential predictive marker for time-to-recurrence. OBJECTIVE • To perform a comprehensive simultaneous assessment of all key members of phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway along with AKT homolog 1 (AKT1) and PIK3 catalytic alpha polypeptide (PIK3CA) mutations in bladder urothelial carcinoma (UC). • Published information is limited to a few studies looking into single or various combinations of members of this pathway with inconsistent results. In particular the expression status of phosphorylated (p-)p70S6 kinase (p70S6K) and p85a subunit of PI3K has not been tested in UC. PATIENTS AND METHODS • Paraffin-embedded transurethral resection tissue from 113 patients with UC was investigated for the association of p85aPI3K, p-AKT, p-mTOR, p-p70S6K and p-4E-BP1 (eukaryotic initiation factor 4E-binding protein 1) expression status, as well as PIK3CA and AKT1 mutations with p-extracellular signal-regulated kinase 1/2 (ERK1/2), fibroblast growth factor receptor 3 (FGFR3), pathological features, recurrence and cancer-specific survival. RESULTS • With the exception of p-p70S6K, all others components of the PI3K/AKT/mTOR pathway were upregulated in UCs as compared with normal urothelium. • p-mTOR expression strongly correlated with its upstream p-AKT and marginally with its downstream p-p70S6K. p85aPI3K and p-ERK1/2 levels were also marginally correlated. • PIK3CA and AKT1 mutations were distinctly uncommon and mutually exclusive, without any association with pathological features. However, the presence of AKT1 mutations was associated with increased FGFR3 levels and was restricted to p85aPI3K immunonegative cases, whereas PIK3CA mutant cases had marginally lower p85aPI3K levels. • The presence of PIK3CA single or combined with AKT1 mutations was associated with shorter recurrence-free survival in univariate survival analysis. An inverse relationship was established between p-4E-BP1 immunopositivity and histological grade or T category, as well as between p-p70S6K levels and T category, the latter relationship being of marginal significance. • p-4E-BP1 nuclear expression was marginally associated with the presence of lymphovascular invasion and adversely affected survival in multivariate, but not in univariate analysis. CONCLUSIONS • PI3K/AKT/mTOR signalling components appear to be differentially implicated in urothelial tumorigenesis and, with the exception of p85aPI3K, are unrelated to the PIK3CA or AKT1 mutational status. • Our findings propose p-4E-BP1 as a potential prognostic marker in UC independent of its association with pathological features, which might assist the selection of patients more likely to benefit from PI3K/AKT/mTOR axis inhibition. • PIK3CA/AKT1 mutational status may have a place in the prediction of time-to-recurrence.

Glyoxalase detoxification system composed of glyoxalase (GLO)-I and GLO-II is ubiquitously expressed and implicated in the protection against cellular damage because of cytotoxic metabolites such as advanced glycation end products (AGEs). Recently, ovarian tissue has emerged as a new target of excessive AGE deposition and has been associated with either a high AGE diet in experimental animals or hyperandrogenic disorders such as polycystic ovarian syndrome (PCOS) in humans. This study was designed to investigate the impact of dietary AGEs and androgens in rat ovarian GLO-I activity of normal nonandrogenized (NAN, group A, n = 18) and androgenized prepubertal (AN) rats (group B, n = 29). Both groups were further randomly assigned, either to a high-AGE (HA) or low-AGE (LA) diet for 3 months. The activity of ovarian GLO-I was significantly reduced in normal NAN animals fed an HA diet compared with an LA diet (p = 0.006). Furthermore, GLO-I activity was markedly reduced in AN animals compared with NAN (p ≤ 0.001) when fed with the corresponding diet type. In addition, ovarian GLO-I activity was positively correlated with the body weight gain (r(s) = 0.533, p0.001), estradiol (r(s) = 0.326, p = 0.033) and progesterone levels (r(s) = 0.500, p0.001). A negative correlation was observed between GLO-I activity and AGE expression in the ovarian granulosa cell layer of all groups with marginal statistical significance (r(s) = -0.263, p = 0.07). The present data demonstrate that ovarian GLO-I activity may be regulated by dietary composition and androgen levels. Modification of ovarian GLO-I activity, observed for the first time in this androgenized prepubertal rat model, may present a contributing factor to the reproductive dysfunction characterizing PCOS.

Replication protein A (RPA) is an ssDNA-binding protein required for the initiation of DNA replication and the stabilization of ssDNA. Collaboration with several molecules, that is, the MCM2-7 complex, has been suggested to be imperative for its multifaceted role. In this study, we investigated the immunohistochemical expression of the RPA2 subunit in correlation with the MCM-2 and MCM-5 and Ki67 index, and assessed its prognostic significance in 76 patients with nonearly ovarian adenocarcinomas, the majority of whom had a serous histotype. RPA2 protein expression was observed in all cases, whereas the staining intensity varied from weak to strong. RPA2 expression was correlated with the tumor stage in the entire cohort and in serous tumors (P=0.0053 in both relationships). Moreover, RPA2 immunoexpression was positively correlated with MCM-2 (P=0.0001) and MCM-5 (P0.0001) expression, but was unrelated to the Ki67 index (P0.10). In multivariate survival analysis, RPA2 expression emerged as an independent predictor of adverse outcome (P0.0001) along with tumor histologic grade. RPA2 remained an independent predictor of survival (P=0.002) even after adjustment for MCM-2 and MCM-5 expression and when analysis was restricted to serous carcinomas (P=0.004). Our results further support the interrelation of RPA2 protein with MCM-2 and MCM-5 in OCs. Moreover, RPA2 protein may play an important role in ovarian tumorigenesis, and may serve as a useful independent molecular marker for stratifying patients with OC in terms of prognosis.

Korkolopoulou P, Levidou G, El-Habr E A, Piperi C, Adamopoulos C, Samaras V, Boviatsis E, Thymara I, Trigka E-A, Sakellariou S, Kavantzas N, Patsouris E & Saetta A A (2012) Histopathology 61, 293–305 Phosphorylated 4E-binding protein 1 (p-4E-BP1): a novel prognostic marker in human astrocytomas Aims: To investigate the significance of the mammalian target of rapamycin (mTOR) pathway in astrocytic tumours, published information in this context being limited, especially regarding phosphorylated 4E-binding protein (p-4E-BP) 1. Methods and results: Paraffin-embedded tissue from 111 patients with astroglial tumours (grades II–IV) was investigated for the association of phosphorylated mTOR (p-mTOR) signalling components with phosphorylated extracellular signal-related kinase 1/2 (p-ERK1/2) and phosphorylated AKT (p-AKT) expression, clinicopathological features, angiogenesis, isocitrate dehydrogenase 1 (IDH1)-R132H, and survival. Expression was also quantified by western blot analysis in 12 cases and in three primary glioma cell cultures following rapamycin treatment. p-mTOR expression correlated with p-4E-BP1 expression and marginally with p-p70S6K expression. p-4E-BP1 expression increased with tumour grade. Rapamycin induced a decline in phosphorylation levels of all three proteins. Nuclear p-AKT and cytoplasmic p-ERK1/2 immunoexpression correlated with p-4E-BP1 expression, whereas cytoplasmic p-AKT expression correlated with p-p70S6K expression. All three proteins were associated with increased angiogenesis but not with IDH1-R132H expression status. p-mTOR adversely affected overall and disease-free survival in univariate analysis. In multivariate survival analysis, the presence of p-4E-BP1 predicted shortened overall survival in the entire cohort and glioblastomas. Conclusions: mTOR signalling components are differentially involved in the acquisition of a more aggressive and angiogenic phenotype in astrocytic tumours. Moreover, p-4E-BP1 emerges as a novel prognostic marker, which might aid in the selection of patients who are more likely to benefit from therapy with mTOR inhibitors.