Gene expression profiling studies initially enabled diffuse large B-cell lymphoma to be divided into germinal center and activated B-cell-like subtypes, which define high- and low-risk patient groups ...when treated with chemotherapy. Attempts to reproduce the prognostic classification immunohistochemically have, however, provided inconsistent results. The aim of this study was to determine whether modified immunohistochemical classification of cell of origin focusing on activated B-cell-like markers could be used to predict the outcome of immunochemotherapy-treated diffuse large B-cell lymphoma patients. The expression of CD10, Bcl-6, MUM1/IRF4, Bcl-2, and FOXP1 was determined immunohistochemically from 88 samples of diffuse large B-cell lymphoma patients treated uniformly with R-CHOP. When the modified classification using MUM1/IRF4 and FOXP1 positivities as activated B-cell-like markers was applied to distinguish the patients between the activated B-cell-like and other diffuse large B-cell lymphoma subtypes, a significantly worse outcome was seen for the patients with the activated B-cell-like phenotype (3-year failure-free survival 63 vs 82%, P=0.048, overall survival 69 vs 85%, P=0.110). Similarly, according to the Muris algorithm, the group 2 patients representing Bcl-2-positive post-germinal center patients showed an inferior outcome in comparison to the group 1 patients (failure-free survival 59 vs 81%, P=0.041, overall survival 67 vs 82%, P=0.159). In contrast, when the classification of the same cohort was performed according to the Hans algorithm, no significant difference in survival was observed between the germinal center and non-germinal center patients. In conclusion, the data suggest that both the modified activated B-cell-like and Muris classifications define the non-germinal center phenotype as an adverse risk factor in R-CHOP-treated diffuse large B-cell lymphoma patients.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in ...large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the Nordic MCL2 trial (screening cohort). Prognostic miRNAs were validated in diagnostic MCL samples from 94 patients of the independent Nordic MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, and miR-378d) were significantly differentially expressed in patients who died of MCL in both cohorts. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new biological MCL International Prognostic Index (MIPI-B)-miR prognosticator, combining expression levels of miR-18b with MIPI-B data. Compared to the MIPI-B, this prognosticator improved identification of high-risk patients with regard to cause-specific, overall, and progression-free survival. Transfection of 2 MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting that miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.
•miR-18b overexpression identified patients with poor prognosis in 2 large prospective homogenously treated MCL cohorts.•miR-18b overexpression adds prognostic information to the MIPI-B prognosticator.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Emerging evidence indicates a major impact for the tumor microenvironment (TME) and immune escape in the pathogenesis and clinical course of classical Hodgkin lymphoma (cHL). We used gene expression ...profiling (n = 88), CIBERSORT, and multiplex immunohistochemistry (n = 131) to characterize the immunoprofile of cHL TME and correlated the findings with survival. Gene expression analysis divided tumors into subgroups with T cell-inflamed and -noninflamed TME. Several macrophage-related genes were upregulated in samples with the non–T cell-inflamed TME, and based on the immune cell proportions, the samples clustered according to the content of T cells and macrophages. A cluster with high proportions of checkpoint protein (programmed cell death protein 1, PD-1 ligands, indoleamine 2,3 dioxygenase 1, lymphocyte-activation gene 3, and T-cell immunoglobulin and mucin domain containing protein 3) positive immune cells translated to unfavorable overall survival (OS) (5-year OS 76% vs 96%; P = .010) and remained an independent prognostic factor for OS in multivariable analysis (HR, 4.34; 95% CI, 1.05-17.91; P = .043). cHL samples with high proportions of checkpoint proteins overexpressed genes coding for cytolytic factors, proposing paradoxically that they were immunologically active. This checkpoint molecule gene signature translated to inferior survival in a validation cohort of 290 diagnostic cHL samples (P < .001) and in an expansion cohort of 84 cHL relapse samples (P = .048). Our findings demonstrate the impact of T cell- and macrophage-mediated checkpoint system on the survival of patients with cHL.
•Composition of the cHL microenvironment is heterogeneous and differs in the proportions of T cells and macrophages.•High T cell and macrophage-mediated checkpoint protein expression in the cHL microenvironment associates with inferior OS.
Display omitted
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The European Cancer Registry-based project on hematologic malignancies (HAEMACARE), set up to improve the availability and standardization of data on hematologic malignancies in Europe, used the ...European Cancer Registry-based project on survival and care of cancer patients (EUROCARE-4) database to produce a new grouping of hematologic neoplasms (defined by the International Classification of Diseases for Oncology, Third Edition and the 2001/2008 World Health Organization classifications) for epidemiological and public health purposes. We analyzed survival for lymphoid neoplasms in Europe by disease group, comparing survival between different European regions by age and sex.
Incident neoplasms recorded between 1995 to 2002 in 48 population-based cancer registries in 20 countries participating in EUROCARE-4 were analyzed. The period approach was used to estimate 5-year relative survival rates for patients diagnosed in 2000-2002, who did not have 5 years of follow up.
The 5-year relative survival rate was 57% overall but varied markedly between the defined groups. Variation in survival within the groups was relatively limited across European regions and less than in previous years. Survival differences between men and women were small. The relative survival for patients with all lymphoid neoplasms decreased substantially after the age of 50. The proportion of 'not otherwise specified' diagnoses increased with advancing age.
This is the first study to analyze survival of patients with lymphoid neoplasms, divided into groups characterized by similar epidemiological and clinical characteristics, providing a benchmark for more detailed analyses. This Europe-wide study suggests that previously noted differences in survival between regions have tended to decrease. The survival of patients with all neoplasms decreased markedly with age, while the proportion of 'not otherwise specified' diagnoses increased with advancing age. Thus the quality of diagnostic work-up and care decreased with age, suggesting that older patients may not be receiving optimal treatment.
Cyclooxygenase (COX) catalyzes synthesis of prostanoids after liberation of arachidonic acid, an important biochemical sequela of cerebral ischemia that aggravates brain injury. We investigated ...expression of inducible COX‐2 in infarcted human brains (symptom duration, 15 hours to 18 days) and found that COX‐2 protein was present in both neuronal and glial cells throughout the brain in accord with infarct topography and duration. These results emphasize the global yet temporally regulated nature of COX‐2 induction during focal ischemia in humans, clearly different from the circumscribed acute expression reported in experimental animal models. We speculate that early induction of COX‐2 may fuel tissue damage through prostanoids and free radicals, and delayed induction in remote brain areas may promote reconstitutive processes in the face of tissue scarring and remodeling of the surviving neural networks.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Gene expression profiling and immunohistochemical studies have demonstrated that nonmalignant tumor infiltrating inflammatory cells contribute to clinical outcome in patients with follicular lymphoma ...(FL). Particularly, tumor-associated macrophage (TAM) content correlates with longer survival rates after immunochemotherapy. Here we investigated the prognostic importance of tumor-associated mast cells (MCs) and their relation to TAMs in patients with FL treated with a combination of rituximab (R) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. Of the 98 patients, 70 received R-CHOP at diagnosis and 28 at relapse. According to Kaplan-Meier estimates, the patients with high MC content had a worse 4-year progression-free survival (PFS) than the ones with low MC content after R-CHOP therapy (34% vs 74%, P = .002). The adverse prognostic value of MCs was seen both for the patients treated at diagnosis and at relapse, whereas no such impact on PFS was observed for the control patients treated with chemotherapy only (P = .4). When the TAM-related PFS was analyzed separately in patients with high and low MC contents, the positive prognostic effect of TAM was seen only in patients with few MCs. Taken together, the data demonstrate that a high MC score is associated with unfavorable prognosis and it eliminates the positive prognostic value of TAMs in patients with FL treated with immunochemotherapy.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Animal experiments have suggested that apoptotic programmed cell death is responsible for an important portion of the delayed ischaemic brain damage. Antiapoptotic signalling through erythropoietin ...(EPO) binding to its receptor (EPOR) is triggered by systemic or local hypoxia and may exist in the post-ischaemic brain, and a neuroprotective effect by EPO was described recently and proposed for clinical stroke treatment. The objective of the study was to determine whether apoptosis occurs in human ischaemic stroke and to describe its topographical distribution. An autopsy cohort consisting of 13 cases of fatal ischaemic stroke (symptom duration from 15 h to 18 days) treated at the Department of Neurology, Helsinki University Central Hospital and 3 controls were studied. DNA damage was investigated by immunofluorescent TUNEL-labelling in combination with apoptotic cell morphology and by visualization of a major signalling system of apoptosis, Fas−FasL (Fas-ligand), by the immunoperoxidase technique. The relationship of EPO and EPOR in the face of TUNEL-labelled and necrotic cell death was co-registered in human cerebral neurons undergoing different stages of ischaemic change. TUNEL-labelled cells with apoptotic morphology were disproportionately more frequent, 148% (30) mean (SE) in the periinfarct versus 97% (22) in the core, as percentage of the cells in the contralateral hemisphere (P = 0.027). The apoptotic cell percentage reached up to 26% (2) of all cells in periinfarct area. A linear correlation was found for Fas and its counterpart FasL expression (rS = 0.774, P < 0.001). Ischaemia induced widespread neuronal expression of EPOR, which was inversely related to the severity of ischaemic neuronal necrosis (P < 0.05). To conclude, these data verify the predominance of apoptosis in the periphery of human ischaemic infarctions. Fas and FasL were linearly overexpressed supporting that this ‘death-receptor’ complex may promote the completion of cell death. Increased EPO signalling may be a cellular response for survival in less severely damaged areas. These results support antiapoptotic therapies against delayed neuronal cell death in human ischaemic stroke.
This study was approved by the local research ethics committee, and patient informed consent was obtained. The purpose of this study was to demonstrate that high-spatial-resolution low-dose ...analyzer-based x-ray computed tomography (CT) can substantially improve the radiographic contrast of breast tissue in vitro when compared with that attained by using diagnostic mammography and CT. An excised human breast tumor was examined by using analyzer-based x-ray imaging with synchrotron radiation. The correspondence between analyzer-based x-ray images and diagnostic mammograms, CT images, and histopathologic findings was determined. Calcifications and fine details of soft tissue, which are at the contrast detection limit on diagnostic mammograms, are clearly visible on planar analyzer-based x-ray images. Analyzer-based x-ray CT yields high contrast from smoothly varying internal structures, such as tumorous mass lesions, corresponding to information on actual structures seen at histopathologic analysis. The mean glandular dose of 1.9 mGy in analyzer-based x-ray CT is approximately equivalent to the dose administered during single-view screening mammography. The improved visibility of mammographically indistinguishable lesions in vitro suggests that analyzer-based x-ray CT may be a valuable method in radiographic evaluation of the breast, thereby justifying further investigations.
Despite improved survival for the patients with diffuse large B-cell lymphoma (DLBCL), the prognosis after relapse is poor. The aim was to identify molecular events that contribute to relapse and ...treatment resistance in DLBCL.
We analysed 51 prospectively collected pretreatment tumour samples from clinically high risk patients treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis with high resolution array comparative genomic hybridization (aCGH) and gene expression microarrays. Major finding was validated at the protein level immunohistochemically in a trial specific tissue microarray series of 70, and in an independent validation series of 146 patients.
We identified 31 genes whose expression changes were strongly associated with copy number aberrations. In addition, gains of chromosomes 2p15 and 18q12.2 were associated with unfavourable survival. The 2p15 aberration harboured COMMD1 gene, whose expression had a significant adverse prognostic impact on survival. Immunohistochemical analysis of COMMD1 expression in two series confirmed the association of COMMD1 expression with poor prognosis.
COMMD1 is a potential novel prognostic factor in DLBCLs. The results highlight the value of integrated comprehensive analysis to identify prognostic markers and genetic driver events not previously implicated in DLBCL.
ClinicalTrials.gov NCT01502982.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
