The prognostic impact of the tumor microenvironment in diffuse large B-cell lymphoma has not been systematically assessed. We analyzed mRNA and antigen expression of monocytes, macrophages, ...lymphocytes, dendritic and natural killer cells in pretreatment tumor samples of patients with high-risk diffuse large B-cell lymphoma using gene expression microarray and immunohistochemistry. The patients were treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis. Of the studied markers for non-malignant inflammatory cells, CD68 expression and CD68(+) macrophage counts correlated with favorable outcome. Five-year progression-free survival rates were 83% and 43% for the patients with high and low CD68 mRNA levels, respectively (P=0.007), while overall survival rates were 83% and 64%, respectively (P=ns). The patients with high CD68(+) macrophage counts had better 5-year progression-free survival (74% versus 40%; P=0.003) and overall survival (90% versus 60%; P=0.009) than the patients with low macrophage counts. Low CD68(+) macrophage count retained its prognostic impact on overall survival with age-adjusted International Prognostic Index RR=5.0 (95% CI 1.024-19.088); P=0.017. The findings were validated in three independent cohorts of patients treated with chemoimmunotherapy. In contrast, in patients treated with chemotherapy, high CD68(+) macrophage count was associated with poor progression-free survival (40% versus 72%; P=0.021) and overall survival (39% versus 72%; P=0.015). Together, the data suggest that macrophages exhibit a dual, treatment-specific role in diffuse large B-cell lymphoma. For the patients treated with chemoimmunotherapy, high pretreatment CD68 mRNA levels and CD68(+) macrophage numbers predict a favorable outcome.
Purpose: Tumor-associated macrophage (TAM) content predicts survival in follicular lymphoma (FL) patients treated with chemotherapy.
The aim of this study was to determine how combination of ...rituximab with chemotherapy influences TAM-associated clinical outcome.
Experimental Design: Expression of a macrophage marker, CD68, was determined immunohistochemically from FL samples of 96 patients treated with
rituximab and cyclophosphamide-Adriamycin-vincristine-prednisone regimen. Of them, 71 received therapy at diagnosis and 25
at relapse. Neutrophil and CD3+ lymphocyte counts were also measured. The median follow-up time for the cohort was 54 months.
Fourty-five patients previously treated with chemotherapy served as a control group.
Results: Consistent with previous studies, high TAM amount was associated with adverse outcome in chemotherapy-treated patients ( P = 0.026). In contrast, after rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone regimen, high TAM content
correlated with longer survival rates. According to Kaplan Meier estimates, the median progression free survival (PFS) was
not reached for patients with high TAM content compared with 45 months for patients with low TAM scores ( P = 0.006). A trend toward a better overall survival (OS) at 5 years was also observed for patients with high TAM content (OS,
97% versus 90%, P = 0.116). The positive prognostic value of TAMs was seen both for the patients treated at diagnosis and at relapse. In multivariate
analyses, TAM content remained an independent prognostic factor for OS and PFS. Neutrophil and CD3+ lymphocyte counts did
not correlate with outcome.
Conclusions: The data suggest that high TAM score is associated with a favorable prognosis in FL patients treated with immunochemotherapy.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Germinal center (GC) and non-GC phenotypes are predictors of outcome in diffuse large B-cell lymphoma (DLBCL) and can be used to stratify chemotherapy-treated patients into low- and high-risk groups. ...To determine how combination of rituximab with chemotherapy influences GC-associated clinical outcome, GC and non-GC phenotypes were identified immunohistochemically from samples of 90 de novo DLBCL patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)–like regimen (immunochemotherapy). One hundred and four patients previously treated with chemotherapy served as a control group. Consistent with previous studies, chemotherapy-treated patients with immunohistochemically defined GC phenotype displayed a significantly better overall (OS) and failure-free survival (FFS) than the non-GC group (OS, 70% vs 47%, P = .012; FFS, 59% vs 30%, P = .001). In contrast, immunohistochemically defined GC phenotype did not predict outcome in immunochemotherapy-treated patients (OS, 77% vs 76%, P = ns; FFS, 68% vs 63%, P = ns). In comparison, International Prognostic Index (IPI) could separate the high-risk patients from low- and intermediate-risk groups (OS, 84% vs 63%, P = .030; FFS, 79% vs 52%, P = .028). We conclude that rituximab in combination with chemotherapy seems to eliminate the prognostic value of immunohistochemically defined GC- and non-GC phenotypes in DLBCL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Male gender is an adverse prognostic factor in Hodgkin’s lymphoma, but no such association has yet been established in non‐Hodgkin lymphomas. Here, we have evaluated whether gender has prognostic ...impact on the survival of patients with B‐cell non‐Hodgkin lymphoma in the postrituximab era of lymphoma therapies. The study populations consisted of 217 diffuse large B‐cell lymphoma (DLBCL) and 110 follicular lymphoma (FL) patients treated with immunochemotherapy. Hundred and sixty chemotherapy‐treated DLBCL patients served as a control group. According to Kaplan–Meier analyses, female patients had a significantly better progression‐free survival than men both in DLBCL (4 yr PFS 75% vs. 60%; P = 0.013) and in FL (4 yr PFS 68% vs. 52%, P = 0.036) patients treated with immunochemotherapy. In chemotherapy‐treated DLBCL patients, no difference in survival between the genders was found. The results support the idea that women seem to respond better to rituximab.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, 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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hodgkin lymphoma (HL) is a malignancy of the lymphatic system that stems from germinal center B-cells. The global annual incidence of HL is 3 in 100,000, and it accounts for about 30% of all ...lymphomas. HL is further divided into four distinct subtypes, of which the classical Hodgkin lymphoma (cHL) constitutes 95 % of cases.
The etiology of cHL is not completely understood. There is strong evidence from epidemiological and molecular biology studies that Epstein-Barr virus infection is associated with cHL pathogenesis. Indeed, about 40% of cHL cases are Epstein-Barr virus (EBV) positive, i.e. they express EBV-encoded RNAs. The role of genetic factors is also acknowledged: familial clustering of cHL has been reported. However, to date a germline translocation affecting KLHDC8B gene is the only known candidate for a penetrant cHL predisposing mutation.
In this work, we studied a family of Middle-Eastern origin in which three out of five children were diagnosed with Epstein-Barr virus (EBV) positive cHL within a 6-year period. We exome sequenced the genomic DNA of three siblings diagnosed with cHL during childhood, and analyzed their shared germline variants using a control set of 3891 samples. In the exome data, all affected siblings displayed a relatively high degree of homozygosity, providing evidence for recessive mode of inheritance. After filtering against controls, 35 shared variants, of which only one was homozygous, remained. The candidate variants were then prioritized using computational methods and their effect to protein function was predicted. This left us with thirteen novel variants: a homozygous 57 bp in-frame deletion in ACAN, a removal of stop codon in LY75-CD302, a nonsense mutation in KIAA0140, and ten missense-type single-nucleotide variants (SNV) predicted damaging by two different computational methods. From these, homozygous deletion in ACAN (encoding for aggrecan) emerges as a candidate mutation for recessive cHL susceptibility. The deletion identified in ACAN removes part of the repeat sequence as well as 9 amino acids from the unique sequence. ACAN has not been associated with tumorigenesis or tumor predisposition thus far but recent research has, however, suggested that noncellular tumor microenvironment components may promote the oncogenic effects of EBV. Recessive pattern of inheritance would also fit the pedigree structure and the relatively high degree of homozygosity observed in affected siblings.
In this study, we identified several feasible candidate genes for cHL predisposition. The pedigree data, the overall variation data, and the homozygous ACAN mutation finding, are compatible with possible recessive inheritance, though other modes of inheritance cannot be excluded. The identified candidate genes provide a platform for validation studies in extended sets of familial cHL samples. Robust identification of additional mutations in families with this intriguing disease susceptibility phenotype would be a breakthrough in cHL risk prediction, and provide valuable clues to the molecular basis of Hodgkin lymphoma.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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