Clinical significance of metabolic tumor volume by PET/CT in stages II and III of diffuse large B cell lymphoma without extranodal site involvement

The objective of this study was to investigate whether metabolic tumor volume (MTV) by positron emission tomography (PET) can be a potential prognostic tool when compared with Ann Arbor stage, in stages II and III nodal diffuse large B cell lymphoma (DLBCL). We evaluated 169 patients with nodal stages II and III DLBCL who underwent measurements with PET prior to rituximab combined with cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). Cutoff point of MTV was measured using the receiver operating characteristic (ROC) curve. During a median period of 36 months, stage II was 59.2% and III was 40.8%. Using the ROC curve, the MTV of 220 cm3 was the cutoff value. The low MTV group (<220 cm3) had longer progression-free survival (PFS) and overall survival (OS), compared with the high MTV group (≥220 cm3) (p < 0.001, p < 0.001). Stage II patients had longer survival than those in stage III (PFS, p = 0.011; OS, p = 0.001). The high MTV group had lower PFS and OS patterns, regardless of stage, compared with the low MTV group (p < 0.001, p < 0.001). Multivariate analysis revealed an association of the high MTV group with lower PFS and OS (PFS, hazard ratio (HR) = 5.300, p < 0.001; OS, HR = 7.009, p < 0.001), but not stage III (PFS, p = 0.187; OS, p = 0.054). Assessment of MTV by PET had more potential predictive power than Ann Arbor stage in the patients that received R-CHOP

Concomitant sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Disease) and diffuse large B-cell lymphoma: a case report

IntroductionSinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman Disease, is a rare and benign source of lymphadenopathy first described in 1969, which mimics neoplastic processes. This disease commonly presents in children and young adults with supra-diaphragmatic lymphadenopathy or extranodal lesions consisting of tissue infiltrates composed of a polyclonal population of histiocytes. Since its description greater than 400 cases have been described, sometimes in patients with a variety of treated and untreated neoplastic diseases. However, the literature contains reports of only 19 cases of Rosai-Dorfman Disease in association with lymphomas, Hodgkin's or non-Hodgkin's. The majority of these cases have the two diagnoses, malignant lymphoma and Rosai-Dorfman Disease, separated in time. Interestingly, infradiaphragmatic lymphadenopathy was a feature in the majority of previously reported cases of Rosai-Dorfman Disease and non-Hodgkin's lymphoma.Case presentationThis report provides details of a case with co-existing sinus histiocytosis with massive lymphadenopathy and diffuse large B cell non-Hodgkin's lymphoma. This case is the fifth described case of simultaneous Rosai-Dorfman Disease and concurrent non-Hodgkin's lymphoma. Unfortunately, the diagnosis of a clinically aggressive diffuse large B cell lymphoma was made at autopsy. The aggressive biological behavior of the diffuse large B cell lymphoma in this patient may have been related to the underlying immune dysregulation believed to be part of the pathophysiology of Rosai-Dorfman Disease.ConclusionTaken together this report and the preceding reports of Rosai-Dorfman Disease and non-Hodgkin's lymphoma suggests that in cases with a diagnosis of Rosai-Dorfman Disease in the setting of prominent infradiaphragmatic lymphadenopathy, clinicians should maintain a high index of suspicion for the presence of occult non-Hodgkin's lymphoma especially if the clinical course is atypical for classic Rosai-Dorfman Disease

Accumulation of Self-Reactive Naive and Memory B Cell Reveals Sequential Defects in B Cell Tolerance Checkpoints in Sjogren's Syndrome

This work was funded by grants number 18237 and 20089 from Arthritis Research UK (http://www.arthritisresearchuk.org) to MB and the William Harvey Research Foundation. EC was recipient of short-term travel fellowships from EMBO (ASTF 318-2010) and EFIS-IL

The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain

BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor

Hierarchical information clustering by means of topologically embedded graphs

We introduce a graph-theoretic approach to extract clusters and hierarchies in complex data-sets in an unsupervised and deterministic manner, without the use of any prior information. This is achieved by building topologically embedded networks containing the subset of most significant links and analyzing the network structure. For a planar embedding, this method provides both the intra-cluster hierarchy, which describes the way clusters are composed, and the inter-cluster hierarchy which describes how clusters gather together. We discuss performance, robustness and reliability of this method by first investigating several artificial data-sets, finding that it can outperform significantly other established approaches. Then we show that our method can successfully differentiate meaningful clusters and hierarchies in a variety of real data-sets. In particular, we find that the application to gene expression patterns of lymphoma samples uncovers biologically significant groups of genes which play key-roles in diagnosis, prognosis and treatment of some of the most relevant human lymphoid malignancies.Comment: 33 Pages, 18 Figures, 5 Table

iASPP is over-expressed in human non-small cell lung cancer and regulates the proliferation of lung cancer cells through a p53 associated pathway

Background iASPP is a key inhibitor of tumour suppressor p53 and is found to be up-regulated in certain malignant conditions. The present study investigated the expression of iASPP in clinical lung cancer, a leading cancer type in the world, and the biological impact of this molecule on lung cancer cells. Methods iASPP protein levels in lung cancer tissues were evaluated using an immunohistochemical method. In vitro, iASPP gene expression was suppressed with a lentvirus-mediated shRNA method and the biological impact after knocking down iASSP on lung cancer cell lines was investigated in connection with the p53 expression status. Results We showed here that the expression of iASPP was significantly higher in lung cancer tissues compared with the adjacent normal tissues. iASPP shRNA treatment resulted in a down-regulation of iASPP in lung cancer cells. There was a subsequent reduction of cell proliferation of the two lung tumour cell lines A459 and 95D both of which had wild-type p53 expression. In contrast, reduction of iASPP in H1229 cells, a cell with little p53 expression, had no impact on its growth rate. Conclusions iASPP regulates the proliferation and motility of lung cancer cells. This effect is intimately associated with the p53 pathway. Together with the pattern of the over-expression in clinical lung cancers, it is concluded that iASPP plays an pivotal role in the progression of lung cancer and is a potential target for lung cancer therapy

Comparison of germinal center markers CD10, BCL6 and human germinal center-associated lymphoma (HGAL) in follicular lymphomas

<p>Abstract</p> <p>Background</p> <p>Recently, human germinal center-associated lymphoma (HGAL) gene protein has been proposed as an adjunctive follicular marker to CD10 and BCL6.</p> <p>Methods</p> <p>Our aim was to evaluate immunoreactivity for HGAL in 82 cases of follicular lymphomas (FLs) - 67 nodal, 5 cutaneous and 10 transformed - which were all analysed histologically, by immunohistochemistry and PCR.</p> <p>Results</p> <p>Immunostaining for HGAL was more frequently positive (97.6%) than that for BCL6 (92.7%) and CD10 (90.2%) in FLs; the cases negative for bcl6 and/or for CD10 were all positive for HGAL, whereas the two cases negative for HGAL were positive with BCL6; no difference in HGAL immunostaining was found among different malignant subtypes or grades.</p> <p>Conclusions</p> <p>Therefore, HGAL can be used in the immunostaining of FLs as the most sensitive germinal center (GC)-marker; when applied alone, it would half the immunostaining costs, reserving the use of the other two markers only to HGAL-negative cases.</p

Clear cell variant of diffuse large B-cell lymphoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Diffuse large B-cell lymphoma is a diffuse proliferation of large neoplastic B lymphoid cells with a nuclear size equal to or exceeding the normal macrophage nuclei. We report a case of a clear cell variant of diffuse large B-cell lymphoma involving a lymph node in the neck, which was clinically suspected of being metastatic carcinoma.</p> <p>Case presentation</p> <p>A 39-year-old Caucasian ethnic Albanian man from Kosovo presented with a rapidly enlarging lymph node in his neck, but he also disclosed B symptoms and fatigue. A cytological aspirate of the lymph node revealed pleomorphic features. Our patient underwent a cervical lymph node biopsy (large excision). The mass was homogeneously fish-flesh, pale white tissue replacing almost the whole structure of the lymph node. The lymph node biopsy showed a partial alveolar growth pattern, which raised clinical suspicion that it was an epithelial neoplasm. With regard to morphological and phenotypic features, we discovered large nodules in diffuse areas, comprising large cells with slightly irregular nuclei and clear cytoplasm admixed with a few mononuclear cells. In these areas, there was high mitotic activity, and in some areas there were macrophages with tangible bodies. Staining for cytokeratins was negative. These areas had the following phenotypes: cluster designation marker 20 (CD20) positive, B-cell lymphoma (Bcl)-2-positive, Bcl-6^-, CD5^-, CD3^-, CD21⁺(in alveolar patterns), prostate-specific antigen-negative, human melanoma black marker 45-negative, melanoma marker-negative, cytokeratin-7-negative and multiple myeloma marker 1-positive in about 30% of cells, and exhibited a high proliferation index marker (Ki-67, 80%).</p> <p>Conclusion</p> <p>According to the immunohistochemical findings, we concluded that this patient has a clear cell variant of diffuse large B-cell lymphoma of activated cell type, post-germinal center cell origin. Our patient is undergoing R-CHOP chemotherapy treatment.</p

Discriminating lymphomas and reactive lymphadenopathy in lymph node biopsies by gene expression profiling

<p>Abstract</p> <p>Background</p> <p>Diagnostic accuracy of lymphoma, a heterogeneous cancer, is essential for patient management. Several ancillary tests including immunophenotyping, and sometimes cytogenetics and PCR are required to aid histological diagnosis. In this proof of principle study, gene expression microarray was evaluated as a single platform test in the differential diagnosis of common lymphoma subtypes and reactive lymphadenopathy (RL) in lymph node biopsies.</p> <p>Methods</p> <p>116 lymph node biopsies diagnosed as RL, classical Hodgkin lymphoma (cHL), diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL) were assayed by mRNA microarray. Three supervised classification strategies (global multi-class, local binary-class and global binary-class classifications) using diagonal linear discriminant analysis was performed on training sets of array data and the classification error rates calculated by leave one out cross-validation. The independent error rate was then evaluated by testing the identified gene classifiers on an independent (test) set of array data.</p> <p>Results</p> <p>The binary classifications provided prediction accuracies, between a subtype of interest and the remaining samples, of 88.5%, 82.8%, 82.8% and 80.0% for FL, cHL, DLBCL, and RL respectively. Identified gene classifiers include LIM domain only-2 (<it>LMO2</it>), Chemokine (C-C motif) ligand 22 (<it>CCL22</it>) and Cyclin-dependent kinase inhibitor-3 (<it>CDK3</it>) specifically for FL, cHL and DLBCL subtypes respectively.</p> <p>Conclusions</p> <p>This study highlights the ability of gene expression profiling to distinguish lymphoma from reactive conditions and classify the major subtypes of lymphoma in a diagnostic setting. A cost-effective single platform "mini-chip" assay could, in principle, be developed to aid the quick diagnosis of lymph node biopsies with the potential to incorporate other pathological entities into such an assay.</p