microRNA Expression in Ethnic Specific Early Stage Breast Cancer: an Integration and Comparative Analysis.

Breast cancer (BC) has a higher incidence in young Lebanese woman as compared to the West. We assessed the microRNA (miRNA) microarray profile of tissues derived from Lebanese patients with early BC and performed mRNA-miRNA integration analysis. 173 miRNAs were significantly dysregulated in 45 BC versus 17 normal adjacent breast tissues, including 74 with a fold change more than two of which 17 were never reported before in cancer. Integration analysis of mRNA-miRNA microarray data revealed a potential role of 51 dysregulated miRNA regulating 719 tumor suppressive or oncogenic mRNA associated with increased proliferation and decreased migration and invasion. We then performed a comparative miRNA microarray profile analysis of BC tissue between these 45 Lebanese and 197 matched American BC patients. Notably, Lebanese BC patients had 21 exclusively dysregulated miRNA (e.g. miR-31, 362-3p, and 663) and 4 miRNA with different expression manner compared to American patients (e.g. miR-1288-star and 324-3p). Some of these differences could reflect variation in patient age at diagnosis or ethnic variation affecting miRNA epigenetic regulation or sequence of miRNA precursors. Our data provide a basis for genetic/epigenetic investigations to explore the role of miRNA in early stage BC in young women, including ethnic specific differences.

Phosphorus Supplementation Mitigated Food Intake and Growth of Rats Fed a Low-Protein Diet.

Background: Low protein intake is associated with various negative health outcomes at any life stage. When diets do not contain sufficient protein, phosphorus availability is compromised because proteins are the major sources of phosphorus. However, whether mineral phosphorus supplementation mitigates this problem is unknown, to our knowledge. Objective: Our goal was to determine the impact of dietary phosphorus supplementation on food intake, weight gain, energy efficiency, body composition, blood metabolites, and liver histology in rats fed a low-protein diet for 9 wk. Methods: Forty-nine 6-wk-old male Sprague-Dawley rats were randomly allocated to 5 groups and consumed 5 isocaloric diets ad libitum that varied only in protein (egg white) and phosphorus concentrations for 9 wk. The control group received a 20% protein diet with 0.3% P (NP-0.3P). The 4 other groups were fed a low-protein (10%) diet with a phosphorus concentration of 0.015%, 0.056%, 0.1%, or 0.3% (LP-0.3P). The rats' weight, body and liver composition, and plasma biomarkers were then assessed. Results: The addition of phosphorus to the low-protein diet significantly increased food intake, weight gain, and energy efficiency, which were similar among the groups that received 0.3% P (LP-0.3P and NP-0.3P) regardless of dietary protein content. In addition, phosphorus supplementation of low-protein diets reduced plasma urea nitrogen and increased total body protein content (defatted). Changes in food intake and efficiency, body weight and composition, and plasma urea concentration were highly pronounced at a dietary phosphorus content <0.1%, which may represent a critical threshold. Conclusions: The addition of phosphorus to low-protein diets improved growth measures in rats, mainly as a result of enhanced energy efficiency. A dietary phosphorus concentration of 0.3% mitigated detrimental effects of low-protein diets on growth parameters.

Undifferentiated Nasopharyngeal Carcinoma Mimicking Hodgkin Lymphoma With CD30 Expression.

The presence of CD30-expressing Hodgkin-like cells with a background of inflammation and eosinophils in a young adolescent is usually diagnostic of classical Hodgkin lymphoma. Herein we present the case of a 12-year-old boy presenting with enlarged cervical lymph node characterized by the presence of Hodgkin-like cells expressing CD30 and EBV-LMP1 with a Hodgkin-like background. The Hodgkin-like cells were negative for CD15, CD20, CD45, and Pax-5. The tumor cells, however, expressed several cytokeratins, confirming the diagnosis of an undifferentiated carcinoma nasopharyngeal type. This case highlights the importance of possessing a high index of suspicion when encountering lymph nodes with Hodgkin-like cells and a Hodgkin-like background, even with CD30 expression, as the differential can include undifferentiated carcinoma nasopharyngeal type.

Activating BRAF Mutations Detected in Mixed Hürthle Cell Carcinoma and Multifocal Papillary Carcinoma of the Thyroid Gland: Report of an Unusual Case and Review of the Literature.

Despite the increase in the incidence of thyroid carcinomas, the occurrence of collision tumors in the thyroid remains a rare event. We present the case of a 69-year-old female who presented to the emergency department with a chief complaint of painful neck swelling. Imaging revealed a large right hemithyroid mass and a left hemithyroid nodule. Fine needle aspiration of the lesions and subsequent total thyroidectomy revealed a Hürthle cell carcinoma in the right lobe and bilateral multicentric papillary carcinoma foci, including 2 foci with a classical pattern and 1 encapsulated follicular variant in the isthmus. BRAF gene mutation analysis revealed V600E gene mutation in the classical variants of papillary carcinoma and in the Hürthle cell carcinoma. The focus of follicular variant of papillary carcinoma in the isthmus and a sample from normal thyroid tissue did not harbor BRAF mutations. This case is remarkable in being an unusual report of a follicular Hürthle cell carcinoma harboring the BRAF V600E mutation and occurring in collision with multifocal papillary carcinoma. Documentation of such cases is important as it helps better understand the pathogenesis, clinical behavior, and radiologic findings of such rare lesions and to determine the optimal treatment modalities.

Programmed Death-Ligand 1 Expression in Muscle-Invasive Bladder Cancer Cystectomy Specimens and Lymph Node Metastasis: A Reliable Treatment Selection Biomarker?

BACKGROUND: The programmed death-1 (PD-1) pathway negatively regulates T-cell activation and has an important role in regulating antitumor host immunity. Monoclonal antibodies directed against PD-1 or the PD-1 ligand (PD-L1) have shown activity in several tumor types with preliminary data suggesting a relationship between PD-L1 expression and response. The aim of this study was to establish the frequency of PD-L1 expression in muscle-invasive bladder cancer and associated lymph node metastasis using immunohistochemistry and to investigate the feasibility of using PD-L1 expression as a biomarker to select patients for PD-1-directed therapy. PATIENTS AND METHODS: Cases of radical cystectomy for muscle-invasive bladder cancer with no exposure to previous chemotherapy were identified and representative slides from archived paraffin-embedded blocks stained with anti-PD-L1 antibody (5H1 clone) were identified. PD-L1 positivity was defined by a 5% expression threshold. RESULTS: Fifty-two radical cystectomy specimens were reviewed. PD-L1 was overexpressed in the tumor cells of 5/52 (9.6%) of cystectomy specimens in this cohort with 17/52 (32.7%) of cases showing PD-L1 overexpression in tumor-infiltrating immune cells. Discordance was observed between PD-L1 expression in lymph node metastasis and the primary tumor. CONCLUSION: Standard assays for PD-L1 expression have yet to be established. The observation of discordance between PD-L1 expression in metastatic sites and primary tumors suggests that prospective biomarker studies should aim to acquire material immediately before treatment initiation rather than archived tissue from resected specimens that might not reflect the current immune-active microenvironment.

Mesothelial Cells Within Vascular Transformation of Mediastinal Lymph Node Sinuses: An Unusual Benign Collision Mimicking Colliding Malignancies.

Vascular transformation of lymph node sinuses represents a rare benign entity mimicking malignant counterparts such as nodal Kaposi sarcoma. The presence of mildly atypical benign mesothelial cells within nodal sinuses raises the possibility of metastatic malignancy. Herein, a rare case of vascular transformation of lymph node sinuses with reactive sinusoidal mesothelial cells is outlined as a unique benign pathology and a potential mimicker of a malignant collision tumor.

Cervical ganglioneuroma in collision with a metastatic undifferentiated carcinoma.

Cervical ganglioneuromas are extremely rare with approximately six case reports. The current report highlights a unique collision tumor between a cervical ganglioneuroma and a metastatic undifferentiated carcinoma arising from a primary gingival mass. A 53-year-old male presented with a 2 cm left gingival mass that was excised and treated with systemic chemotherapy. Consequently, 9 months later, he developed a 3.2 cm left submandibular mass followed by recurrence of the left gingival mass. From the clinicopathologic perspective, this had to be separated from the differentials: ganglioneuroblastoma or metastatic involvement of a lymph node from primary gingival undifferentiated carcinoma.

ST1926, an orally active synthetic retinoid, induces apoptosis in chronic myeloid leukemia cells and prolongs survival in a murine model.

The tyrosine kinase inhibitor, imatinib, is the first line of treatment for chronic myeloid leukemia (CML) patients. Unfortunately, patients develop resistance and relapse due to bcr-abl point mutations and the persistence of leukemia initiating cells (LIC). Retinoids regulate vital biological processes such as cellular proliferation, apoptosis, and differentiation, in particular of hematopoietic progenitor cells. The clinical usage of natural retinoids is hindered by acquired resistance and undesirable side effects. However, bioavailable and less toxic synthetic retinoids, such as the atypical adamantyl retinoid ST1926, have been developed and tested in cancer clinical trials. We investigated the preclinical efficacy of the synthetic retinoid ST1926 using human CML cell lines and the murine bone marrow transduction/transplantation CML model. In vitro, ST1926 induced irreversible growth inhibition, cell cycle arrest and apoptosis through the dissipation of the mitochondrial membrane potential and caspase activation. Furthermore, ST1926 induced DNA damage and downregulated BCR-ABL. Most importantly, oral treatment with ST1926 significantly prolonged the longevity of primary CML mice, and reduced tumor burden. However, ST1926 did not eradicate LIC, evident by the ability of splenocytes isolated from treated primary mice to develop CML in untreated secondary recipients. These results support a potential therapeutic use of ST1926 in CML targeted therapy.

ASPL-TFE3 translocation in vulvovaginal alveolar soft part sarcoma.

Alveolar soft part sarcoma of the vulvovaginal region is limited to only 8 reported vaginal cases and 1 vulvar case in the English literature. The histogenesis of the tumor remains intriguing with postulates favoring a myogenic versus nonmyogenic origin. A reciprocal translocation for ASPL-TFE3 gene fusion, frequently detected in ~90% of cases, combined with TFE3 protein immunoexpression are highly sensitive and specific methods for diagnostic confirmation. The current report describes a unique case of vulvovaginal alveolar soft part sarcoma showing the classic morphologic features with documentation of TFE3 protein expression and the ASPL-TFE3 gene rearrangement. Furthermore, a brief review of the literature of vulvar and vaginal alveolar soft part sarcoma cases with the various treatment modalities is outlined.

Follicular dendritic cell sarcoma of the head and neck expressing thyroid transcription factor-1: a case report with clinicopathologic and immunohistochemical literature review.

Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm of follicular dendritic cells, most commonly affecting the lymph nodes and extranodal soft tissues of the head and neck, but also potentially arising in any visceral organ. FDCS with its diverse morphologies raises an occasionally challenging differential of primary and metastatic tumors with overlapping histologic and immunohistochemical features. When involving the head and neck, FDCS may be confused with squamous cell carcinoma, undifferentiated carcinoma, extracranial meningioma, and variants of papillary thyroid carcinoma. We describe here a case of FDCS showing nuclear grooves, intranuclear pseudoinclusions, diffuse epithelial membrane antigen and focal cytokeratin staining, and the first documented report of positivity for thyroid transcription factor-1. A discussion of the differential diagnosis and potential diagnostic pitfalls in FDCS brought forth by thyroid transcription factor-1 immunoreactivity and a full review of clinicopathologic and immunohistochemical features of head and neck FDCS are presented.

Effective targeting of chronic myeloid leukemia initiating activity with the combination of arsenic trioxide and interferon alpha.

Imatinib is the standard of care in chronic meloid leukemia (CML) therapy. However, imatinib is not curative since most patients who discontinue therapy relapse indicating that leukemia initiating cells (LIC) are resistant. Interferon alpha (IFN) induces hematologic and cytogenetic remissions and interestingly, improved outcome was reported with the combination of interferon and imatinib. Arsenic trioxide was suggested to decrease CML LIC. We investigated the effects of arsenic and IFN on human CML cell lines or primary cells and the bone marrow retroviral transduction/transplantation murine CML model. In vitro, the combination of arsenic and IFN inhibited proliferation and activated apoptosis. Importantly, arsenic and IFN synergistically reduced the clonogenic activity of primary bone marrow cells derived from CML patients. Finally, in vivo, combined interferon and arsenic treatment, but not single agents, prolonged the survival of primary CML mice. Importantly, the combination severely impaired engraftment into untreated secondary recipients, with some recipients never developing the disease, demonstrating a dramatic decrease in CML LIC activity. Arsenic/IFN effect on CML LIC activity was significantly superior to that of imatinib. These results support further exploration of this combination, alone or with imatinib aiming at achieving CML eradication rather than long-term disease control.

Propafenone hepatotoxicity: report of a new case and review of the literature.

Propafenone is a class Ic antiarrhythmic drug. It is a beta-adrenergic blocker that causes bradycardia and bronchospasm. It is metabolized primarily in the liver. Its bioavailability and plasma concentration differ among patients under long-term therapy. They are genetically determined by the hepatic cytochrome P-450 2D6. Hepatic toxicity is highly uncommon. To date, only eight patients were reported in the reviewed world literature. In this article, one new case will be reported emphasizing the importance of medication history taking in patients presenting with new-onset liver enzymes abnormalities.

Calcaneal osteosarcoma: a rare cause of heel pain in the paediatric population.

Osteosarcoma is the most common primary non-haemopoietic malignant bone tumour in children and adolescents. However, it rarely occurs in the calcaneus with only a few case reports in the literature. We report a case of a 14-year-old boy with calcaneal osteosarcoma, who presented with heel pain followed by swelling. The pain was initially thought to be related to a benign process and treated with analgesics, delaying the diagnosis. We discuss the clinical presentation, the differential diagnosis, multi-imaging and pathological findings of a calcaneal osteosarcoma, its clinical outcome and the importance of early diagnosis to improve outcome.

Extended use of serum free light chain as a biomarker in lymphoproliferative disorders: a comprehensive review.

Serum free light chain (sFLC) assays were shown to improve detection, management, and prognostication in plasma cell disorders. Recently, sFLC assays improved detection of M proteins when combined with standard methods of protein electrophoresis/immunofixation in patients with non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL). Incidence of abnormal sFLC ratio (sFLCr) varied from 0% to 36% and 29.7% to 59% in NHL and CLL, respectively. Increased sFLC levels or abnormal sFLCr predict shorter overall survival in early-stage CLL. Furthermore, abnormal sFLCr correlated with advanced disease stage and poorer outcome. In diffuse large B-cell lymphomas, increased sFLC was demonstrated as an independent, adverse prognostic factor for overall/event-free survival. Moreover, abnormal sFLCr can be a diagnostic tool in central nervous system lymphomas. Finally, the quantitative FLC assay has the potential to become a new, easily measured biomarker for predicting prognosis and enhanced detection in NHL/CLL. It may be used serially at follow-up evaluations to provide clues to relapse.

Variability in hormone and growth factor receptor expression in primary versus recurrent, metastatic, and post-neoadjuvant breast carcinoma.

The introduction of selective molecular targeted therapy, specifically tamoxifen and trastuzumab, has significantly altered the clinical behavior of breast carcinoma. Several questions remain, however, regarding potential phenotypic drifts in estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor (Her-2/neu) expression between the primary and metastatic site. Whether patients should be tested for ER, PR, and Her-2/neu expression in the nodal or distant metastatic site, local recurrence and following neoadjuvant therapy, and whether this has an effect on prognosis remains elusive. A review of 45 studies addressing ER, PR, and Her-2/neu expression in lymph node metastasis, distant metastasis, local recurrence, and post-neoadjuvant therapy revealed the following average phenotypic drift in ER, PR, and Her-2/neu expression, respectively: 13.1 % (median = 10.0 %), 13.8 % (median = 16.0 %), and 7.7 % (median = 5.0 %) for lymph node metastasis; 21.8 % (median = 19.5 %), 30.8 % (median = 33.5 %), and 7.6 % (median = 6.1 %) for distant metastasis; 19.8 % (median = 13.4 %), 27.1 % (median = 28.6 %), and 6.6 % (median = 1.6 %) for local recurrence; and 12.9 % (median = 8.0 %), 32.0 % (median = 20.0 %), and 8.9 % (median = 0 %) post-neoadjuvant therapy. The above findings support the notion of re-evaluating ER, PR, and Her-2/neu expression in distant metastasis, lymph node metastasis and to a lesser extent local recurrence. The effects of neoadjuvant therapy on receptor expression are more pronounced for PR, which may have a prognostic role in therapy efficacy.

Myasthenia gravis developing in a patient with CNS lymphoma.

A patient was initially diagnosed with right basal ganglia lymphoma causing left hemiparesis. His disease was resistant to intravenous methotrexate, so he received radiation therapy with remarkable regression of the mass. However, 6 months after his initial diagnosis, he developed symmetric weakness of the proximal muscles. Electromyography was consistent with myasthenia gravis and anti-acetylcholine receptor antibodies were elevated. Treatment with pyridostigmine and corticosteroids improved his symptoms. The residual lymphoma was further treated with rituximab and temozolomide with complete resolution. Pyridostigmine and corticosteroids were stopped after 14 months of initiation with good results. Our case is the first case report of paraneoplastic myasthenia gravis developing in a patient with primary CNS lymphoma. The diagnosis of paraneoplastic myasthenia should be considered in patients with CNS lymphoma who develop muscle weakness and speech problems.

Aberrant angiogenic characteristics of human brain arteriovenous malformation endothelial cells.

OBJECTIVE: To identify and characterize the phenotypic and functional differences of endothelial cells derived from cerebral arteriovenous malformations (AVM), as compared with endothelial cells derived from a normal brain. METHODS: Isolated AVM brain endothelial cells and control brain endothelial cells were evaluated immunohistochemically for expression of the endothelial cell markers von Willebrand factor and CD31, as well as angiogenic factors including vascular endothelial growth factor A, interleukin-8, and endothelin-1. Vascular endothelial growth factor receptors 1 and 2 were also evaluated using immunohistochemistry techniques. Functional assays evaluated cell proliferation, cytokine production, tubule formation, and cell migration using the modified Boyden chamber technique. RESULTS: Endothelial cells derived from AVMs expressed high levels of vascular endothelial growth factor A and significantly overexpressed the vascular endothelial growth factor receptors 1 and 2 (P < 0.05), as compared with control endothelial cells. In addition, comparison to control brain endothelial cells demonstrated that AVM brain endothelial cells proliferated faster, migrated more quickly, and produced aberrant tubule-like structures. CONCLUSION: Endothelial cells derived from cerebral AVMs are highly activated cells overexpressing proangiogenic growth factors and exhibiting abnormal functions consistent with highly activated endothelial cells.

Chromatid recommensuration after segmental duplication.

BACKGROUND: Midsegment duplication (dup) of chromatid arms may be symmetric or asymmetric. It can be argued that every dup should yield a discommensured RC with (a) loss of at least one duplicated unit to the template counterpart and; (b) deletion of all sections of the replicating chromatid arm that are distal to both the gap left by the duplicating process and the segment closest to the centromere. HYPOTHESIS: Mechanisms capable of recommensuring the stack of chromatids after topological shifts of duplicated units (dups) are discussed. The mechanics might fail in few cases, which are discussed in terms of statistics and scalability. CONCLUSION: The dynamics of the highly non-linear processes discussed here may be relevant to duplications of smaller (epsilon) subunits such as telomeric units within malignant genomes.

Glioma-associated endothelial cells show evidence of replicative senescence.

The innately programmed process of replicative senescence has been studied extensively with respect to cancer, but primarily from the perspective of tumor cells overcoming this stringent innate barrier and acquiring the capacity for unlimited proliferation. In this study, we focus on the potential role of replicative senescence affecting the non-transformed endothelial cells of the blood vessels within the tumor microenvironment. Based on the well-documented aberrant structural and functional features of blood vessels within solid tumors, we hypothesized that tumor-derived factors may lead to premature replicative senescence in tumor-associated brain endothelial cells (TuBEC). We show here that glioma tissue, but not normal brain tissue, contains cells that express the signature of replicative senescence, senescence-associated beta-galactosidase (SA-beta-gal), on CD31-positive endothelial cells. Primary cultures of human TuBEC stain for SA-beta-gal and exhibit characteristics of replicative senescence, including increased levels of the cell cycle inhibitors p21 and p27, increased resistance to cytotoxic drugs, increased growth factor production, and inability to proliferate. These data provide the first demonstration that tumor-derived brain endothelial cells may have reached an end-stage of differentiation known as replicative senescence and underscore the need for anti-angiogenic therapies to target this unique tumor-associated endothelial cell population.