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Germinal center B-cell (GCB) DLBCL ( I n i = 60) displayed a differential somatic signature with enrichment of I EZH2 i , I TNFRSF14 i , I BCL2, ACTB, SOCS1, i and I FAS i mutations (Fisher's Exact, I p i < 10 SP -4 sp ), whereas mutations in I CDKN2A i , I PRDM1 i , I MYD88, i and I CD79B i were significantly enriched in non-GCB pts ( I p i < 10 SP -4 sp , I n i = 44). B Background: b Diffuse large B-cell lymphoma (DLBCL) harbors striking clinical and molecular heterogeneity, which continues to encumber risk stratification with a consequently high rate of refractory/relapsed patients (pts). EXPLORING DIFFERENTIAL MUTATIONAL DISTRIBUTION BY TARGETED SEQUENCING IN A R-CHOP TREATED COHORT OF DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS. [Extracted from the article]

Background The purpose of this study was to investigate whether an initial post-operative lactate level is a predictor of mortality, need for peritoneal dialysis ( PD), duration of intubation or length of stay ( LOS) in the intensive care unit ( ICU) in children undergoing cardiac surgery. Method A retrospective, observational follow-up study was conducted in 206 children undergoing cardiac surgery from 2006 to 2007. Multivariate logistics regression analyses were performed to determine whether the lactate level was an independent risk factor. The lactate concentration at arrival in the ICU, outcome and risk factors (patient demographics, surgical complexity, duration of cardiopulmonary bypass and inotropic score) were obtained from the electronic patient data management program and medical records. Result The median (interquartile range) lactate level was 1.9 mmol/l (1.3-2.7) in children immediately after cardiac surgery and a mortality of 3.9%. Eight percent of the children had a lactate level higher than 4.5 mmol/l. An increased lactate level ≥4.5 mmol/l resulted in an odds ratio (95% confidence intervals) of 8.4 (1.5-46.1) for mortality and an odds ratio of 16.9 (2.7-106.8) for PD after adjusting for Risk Adjustment for Congenital Heart Surgery 1. Because of the low number of deaths, limited confounder analysis was performed. Duration of intubation and LOS in the ICU were not associated with the initial lactate level when adjusting for confounders. Conclusion The initial post-operative lactate level was a predictor of mortality and need for PD in children undergoing surgery for congenital heart disease. [ABSTRACT FROM AUTHOR]

The INK4a/ARF locus at chromosome 9p21 encodes two structurally and functionally distinct molecules with tumor-suppressive properties. p16[SUPINK4a] controls cell cycle progression by inhibiting phosphorylation of the retinoblastoma protein (Rb), while ARF prevents MDM2-mediated degradation of p53. By using a panel of PCR-based methods, we have examined the status of the p16[SUPINK4a], ARF and p53 genes in 123 cases of non-Hodgkin's lymphoma (NHL) at diagnosis. Alterations of one or more of these genes were detected in seven of 36 (19%) cases with low- to intermediate-grade histology, and in 35 of 87 (40%) cases with aggressive histology. For the aggressive lymphomas, the Kaplan-Meier estimate of overall survival for cases with disruption of either p16[SUPINK4a] or the ARF-p53 pathway was not different from cases with retention of both pathways (5-year survival 45% vs 35%; P = 0.85), suggesting that selective inactivation of one of the pathways does not significantly influence overall survival. By contrast, the 5-year survival was only 7% for cases with concurrent disruption of p16[SUPINK4a] and the ARF-p53 pathway vs 38% for cases with retention of one or both pathways (P = 0.005). Similar results were obtained when the analysis was confined to diffuse large B cell lymphomas (P = 0.019). On stepwise multivariate regression analysis including factors from the international prognostic index, concurrent disruption of p16[SUPINK4a] and the ARF-p53 pathway was an independent negative prognostic factor in NHL with aggressive histology (P = 0.006). Our results suggest that the compound status of the p16[SUPINK4a] and ARF-p53 pathways is a major determinant of outcome in NHL. [ABSTRACT FROM AUTHOR]

The INK4a/ARF locus at chromosome 9p21 encodes two structurally and functionally distinct molecules with tumor-suppressive properties. p16INK4a controls cell cycle progression by inhibiting phosphorylation of the retinoblastoma protein (Rb), while ARF prevents MDM2-mediated degradation of p53. By using a panel of PCR-based methods, we have examined the status of the p16INK4a, ARF and p53 genes in 123 cases of non-Hodgkin's lymphoma (NHL) at diagnosis. Alterations of one or more of these genes were detected in seven of 36 (19%) cases with low- to intermediate-grade histology, and in 35 of 87 (40%) cases with aggressive histology. For the aggressive lymphomas, the Kaplan-Meier estimate of overall survival for cases with disruption of either p16INK4a or the ARF-p53 pathway was not different from cases with retention of both pathways (5 year survival 45% vs 35%; P= 0.85), suggesting that selective inactivation of one of the pathways does not significantly influence overall survival. By contrast, the 5-year survival was only 7% for cases with concurrent disruption of p16INK4a and the ARF-p53 pathway vs 38% for cases with retention of one or both pathways (P = 0.005). Similar results were obtained when the analysis was confined to diffuse large B cell lymphomas (P= 0.019). On stepwise multivariate regression analysis including factors from the international prognostic index, concurrent disruption of p16INK4a and the ARF-p53 pathway was an independent negative prognostic factor in NHL with aggressive histology (P = 0.006). Our results suggest that the compound status of the p16INK4a and ARF-p53 pathways is a major determinant of outcome in NHL. [ABSTRACT FROM AUTHOR]

In the present study, we analysed 34 de novo diffuse large B cell lymphoma (DLCL) from a population-based lymphoma registry for alterations of the RB1 pathway at the genetic (RB1 and CDK4) and protein (pRb, cyclin D1, cyclin D3, CDK4, and E2F-1) level. The results were correlated with the data from our previous studies of CDKN2A deletion and hypermethylation, other p53 pathway components, p27Kip1 expression, and proliferation, as well as with clinical outcome, including prognosis. We found aberrant pRb expression in four (12%) of 34 DLCLs. One of these had a point mutation in intron 3 10 bp downstream of exon 3 generating a novel splice signal. Seven tumours (21%) showed cyclin D3 overexpression, including all three thyroid lymphomas (P = 0.006). Cyclin D3 overexpression and p16INK4A/pRb aberrations were mutually exclusive, supporting an oncogenic role for cyclin D3 in DLCL. p16INK4A inactivation, cyclin D3 overexpression, or aberrant pRb expression was identified in 18 of 34 DLCLs (53%). Combining these results with our previous p53 pathway studies showed that 82% of the de novo DLCLs had alterations of these pathways, and that both pathways were altered in 13 cases (38%). Low E2F-1 expression was associated with treatment failure (P = 0.020), and multivariate analysis of overall survival identified both low E2F-1 expression (relative risk = 6.9; P = 0.0037) and p16INK4A inactivation (relative risk = 3.3; P = 0.0247) as independent prognostic markers. These data support a role of E2F-1 as tumour suppressor gene in lymphoma and strongly suggest that the RB1 and p53 pathways are important in the development of de novo DLCL. Furthermore, low E2F-1 expression and p16INK4A inactivation may serve as prognostic markers for patients with this type of lymphoma. [ABSTRACT FROM AUTHOR]

The two gene products of the CDKN2A gene, p16 and p19ARF, have recently been linked to each of two major tumour suppressor pathways in human carcinogenesis, the RB1 pathway and the p53 pathway. p16 inhibits the phosphorylation of the retinoblastoma gene product by cyclin D-dependent kinases, whereas p19ARF targets MDM2, a p53 inhibitory protein, for degradation. A deletion of CDKN2A would therefore disturb both pathways. To explore the p53 pathway genes as a functional unit in diffuse large B cell non-Hodgkin's lymphomas (DLCL), we wanted to see whether there exists mutually exclusiveness of aberrations of CDKN2A, MDM2 and p53, since this has not been analysed previously. We investigated 37 DLCL for aberrations of p15, p16, p19ARF, MDM2, and p53 at the epigenetic, genetic and/or protein levels. Homozygous deletion of CDKN2A was detected in seven (19%) of 37 tumours, and another three cases were hypermethylated at the 5' CpG island of p16. No point mutations were found in CDKN2B or CDKN2A. Immunohistochemical staining of formalin-fixed, paraffin-embedded tissue for p16 confirmed these results, as all tumours with alterations of CDKN2A were p16 immunonegative. We found p53 mutations in eight (22%) cases and MDM2 overexpression in 16 (43%) tumours. Twenty-three (62%) tumours had alterations of one or more p53 pathway components (p53, p19ARF and MDM2). Furthermore, 7/9 (78%) p16-immunonegative tumours showed co-aberration of p53 and/or MDM2. The lack of correlation between these aberrations suggests that DLCL acquire additional growth advantage by inactivating both of these critical regulatory pathways. [ABSTRACT FROM AUTHOR]

The model of insertions and deletions in biological sequences, first formulated by Thorne, Kishino, and Felsenstein in 1991 (the TKF91 model), provides a basis for performing alignment within a statistical framework. Here we investigate this model.Firstly, we show how to accelerate the statistical alignment algorithms several orders of magnitude. The main innovations are to confine likelihood calculations to a band close to the similarity based alignment, to get good initial guesses of the evolutionary parameters and to apply an efficient numerical optimisation algorithm for finding the maximum likelihood estimate. In addition, the recursions originally presented by Thorne, Kishino and Felsenstein can be simplified. Two proteins, about 1500 amino acids long, can be analysed with this method in less than five seconds on a fast desktop computer, which makes this method practical for actual data analysis.Secondly, we propose a new homology test based on this model, where homology means that an ancestor to a sequence pair can be found finitely far back in time. This test has statistical advantages relative to the traditional shuffle test for proteins.Finally, we describe a goodness-of-fit test, that allows testing the proposed insertion-deletion (indel) process inherent to this model and find that real sequences (here globins) probably experience indels longer than one, contrary to what is assumed by the model., (Copyright 2000 Academic Press.)

In order to survive, cells need tight control of cell cycle progression. The control mechanisms are often lost in human cancer cells. The cell cycle is driven forward by cyclin-dependent kinases (CDKs). The CDK inhibitors (CKIs) are important regulators of the CDKs. As the name implies, CKIs were initially shown to negatively regulate CDK activity. However, recent data indicates that the members of the Kip/Cip family of CKIs, including p27, exert both positive and negative regulation of CDK activity at the G1/S phase transition. Mutations of Kip/Cip genes are rare, but p27 knockout mice are tumor prone when challenged with carcinogenic stimuli. Numerous studies of various human non-hematological tumors have identified low expression of p27 as a predictor of poor prognosis. In non-Hodgkin's lymphoma (NHL), we and others have also shown the independent prognostic value of p27 expression. In distinct NHL entities however, shortened survival seems to correlate with high expression of p27. For definitive assessment of the role played by p27 in lymphomagenesis, and the prognostic value of p27 in these tumors, further studies of distinct NHL entities are needed. This review addresses the function of p27 and the other Kip/Cip proteins in G1/S phase transition and their possible role in tumorigenesis with emphasis on p27 and NHL.

MDM2 is an oncoprotein involved in the regulation of p53. MDM2 exerts its tumorigenic potential through p53-dependent and -independent mechanisms. It is frequently overexpressed in various malignancies. Little is known about the prognostic value of MDM2 expression in non-Hodgkin's lymphomas (NHL). We analyzed MDM2 expression immunohistochemically in 188 NHL cases from a prospective population-based NHL registry. The aim was to identify MDM2 expression profiles in various histological NHL subtypes and analyze whether MDM2 expression correlated with clinical variables and p53 status. MDM2 overexpression was present in 42 (22%) of 188 cases. The frequency was highest in aggressive/very aggressive NHL (P < .0001). Furthermore, within follicle center lymphomas, MDM2 overexpression was associated with higher-grade disease (P = .008). MDM2 overexpression was not related to a phenotype indicating altered p53. In univariate analysis MDM2 overexpression associated with short survival in follicle center lymphomas (P = .0256), extranodal marginal zone lymphomas (P < .0001), and mantle cell lymphomas (P = .0047). The relation to poor prognosis was maintained in a Cox regression analysis including known prognostic factors (relative risk 5.5, P = .0022). The results of the present study suggest that MDM2 may play a role in lymphomagenesis and lymphoma progression through p53-independent mechanisms, and that MDM2 overexpression identifies a small fraction of follicle center lymphomas, extranodal marginal zone lymphomas, and mantle cell lymphomas with poor prognosis.

Mutation of the p53 gene has been associated with treatment failure and poor outcome in various malignancies. It has been suggested that immunohistochemical analysis of p53 and p21Waf1, a downstream target, can be used to screen for p53 gene mutations. We determined the value of immunohistochemical screening for p53 gene mutations as a prognostic marker in a population-based group of B- and T-cell non-Hodgkin's lymphomas (NHLs). On the basis of p53 gene mutation status and immunohistochemically detected p53 and p21Waf1 expression in 34 lymphomas, we established an immunophenotype (delta p53) correlating with p53 gene mutation. The immunohistochemical analysis was extended to encompass 199 lymphomas from a population-based registry and was correlated with clinical parameters. Delta p53 showed 100% concordance with p53 gene mutation and was detected in 42 cases (21%). Multivariate analysis of advanced stage lymphomas showed that delta p53 was independently associated with treatment failure (relative risk, 3.8; P = 0.001). Delta p53 predicted poor survival when analyzing all patients (P = 0.0001), as well as B-cell (P = 0.04) and T-cell NHL (P = 0.000002). In multivariate analysis, delta p53 (relative risk, 2.2; P = 0.001) maintained prognostic significance. The impact on prognosis of delta p53 was highly significant in the low-intermediate-risk group (P = 0.00002). Comparing survival of the aggressive lymphoma patients in this group showed that the 8 delta p53 patients died within 1 year, whereas the median survival of the 28 non-delta p53 patients was 36 months. These results suggest that immunohistochemically assessed p53 status may predict treatment response and outcome in B- and T-cell NHL patients.

The selection criteria and treatment of a form of vestibular disorder labeled 'disabling positional vertigo' (DPV) are given. Microvascular decompression of the auditory-vestibular nerve in 207 patients with DPV resulted in a cure rate of 79%. However, most of the patients with DPV (approximately 80%) were successfully treated by medication.