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Summary: Mantle cell lymphoma (MCL) is still considered incurable and the course of the disease is highly variable. Established risk factors include the Mantle Cell Lymphoma International Prognostic Index (MIPI) and the quantification of the proliferation rate of the tumour cells, e.g. by Ki‐67 immunohistochemistry. In this study, we aimed to validate the prognostic value of the gene expression‐based MCL35 proliferation assay in patient cohorts from randomized trials of the European Mantle Cell Lymphoma Network. Using this assay, we analysed the gene expression proliferation signature in routine diagnostic lymph node specimens from MCL Younger and MCL Elderly trial patients, and the calculated MCL35 score was used to assign MCL patients to low (61%), standard (27%) or high (12%) risk groups with significantly different outcomes. We confirm here in our prospective clinical trial cohort of MCL patients, that the MCL35 assay is strongly prognostic, providing additional information to the Ki‐67 index and the MIPI. Thus, this robust assay may assist in making treatment decisions or in devising risk‐adapted prospective clinical trials in the future. [ABSTRACT FROM AUTHOR]

The article focuses on a study related to exploring whether single nucleotide polymorphism (SNP) will be clinical outcome predictive in multiple myeloma (MM) or not, using autologous stem cell support and high-dose melphalan. Topics discussed include assumption of polygenic phenomenon for MM risk; treatment of patients with thalidomide monotherapy; and use of SNP in TP53 is predictive of clinical outcome in MM.

The differential diagnosis of 46,XY disorders of sex development (DSD) is based on the distinction between forms of gonadal dysgenesis and disorders of androgen biosynthesis and action. However, clinical and endocrine evaluations are often not conclusive. Here, we describe an adolescent female with hirsutism and hyperandrogenization at puberty. Her karyotype was 46,XY, and clinical investigation demonstrated clitoromegaly, but no uterine remnants were detected. Histology of the gonads revealed a testicular structure with a Sertoli-cell-only pattern. Endocrine evaluation showed hypergonadotropic hypogonadism, and the Sertoli cell markers inhibin B and anti-Müllerian hormone were also low. Several molecular genetic studies were initiated. While analyses of the androgen receptor gene, the SRD5A2 gene and HSD17B3 gene were uninformative, a novel p.L230R mutation was found in the NR5A1 gene. A mutant construct proved a severe dysfunction of this variant in functional analysis after recreation and transfection into HeLa cells. We conclude that the NR5A1 p.L230R mutation most likely leads to a spatial and time-dependent Leydig cell and Sertoli cell dysfunction during development not causing the classical gonadal dysgenesis phenotype. This case demonstrates that the current classification should be updated to encompass the overlapping phenotypes of some genetic conditions within 46,XY DSD. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the study on the prognostic impact of RAS mutations on clinical outcome of patients with multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation.

Background and Purpose Angiotensin AT1 receptor antagonists induce weight loss; however, the mechanism underlying this phenomenon is unknown. The Mas receptor agonist angiotensin-(1-7) is a metabolite of angiotensin I and of angiotensin II . As an agonist of Mas receptors, angiotensin-(1-7) has beneficial cardiovascular and metabolic effects. Experimental Approach We investigated the anti-obesity effects of transgenically overexpressed angiotensin-(1-7) in rats. We secondly examined whether weight loss due to telmisartan (8 mg·kg−1·d−1) in diet-induced obese Sprague Dawley ( SD) rats can be blocked when the animals were co-treated with the Mas receptor antagonist A779 (24 or 72 μg·kg−1·d−1). Key Results In contrast to wild-type controls, transgenic rats overexpressing angiotensin-(1-7) had 1.) diminished body weight when they were regularly fed with chow; 2.) were protected from developing obesity although they were fed with cafeteria diet ( CD); 3.) showed a reduced energy intake that was mainly related to a lower CD intake; 5.) remained responsive to leptin despite chronic CD feeding; 6.) had a higher, strain-dependent energy expenditure, and 7.) were protected from developing insulin resistance despite CD feeding. Telmisartan-induced weight loss in SD rats was partially antagonized after a high, but not a low dose of A779. Conclusions and Implications Angiotensin-(1-7) regulated food intake and body weight and contributed to the weight loss after AT1 receptor blockade. Angiotensin-(1-7)-like agonists may be drug candidates for treating obesity. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV)-associated diffuse large B-cell lymphoma (DLBCL) of the elderly constitutes a provisional clinicopathological entity in the current World Health Organization (WHO) classification and its genomic features remain sparsely characterized. We investigated a cohort of 26 cases of untreated de novo EBV-positive DLBCL of the elderly by high-resolution array-based comparative genomic profiling and fluorescence in situ hybridization (FISH). Moreover, we screened for activating mutations affecting nuclear factor (NF)-κB pathway signaling and chromatin remodeling (EZH2, CD79B, CARD11 and MYD88) due to their impact of gene expression signatures and postulated upcoming therapeutic targetability. We identified an overlap between genomic aberrations previously described to be exclusive features of plasmablastic lymphoma (PL), post-transplant lymphoproliferative disorder (PTLD) and DLBCL, respectively, indicating a close cytogenetic relationship between these entities. Few mutations affecting CD79B and CARD11 and no MYD88 mutations were detectable, hinting at EBV-mediated activation of NF-κB as an alternative to pathologically enforced B-cell receptor signaling in this rare entity. [ABSTRACT FROM AUTHOR]

Double-hit lymphomas (DHL) with MYC and either BCL2 or BCL6 rearrangements are rare neoplasms with an aggressive clinical presentation and grim prognosis. Moreover, molecular characterization of DHL remains insufficient, and especially the role of TP53 pathway disruption is unknown. We employed a next-generation sequencing approach to investigate the mutational status of TP53 in DHL and correlated genomic data with immunohistochemical reactivity for p53. We identified TP53 mutations in MYC+/BCL2+ lymphomas at a frequency intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. Remarkably, TP53 mutations were particularly scarce in MYC+/BCL6+ lymphomas. Our findings indicate a significant difference between these two types of DHL at a molecular level with pathogenetic implications, as arguably, TP53 mutations inhibiting p53 mediated promotion of apoptosis pose a synergistic advantage in clonal evolution of cells with malignantly enforced overexpression of BCL2. Immunohistochemical staining appears to be a sensitive surrogate of TP53 mutation status with moderate specificity. [ABSTRACT FROM AUTHOR]

The article presents research on the mutation status of nodal marginal zone lymphoma (NMZL) and the recurrent lesions. Topics discussed include an overview of NMZL, the analysis of the mutation status of transmembrane proteins CD79A , CD79B and MYD88, and the expected pattern of mutations and their genetic variations.

Abstract: Objective: The aim of this study was to validate the role of p16INK4a immunocytochemistry as a marker of cervical epithelial neoplasia in cytology and biopsy samples. Methods: During the period of 4 years a total of 501 immunocytochemistry stains in cytology and biopsy samples were performed. The cytology smears were obtained from two independent laboratories of women with low-grade squamous intraepithelial lesion interpretation of Pap test or ThinPrep. Additionally, a selection of paraffin blocks from cases diagnosed previously with squamous intraepithelial lesion and cervical cancer were immunostained. Results: Among 312 cytology samples analyzed by immunocytochemistry, 36.2% were positive for p16INK4a. Negative cases were followed-up with conventional Pap smear and 86.9% showed regression. Among positive patients, 14 underwent surgery and 100% exhibited squamous intraepithelial lesion. In additional immunohistochemical analysis of selected biopsies from our archive, we found that the ratio of positivity for p16INK4a increased from 40% in L-SIL/CIN1 to 69.8% in H-SIL/CIN2 to 100% in H-SIL/CIN3 and squamous cell carcinoma. A relatively low number (24%) of cases with squamous metaplasia revealed focal and/or sporadic staining in the superficial layers of the epithelium. All the cases of cervical adenocarcinoma and mesonephric carcinoma were positive for p16INK4a. Conclusion: p16INK4a is a useful additional marker for interpretation of problematic Pap smears and reduces the variability during evaluation of suspicious biopsies of the uterine cervix. [Copyright &y& Elsevier]

Dendritic cell neoplasms of the World Health Organization classification comprise Langerhans cell histiocytosis, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, follicular dendritic cell sarcoma, and dendritic cell sarcoma, not otherwise specified. Several studies based on immunohistochemical and ultrastructural analysis tried to further clarify the origin of these neoplasms which are thought to derive from mesenchymal or bone marrow precursors. Lymphatic vessel endothelium hyaluronan receptor-1 (LYVE-1) was recently described as a marker for lymphatic endothelium which is expressed on normal liver blood sinusoid lining cells, spleen endothelium, activated tissue macrophages, blood vessels in the lung, endothelial cells of lymphatic sinuses, and in fibroblastic reticular cells in lymph nodes. We present a case of LYVE-1-positive reticulum cell neoplasm in an axillary lymph node. To the best of our knowledge, there has been no report about LYVE-1 expression in histiocytic or dendritic cell neoplasms so far. Due to the assumed specificity of this antibody, we propose designation of this reticulum cell sarcoma as lymphatic sinus lining cell sarcoma which might finally represent another subtype of reticulum cell sarcomas. [ABSTRACT FROM AUTHOR]