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Background and Aims: The results of class prediction and the determination of prognostic markers in diffuse large B-cell lymphoma (DLBCL) have been variably reported. Apart from biological variations, this may be caused by differences in laboratory techniques, scoring definitions and inter-and intra-observer variation. In this study, an international collaboration of clinical lymphoma research groups has concentrated on validation and standardisation of immunohistochemistry of the currently potentially interesting prognostic markers in DLBCL. Methods: Sections of a tissue microarray with 36 cases of DLBCL were stained in eight laboratories with antibodies to CD20, CD5, bcl-2, bcl-6, CD10, HLA-DR, MUM-1 and Ki-67 according to local methods. The study was performed in two rounds, firstly focused on the evaluation of laboratory staining variation, and secondly on the scoring variation. Results: Different techniques resulted in highly variable results and poor reproducibility for almost all markers. Reproducibility of the nuclear markers was highly sensitive to technical variations, including immunological enhancement techniques (agreements 34%). With elimination of variation due to staining and uniformly agreed on scoring criteria, significant improvement was seen; however less so for bcl-6 and Ki-67 (agreement 53-58%). Absence of internal controls that preclude scoring, significantly influenced the results for CD10 and bcl-6. Conclusion: Semi-quantitative immunohistochemistry for subclassification of DLBCL is feasible, but with varying rates of concordance for different markers and only using optimised techniques and strict scoring criteria. These findings may explain the wide variation in prognostic impact reported in the literature. Harmonisation of techniques and centralised consensus review appears mandatory when using immunohistochemical biomarkers for treatment stratification.

Contains fulltext : 79658.pdf (Publisher’s version ) (Closed access) Not all patients with squamous cell carcinomas of the head and neck (HNSCC) benefit from concurrent cisplatin-based chemoradiation, but reliable predictive markers for outcome after chemoradiation are scarce. We have investigated potential prognostic biomarkers for outcome in a large group of patients. Ninety-one tumor biopsies taken from consecutive HNSCC patients were evaluated for protein expression on a tissue microarray. Using immunohistochemistry, 18 biomarkers, involved in various cellular pathways were investigated. Univariable and multivariable proportional hazard analyses were performed to investigate associations between each individual marker and outcome. In addition, the global test was used to test all variables simultaneously and selected combinations of markers for an overall association with local control. Univariable analysis showed statistically significant increased relative risks of RB, P16 and MRP2 for local control and MDR1 and HIF-1alpha for overall survival. MRP2, MDR1 and P16 levels were positively associated with outcome whereas RB and HIF-1alpha had a negative relationship. Using Goeman's global testing no combination of markers was identified that was associated with local control. Grouping the markers according to their function revealed an association between a combination of 3 markers (P16, P21 and P27) and outcome (p = 0.05) was found. In the multivariable analysis, MRP2 and RB remained significant independent predictive markers for local control. This study describes the prognostic value of biomarkers for the outcome in patients uniformly treated with concurrent chemoradiation. MRP2 and RB were found to be associated with outcome in patients treated with concurrent chemoradiation.

Inflammatory conditions are characterized by activation of the transcription factor nuclear factor kappa B (NF-kappaB), resulting in the expression of NF-kappaB-regulated, inflammation-related genes, such as inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2). Expression of these genes contributes to the survival of cells. Indeed, exposure to pro-inflammatory cytokines in the absence of NF-kappaB activation leads to apoptosis. 1,2 Chronic inflammatory conditions are accompanied by constitutive activation of NF-kappaB and hence, to the continuous expression of pro-survival genes, as has been observed in chronic gastritis. 3 Although beneficial for the survival of cells during exposure to inflammatory stress, the continuous activation of NF-kappaB may also pose a risk: cells with a pro-survival phenotype may give rise to continuously proliferating cells and may thus be tumorigenic. Progression to a malignant phenotype of these cells will most likely involve additional changes in the expression of non-NF-kappaBregulated genes e.g. a shift in the balance of pro- and anti-apoptotic genes towards a more antiapoptotic phenotype. Literature on inflammation-related genes and the apoptotic balance in pre-malignant and malignant conditions in the gastro-intestinal tract is still scarce and conflicting. In this review, we aim to give an overview of the existing literature and we will focus on inflammation- and apoptosis-related genes in the sequence of normal epithelium-inflamed epithelium-metaplasia-dysplasia-cancer in the gastrointestinal tract, in particular esophagus (Barrett's esophagus: BE), stomach (gastritis) and colon (inflammatory bowel disease: IBD).

With rising age the incidence of non-Hodgkin's lymphoma (NHL), together with the fact that the proportion of people older than 65 years in Western populations will double during the next 40 years, poses the challenge to adequately meet the needs of elderly patients. After a general introduction on cancer in the elderly, a review is given concerning aspects of epidemiology and prognostic factors of NHL. Therapeutic strategies, including the use of hematopoietic growth factors, for the elderly with aggressive NHL are discussed. The future role for so-called comprehensive geriatric assessment (CGA) to appropriately determine treatment possibilities is emphasized. Much scientific work has to be performed before the true value of CGA instruments can be acknowledged. Screening instruments are discussed and the role for specially trained oncology nurses in the assessment process is stipulated.

Background and Aims: The results of class prediction and the determination of prognostic markers in diffuse large B-cell lymphoma (DLBCL) have been variably reported. Apart from biological variations, this may be caused by differences in laboratory techniques, scoring definitions and inter-and intra-observer variation. In this study, an international collaboration of clinical lymphoma research groups has concentrated on validation and standardisation of immunohistochemistry of the currently potentially interesting prognostic markers in DLBCL. Methods: Sections of a tissue microarray with 36 cases of DLBCL were stained in eight laboratories with antibodies to CD20, CD5, bcl-2, bcl-6, CD10, HLA-DR, MUM-1 and Ki-67 according to local methods. The study was performed in two rounds, firstly focused on the evaluation of laboratory staining variation, and secondly on the scoring variation. Results: Different techniques resulted in highly variable results and poor reproducibility for almost all markers. Reproducibility of the nuclear markers was highly sensitive to technical variations, including immunological enhancement techniques (agreements 34%). With elimination of variation due to staining and uniformly agreed on scoring criteria, significant improvement was seen; however less so for bcl-6 and Ki-67 (agreement 53-58%). Absence of internal controls that preclude scoring, significantly influenced the results for CD10 and bcl-6. Conclusion: Semi-quantitative immunohistochemistry for subclassification of DLBCL is feasible, but with varying rates of concordance for different markers and only using optimised techniques and strict scoring criteria. These findings may explain the wide variation in prognostic impact reported in the literature. Harmonisation of techniques and centralised consensus review appears mandatory when using immunohistochemical biomarkers for treatment stratification.

Follicular lymphoma (FL), except grade 3B, is characterized by the chromosomal translocation t(14;18)(q32;q21), which results in over-expression of the Bcl-2 protein. Ten per-cent of all FLs, however, do not show Bcl-2 protein expression with standard immunohistochemistry using a monoclonal Bcl-2 antibody against residues 41-54 of the Bcl-2 protein. In this study, the biological background of 18 Bcl-2-negative FL cases grade I, II, or IIIa was investigated by immunohistochemical staining and western blot analysis with alternative antibodies. Bcl-2 protein was demonstrated in five of the 18 cases and all of these carried the t(14;18) translocation. Of the 13 cases that were Bcl-2 negative with alternative antibodies, 12 lacked the t(14;18) translocation. PCR and subsequent sequence analysis of cDNA demonstrated that three cases with a t(14;18) contained somatic mutations in the translocated BCL2 gene, resulting in amino acid replacements in the region of the epitope recognized by the antibody. In conclusion, the majority of Bcl-2-negative FL lack a t(14;18) but a significant subset of these tumours are false negative due to mutations in the BCL2 gene. These findings may have consequences for the use of Bcl-2 immunohistochemistry for diagnostic purposes. Copyright (C) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.

New knowledge of the pathophysiology and evolution of hypoxic-ischemic brain injuries has made feasible interventions to improve clinical outcomes for newborns surviving birth asphyxia. Brain injury following hypoxic-ischemic insult is a complex process evolving over hours to days, which provides a unique window of opportunity for neuroprotective treatment interventions. The specific pathologic processes preceding the onset of irreversible cerebral injury appear to be a combination of several mechanisms that are variable according to the severity and duration of the insult and to biochemical modifications in the brain. Advances in neuroimaging, brain monitoring techniques, and tissue biomarkers have improved the ability to diagnose, monitor, and care for newborn infants with neonatal encephalopathy, as well as to predict their outcome. The role of oxidative stress in newborn morbidity with respect to the higher risk of free radical damage in these babies is growing. However, challenges remain in early identification of infants at risk for neonatal encephalopathy, determination of timing and extent of hypoxic-ischemic brain injury, as well as optimal management and treatment duration. Potential neuroprotective strategies targeting different pathways leading to neuronal cell death in response to hypoxic-ischemic insult have been investigated: hypothermia, erythropoietin, iminobiotin, deferioxamine, magnesium, allopurinol, xenon, melatonin and statins. Hypothermia is currently the only recognized beneficial therapy. However, many infants still develop significant adverse outcomes. It is becoming evident that the association of moderate hypothermia with neuroprotective drugs may enhance the outcome. By virtue of their pleiotropic effects without toxic effects, melatonin and statins may act at different levels of the multiple mechanisms responsible for the progression of the neurodegenerative process and represent promising neuroprotectants, alone or as additional adjunctive therapy, for reducing brain injury and its long-term sequelae in infants. More clinical studies are needed to clarify the role of these potential neuroprotective drugs.