First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)--a systematic review and individual patient data meta-analysis.

BACKGROUND: To investigate prognosis and effects of first-line therapy in elderly primary central nervous system lymphoma (PCNSL) patients. PATIENTS AND METHODS: A systematic review of studies about first-line therapy in immunocompetent patients ≥60 years with PCNSL until 2014 and a meta-analysis of individual patient data from eligible studies and international collaborators were carried out. RESULTS: We identified 20 eligible studies; from 13 studies, we obtained individual data of 405 patients, which were pooled with data of 378 additional patients (N = 783). Median age and Karnofsky Performance Score (KPS) was 68 years (range: 60-90 years) and 60% (range: 10%-100%), respectively. Treatments varied greatly, 573 (73%) patients received high-dose methotrexate (HD-MTX)-based therapy. A total of 276 patients received whole-brain radiotherapy (median 36 Gy, range 28.5-70 Gy). KPS ≥ 70% was the strongest prognostic factor for mortality [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.41-0.62]. After a median follow-up of 40 months, HD-MTX-based therapy was associated with improved survival (HR 0.70, 95% CI 0.53-0.93). There was no difference between HD-MTX plus oral chemotherapy and more aggressive HD-MTX-based therapies (HR 1.39, 95% CI 0.90-2.15). Radiotherapy was associated with an improved survival, but correlated with an increased risk for neurological side-effects (odds ratio 5.23, 95% CI 2.33-11.74). CONCLUSIONS: Elderly PCNSL patients benefit from HD-MTX-based therapy, especially if combined with oral alkylating agents. More aggressive HD-MTX protocols do not seem to improve outcome. WBRT may improve outcome, but is associated with increased risk for neurological side-effects. Prospective trials for elderly PCNSL patients are warranted.

Bone morphogenetic protein modulator BMPER is highly expressed in malignant tumors and controls invasive cell behavior.

Bone morphogenetic proteins (BMPs) are growth factors that exert important functions in cell proliferation, migration and differentiation. Till date, multiple human tumors have been reported to display a dysregulation of several members of the BMP pathway that is associated with enhanced malignant tumor growth and metastasis. BMPER (BMP endothelial cell precursor-derived regulator) is a direct BMP modulator that is necessary for BMPs to exert their full-range signaling activity. Moreover, BMPER is expressed by endothelial cells and their progenitors, and has pro-angiogenic features in these cells. Here, we describe the expression of BMPER in human specimens of lung, colon and cervix carcinomas and cell lines derived from such carcinomas. In contrast to healthy tissues, BMPER is highly expressed upon malignant deterioration. Functionally, loss of BMPER in the lung tumor cell line A549 impairs proliferation, migration, invasion as well as tumor cell-induced endothelial cell sprout formation. In contrast, stimulation of A549 cells with exogenous BMPER had no further effect. We found that the BMPER effect may be transduced by regulation of the BMP target transcription factor inhibitor of DNA binding 1 (Id1) and matrix metalloproteinases (MMPs) 9 and 2. These facilitators of cell migration are downregulated when BMPER is absent. To prove the relevance of our in vitro results in vivo, we generated Lewis lung carcinoma cells with impaired BMPER expression and implanted them into the lungs of C57BL/6 mice. In this model, the absence of BMPER resulted in severely reduced tumor growth and tumor angiogenesis. Taken together, these data unequivocally demonstrate that the BMP modulator BMPER is highly expressed in malignant tumors and tumor growth is dependent on the presence of BMPER.

Expression of CD44, ICAM-1 and N-CAM in colorectal cancer. Correlation with the tumor stage and the phenotypical characteristics of tumor-infiltrating lymphocytes.

The cellular adhesion molecules (CAMs) CD44s, CD44v6, CD44v10, ICAM-1 and N-CAM were immunohistologically detected in colorectal cancers using the APAAP method. The expression of CD44s and CD44v6 was associated with the presence of lymph node metastases in the examined tumors. The pattern of ICAM-1 expression was inversely related to that of CD44, i.e. lower numbers of ICAM-1 positive cells were observed in metastasizing tumors. An intense focal staining of N-CAM was observed in the majority of the metastasizing tumors. The expression of CD44v, ICAM-1 or N-CAM on tumor cells did not correlate with the density of the tumor-infiltrating lymphocytes (TIL) within the tumors. The flowcytometric analysis of TIL showed a significant accumulation of CD25+ and HLA-DR+ cells and a reduced number of CD45RA+ cells as compared to autologous peripheral blood lymphocytes (PBL) or intraepithelial lymphocytes of the colon mucosa (IEL). These phenotypic characteristics of TIL did not correlate with the CAMexpression on tumor cells.

Phenotypical and functional differences of tumor-infiltrating lymphocytes from human colorectal cancers induced by costimulation with rIL-2 and rIL-4 in vitro.

The influence of recombinant human interleukin-4 (rIL-4) on the proliferation and cytotoxic activity of tumor-infiltrating lymphocytes (TIL) from human colorectal cancers was investigated TIL and peripheral blood lymphocytes (PBL) were cultured for 3-5 weeks. Under simultaneous stimulation with rIL-2 and rIL-4 the proliferation of TIL was less pronounced compared to stimulation with rIL-2 alone. In rIL-2 expanded TIL an outgrowth of CD56+ cells was observed. Concordantly, the expression of CD3+ cells was low. The number of CD56+ cells could be reduced significantly in TIL and PBL by stimulation with rIL-2 and rIL-4 simultaneously while the number of CD3+ cells increased. In TIL and PBL co-stimulation with rIL2 and rIL-4 resulted in higher CD4/CD8 ratios as compared to expansion with rIL-2 alone. In a 72 hour cytotoxicity assay the rIL-2/rIL-4 expanded TIL and PBL showed a lower lytic activity against autologous tumor targets in comparison to the rIL-2 expanded lymphocytes. In contrast, the cytotoxic activity of rIL-2/rIL-4 cultured TIL against allogeneic tumor cells was higher than in rIL-2 stimulated TIL.

Morphological and functional characteristics of tumor-infiltrating lymphocytes from human colorectal cancers after stimulation with rIL-2.

Tumor-infiltrating lymphocytes (TILs) from colorectal cancers were separated from tumor cells by enzymatic and mechanical tissue disaggregation and discontinuous density gradients. Peripheral blood lymphocytes (PBLs) were isolated using the same procedure. The freshly separated TILs and PBLs were analyzed phenotypically by flow cytometry. The CD4+/CD8+ ratios of the freshly isolated TILs and PBLs were comparable (> 1 in both lymphocyte populations). CD25+, HLA-DR+ and CD56+ cells were significantly more frequent in the TIL than in the PBL population. However, the number of CD45RA+ cells was lower in the TILs as compared to PBLs, while CD29+ accumulated by about 90% in TILs. TILs and autologous PBLs were expanded in vitro with rIL-2. The mean rate of proliferation after 4 weeks was 642-fold in TIL cultures and 335-fold in PBLs. More than 90% of the rIL-2-expanded lymphocytes expressed CD2 and the great majority was CD29+. Stimulation with rIL-2 in vitro induced an outgrowth of CD56+ cells mainly in the TILs. Accordingly the expression of CD3+ and alpha/beta receptor in the TILs was low. Those cells which phenotypically represented lymphokine-activated killer cells displayed a lytic activity against the autologous tumor as well as against allogeneic K562 and Daudi targets. In accordance with the better proliferative response of TILs in long-term cultures with rIL-2, the lytic activity of TILs against autologous and allogeneic tumor targets was significantly higher as compared to PBLs.

Phenotypical and functional characteristics of tumor-infiltrating lymphocytes from colon carcinomas stimulated with rIL-2 and rIL-4 in vitro: comparison with lymphocytes of the normal colon mucosa and the peripheral blood.

The phenotypical composition of tumor-infiltrating lymphocytes (TIL) from colorectal carcinomas was compared with that of intraepithelial lymphocytes of the autologous normal colon mucosa (IEL) and autologous peripheral blood lymphocytes (PBL). The CD4+/CD8+ ratios of the freshly isolated TIL, IEL and PBL were comparable and always > 1. CD25+, HLA-DR+ and CD56+ cells accumulated significantly in the TIL, while CD45RA+ cells were less frequent compared to the autologous IEL and PBL. CD29+ memory-cells were found with the highest frequency in the TIL. Stimulation with rIL-2 in vitro induced an outgrowth of CD56+ cells in the TIL. Concordantly the expression of CD3+ and the alpha/beta T-cell receptor was low. In a standard 51Cr-release assay these phenotypically LAK-cells representing effectors displayed an unspecific lytic activity against the autologous tumor as well as against allogeneic K562 and Daudi targets. The number of CD56+ cells could be reduced in TIL and PBL by simultaneous stimulation with rIL-2 and rIL-4, while the number of CD3+ cells increased.