Abdullah H. Feroze

Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities

Quantitative imaging stratifies glioblastoma into three different phenotypes with distinct molecular activities independent of established molecular markers and clinical status. Brain images create cancer clusters When directing therapies toward tumors, a sample of the cancerous tissue is needed to identify molecular targets. For patients with glioblastoma, however, it is invasive to biopsy the brain. Itakura et al. sought to identify noninvasive determinants of tumor phenotype that would potentially correlate with molecular pathways, thus allowing for targeted therapy without such brain invasion. The authors used magnetic resonance imaging to look at solitary, unilateral tumors from 121 glioblastoma patients and then generated nearly 400 unique image features that could be used to describe each tumor. The tumors could be grouped into three different phenotypes or “clusters”: pre-multifocal cluster, with highly irregular tumor shapes; spherical cluster, with defined edges; and rim-enhancing cluster, with a hypointense center ringed by hyperintensity. The distinct clusters were further validated in a separate cohort of 144 patients. These clusters could be used to stratify patients not only according to molecular pathways for targeted therapy but also by survival, indicating the potential for such noninvasive image-based quantitative biomarkers to be used for patient prognosis. Glioblastoma (GBM) is the most common and highly lethal primary malignant brain tumor in adults. There is a dire need for easily accessible, noninvasive biomarkers that can delineate underlying molecular activities and predict response to therapy. To this end, we sought to identify subtypes of GBM, differentiated solely by quantitative magnetic resonance (MR) imaging features, that could be used for better management of GBM patients. Quantitative image features capturing the shape, texture, and edge sharpness of each lesion were extracted from MR images of 121 single-institution patients with de novo, solitary, unilateral GBM. Three distinct phenotypic “clusters” emerged in the development cohort using consensus clustering with 10,000 iterations on these image features. These three clusters—pre-multifocal, spherical, and rim-enhancing, names reflecting their image features—were validated in an independent cohort consisting of 144 multi-institution patients with similar tumor characteristics from The Cancer Genome Atlas (TCGA). Each cluster mapped to a unique set of molecular signaling pathways using pathway activity estimates derived from the analysis of TCGA tumor copy number and gene expression data with the PARADIGM (Pathway Recognition Algorithm Using Data Integration on Genomic Models) algorithm. Distinct pathways, such as c-Kit and FOXA, were enriched in each cluster, indicating differential molecular activities as determined by the image features. Each cluster also demonstrated differential probabilities of survival, indicating prognostic importance. Our imaging method offers a noninvasive approach to stratify GBM patients and also provides unique sets of molecular signatures to inform targeted therapy and personalized treatment of GBM.

Nanotechnology in bone tissue engineering

UNLABELLED Nanotechnology represents a major frontier with potential to significantly advance the field of bone tissue engineering. Current limitations in regenerative strategies include impaired cellular proliferation and differentiation, insufficient mechanical strength of scaffolds, and inadequate production of extrinsic factors necessary for efficient osteogenesis. Here we review several major areas of research in nanotechnology with potential implications in bone regeneration: 1) nanoparticle-based methods for delivery of bioactive molecules, growth factors, and genetic material, 2) nanoparticle-mediated cell labeling and targeting, and 3) nano-based scaffold construction and modification to enhance physicochemical interactions, biocompatibility, mechanical stability, and cellular attachment/survival. As these technologies continue to evolve, ultimate translation to the clinical environment may allow for improved therapeutic outcomes in patients with large bone deficits and osteodegenerative diseases. FROM THE CLINICAL EDITOR Traditionally, the reconstruction of bony defects has relied on the use of bone grafts. With advances in nanotechnology, there has been significant development of synthetic biomaterials. In this article, the authors provided a comprehensive review on current research in nanoparticle-based therapies for bone tissue engineering, which should be useful reading for clinicians as well as researchers in this field.

Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway

The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSCs) requires Notch (N) signaling. How N regulates NSC behavior is not well understood. Here we show that canonical N signaling cooperates with a noncanonical N signaling pathway to mediate N-directed NSC regulation. In the noncanonical pathway, N interacts with PTEN-induced kinase 1 (PINK1) to influence mitochondrial function, activating mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling. Importantly, attenuating noncanonical N signaling preferentially impaired the maintenance of Drosophila and human cancer stem cell-like tumor-forming cells. Our results emphasize the importance of mitochondria to N and NSC biology, with important implications for diseases associated with aberrant N signaling.

Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors

Anti-CD47 antibody is effective for treating malignant pediatric brain tumors without detectable toxicity in patient-derived xenograft models. Brain tumors, meet macrophages A protein called CD47 is often expressed on the surface of tumor cells, where it serves as a “don’t eat me” signal that blocks macrophages from attacking the tumor. To overcome this signal and allow the macrophages to “eat” tumor cells, Gholamin et al. engineered a humanized antibody that blocks CD47 signaling. The researchers tested the efficacy of this antibody in patient-derived xenograft models of a variety of pediatric brain tumors. The treatment was successful at inhibiting CD47, killing tumor cells, and prolonging the animals’ survival, all without toxic effects on normal tissues. Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.

Experience with intraoperative navigation and imaging during endoscopic transnasal spinal approaches to the foramen magnum and odontoid

OBJECT In this study the authors share their experience using intraoperative spinal navigation and imaging for endoscopic transnasal approaches to the odontoid in 5 patients undergoing C1-2 surgery for basilar invagination at Stanford Hospital and Clinics from 2010 to 2013. METHODS Of these 5 patients undergoing C1-2 surgery for basilar invagination, 4 underwent a 2-tiered anterior C1-2 resection with posterior occipitocervical fusion during a first stage surgery, followed by endoscopic endonasal odontoidectomy in a separate setting. Intraoperative stereotactic navigation was performed using a surgical navigation system in all cases. Navigation accuracy, characterized as target registration error, ranged between 0.8 mm and 2 mm, with an average of 1.2 mm. Intraoperative imaging using a CT scanner was also performed in 2 patients. RESULTS Endoscopic decompression of the brainstem was achieved in all patients, and no intraoperative complications were encountered. All patients were extubated within 24 hours after surgery and were able to swallow within 48 hours. After appropriate initial reconstruction of the defect at the craniocervical junction, no postoperative CSF leakage, arterial injury, or need for reoperation was encountered; 1 patient developed mild postoperative velopharyngeal insufficiency that resolved by the 6-month follow-up evaluation. There were no deaths and no patients required tracheostomy placement. The average inpatient stay after surgery varied between 72 and 96 hours, without extended intensive care unit stays for any patient. CONCLUSIONS Technologies such as intraoperative CT scanning and merged MRI/CT can provide the surgeon with detailed, virtual real-time information about the extent of complex endoscopic vertebral segment resection and brainstem decompression and lessens the prospect of revision or secondary procedures in this challenging surgical corridor. Moreover, patients experience limited morbidity and can tolerate early oral intake after transnasal endoscopic odontoidectomy. Essential to the successful undertaking of these endoscopic adventures is 1) an understanding of the endoscopic nasal, skull base, and neurovascular anatomy; 2) advanced and extended-length instrumentation including navigation; and 3) a team approach between experienced rhinologists and spine surgeons comfortable with endoscopic skull base techniques.

Leukotriene B4 antagonism ameliorates experimental lymphedema

Lymphedema is a common debilitating condition with very limited treatment options, and leukotriene B4 may be a key pathogenic molecule and therapeutic target. Lightening the burden of lymphedema There are currently no targeted treatments for lymphedema, the painful swelling of limbs that can occur after surgery or cancer treatment. To validate a potential therapeutic target, Tian et al. examined the role that leukotriene B4 (LTB4) plays in acquired lymphedema. LTB4 was elevated in patient serum and was counterproductive to lymphatic repair in a mouse lymphatic surgery model, likely due to its various effects on lymphatic endothelial cell function and growth. Accordingly, blocking LTB4 ameliorated clinical symptoms in the mice. A clinical trial testing a compound that antagonizes LTB4 is already underway, indicating that relief for lymphedema patients may be just around the corner. Acquired lymphedema is a cancer sequela and a global health problem currently lacking pharmacologic therapy. We have previously demonstrated that ketoprofen, an anti-inflammatory agent with dual 5-lipoxygenase and cyclooxygenase inhibitory properties, effectively reverses histopathology in experimental lymphedema. We show that the therapeutic benefit of ketoprofen is specifically attributable to its inhibition of the 5-lipoxygenase metabolite leukotriene B4 (LTB4). LTB4 antagonism reversed edema, improved lymphatic function, and restored lymphatic architecture in the murine tail model of lymphedema. In vitro, LTB4 was functionally bimodal: Lower LTB4 concentrations promoted human lymphatic endothelial cell sprouting and growth, but higher concentrations inhibited lymphangiogenesis and induced apoptosis. During lymphedema progression, lymphatic fluid LTB4 concentrations rose from initial prolymphangiogenic concentrations into an antilymphangiogenic range. LTB4 biosynthesis was similarly elevated in lymphedema patients. Low concentrations of LTB4 stimulated, whereas high concentrations of LTB4 inhibited, vascular endothelial growth factor receptor 3 and Notch pathways in cultured human lymphatic endothelial cells. Lymphatic-specific Notch1−/− mice were refractory to the beneficial effects of LTB4 antagonism, suggesting that LTB4 suppression of Notch signaling is an important mechanism in disease maintenance. In summary, we found that LTB4 was harmful to lymphatic repair at the concentrations observed in established disease. Our findings suggest that LTB4 is a promising drug target for the treatment of acquired lymphedema.

Casein kinase 2α regulates glioblastoma brain tumor-initiating cell growth through the β-catenin pathway.

Glioblastoma (GBM) is the most common and fatal primary brain tumor in humans, and it is essential that new and better therapies are developed to treat this disease. Previous research suggests that casein kinase 2 (CK2) may be a promising therapeutic target for GBMs. CK2 has enhanced expression or activity in numerous cancers, including GBM, and it has been demonstrated that inhibitors of CK2 regressed tumor growth in GBM xenograft mouse models. Our studies demonstrate that the CK2 subunit, CK2α, is overexpressed in and has an important role in regulating brain tumor-initiating cells (BTIC) in GBM. Initial studies showed that two GBM cell lines (U87-MG and U138) transduced with CK2α had enhanced proliferation and anchorage-independent growth. Inhibition of CKα using siRNA or small-molecule inhibitors (TBBz, CX-4945) reduced cell growth, decreased tumor size, and increased survival rates in GBM xenograft mouse models. We also verified that inhibition of CK2α decreased the activity of a well-known GBM-initiating cell regulator, β-catenin. Loss of CK2α decreased two β-catenin-regulated genes that are involved in GBM-initiating cell growth, OCT4 and NANOG. To determine the importance of CK2α in GBM stem cell maintenance, we reduced CK2α activity in primary GBM samples and tumor spheres derived from GBM patients. We discovered that loss of CK2α activity reduced the sphere-forming capacity of BTIC and decreased numerous GBM stem cell markers, including CD133, CD90, CD49f and A2B5. Our study suggests that CK2α is involved in GBM tumorigenesis by maintaining BTIC through the regulation of β-catenin.

Evolution of cranioplasty techniques in neurosurgery: historical review, pediatric considerations, and current trends.

Cranial bone repair is one of the oldest neurosurgical practices. Reconstructing the natural contours of the skull has challenged the ingenuity of surgeons from antiquity to the present day. Given the continuous improvement of neurosurgical and emergency care over the past century, more patients survive such head injuries, thus necessitating more than ever before a simple, safe, and durable means of correcting skull defects. In response, numerous techniques and materials have been devised as the art of cranioplasty has progressed. Although the goals of cranioplasty remain the same, the evolution of techniques and diversity of materials used serves as testimony to the complexity of this task. This paper highlights the evolution of these materials and techniques, with a particular focus on the implications for managing pediatric calvarial repair and emerging trends within the field.

Identification of novel synergistic targets for rational drug combinations with PI3 kinase inhibitors using siRNA synthetic lethality screening against GBM

Several small molecules that inhibit the PI3 kinase (PI3K)-Akt signaling pathway are in clinical development. Although many of these molecules have been effective in preclinical models, it remains unclear whether this strategy alone will be sufficient to interrupt the molecular events initiated and maintained by signaling along the pathways because of the activation of other pathways that compensate for the inhibition of the targeted kinase. In this study, we performed a synthetic lethality screen to identify genes or pathways whose inactivation, in combination with the PI3K inhibitors PX-866 and NVPBEZ-235, might result in a lethal phenotype in glioblastoma multiforme (GBM) cells. We screened GBM cells (U87, U251, and T98G) with a large-scale, short hairpin RNA library (GeneNet), which contains 43 800 small interfering RNA sequences targeting 8500 well-characterized human genes. To decrease off-target effects, we selected overlapping genes among the 3 cell lines that synergized with PX-866 to induce cell death. To facilitate the identification of potential targets, we used a GSE4290 dataset and The Cancer Genome Atlas GBM dataset, identifying 15 target genes overexpressed in GBM tissues. We further analyzed the selected genes using Ingenuity Pathway Analysis software and showed that the 15 genes were closely related to cancer-promoting pathways, and a highly interconnected network of aberrations along the MYC, P38MAPK, and ERK signaling pathways were identified. Our findings suggest that inhibition of these pathways might increase tumor sensitivity to PX-866 and therefore represent a potential clinical therapeutic strategy.

Endovascular management of cerebral venous sinus thrombosis

Cerebral venous sinus thrombosis (CVST) is characterized by formation of widespread thrombus within the cerebral venous sinus system. CVST can cause venous hypertension, venous infarcts, hemorrhage and seizures. It is managed in most cases with systemic anticoagulation through the use of heparin to resolve the thrombus. Patients that demonstrate clinical deterioration while on heparin are often treated with endovascular strategies to recanalize the sinuses. We present the case of a patient with widespread CVST, involving his superior sagittal sinuses and bilateral transverse sigmoid sinuses, who was treated with a combination of endovascular therapies. The video can be found here: http://youtu.be/w3wAGlT7h8c .