Sander Idema

Higher complications and no improvement in mortality in the ACGME resident duty-hour restriction era: an analysis of more than 107,000 neurosurgical trauma patients in the Nationwide Inpatient Sample database.

BACKGROUND The Accreditation Council for Graduate Medical Education resident duty-hour restrictions were implemented in July 2003 based on the supposition that resident fatigue contributes to medical errors. OBJECTIVE To examine the effect of duty-hour restrictions on outcome in neurotrauma patients. METHODS The Nationwide Inpatient Sample database was analyzed for a time period with no restrictions (years 1999-2002) compared with a period with restrictions (years 2005-2008) for (1) mortality and (2) complications. We analyzed both teaching and nonteaching hospitals to account for potential differences attributed to non-resident-related factors. RESULTS There were 107,006 teaching hospital and 115,604 nonteaching hospital admissions for neurotrauma. Multivariate logistic regression demonstrated significantly more complications in the time period with restrictions in teaching hospitals. In nonteaching hospitals, there was no difference in complications. In both teaching and nonteaching hospitals, there was no difference in mortality between the 2 time periods. For teaching and nonteaching hospitals, there was no difference in hospital length of stay, but hospital charges were significantly higher in the period with restrictions. The occurrence of a complication was significantly associated with longer hospital length of stay and higher hospital charges in both time periods in both teaching and nonteaching hospitals. CONCLUSION The implementation of the Accreditation Council for Graduate Medical Education resident duty-hour restrictions was associated with increased complications and no change in mortality for neurotrauma patients in teaching hospitals. In nonteaching hospitals, there was no change in complications and mortality. The occurrence of a complication was associated with longer length of stay and higher hospital charges in both time periods in both teaching and nonteaching hospitals.

Tissue Inhibitor of Metalloproteinase-3 Expression from an Oncolytic Adenovirus Inhibits Matrix Metalloproteinase Activity In vivo without Affecting Antitumor Efficacy in Malignant Glioma

Oncolytic adenoviruses exhibiting tumor-selective replication are promising anticancer agents. Insertion and expression of a transgene encoding tissue inhibitor of metalloproteinase-3 (TIMP-3), which has been reported to inhibit angiogenesis and tumor cell infiltration and induce apoptosis, may improve the antitumor activity of these agents. To assess the effects of TIMP-3 gene transfer to glioma cells, a replication-defective adenovirus encoding TIMP-3 (Ad.TIMP-3) was employed. Ad.TIMP-3 infection of a panel of glioma cell cultures decreased the proliferative capacity of these cells and induced morphologic changes characteristic for apoptosis. Next, a conditionally replicating adenovirus encoding TIMP-3 was constructed by inserting the TIMP-3 expression cassette into the E3 region of the adenoviral backbone containing a 24-bp deletion in E1A. This novel oncolytic adenovirus, AdDelta24TIMP-3, showed enhanced oncolytic activity on a panel of primary cell cultures and two glioma cell lines compared with the control oncolytic virus AdDelta24Luc. In vivo inhibition of matrix metalloproteinase (MMP) activity by AdDelta24TIMP-3 was shown in s.c. glioma xenografts. The functional activity of TIMP-3 was imaged noninvasively using a near-IR fluorescent MMP-2-activated probe. Tumoral MMP-2 activity was significantly reduced by 58% in the AdDelta24TIMP-3-treated tumors 24 hours after infection. A study into the therapeutic effects of combined oncolytic and antiproteolytic therapy was done in both a s.c. and an intracranial model for malignant glioma. Treatment of s.c. (U-87MG) or intracranial (U-87deltaEGFR) tumors with AdDelta24TIMP-3 and AdDelta24Luc both significantly inhibited tumor growth and prolonged survival compared with PBS-treated controls. However, expression of TIMP-3 in the context of AdDelta24 did not significantly affect the antitumor efficacy of this oncolytic agent.

Monitoring of tumor growth and post-irradiation recurrence in a diffuse intrinsic pontine glioma mouse model.

Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy because of its diffuse infiltrative growth pattern. Translational research suffers from the lack of a representative DIPG animal model. Hence, human E98 glioma cells were stereotactically injected into the pons of nude mice. The E98 DIPG tumors presented a strikingly similar histhopathology to autopsy material of a DIPG patient, including diffuse and perivascular growth, brainstem‐ and supratentorial invasiveness and leptomeningeal growth. Magnetic resonance imaging (MRI) was effectively employed to image the E98 DIPG tumor. [18F] 3′‐deoxy‐3′‐[18F]fluorothymidine (FLT) positron emission tomography (PET) imaging was applied to assess the subcutaneous (s.c.) E98 tumor proliferation status but no orthotopic DIPG activity could be visualized. Next, E98 cells were cultured in vitro and engineered to express firefly luciferase and mCherry (E98‐Fluc‐mCherry). These cultured E98‐Fluc‐mCherry cells developed focal pontine glioma when injected into the pons directly. However, the diffuse E98 DIPG infiltrative phenotype was restored when cells were injected into the pons immediately after an intermediate s.c. passage. The diffuse E98‐Fluc‐mCherry model was subsequently used to test escalating doses of irradiation, applying the bioluminescent Fluc signal to monitor tumor recurrence over time. Altogether, we here describe an accurate DIPG mouse model that can be of clinical relevance for testing experimental therapeutics in vivo.

AdΔ24 and the p53-expressing variant AdΔ24-p53 achieve potent anti-tumor activity in glioma when combined with radiotherapy

The conditionally replicating adenovirus (CRAd) AdΔ24‐p53 replicates selectively in Rb mutant cells, and encodes the p53 suppressor protein. It has shown improved oncolytic potency compared to the parental control AdΔ24. As exogenous p53 has been shown to enhance radiosensitivity, the combination of AdΔ24‐p53 and AdΔ24 with radiotherapy was assessed in vitro and in vivo against the therapy resistant gliomas.

Expression of p53, or targeting towards EGFR, enhances the oncolytic potency of conditionally replicative adenovirus against neuroblastoma

Advanced stage and relapsing neuroblastoma (NB) has a poor prognosis with frequent treatment failures, warranting new treatment options and enhanced local tumor control. Treatment with conditionally replicative adenoviruses (CRAds) has shown effectiveness in various preclinical cancer models, but has not yet been evaluated for local control of NB. Here, we tested the efficacy of the CRAd AdΔ24 and of two AdΔ24 derivatives against NB. Derivative AdΔ24‐425S11 infects cells deficient in coxsackie/adenovirus receptor (CAR) via the epidermal growth factor receptor (EGFR). Derivative AdΔ24‐p53 expresses the tumor suppressor protein p53 to promote oncolysis.

Identifying the epileptogenic zone in interictal resting-state MEG source-space networks.

In one third of patients, seizures remain after epilepsy surgery, meaning that improved preoperative evaluation methods are needed to identify the epileptogenic zone. A potential framework for such a method is network theory, as it can be applied to noninvasive recordings, even in the absence of epileptiform activity. Our aim was to identify the epileptogenic zone on the basis of hub status of local brain areas in interictal magnetoencephalography (MEG) networks.

Swarm Intelligence-Enhanced Detection of Non-Small-Cell Lung Cancer Using Tumor-Educated Platelets

Summary Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92–0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83–0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources.

In Vivo Accuracy of a Frameless Stereotactic Drilling Technique for Diagnostic Biopsies and Stereoelectroencephalography Depth Electrodes

BACKGROUND Accurate frameless neuronavigation is highly important in cranial neurosurgery. The accuracy demonstrated in phantom models might not be representative for results in patients. Few studies describe the in vivo quantitative accuracy of neuronavigation in patients. The use of a frameless stereotactic drilling technique for stereoelectroencephalography depth electrode implantation in epilepsy patients, as well as diagnostic biopsies, provides a unique opportunity to assess the accuracy with postoperative imaging of preoperatively planned trajectories. METHODS In 7 patients with refractory epilepsy, 89 depth electrodes were implanted using a frameless stereotactic drilling technique. Each electrode was planned on a preoperative magnetic resonance and computed tomographic scan, and verified on postoperative computed tomographic scan. After fusion of preoperative and postoperative imaging, the accuracy for each electrode was calculated as the Euclidean distance between the planned and observed position of the electrode tip. RESULTS The median Euclidean distance between planned and observed electrode implantations was 3.5 mm (95% confidence interval, 2.9-3.9 mm) with a range of 1.2-13.7 mm. CONCLUSIONS In this study, we showed that the in vivo accuracy of our frameless stereotactic drilling technique, suitable for stereoelectroencephalography depth electrode placement and diagnostic brain biopsies, was 3.5 mm.

Convection enhanced delivery of carmustine to the murine brainstem: a feasibility study.

BACKGROUND Systemic delivery of therapeutic agents remains ineffective against diffuse intrinsic pontine glioma (DIPG), possibly due to an intact blood-brain-barrier (BBB) and to dose-limiting toxicity of systemic chemotherapeutic agents. Convection-enhanced delivery (CED) into the brainstem may provide an effective local delivery alternative for DIPG patients. NEW METHOD The aim of this study is to develop a method to perform CED into the murine brainstem and to test this method using the chemotherapeutic agent carmustine (BiCNU). To this end, a newly designed murine CED catheter was tested in vitro and in vivo. After determination of safety and distribution, mice bearing VUMC-DIPG-3 and E98FM-DIPG brainstem tumors were treated with carmustine dissolved in DW 5% or carmustine dissolved in 10% ethanol. RESULTS Our results show that CED into the murine brainstem is feasible and well tolerated by mice with and without brainstem tumors. CED of carmustine dissolved in 5% DW increased median survival of mice with VUMC-DIPG-3 and E98FM-DIPG tumors with 35% and 25% respectively. Dissolving carmustine in 10% ethanol further improved survival to 45% in mice with E98FM-DIPG tumors. COMPARISON WITH EXISTING METHODS Since genetically engineered and primary DIPG models are currently only available in mice, murine CED studies have clear advantages over CED studies in other animals. CONCLUSION CED in the murine brainstem can be performed safely, is well tolerated and can be used to study efficacy of chemotherapeutic agents orthotopically. These results set the foundation for more CED studies in murine DIPG models.

Therapeutic concentrations of anti-epileptic drugs do not inhibit the activity of the oncolytic adenovirus Delta24-RGD in malignant glioma

The oncolytic adenovirus Delta24‐RGD is currently being tested in phase I trials for the treatment of glioblastoma (GBM). Literature suggests that frequently prescribed anticonvulsants for these patients, phenytoin (PHE), valproic acid (VPA) and levetiracetam (LEV), may interfere with cellular mechanisms of cancer or oncolytic virus activity. We therefore investigated the direct effects of these drugs on Delta24‐RGD infection and oncolytic activity.