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Multi-contrast magnetic resonance (MR) image registration is useful in the clinic to achieve fast and accurate imaging-based disease diagnosis and treatment planning. Nevertheless, the efficiency and performance of the existing registration algorithms can still be improved. In this paper, we propose a novel unsupervised learning-based framework to achieve accurate and efficient multi-contrast MR image registration. Specifically, an end-to-end coarse-to-fine network architecture consisting of affine and deformable transformations is designed to improve the robustness and achieve end-to-end registration. Furthermore, a dual consistency constraint and a new prior knowledge-based loss function are developed to enhance the registration performances. The proposed method has been evaluated on a clinical dataset containing 555 cases, and encouraging performances have been achieved. Compared to the commonly utilized registration methods, including VoxelMorph, SyN, and LT-Net, the proposed method achieves better registration performance with a Dice score of 0.8397± 0.0756 in identifying stroke lesions. With regards to the registration speed, our method is about 10 times faster than the most competitive method of SyN (Affine) when testing on a CPU. Moreover, we prove that our method can still perform well on more challenging tasks with lacking scanning information data, showing the high robustness for the clinical application.

Patients with malignant glioma (MG) are often treated with corticosteroids to reduce cerebral edema, but chronic use of steroids may cause glucose intolerance and development of type 2 diabetes (Db). Individuals with Db not only have significantly higher likelihood of developing malignant tumors, but also, have a higher risk of cancer-related mortality than non-Db patients. The goal of this study was to evaluate the effect of hyperglycemia on glioma growth in mouse models. Because MG are heterogeneous tumors with both invasive and “nodular” phenotypes, two different syngeneic glioma models were examined in streptozotocin-induced Db mice. We found that in the GL261 gliomas that typically grow as “nodular” tumors, hyperglycemia activated receptor for advanced glycation endproducts (RAGE) by upregulating HMGB1 expression, and promoted tumor growth irrespective of tumor microenvironment (TME). Similarly, the K-Luc gliomas, which are invasive and elicit a robust macrophage infiltration, grew faster in subcutaneous (s.c.) location in Db mice. However, intracranial (i.c.) K-luc gliomas were smaller and less invasive in hyperglycemic mice. Our studies showed that a reduction in K-Luc growth in the brains of Db mice was mostly due to the abrogation of inflammatory responses and suppression of pro-inflammatory cytokines such as IL-1b and IL-6 in TME. We conclude that hyperglycemia may enhance glioma growth by activating the RAGE pathway and suppressing antitumor responses. But, suppression of tumor inflammation may also inhibit glioma growth by abrogating i.c. tumor invasion under hyperglycemic conditions.

The aim of the present study was to measure the prevalence of multimorbidity in Bangladesh, India and China, and to assess the relationship between multimorbidity and patient's opinion regarding their involvement in healthcare decision-making and overall satisfaction of healthcare system. Cross-sectional data on 18 696 men and women aged 18 and above were collected from the World Health Survey of World Health Organization (WHO). Outcome variables were subjective rating of (1) healthcare system's ability to involve patients in decision-making, and (2) satisfaction with the way healthcare system runs in the country. Self-reported chronic conditions were used to measure the prevalence of multimorbidity. Out of 9 chronic conditions, back pain, arthritis, and chronic cough appeared to be the most prevalent ones among majority of the participants. About one-third of the participants in China (30.7%) and two-thirds in Bangladesh (66.1%) and India (66.6%) reported having at least one chronic illness. Prevalence of multimorbidity was highest in India (34.3%) followed by Bangladesh (28.8%) and China (14.3%). In Bangladesh, India and China, respectively 70.5%, 41.7%, 61.3% women and 54.5%, 42.8% and 58.8 % men expressed dissatisfaction regarding the way healthcare system runs in their country. In Bangladesh and India, men who were living with multimorbidity were more likely to rate the patient-centeredness as "bad" than those who had no disease illness. This study suggests that the prevalence of multimorbidity was remarkably high especially in Bangladesh and India. Higher likelihood of dissatisfaction about healthcare system among multimorbid patients might be indicative of inadequacy in the provision of care in qualitative and quantitative terms.

Microglia (MG) and macrophages (MPs) represent a significant component of the inflammatory response to gliomas. When activated, MG/MP release a variety of pro-inflammatory cytokines, however, they also secrete anti-inflammatory factors that limit their cytotoxic function. The balance between pro and anti-inflammatory functions dictates their antitumor activity. To evaluate potential variations in MG and MP function in gliomas, we isolated these cells (and other Gr1+ cells) from intracranial GL261 murine gliomas by FACS and evaluated their gene expression profiles by microarray analysis. As expected, arginase 1 (Arg1, M2 marker) was highly expressed by tumor-associated Gr1+, MG and MP. However, in contrast to MP and Gr1+ cells that expressed Arg1 shortly after tumor trafficking, Arg1 expression in MG was delayed and occurred in larger tumors. Interestingly, depletion of MPs in tumors did not prevent MG polarization, suggesting direct influence of tumor-specific factors on MG Arg1 upregulation. Finally, Arg1 expression was confirmed in human GBM samples, but most Arg1+ cells were neutrophils and not MPs. These findings confirm variations in tumor MG and MP polarization states and its dependency on tumor microenvironmental factors.

2066 Background: WT2725 is a Wilms’ tumor (WT1)-derived-oligopeptide vaccine intended to induce WT1 specific cytotoxic T-lymphocytes against WT1 positive tumors in HLA-A*0201+ or HLA-A*0206+. This first in human study of WT2725 was conducted to evaluate the safety, tolerability, and efficacy. Methods: Subjects with progressive or recurrent glioblastoma (GBM), acute myeloid leukemia (AML) (patients in morphologic remission with minimal residual disease determined by WT1 RT-PCR were allowed), non-small cell lung cancer (NSCLC), or ovarian cancer despite standard therapy were treated with 0.3, 0.9, 3, and 9 mg of WT2725 subcutaneously (s.c.) every week for 4 weeks, then every other week for 6 weeks, and every 4 weeks thereafter until progression or other discontinuation event (part 1); and with 18 mg and 27 mg of WT2725 s.c. every week for 8 weeks, then every other week for 10 weeks, and every 4 weeks thereafter until progression or other discontinuation event (part 2). Responses were evaluated by Immune-related Response Criteria (irRC) for solid tumors and modified International Working Group (IWG) for AML. Results: 62 subjects were dosed, the most frequent adverse events were grade 1 injection site reactions (no grade 3 injection site reactions or dose limiting toxicities observed). Of the 21 GBM subjects who were dosed, seven survived for ≥ 1 year (33%). Of these seven subjects, three survived for ≥18 months (14%), and two for ≥2 years (both in complete radiologic remission, 9.5%). One of the seven subjects with ≥1 year survival had previous treatment with bevacizumab. Two subjects continue dosing (1 complete response with no measurable disease >3 years and 1 partial response > 13 months on study). Results in subjects with non-GBM tumors (12 subjects with AML, 21 with ovarian CA, 7 with NSCLC, and 1 other cancer) are not presented here. WT1-specific CTLs and tumor burden was monitored. WT1 specific CTLs were associated with decrease of tumor burden in two patients with low tumor burden. Some patients with high disease burden did not respond. Conclusions: Preliminary data suggests WT2725 is well tolerated with potential antitumor activity in GBM patients, supporting future development of WT2725 for treatment of GBM in selected subjects. Clinical trial information: NCT01621542.

Interaction of RAGE with its ligands can promote tumor progression, invasion and angiogenesis. Although blockage of RAGE signaling has been proposed as a potential anti-cancer therapy, the contribution of RAGE expression in tumor microenvironement (TME) to tumorigenesis has not been investigated in detail. Here, we evaluated the effect of genetic depletion of RAGE in TME on the growth of gliomas. In both invasive and non-invasive glioma models, animal survival was prolonged in Rage−/- mice. This improvement in animal survival, however, was not due to changes in tumor growth rate, but a reduction in tumor-associated inflammation in Rage−/- mice. Furthermore, RAGE ablation in TME abrogated angiogenesis by downregulating the expression of pro-angiogenic factors which prevented vessel pruning, and resulted in the generation of leaky vasculature. These alterations, however, were most prominent in non-invasive gliomas where the expression of VEGF and pro-inflammatory cytokines were also lower in Rage−/- tumor-associated macrophages. Interestingly, reconstituting Rage−/- tumor macrophages with either wild-type microglia or macrophages normalized tumor vascularity. This is the first report to demonstrate the pro-angiogenic function of RAGE signaling in tumor macrophages and underscores the complex role of RAGE and its ligands in gliomagenesis.

Factors released by glioma-associated microglia/macrophages (GAMs) play an important role in the growth and infiltration of tumors. We have previously demonstrated that the co-chaperone stress-inducible protein 1 (STI1) secreted by microglia promotes proliferation and migration of human glioblastoma (GBM) cell lines in vitro. In the present study, in order to investigate the role of STI1 in a physiological context, we used a glioma model to evaluate STI1 expression in vivo. Here, we demonstrate that STI1 expression in both the tumor and in the infiltrating GAMs and lymphocytes significantly increased with tumor progression. Interestingly, high expression of STI1 was observed in macrophages and lymphocytes that infiltrated brain tumors, whereas STI1 expression in the circulating blood monocytes and lymphocytes remained unchanged. Our results correlate, for the first time, the expression of STI1 and glioma progression, and suggest that STI1 expression in GAMs and infiltrating lymphocytes is modulated by the brain tumor microenvironment.

S100B, a member of the multigene family of Ca2 + -binding proteins, is overexpressed by most malignant gliomas but its biological role in gliomagenesis is unclear. Recently, we demonstrated that low concentrations of S100B attenuated microglia activation through the induction of STAT3. Furthermore, S100B downregulation in a murine glioma model inhibited macrophage trafficking and tumor growth. Based on these observations, we hypothesized that S100B inhibitors may have antiglioma properties through modulation of tumor microenvironment. To discover novel S100B inhibitors, we developed a high-throughput screening cell-base S100B promoter-driven luciferase reporter assay. Initial screening of 25,904 compounds in NIH and ChemBridge libraries identified 1297 hits with >85% S100B inhibitory activity. One compound, duloxetine (Dul, a serotonin-norepinephrine reuptake inhibitor) was selected for the initial proof-of-concept studies. At low concentrations (1-5 □M) Dul inhibited S100B and CCL2 production by mouse GL261 glioma cell lines, but had minimal cytotoxic activity. In vivo, Dul (30 mg/kg/14 days) inhibited S100B production, altered polarization and trafficking of macrophages and abrogated the growth of intracranial GL261 gliomas. Dul therapeutic efficacy, however, was not observed in the K-Luc glioma model that expresses low levels of S100B. These findings affirm the role of S100B in gliomagenesis and justify the development of S100B inhibitors for glioma therapy.