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Background: The role of extent of surgical resection (EOR) on clinical outcomes in patients with low-grade glioma requires further examination. Methods: We systematically searched MEDLINE, Embase, and the Cochrane Library for studies published between January 1, 1990 and January 5, 2018 on predefined patient outcomes regarding different EOR of low-grade glioma. Results: Our literature search yielded 60 studies including 13,289 patients. Pooled estimates of overall survival showed an increase from 3.79 years (95% CI, 2.37–5.22) in the biopsy group to 6.68 years (95% CI, 4.19–9.16) in STR to 10.65 years (95% CI, 6.78–14.52) in GTR. When compared to STR, GTR prolonged progression-free survival by 2.08 years (95% CI, 0.26–3.89; P=0.025). Pooled estimates of seizure control showed an improvement from 47.8% (95% CI, 26.7–69.6) with biopsy to 54.2% (95% CI, 48.7–59.6) with STR to 81.0% (95% CI, 74.6–86.2) with GTR. Compared to STR, GTR delayed malignant transformation (RR, 0.43; 95% CI, 0.20–0.93; P=0.032), without increasing postoperative mortality (RR, 0.38; 95% CI, 0.07–1.97; P=0.250) or morbidity (RR, 1.22; 95% CI, 0.65–2.28; P=0.540). Conclusions: Among patients with low grade gliomas, higher degrees of safe EOR, were associated with longer overall and progression-free survival, better seizure control, and delayed malignant transformation, without increased mortality or morbidity.
Background: Children diagnosed with medulloblastoma (MB) that are refractory to upfront therapy or experience recurrence have very poor prognoses. Reports of phase I and II studies for these children exist, but bear significant treatment related morbidity and mortality. Methods: A retrospective review of children diagnosed with a pediatric MB from 2002-2015 from the McMaster Pediatric Brain Tumour Study Group (PBTSG) captured a number of pediatric recurrent MB. Results: Over the 13-year period, 31 children with a histological diagnosis of MB were treated. At two years, 21 (67.7%) of 31 patients were free of recurrence and 25 (80.6%) survived. Thirteen children had recurrent or treatment refractory MB. mean time to recurrence was 14.6 months. The mean follow-up for survivors of recurrent MB was 4.0 years. In 3 recurrent MB, the disease had significantly progressed and the patients palliated. For the remaining children, therapy offered included surgery, radiation, and chemotherapy agents either in isolation or in varying combinations. Conclusions: Recurrent MB in our cohort carried a poor prognosis despite administration of salvage therapy. Though there is standardization of the upfront treatment exists, we observed great heterogeneity in the treatment of our 13 patients experiencing recurrence. A greater understanding of the biology of recurrent MB has the potential to guide salvage therapy.
Background: The surgical risk factors and neuro-imaging characteristics associated with cerebellar mutism (CM) remain unclear and require further investigation. We aimed to examine surgical and MRI findings associated with CM in children following posterior fossa tumor resection. Methods: Using our data registry, we retrospectively collected data from pediatric patients who acquired CM and were matched based on age and pathology type with patients not acquiring CM after posterior fossa surgery. The strength of association between surgical and MRI variables and CM were examined using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Results: A total of 22 patients were included. Medulloblastoma was the most common pathology among CM patients (91%). Tumor attachment to the floor of the fourth ventricle (OR, 6; 95% CI, 0.7-276), calcification/hemosiderin deposition (OR 7; 95% CI 0.9-315.5), and post-operative peri-ventricular ischemia on MRI (OR, 5; 95% CI, 0.5-236.5) were found to have the highest association with CM. Conclusions: Our results may suggest that tumor attachment to the floor of the fourth ventricle, pathological calcification, and post-operative ischemia are relatively more prevalent in patients with CM. Collectively, our work calls for a larger multi-institutional study of CM patients to further investigate the determinants and management of CM to potentially minimize its development and predict onset.
Medulloblastoma (MB) is the most common malignant pediatric brain tumour, and is categorized into four molecular subgroups, with Group 3 MB having the worst prognosis due to the highest rate of metastatic dissemination and relapse. In this work, we describe the epigenetic regulator Bmi1 as a novel therapeutic target for treatment of recurrent Group 3 MB. Through comparative profiling of primary and recurrent MB, we show that Bmi1 defines a treatment-refractory cell population that is uniquely targetable by a novel class of small molecule inhibitors. We have optimized an in vivo mouse-adapted therapy model that has the advantage of generating recurrent, human, treatment-refractory MBs. Our preliminary studies showed that although chemoradiotherapy administered to mice engrafted with human MB showed reduction in tumour size, Bmi1 expression was enriched in the post-treatment residual tumour. Furthermore, we found that knockdown of Bmi1 in human recurrent MB cells decreases proliferation and self-renewing capacities of MB cells in vitro as well as both tumour size and extent of spinal leptomeningeal metastases in vivo. Oral administration of a potent Bmi1 inhibitor, PTC 028, resulted in a marked reduction in tumour burden and an increased survival in treatment cohort. Bmi1 inhibitors showed high specificity for MB cells and spared normal human neural stem cells, when treated with doses relevant for MB cells. As Group 3 medulloblastoma is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious agent such as Bmi1 inhibitor could be rapidly transitioned to clinical trials.
Medulloblastoma (MB), the most common malignant pediatric brain tumor, is categorized into four molecular subgroups. Given the high rate of metastatic dissemination at diagnosis and recurrence in Group 3 MBs, these patients have the worst clinical outcome with a 5-year survivorship of approximately 50%. By adapting the existing COG (Children’s Oncology Group) Protocol for children with newly diagnosed high-risk MB, for treatment of immuno-deficient mice intracranially engrafted with human MB brain tumour initiating cells we aim to identify and characterize the treatment-refractory cell population in Group 3 MBs. Mice were sacrificed at multiple time points during the course of tumor development and therapy: (i) at engraftment; (ii) post-radiation; (iii) post-radiation and chemotherapy; and (iv) at MB recurrence. MB cell populations recovered separately from brains and spines were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy. We report a higher expression of CD133, Sox2 and Bmi1 in addition to increased self-renewal capacity following chemoradiotherapy treatment. The enrichment map constructed from global gene expression analysis showed an increase in pathways regulating self-renewal, DNA repair and chemoresistance post-therapy despite the apparent decrease in tumour size and vascularity. Additionally, from gene expression at MB recurrence, we identified a list of genes that negatively correlate with survival in patients diagnosed with Group 3 MB. A differential genomic profile of the “treatment-responsive” tumors against those that fail therapy may contribute to discovery of novel therapeutic approaches for the most aggressive subgroup of MB.
Brain Metastases (BM) represent a leading cause of cancer mortality. While metastatic lesions contain subclones derived from their primary lesion, their functional characterization has been limited by a paucity of preclinical models accurately recapitulating the stages of metastasis. This work describes the isolation of a unique subset of metastatic stem-like cells from primary human patient samples of BM, termed brain metastasis initiating cells (BMICs). Utilizing these BMICs we have established a novel patient-derived xenograft (PDX) model of BM that recapitulates the entire metastatic cascade, from primary tumor initiation to micro-metastasis and macro-metastasis formation in the brain. We then comprehensively interrogated human BM to identify genetic regulators of BMICs using in vitro and in vivo RNA interference screens, and validated hits using both our novel PDX model as well as primary clinical BM specimens. We identified SPOCK1 and TWIST2 as novel BMIC regulators, where in our model SPOCK1 regulated BMIC self-renewal and tumor initiation, and TWIST2 specifically regulated cell migration from lung to brain. A prospective cohort of primary lung cancer specimens was used to establish that SPOCK1 and TWIST2 were only expressed in patients who ultimately developed BM, thus establishing both clinical and functional utility for these gene products. This work offers the first comprehensive preclinical model of human brain metastasis for further characterization of therapeutic targets, identification of predictive biomarkers, and subsequent prophylactic treatment of patients most likely to develop BM. By blocking this process, metastatic lung cancer would effectively become a localized, more manageable disease.
Brain tumours represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant pediatric brain tumour. Current molecular Nsubgroups of MB recognize distinct disease entities of which activated Wnt signaling (monosomy 6, exon 3 mutations in CTNNB1, and Wnt gene signature) is associated with a distinct subgroup and the best overall outcome. In contrast, only non-Wnt MBs are characterized by metastatic disease, increased rate of recurrence, and poor overall survivorship. Given the excellent clinical outcome in patients with Wnt-driven MB, we aimed to convert treatment-resistant MB subgroups into an ostensibly benign tumour through selective targeting by small molecule Wnt agonists (Wnt3A), GSK3 inhibitors (CHIR99021), and transgenic lines containing a stabilized beta-catenin mutant. Activated Wnt signaling resulted in decreased in vitro self-renewal and promoted differentiation within primary human MB stem cells. The clinical relevance of these findings were demonstrated with an in vivo survival advantage in mice containing orthotopic injections of cells containing a stabilized beta-catenin mutant representative of constitutively active Wnt signaling. Xenografts generated from Wnt-activated tumours were much smaller in size, maintained a much lower rate of proliferation, and reduction in key MB stem cell self-renewal genes (Bmi1, Sox2, Msi1, FoxG1). Our work establishes activated Wnt signaling as a novel treatment paradigm in childhood MB, while providing evidence for the context-specific tumour suppressive function of the canonical Wnt pathway.
Magnetization due to a magnetic moment contributes to the non-oscillating magnetic field in a plasma. The dynamics ofclassically bound electrons in the presence of an applied circularly polarized strong electromagnetic field in the reflection region generates this field. The special case of its resonant generation when the frequency of a right circularlypolarized wave is equal to the ion gyration frequency is studied here. Another source of non-oscillating magnetization isthe interaction of electromagnetic fields, including fields in the Alfvén-wave frequency range, with a cold collisionless fully ionized magnetized plasma also in the reflection region. The induced field from a left circularly polarized field at Alfvén-wave frequencies is paramagnetic, inversely proportional to the square of the ambient field and independent of the mass per particle of both electrons and ions. The induced field from a right circularly polarized field at Alfvén-wave frequencies is diamagnetic, inversely proportional to the cube of the ambient field and depends directly on the plasma mass density.
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