Predictive MGMT status in a homogeneous cohort of IDH wildtype glioblastoma patients

Methylation of the O(6)-Methylguanine-DNA methyltransferase (MGMT) promoter is predictive for treatment response in glioblastoma patients. However, precise predictive cutoff values to distinguish "MGMT methylated" from "MGMT unmethylated" patients remain highly debated in terms of pyrosequencing (PSQ) analysis. We retrospectively analyzed a clinically and molecularly very well-characterized cohort of 111 IDH wildtype glioblastoma patients, who underwent gross total tumor resection and received standard Stupp treatment. Detailed clinical parameters were obtained. Predictive cutoff values for MGMT promoter methylation were determined using ROC curve analysis and survival curve comparison using Log-rank (Mantel-Cox) test. MGMT status was analyzed using pyrosequencing (PSQ), semi-quantitative methylation specific PCR (sqMSP) and direct bisulfite sequencing (dBiSeq). Highly methylated (> 20%) MGMT correlated with significantly improved progression-free survival (PFS) and overall survival (OS) in our cohort. Median PFS was 7.2 months in the unmethylated group (UM, 20% mean methylation). Median OS was 13.4 months for UM, 17.9 months for LM and 29.93 months for HM. Within the LM group, correlation of PSQ and sqMSP or dBiSeq was only conclusive in 51.5% of our cases. ROC curve analysis revealed superior test precision for survival if additional sqMSP results were considered (AUC = 0.76) compared to PSQ (cutoff 10%) alone (AUC = 0.67). We therefore challenge the widely used, strict PSQ cutoff at 10% which might not fully reflect the clinical response to alkylating agents and suggest applying a second method for MGMT testing (e.g. MSP) to confirm PSQ results for patients with LM MGMT levels if therapeutically relevant

CXCL16-mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway

Objective Rheumatoid arthritis (RA) is characterized by profound mononuclear cell (MNC) recruitment into synovial tissue (ST), thought to be due in part to tumor necrosis factor Α (TNFΑ), a therapeutic target for RA. Although chemokines may also be involved, the mechanisms remain unclear. We undertook this study to examine the participation of CXCL16, a novel chemokine, in recruitment of MNCs to RA ST in vivo and to determine the signal transduction pathways mediating this process. Methods Using a human RA ST–SCID mouse chimera, immunohistochemistry, enzyme-linked immunosorbent assay, real-time reverse transcription–polymerase chain reaction, flow cytometry, and in vitro chemotaxis assays, we defined the expression and function of CXCL16 and its receptor, CXCR6, as well as the signal transduction pathways utilized by them for MNC homing in vitro and in vivo. Results CXCL16 was markedly elevated in RA synovial fluid (SF) samples, being as high as 145 ng/ml. Intense macrophage and lining cell staining for CXCL16 in RA ST correlated with increased CXCL16 messenger RNA levels in RA ST compared with those in osteoarthritis and normal ST. By fluorescence-activated cell sorting analysis, one-half of RA SF monocytes and one-third of memory lymphocytes expressed CXCR6. In vivo recruitment of human MNCs to RA ST implanted in SCID mice occurred in response to intragraft injection of human CXCL16, a response similar to that induced by TNFΑ. Lipofection of MNCs with antisense oligodeoxynucleotides for ERK-1/2 resulted in a 50% decline in recruitment to engrafted RA ST and a 5-fold decline in recruitment to regional lymph nodes. Interestingly, RA ST fibroblasts did not produce CXCL16 in response to TNFΑ in vitro, suggesting that CXCL16 protein may function in large part independently of TNFΑ. Conclusion Taken together, these results point to a unique role for CXCL16 as a premier MNC recruiter in RA and suggest additional therapeutic possibilities, targeting CXCL16, its receptor, or its signaling pathways.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49514/1/21662_ftp.pd

Management of pineal region tumors in a pediatric case series

Pineal region tumors commonly present with non-communicating hydrocephalus. These heterogeneous histological entities require different therapeutic regimens. We evaluated our surgical experience concerning procurance of a histological diagnosis, management of hydrocephalus, and choice of antitumoral treatment. We analyzed the efficacy of neuroendoscopic biopsy and endoscopic third ventriculocisternostomy (ETV) in patients with pineal region tumors between 2006 and 2019 in a single-center retrospective cross-sectional study with regard to diagnostic yield, hydrocephalus treatment, as well as impact on further antitumoral management. Out of 28 identified patients, 23 patients presented with untreated hydrocephalus and 25 without histological diagnosis. One patient underwent open biopsy, and 24 received a neuroendoscopic biopsy with concomitant hydrocephalus treatment if necessary. Eighteen primary ETVs, 2 secondary ETVs, and 2 ventriculoperitoneal shunts (VPSs) were performed. Endoscopic biopsy had a diagnostic yield of 95.8% (23/24) and complication rates of 12.5% (transient) and 4.2% (permanent), respectively. ETV for hydrocephalus management was successful in 89.5% (17/19) with a median follow-up of more than 3 years. Following histological diagnosis, 8 patients (28.6%) underwent primary resection of their tumor. Another 9 patients underwent later-stage resection after either adjuvant treatment (n = 5) or for progressive disease during observation (n = 4). Eventually, 20 patients received adjuvant treatment and 7 were observed after primary management. One patient was lost to follow-up. Heterogeneity of pineal region tumor requires histological confirmation. Primary biopsy of pineal lesions should precede surgical resection since less than a third of patients needed primary surgical resection according to the German pediatric brain tumor protocols. Interdisciplinary decision making upfront any treatment is warranted in order to adequately guide treatment

High-grade astrocytoma with piloid features (HGAP): the Charité experience with a new central nervous system tumor entity

Purpose: High-grade astrocytoma with piloid features (HGAP) is a recently described brain tumor entity defined by a specific DNA methylation profile. HGAP has been proposed to be integrated in the upcoming World Health Organization classification of central nervous system tumors expected in 2021. In this series, we present the first single-center experience with this new entity. Methods: During 2017 and 2020, six HGAP were identified. Clinical course, surgical procedure, histopathology, genome-wide DNA methylation analysis, imaging, and adjuvant therapy were collected. Results: Tumors were localized in the brain stem (n = 1), cerebellar peduncle (n = 1), diencephalon (n = 1), mesencephalon (n = 1), cerebrum (n = 1) and the thoracic spinal cord (n = 2). The lesions typically presented as T1w hypo- to isointense and T2w hyperintense with inhomogeneous contrast enhancement on MRI. All patients underwent initial surgical intervention. Three patients received adjuvant radiochemotherapy, and one patient adjuvant radiotherapy alone. Four patients died of disease, with an overall survival of 1.8, 9.1, 14.8 and 18.1 months. One patient was alive at the time of last follow-up, 14.6 months after surgery, and one patient was lost to follow-up. Apart from one tumor, the lesions did not present with high grade histology, however patients showed poor clinical outcomes. Conclusions: Here, we provide detailed clinical, neuroradiological, histological, and molecular pathological information which might aid in clinical decision making until larger case series are published. With the exception of one case, the tumors did not present with high-grade histology but patients still showed short intervals between diagnosis and tumor progression or death even after extensive multimodal therapy

Arteriovenous Passage Times and Visual Field Progression in Normal Tension Glaucoma

Purpose. Fluorescein angiographic studies revealed prolonged arteriovenous passage (AVP) times and increased fluorescein filling defects in normal tension glaucoma (NTG) compared to healthy controls. The purpose of this study was to correlate baseline AVP and fluorescein filling defects with visual field progression in patients with NTG. Patients and Methods. Patients with a follow-up period of at least 3 years and at least 4 visual field examinations were included in this retrospective study. Fluorescein angiography was performed at baseline using a confocal scanning laser ophthalmoscope (SLO, Rodenstock Instr.); fluorescein filling defects and AVP were measured by digital image analysis and dye dilution curves (25 Hz). Visual field progression was evaluated using regression analysis of the MD (Humphrey-Zeiss, SITA-24-2, MD progression per year (dB/year)). 72 patients with NTG were included, 44 patients in study 1 (fluorescein filling defects) and 28 patients in study 2 (AVP). Results. In study 1 (mean follow-up years, visual field tests), MD progression per year ( dB/year) was significantly correlated to the age (, ) but not to fluorescein filling defects, IOP, or MD at baseline. In study 2 (mean follow-up years, visual field tests), MD progression per year ( dB/year) was significantly correlated to AVP (, ) but not to age, IOP, or MD at baseline. Conclusion. Longer AVP times at baseline are correlated to visual field progression in NTG. Impaired retinal blood flow seems to be an important factor for glaucoma progression

Tumor-Associated Microglia/Macrophages as a Predictor for Survival in Glioblastoma and Temozolomide-Induced Changes in CXCR2 Signaling with New Resistance Overcoming Strategy by Combination Therapy

Tumor recurrence is the main challenge in glioblastoma (GBM) treatment. Gold standard therapy temozolomide (TMZ) is known to induce upregulation of IL8/CXCL2/CXCR2 signaling that promotes tumor progression and angiogenesis. Our aim was to verify the alterations on this signaling pathway in human GBM recurrence and to investigate the impact of TMZ in particular. Furthermore, a combi-therapy of TMZ and CXCR2 antagonization was established to assess the efficacy and tolerability. First, we analyzed 76 matched primary and recurrent GBM samples with regard to various histological aspects with a focus on the role of TMZ treatment and the assessment of predictors of overall survival (OS). Second, the combi-therapy with TMZ and CXCR2-antagonization was evaluated in a syngeneic mouse tumor model with in-depth immunohistological investigations and subsequent gene expression analyses. We observed a significantly decreased infiltration of tumor-associated microglia/macrophages (TAM) in recurrent tumors, while a high TAM infiltration in primary tumors was associated with a reduced OS. Additionally, more patients expressed IL8 in recurrent tumors and TMZ therapy maintained CXCL2 expression. In mice, enhanced anti-tumoral effects were observed after combi-therapy. In conclusion, high TAM infiltration predicts a survival disadvantage, supporting findings of the tumor-promoting phenotype of TAMs. Furthermore, the combination therapy seemed to be promising to overcome CXCR2-mediated resistance

Government‒business relations in multilevel systems: the effect of conflict perception on venue choice

In multilevel systems, organised interests, including business firms, can pursue their political goals at different levels. At the same time, national systems of interest representation provide important incentive structures for corporate political behaviour. In this context, corporate political strategy is guided by firms’ perceptions of their relationship with policy-makers. If this relationship is under strain in one venue, firms shift their lobbying effort to alternative venues, subject to constraints reflecting national institutional legacies. Using survey data on 56 large German and British firms, the article investigates empirically how perceptions of government‒business relations and national systems of interest representation interact to shape the political behaviour of large firms in multilevel systems. The analysis shows that perceived conflict with public authorities at the national level leads to increased business lobbying at the EU level. Furthermore, national types of interest representation shape relative business engagement at the EU level as well as the readiness of firms to shift venue

Government‒business relations in multilevel systems: the effect of conflict perception on venue choice

In multilevel systems, organised interests, including business firms, can pursue their political goals at different levels. At the same time, national systems of interest representation provide important incentive structures for corporate political behaviour. In this context, corporate political strategy is guided by firms’ perceptions of their relationship with policy-makers. If this relationship is under strain in one venue, firms shift their lobbying effort to alternative venues, subject to constraints reflecting national institutional legacies. Using survey data on 56 large German and British firms, the article investigates empirically how perceptions of government‒business relations and national systems of interest representation interact to shape the political behaviour of large firms in multilevel systems. The analysis shows that perceived conflict with public authorities at the national level leads to increased business lobbying at the EU level. Furthermore, national types of interest representation shape relative business engagement at the EU level as well as the readiness of firms to shift venue

Clinical Study Arteriovenous Passage Times and Visual Field Progression in Normal Tension Glaucoma

properly cited. Purpose. Fluorescein angiographic studies revealed prolonged arteriovenous passage (AVP) times and increased fluorescein filling defects in normal tension glaucoma (NTG) compared to healthy controls. The purpose of this study was to correlate baseline AVP and fluorescein filling defects with visual field progression in patients with NTG. Patients and Methods. Patients with a follow-up period of at least 3 years and at least 4 visual field examinations were included in this retrospective study. Fluorescein angiography was performed at baseline using a confocal scanning laser ophthalmoscope (SLO, Rodenstock Instr.); fluorescein filling defects and AVP were measured by digital image analysis and dye dilution curves (25 Hz). Visual field progression was evaluated using regression analysis of the MD (Humphrey-Zeiss, SITA-24-2, MD progression per year (dB/year)). 72 patients with NTG were included, 44 patients in study 1 (fluorescein filling defects) and 28 patients in study 2 (AVP). Results. In study 1 (mean followup 6.6 ± 1.9 years, 10 ± 5 visual field tests), MD progression per year (−0.51 ± 0.59 dB/year) was significantly correlated to the age ( = 0.04, = −0.29) but not to fluorescein filling defects, IOP, or MD at baseline. In study 2 (mean follow-up 6.6 ± 2.2 years, 10 ± 5 visual field tests), MD progression per year (−0.45 ± 0.51 dB/year) was significantly correlated to AVP ( = 0.03, = 0.39) but not to age, IOP, or MD at baseline. Conclusion. Longer AVP times at baseline are correlated to visual field progression in NTG. Impaired retinal blood flow seems to be an important factor for glaucoma progression

Integrated information increases with fitness in the evolution of animats

One of the hallmarks of biological organisms is their ability to integrate disparate information sources to optimize their behavior in complex environments. How this capability can be quantified and related to the functional complexity of an organism remains a challenging problem, in particular since organismal functional complexity is not well-defined. We present here several candidate measures that quantify information and integration, and study their dependence on fitness as an artificial agent ("animat") evolves over thousands of generations to solve a navigation task in a simple, simulated environment. We compare the ability of these measures to predict high fitness with more conventional information-theoretic processing measures. As the animat adapts by increasing its "fit" to the world, information integration and processing increase commensurately along the evolutionary line of descent. We suggest that the correlation of fitness with information integration and with processing measures implies that high fitness requires both information processing as well as integration, but that information integration may be a better measure when the task requires memory. A correlation of measures of information integration (but also information processing) and fitness strongly suggests that these measures reflect the functional complexity of the animat, and that such measures can be used to quantify functional complexity even in the absence of fitness data.Comment: 27 pages, 8 figures, one supplementary figure. Three supplementary video files available on request. Version commensurate with published text in PLoS Comput. Bio