Chemotherapeutic Stress Induces Transdifferentiation of Glioblastoma Cells to Endothelial Cells and Promotes Vascular Mimicry.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor affecting adults, with a median survival of approximately 21 months. One key factor underlying the limited efficacy of current treatment modalities is the remarkable plasticity exhibited by GBM cells, which allows them to effectively adapt to changes induced by anticancer therapeutics. Moreover, GBM tumors are highly vascularized with aberrant vessels that complicate the delivery of antitumor agents.

Hitting a Moving Target: Glioma Stem Cells Demand New Approaches in Glioblastoma Therapy.

Background: Glioblastoma multiforme (GBM) continues to devastate patients and outfox investigators and clinicians despite the preponderance of research directed at its biology, pathogenesis and therapeutic advances. GBM routinely outlasts multidisciplinary treatment protocols, almost inevitably recurring in a yet more aggressive and resistant form with distinct genetic differences from the original tumor. Attempts to glean further insight into GBM point increasingly toward a subpopulation of cells with a stem-like phenotype.

Dedifferentiation of Glioma Cells to Glioma Stem-like Cells By Therapeutic Stress-induced HIF Signaling in the Recurrent GBM Model.

Increasing evidence exposes a subpopulation of cancer cells, known as cancer stem cells (CSCs), to be critical for the progression of several human malignancies, including glioblastoma multiforme. CSCs are highly tumorigenic, capable of self-renewal, and resistant to conventional therapies, and thus considered to be one of the key contributors to disease recurrence. To elucidate the poorly understood evolutionary path of tumor recurrence and the role of CSCs in this process, we developed patient-derived xenograft glioblastoma recurrent models induced by anti-glioma chemotherapy, temozolomide.

Single dose GLP toxicity and biodistribution study of a conditionally replicative adenovirus vector, CRAd-S-pk7, administered by intracerebral injection to Syrian hamsters.

Background: CRAd-S-pk7 is a conditionally replicative oncolytic adenoviral vector that contains a survivin promoter and a pk7 fiber modification that confer tumor-specific transcriptional targeting and preferential replication in glioma while sparing the surrounding normal brain parenchyma.

Methods: This IND-enabling study performed under GLP conditions evaluated the toxicity and biodistribution of CRAd-S-pk7 administered as a single intracerebral dose to Syrian hamsters, a permissive model of adenoviral replication. Two hundred and forty animals were stereotactically administered either vehicle (n = 60) or CRAd-S-pk7 at 2.

Cell-Penetrating Peptide-Modified Gold Nanoparticles for the Delivery of Doxorubicin to Brain Metastatic Breast Cancer.

As therapies continue to increase the lifespan of patients with breast cancer, the incidence of brain metastases has steadily increased, affecting a significant number of patients with metastatic disease. However, a major barrier toward treating these lesions is the inability of therapeutics to penetrate into the central nervous system and accumulate within intracranial tumor sites. In this study, we designed a cell-penetrating gold nanoparticle platform to increase drug delivery to brain metastatic breast cancer cells.

The relationship between obesity and symptomatic Chiari I malformation in the pediatric population.

Background: Concomitant with the rise in childhood obesity in the United States is an increase in the diagnosis of Chiari I malformation (CM1).

Objective: To discern a correlation between obesity and CM1, defined as >5 mm of cerebellar tonsillar descent on sagittal magnetic resonance imaging.

Methods: Charts of CM1 patients aged 2-20 years were retrospectively reviewed.

Viral Vector Production: Adenovirus.

Adenoviral vectors have proven to be valuable resources in the development of novel therapies aimed at targeting pathological conditions of the central nervous system, including Alzheimer's disease and neoplastic brain lesions. Not only can some genetically engineered adenoviral vectors achieve remarkably efficient and specific gene delivery to target cells, but they also may act as anticancer agents by selectively replicating within cancer cells.Due to the great interest in using adenoviral vectors for various purposes, the need for a comprehensive protocol for viral vector production is especially apparent.

Analysis of survival in pediatric high-grade brainstem gliomas: A population-based study.

Background: The purpose of this study was to use the National Cancer Institutes' Surveillance, Epidemiology, and End Results (SEER) database to perform a large-scale analysis of brainstem anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Use of the SEER database gave us a larger sample size of this rare tumor type, allowing for the analysis of the relationship between prognostic factors and survival.

Materials And Methods: We selected pediatric patients (<18 years old) from the SEER database with histologically confirmed diagnoses of primary high-grade gliomas (World Health Organization Grade III/IV) of the brainstem.

MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells.

Neural stem cell (NSC)-based carriers have been presented as promising therapeutic tools for the treatment of infiltrative brain tumors due to their intrinsic tumor homing property. They have demonstrated the ability to migrate towards distant tumor microsatellites and effectively deliver the therapeutic payload, thus significantly improving survival in experimental animal models for brain tumor. Despite such optimistic results, the efficacy of NSC-based anti-cancer therapy has been limited due to the restricted tumor homing ability of NSCs.

The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence.

Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glioblastoma. They are able to self-renew, recapitulate a whole tumor, and differentiate into other specific glioblastoma multiforme (GBM) subpopulations. Therefore, they have been held responsible for malignant relapse after primary standard therapy and the poor prognosis of recurrent GBM.

Minimally Invasive Transforaminal Lumbar Interbody Fusion (TLIF) for Spondylolisthesis in 282 Patients: In Situ Arthrodesis versus Reduction.

Objective: The benefits of spondylolisthesis reduction via minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) remain poorly understood. The purpose was to compare the complications, perioperative factors, and fusion rates in patients undergoing MI-TLIF for degenerative spondylolisthesis between those in whom reduction was or was not performed.

Inclusion Criteria: 1) patients who underwent a 1, 2, or 3 level MI-TLIF and 2) had a preoperative diagnosis of degenerative spondylolisthesis (Meyerding grade >0).

Intraoperative and perioperative complications in minimally invasive transforaminal lumbar interbody fusion: a review of 513 patients.

OBJECT Transforaminal lumbar interbody fusion (TLIF) has become one of the preferred procedures for circumferential fusion in the lumbar spine. Over the last decade, advances in surgical techniques have enabled surgeons to perform the TLIF procedure through a minimally invasive approach (MI-TLIF). There are a few studies reported in the medical literature in which perioperative complication rates of MI-TLIF were evaluated; here, the authors present the largest cohort series to date.

Blood-brain barrier permeable gold nanoparticles: an efficient delivery platform for enhanced malignant glioma therapy and imaging.

The blood-brain barrier (BBB) remains a formidable obstacle in medicine, preventing efficient penetration of chemotherapeutic and diagnostic agents to malignant gliomas. Here, a transactivator of transcription (TAT) peptide-modified gold nanoparticle platform (TAT-Au NP) with a 5 nm core size is demonstrated to be capable of crossing the BBB efficiently and delivering cargoes such as the anticancer drug doxorubicin (Dox) and Gd(3+) contrast agents to brain tumor tissues. Treatment of mice bearing intracranial glioma xenografts with pH-sensitive Dox-conjugated TAT-Au NPs via a single intravenous administration leads to significant survival benefit when compared to the free Dox.

Antiglioma oncolytic virotherapy: unattainable goal or a success story in the making?

Initial observations from as early as the mid-1800s suggested that patients suffering from hematological malignancies would transiently go into remission upon naturally contracting viral infections laid the foundation for the oncolytic virotherapy research field. Since then, research focusing on anticancer oncolytic virotherapy has rapidly evolved. Today, oncolytic viral vectors have been engineered to stimulate and manipulate the host immune system, selectively targeting tumor tissues while sparing non-neoplastic cells.

The potential of polymeric micelles in the context of glioblastoma therapy.

Glioblastoma multiforme (GBM), a type of malignant glioma, is the most common form of brain cancer found in adults. The current standard of care for GBM involves adjuvant temozolomide-based chemotherapy in conjunction with radiotherapy, yet patients still suffer from poor outcomes with a median survival of 14.6 months.

Measuring surgical outcomes in subaxial degenerative cervical spine disease patients: minimum clinically important difference as a tool for determining meaningful clinical improvement.

Background: Although the concept of minimum clinically important difference (MCID) as a measurement of surgical outcome has been extensively studied, there is lack of consensus on the most valid or clinically relevant MCID calculation approach.

Objective: To compare the range of MCID threshold values obtained by different anchor-based and distribution-based approaches to determine the best clinically meaningful and statistically significant MCID for our studied group.

Methods: Eighty-eight consecutive patients undergoing surgery for subaxial degenerative cervical spine disease were analyzed from a prospective blinded database.

Fibrin-binding, peptide amphiphile micelles for targeting glioblastoma.

Glioblastoma-targeted drug delivery systems facilitate efficient delivery of chemotherapeutic agents to malignant gliomas, while minimizing systemic toxicity and side effects. Taking advantage of the fibrin deposition that is characteristic of tumors, we constructed spherical, Cy7-labeled, targeting micelles to glioblastoma through the addition of the fibrin-binding pentapeptide, cysteine-arginine-glutamic acid-lysine-alanine, or CREKA. Conjugation of the CREKA peptide to Cy7-micelles increased the average particle size and zeta potential.

Inhibition of MMP14 potentiates the therapeutic effect of temozolomide and radiation in gliomas.

Metalloproteinases are membrane-bound proteins that play a role in the cellular responses to antiglioma therapy. Previously, it has been shown that treatment of glioma cells with temozolomide (TMZ) and radiation (XRT) induces the expression of metalloproteinase 14 (MMP14). To investigate the role of MMP14 in gliomagenesis, we used several chemical inhibitors which affect MMP14 expression.

The impact of obesity on surgeon ratings and patient-reported outcome measures after degenerative cervical spine disease surgery.

Objective: Obesity is a growing public health problem. A considerable number of patients undergoing cervical spine surgery are obese, but the correlation between obesity and surgical outcome is still unclear. In this study, we investigated the impact of body mass index (BMI) on patients' and surgeons' perception of spine surgery outcomes.

Usefulness of minimum clinically important difference for assessing patients with subaxial degenerative cervical spine disease: statistical versus substantial clinical benefit.

Background: The measurement of the therapeutic outcome of cervical spine surgeries commonly relies on four main patient reported outcomes (PROs): Neck Disability Index (NDI), Visual Analog Scale (VAS) for pain, and Short Form-36 (SF-36) Physical (PCS) and Mental (MCS) Component Summary. However, the clinical impact of such scores and how they could effectively measure therapeutic efficacy remains unclear. In this context, the concept of minimum clinically important difference (MCID) is developing into the standard by which to evaluate treatments, patient satisfaction and cost-effectiveness.

Multifunctional nanoparticles for brain tumor imaging and therapy.

Brain tumors are a diverse group of neoplasms that often carry a poor prognosis for patients. Despite tremendous efforts to develop diagnostic tools and therapeutic avenues, the treatment of brain tumors remains a formidable challenge in the field of neuro-oncology. Physiological barriers including the blood-brain barrier result in insufficient accumulation of therapeutic agents at the site of a tumor, preventing adequate destruction of malignant cells.

The timing of neural stem cell-based virotherapy is critical for optimal therapeutic efficacy when applied with radiation and chemotherapy for the treatment of glioblastoma.

Glioblastoma multiforme (GBM) remains fatal despite intensive surgical, radiotherapeutic, and chemotherapeutic interventions. Neural stem cells (NSCs) have been used as cellular vehicles for the transportation of oncolytic virus (OV) to therapeutically resistant and infiltrative tumor burdens throughout the brain. The HB1.

Nanoparticle-programmed self-destructive neural stem cells for glioblastoma targeting and therapy.

A 3-step glioblastoma-tropic delivery and therapy method using nanoparticle programmed self-destructive neural stem cells (NSCs) is demonstrated in vivo: 1) FDA-approved NSCs for clinical trials are loaded with pH-sensitive MSN-Dox; 2) the nanoparticle conjugates provide a delayed drug-releasing mechanism and allow for NSC migration towards a distant tumor site; 3) NSCs eventually undergo cell death and release impregnated MSN-Dox, which subsequently induces toxicity towards surrounding glioma cells.

Measuring surgical outcomes in cervical spondylotic myelopathy patients undergoing anterior cervical discectomy and fusion: assessment of minimum clinically important difference.

Object: The concept of minimum clinically important difference (MCID) has been used to measure the threshold by which the effect of a specific treatment can be considered clinically meaningful. MCID has previously been studied in surgical patients, however few studies have assessed its role in spinal surgery. The goal of this study was to assess the role of MCID in patients undergoing anterior cervical discectomy and fusion (ACDF) for cervical spondylotic myelopathy (CSM).