Superiority of PCNU over AZQ in the treatment of primary brain tumors: results of a prospective randomized trial (81-20) by the brain tumor study group

Despite constant progress in basic and translational research, cancer is still one of the leading cause of death. In particular, tumors of the central nervous system (CNS) are usually associated with dismal prognosis. Although about 100 distinct subtypes of primary CNS tumors have been classified molecularly, metastases derived from primaries outside the CNS (= brain metastases, BrM) are more frequently observed across brain tumor patients. It is estimated that approximately 20 - 40 % of all cancer patients will develop BrM during their course of disease, and basically every tumor type is able to metastasize to the brain. Nevertheless, BrM are most frequently derived from primaries of the lung, breast, and skin (melanoma). Treatment options for patients with BrM are very limited, and standard of care therapies include surgery, ionizing radiation (e.g. whole brain radio-therapy, WBRT), and some systemic and immuno-therapeutic approaches. The brain represents a unique organ, which in part is due to the presence of the blood-brain barrier, a unit of the neuro-vascular interface ensuring tightly regulated exchange of nutrients, molecules, and cells. Furthermore, apart from microglia the brain parenchyma does not harbor other immune cells. Those cells however can be found at the borders of the CNS residing in the meninges, for instance. Based on recent insight on the immune landscape in the CNS, a paradigm shift occurred after which the brain is no longer regarded as immune-privileged but rather immune distinct. The phenomenon of immune cell infiltration has been described before in the context of neurological disorders including Multiple Sclerosis, as well as in brain tumors. Since the development of immune-therapeutic approaches for tumors outside the CNS that aim to evoke sustainable anti-tumor effects, it became increasingly interesting to understand and harness the immune landscape (= tumor microenvironment, TME) of brain tumors, as well. Interestingly, most of the knowledge about the TME is based on studies of primary brain tumors. However, it is known that BrM compared to primary brain tumors induce a different TME like e.g. the recruitment of much more lymphocytes, which is one of the reasons primary brain tumors are considered immunologically “cold” and poorly respond to immuno-therapies. Previous insight into the functional contribution of tumor-associated cells in BrM progression revealed for example that brain-resident cell types (e.g. astrocytes or microglia) promote BrM development and outgrowth. However, until recently a comprehensive view on the cellular composition and functional role of the brain metastases-associated TME was missing and little was known how it changes during tumor progression or standard therapy. Hence, within this thesis it was sought to describe novel aspects of the TME of preclinical BrM models, which include two xenograft and one syngeneic mouse model. BrM was induced via intra-cardiac injection of tumor cells with a high brain tropism. Both xenograft models were based on immuno-compromised nude mice (Balb/c nude) and included the melanoma-to-brain (M2B) model H1_DL2, and the lung-to-brain (L2B) model H2030. In addition the breast-to-brain model 99LN-BrM was used in wild-type mice (BL6), and therefore represented an immuno-competent, syngeneic model. First BrMs could be detected in the xenograft models at 3 weeks after injection, whereas first 99LN BrMs were detected at 5 weeks. BrM development and progression were monitored by bioluminescence imaging once per week in the xenograft models. Tumor progression in the 99LN model was examined by magnetic resonance imaging. Based on the measurement methods, and for further histologic and cytometric experiments, mice were stratified into groups with small or large BrMs, respectively. Some initial immuno-stainings confirmed previous findings, showing that brain-resident cells like astrocytes and microglia become activated in the presence of tumor cells, whereas neurons for example rather give the impression of passive bystanders. Importantly, an accumulation of IBA1+ cells was observed during BrM progression. IBA1 is a pan-macrophage marker that stains all tumor-associated macrophages (TAMs). However previous work suggested that the TAM population consists of at least two main subpopulations in BrM as well: the resident-infiltrating microglia (MG, TAM-MG), as well as the peripheral and monocytic-derived macrophages (TAM-MDM). Since both cell types within the tumor share morphological traits, and due to the lack of markers to distinguish them, an exact discrimination of both cell types was complicated in the past. Recently, an integrative lineage-tracing-based study identified the integrin CD49d as MDM-specific in the context of brain tumor-associated myeloid cells, hence enabling a reliable dissection of both TAM populations in e.g. flow cytometric experiments. One of the main aims of this thesis was to dissect the myeloid TME in the three different BrM models during tumor progression. Using a 5-marker flow cytometry (FCM) (CD45/CD11b/Ly6C/Ly6G/CD49d) approach, the following cell populations were examined in more detail: granulocytes, inflammatory monocytes, MDM, and MG. ...

Download Full-text

Results of a randomized trial comparing intra-arterial cisplatin and intravenous PCNU for the treatment of primary brain tumors in adults: Brain Tumor Cooperative Group trial 8420A

Journal of Neuro-Oncology ◽

10.1007/bf01057758 ◽

1995 ◽

Vol 25 (2) ◽

pp. 143-154 ◽

Cited By ~ 21

Author(s):

Emile M. Hiesiger ◽

Sylvan B. Green ◽

William R. Shapiro ◽

Peter C. Burger ◽

Robert G. Selker ◽

...

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Randomized Trial ◽

Cooperative Group ◽

Primary Brain Tumors ◽

Group Trial

Download Full-text

Neuroinflammation in Autoimmune Disease and Primary Brain Tumors: The Quest for Striking the Right Balance

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.716947 ◽

2021 ◽

Vol 15 ◽

Author(s):

Dana Mitchell ◽

Jack Shireman ◽

Elizabeth A. Sierra Potchanant ◽

Montserrat Lara-Velazquez ◽

Mahua Dey

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Primary Brain Tumor ◽

Primary Brain Tumors ◽

Neuroinflammatory Disease ◽

Pathological Conditions ◽

The Central Nervous System ◽

The Right ◽

The Brain ◽

Cns Malignancies

According to classical dogma, the central nervous system (CNS) is defined as an immune privileged space. The basis of this theory was rooted in an incomplete understanding of the CNS microenvironment, however, recent advances such as the identification of resident dendritic cells (DC) in the brain and the presence of CNS lymphatics have deepened our understanding of the neuro-immune axis and revolutionized the field of neuroimmunology. It is now understood that many pathological conditions induce an immune response in the CNS, and that in many ways, the CNS is an immunologically distinct organ. Hyperactivity of neuro-immune axis can lead to primary neuroinflammatory diseases such as multiple sclerosis and antibody-mediated encephalitis, whereas immunosuppressive mechanisms promote the development and survival of primary brain tumors. On the therapeutic front, attempts are being made to target CNS pathologies using various forms of immunotherapy. One of the most actively investigated areas of CNS immunotherapy is for the treatment of glioblastoma (GBM), the most common primary brain tumor in adults. In this review, we provide an up to date overview of the neuro-immune axis in steady state and discuss the mechanisms underlying neuroinflammation in autoimmune neuroinflammatory disease as well as in the development and progression of brain tumors. In addition, we detail the current understanding of the interactions that characterize the primary brain tumor microenvironment and the implications of the neuro-immune axis on the development of successful therapeutic strategies for the treatment of CNS malignancies.

Download Full-text

919: Ureteral Extension in Childhood Renal Tumors: A Report From the National Wilms Tumor Study Group (NWTSG)

The Journal of Urology ◽

10.1016/s0022-5347(18)31147-9 ◽

2007 ◽

Vol 177 (4S) ◽

pp. 305-305

Author(s):

Shane Daley ◽

Michael Ritchey ◽

Robert Shamberger ◽

Robert Sawin ◽

Thomas Hamilton ◽

...

Keyword(s):

Wilms Tumor ◽

Renal Tumors ◽

Study Group ◽

Tumor Study ◽

Tumor Study Group

Download Full-text