School of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina Department of Pathology, Clinical Center, University of Sarajevo, Sarajevo, Bosnia and Herzegovina Department of Radiology, Clinical Center, University of Sarajevo, Sarajevo, Bosnia and Herzegovina Department of Oncology, Clinical Center, University of Sarajevo, Sarajevo, Bosnia and Herzegovina College of Medicine, Qatar University, Doha, Qatar

Epstein–Barr virus (EBV) has been recently shown to be co-present with high-risk human papillomaviruses (HPVs) in human cervical cancer; thus, these oncoviruses play an important role in the initiation and/or progression of this cancer. Accordingly, our group has recently viewed the presence and genotyping distribution of high-risk HPVs in cervical cancer in Syrian women; our data pointed out that HPVs are present in 42/44 samples (95%). Herein, we aim to explore the co-prevalence of EBV and high-risk HPVs in 44 cervical cancer tissues from Syrian women using polymerase chain reaction, immunohistochemistry, and tissue microarray analyses. We found that EBV and high-risk HPVs are co-present in 15/44 (34%) of the samples. However, none of the samples was exclusively EBV-positive. Additionally, we report that the co-expression of LMP1 and E6 genes of EBV and high-risk HPVs, respectively, is associated with poorly differentiated squamous cell carcinomas phenotype; this is accompanied by a strong and diffuse overexpression of Id-1 (93% positivity), which is an important regulator of cell invasion and metastasis. These data imply that EBV and HPVs are co-present in cervical cancer samples in the Middle East area including Syria and their co-presence is associated with a more aggressive cancer phenotype. Future investigations are needed to elucidate the exact role of EBV and HPVs cooperation in cervical carcinogenesis.

Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients′ survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients. In the current review, we survey recent therapeutic strategies, as well as molecular profiling data on MM, with emphasis on relapsed and refractory cases. A critical appraisal of novel findings and of their potential therapeutic implications will be discussed in detail, along with the author’s own experiences/views.

Discoidin domain receptors DDR1 and DDR2 are the only receptor tyrosine kinases that bind to and signal in response to collagen. In cancer, DDRs have been shown to play a key role in mediating the crosstalk between tumor cells and the stromal collagen matrix. Because prostate cancer (PCa) preferentially metastasizes to bone, a collagen-rich microenvironment, we set out to investigate the role of DDR1 in intraosseous growth of PC3 cells, a human PCa cell line that expresses DDR1 but not DDR2. PC3 cells were engineered to express short hairpin RNAs (shRNAs) against DDR1, or a scrambled shRNA as a control. These cells were inoculated into the tibiae of male SCID mice, and then bone response and intraosseous tumor growth evaluated by X-ray and histomorphometry. Whereas no differences were observed in bone response (osteolytic lesions), downregulation of DDR1 in PC3 cells was associated with a significant increase in intraosseous tumor growth when compared to control PC3 cells (P Citation Format: R. Daniel Bonfil, Anjum Sohail, Semir Vranic, Daniel S. Oliveira, Dongping Shi, Wei Chen, Hyejeong Jang, Allen D. Saliganan, Benjamin D. Wasinski, Hyeong-Reh C. Kim, Rafael A. Fridman. Discoidin domain receptor 1 (DDR1): A potential suppressor of prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1070.

Oncoviruses are implicated in around 20% of all human cancers including both solid and non-solid malignancies. Epstein–Barr virus (EBV) and human papillomaviruses (HPVs) are the most common oncoviruses worldwide. Currently, it is well established that onco-proteins of EBV (LMP1, LMP2A, and EBNA1) and high-risk HPVs (E5 and E6/E7) play an important role in the initiation and/or progression of several human carcinomas, including cervical, oral, and breast. More significantly, it has been recently pointed out that viral onco-proteins of EBV and high-risk HPVs can be co-present and consequently cooperate to initiate and/or amplify epithelial–mesenchymal transition (EMT), which is the hallmark of cancer progression and metastasis. This could occur by β-catenin, JAK/STAT/SRC, PI3k/Akt/mTOR, and/or RAS/MEK/ERK signaling pathways, which onco-proteins of EBV and HPVs share. This review presents the most recent advances related to EBV and high-risk HPVs onco-proteins interactions and their roles in the progression of human carcinomas especially oral and breast via the initiation of EMT.

Gliomas are the most common malignant brain tumors and account for around 60% of all primary central nervous system cancers. Glioblastoma multiforme (GBM) is a grade IV glioma associated with a poor outcome despite recent advances in chemotherapy. The etiology of gliomas is unknown, but neurotropic viruses including the Epstein–Barr virus (EBV) that is transmitted via salivary and genital fluids have been implicated recently. EBV is a member of the gamma herpes simplex family of DNA viruses that is known to cause infectious mononucleosis (glandular fever) and is strongly linked with the oncogenesis of several cancers, including B-cell lymphomas, nasopharyngeal, and gastric carcinomas. The fact that EBV is thought to be the causative agent for primary central nervous system (CNS) lymphomas in immune-deficient patients has led to its investigations in other brain tumors including gliomas. Here, we provide a review of the clinical literature pertaining to EBV in gliomas and discuss the possibilities of this virus being simply associative, causative, or even an experimental artifact. We searched the PubMed/MEDLINE databases using the following key words such as: glioma(s), glioblastoma multiforme, brain tumors/cancers, EBV, and neurotropic viruses. Our literature analysis indicates conflicting results on the presence and role of EBV in gliomas. Further comprehensive studies are needed to fully implicate EBV in gliomagenesis and oncomodulation. Understanding the role of EBV and other oncoviruses in the etiology of gliomas, would likely open up new avenues for the treatment and management of these, often fatal, CNS tumors.

Epstein–Barr virus (EBV) belongs to the group of gamma-herpes viruses and was the first recognized human oncovirus. EBV is responsible for infectious mononucleosis and multiple lymphoid and epithelial malignancies including B-cell lymphomas (Burkitt lymphoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disorder), various T-cell/NK lymphoproliferative disorders, nasopharyngeal carcinoma, and gastric carcinoma, respectively. In addition, the presence of EBV has been documented in other cancers including breast, prostate, oral, and salivary gland carcinomas. The presence and role of EBV in cervical cancer and its precursor lesions (CIN) have also been described, but the results from the literature are inconsistent, and the causal role of EBV in cervical cancer pathogenesis has not been established yet. In the present review, we briefly surveyed and critically appraised the current literature on EBV in cervical cancer and its variants (lymphoepithelioma-like carcinoma) as well as its precursor lesions (CIN). In addition, we discussed the possible interactions between EBV and human papilloma virus as well as between EBV and immune checkpoint regulators (PD-L1). Though further studies are needed, the available data suggest a possible causal relationship between EBV and cervical cancer pathogenesis.

Olfactory neuroblastoma (ONB) is a rare, locally aggressive, malignant neoplasm originating in the olfactory epithelium in the nasal vault. The recurrence rate of ONB remains high and there are no specific treatment guidelines for recurrent/metastatic ONBs. This study retrospectively evaluated 23 ONB samples profiled at Caris Life Sciences (Phoenix, Arizona) using DNA sequencing (Sanger/NGS [Illumina], n = 15) and gene fusions (Archer FusionPlex, n = 6), whole genome RNA microarray (HumanHT-12 v4 beadChip, Illumina, n = 4), gene copy number assays (chromogenic and fluorescent in situ hybridization), and immunohistochemistry. Mutations were detected in 63% ONBs including TP53, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, and SMAD4 genes. Twenty-one genes were over-expressed and 19 genes under-expressed by microarray assay. Some of the upregulated genes included CD24, SCG2, and IGFBP-2. None of the cases harbored copy number variations of EGFR, HER2 and cMET genes, and no gene fusions were identified. Multiple protein biomarkers of potential response or resistance to classic chemotherapy drugs were identified, such as low ERCC1 [cisplatin sensitivity in 10/12], high TOPO1 [irinotecan sensitivity in 12/19], high TUBB3 [vincristine resistance in 13/14], and high MRP1 [multidrug resistance in 6/6 cases]. None of the cases (0/10) were positive for PD-L1 in tumor cells. Overexpression of pNTRK was observed in 67% (4/6) of the cases without underlying genetic alterations. Molecular alterations detected in our study (e.g., Wnt and cKIT/PDGFRA pathways) are potentially treatable using novel therapeutic approaches. Identified protein biomarkers of response or resistance to classic chemotherapy could be useful in optimizing existing chemotherapy treatment(s) in ONBs.

Breast carcinoma with neuroendocrine features (BCNF) is a rare entity that is defined by a neuroendocrine (NE) architecture and cytomorphology combined with an immunohistochemical expression of chromogranin A or B and/or synaptophysin. According to the 2012 World Health Organization (WHO) classification, they are classified into three subtypes: invasive breast carcinoma with NE differentiation, well-differentiated NE tumor, and poorly differentiated small cell carcinoma. BCNF are typically positive for the estrogen and progesterone receptor and negative for Her-2/ neu protein. The clinical features are not sufficiently specific to distinguish BCNF from other breast carcinomas. BCNF can mimic benign lesions on mammography, so the additional use of ultrasound or MRI can improve detection. Other imaging tests are useful to detect or rule out metastatic disease. Although standardized treatment guidelines have not yet been established, the mainstay of treatment for early BCNFs is surgery. Adjuvant treatment decisions should be individualized and should take into consideration the prognostic and predictive factors, clinical evidence and the patient’s overall health treatment preferences. Therapeutic options in the metastatic setting include surgery, chemotherapy, peptide receptor radionuclide therapy and molecular-targeted agents. These options are not mutually exclusive and are interchangeable. 1 Department of Radiotherapy and Medical Oncology, Clinical Hospital Center “Sestre milosrdnice”, Zagreb, Croatia 2 “Ljudevit Jurak” Pathology Department, Clinical Hospital Center “Sestre milosrdnice“, Pathology Department, Medical Faculty Zagreb, University of Zagreb, Croatia 3 Caris Life Sciences, Phoenix, AZ, United States of America 4 Division of Anatomic and Molecular Pathology, Washington University School of Medicine, Saint Louis, MO, United States of America 5 Department of Pathology, University of Sarajevo Clinical Center, Sarajevo, Bosnia and Herzegovina 6 School of Medicine, University of Sarajevo, Sarajevo, Bosnia Petra Jurčić1, Božo Krušlin2, Zoran Gatalica3, Souzan Sanati4, Semir Vranić5,6 Corresponding author: Semir Vranić, M.D., Ph.D., Assistant Professor of Pathology, Department of Pathology, University of Sarajevo Clinical Center and School of Medicine, Bolnička 25, BA-71000 Sarajevo, Bosnia and Herzegovina, E-mail: semir.vranic@gmail. com DOI: 10.21040/eom/2016.2.2.6. Received: May 25th 2016 Accepted: June 10th 2016 Published: June 15th 2016 Copyright: © Copyright by Association for Endocrine Oncology and Metabolism. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ flicenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is