Salvage stereotactic radiosurgery for recurrent gliomas with prior radiation therapy.

This study aims to assess the viability of salvage stereotactic radiosurgery (SRS) for recurrent malignant gliomas through assessing overall survival, local control and toxicity. We performed a retrospective review of 65 patients with 76 lesions (55 high-grade, 21 low-grade) treated with salvage SRS between 2002 and   2012. Median follow-up from salvage SRS was 14.9 months (IQR: 0.9-28.1), 8.3 months (IQR: 4.0-13.3) and 8.5 months (IQR: 3.9-15.8) for low-grade, high-grade, and combined, respectively. A 12-month overall survival from salvage SRS was 68.4, 38.7 and 47.3% for low-grade, high-grade and combined respectively. A total of 6-month local control was 86.2, 53.8 and 65.3% for low-grade, high-grade and combined, respectively. Our results indicate salvage SRS can provide acceptable survival and local control with minimal toxicity.

ICES (Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery) for Brain Hemorrhage: A Multicenter Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a devastating disease without a proven therapy to improve long-term outcome. Considerable controversy about the role of surgery remains. Minimally invasive endoscopic surgery for ICH offers the potential of improved neurological outcome. METHODS: We tested the hypothesis that intraoperative computerized tomographic image-guided endoscopic surgery is safe and effectively removes the majority of the hematoma rapidly. A prospective randomized controlled study was performed on 20 subjects (14 surgical and 4 medical) with primary ICH of >20 mL volume within 48 hours of ICH onset. We prospectively used a contemporaneous medical control cohort (n=36) from the MISTIE trial (Minimally Invasive Surgery and r-tPA for ICH Evacuation). We evaluated surgical safety and neurological outcomes at 6 months and 1 year. RESULTS: The intraoperative computerized tomographic image-guided endoscopic surgery procedure resulted in immediate reduction of hemorrhagic volume by 68±21.6% (interquartile range 59-84.5) within 29 hours of hemorrhage onset. Surgery was successfully completed in all cases, with a mean operative time of 1.9 hours (interquartile range 1.5-2.2 hours). One surgically related bleed occurred peri-operatively, but no patient met surgical safety stopping threshold end points for intraoperative hemorrhage, infection, or death. The surgical intervention group had a greater percentage of patients with good neurological outcome (modified Rankin scale score 0-3) at 180 and 365 days as compared with medical control subjects (42.9% versus 23.7%; P=0.19). CONCLUSIONS: Early computerized tomographic image-guided endoscopic surgery is a safe and effective method to remove acute intracerebral hematomas, with a potential to enhance neurological recovery. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00224770.

The early days of hemostasis in neurosurgery.

Two key discoveries in the 19th century--infection control and the development of general anesthesia--provided an impetus for the rapid advancement of surgery, especially within the field of neurosurgery. Yet the field of neurosurgery would not have existed in the modern sense without the development and advancement of techniques in hemostasis. Improvement in intraoperative hemostasis came more gradually but was no less important to enhancing neurosurgical outcomes. The history of hemostasis in neurosurgery is often overlooked. Herein, the authors briefly review the historical progression of hemostatic techniques since the beginning of the early modern era of neurosurgery.

Clinical Features Associated with Outcomes and Biomarker Analysis of Dabrafenib plus Trametinib Treatment in Patients with BRAF-Mutant Melanoma Brain Metastases.

PURPOSE: This study aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis was also conducted as part of the synergistic COMBI-BRV trial (BRV116521), to identify molecular and immunologic changes associated with dabrafenib in MBMs and extracranial metastases (ECM). PATIENTS AND METHODS: Post hoc analysis was performed for baseline features of patients (n = 125) enrolled in COMBI-MB. Analyses were performed to identify baseline clinical features associated with intracranial response rate (ICRR), progression-free survival (PFS), and overall survival (OS).Exploratory biomarker analysis was performed on biospecimen collected in the COMBI-BRV trial in which patients with BRAF-mutant, resectable MBM were treated with dabrafenib for 10 to 14 days prior to craniotomy. Accessible ECM were resected or biopsied at the time of craniotomy. Biospecimens underwent molecular and immunologic profiling for comparative analyses. RESULTS: In COMBI-MB baseline treatment with corticosteroids was independently associated with lower ICRR [39% vs. 63%; OR, 0.323; 95 % confidence interval (CI), 0.105-0.996; P = 0.049] and shorter PFS (HR, 1.93; 95% CI, 1.06-3.51; P = 0.031). Additional significant associations identified in the multivariate analysis were improved PFS in patients with a BRAFV600E genotype (HR, 0.565; 95% CI, 0.321-0.996; P = 0.048) and improved OS in patients with Eastern Cooperative Oncology Group 0 (HR, 0.44; 95% CI, 0.25-0.78; P = 0.005). CONCLUSIONS: Corticosteroid treatment was associated with reduced ICRR and PFS in COMBI-MB, similar to results with immunotherapy for MBMs. Baseline corticosteroid treatment is a key factor to consider in MBM patient management and clinical trial design/interpretation.

Mechanical stability of well-functioning tibial baseplates from postmortem-retrieved total knee arthroplasties.

In joint replacement, cyclic motion at the bone-prosthesis interface is considered a precursor to component loosening. This study characterized the mechanical stability of 13 total knee arthroplasties harvested postmortem after an average time in situ of 10.3 years. With loads applied to the medial and then the lateral tibial plateau, motion between the tibial component and underlying bone was measured with extensometers. The amount of motion between the tibial component and underlying bone under medial and lateral loads of 500 N and then twice body weight was typically less than 20 microm. Tray depression under load application and the liftoff on the contralateral side indicated that the tibial stems limited implant rotation and that implant fixation did not deteriorate with time in situ.

Hemorrhage rates after external ventricular drain placement.

OBJECT: External ventricular drain (EVD) placement is one of the most common neurosurgical procedures performed. Rates and significance of hemorrhage associated with this procedure have not been well quantified. METHODS: All adults who underwent EVD placement at the University of Pittsburgh Medical Center between July 2002 and June 2003 were evaluated for catheter-associated hemorrhage. Patients without postprocedural imaging were excluded. RESULTS: Seventy-seven (41%) of 188 EVDs were associated with imaging evidence of hemorrhage after either placement or removal. Most of these were insignificant, punctate intraparenchymal, or trace subarachnoid hemorrhages (51.9%). Thirty-seven (19.7%) were associated with larger hemorrhages, which were divided into 3 groups according to volume of hemorrhage: 16 patients (8.5%) had < 15 ml of hemorrhage, 20 (10.6%) had hemorrhages of > 15 ml or associated intraventricular hemorrhage, and in 1 case there was a subdural hematoma that required surgical evacuation. No hemorrhages larger than punctate or trace were seen after EVD removal. Hemorrhage was associated with 44.3% of EVDs placed in an intensive care unit compared with 34.8% in EVDs placed in the operating room (p > 0.10). CONCLUSIONS: External ventricular drain placement has a significant risk of associated hemorrhage. However, the hemorrhages are rarely large and almost never require surgical intervention. There is a favorable trend, but no significant risk reduction when EVDs are placed in the operating room rather than the intensive care unit.

Completely endoscopic resection of intraparenchymal brain tumors.

OBJECT: The authors introduce a novel technique of intraparenchymal brain tumor resection using a rod lens endoscope and parallel instrumentation via a transparent conduit. METHODS: Over a 4-year period, 21 patients underwent completely endoscopic removal of a subcortical brain lesion by means of a transparent conduit. Image guidance was used to direct the cannulation and resection of all lesions. Postoperative MR imaging or CT was performed to assess for residual tumor in all patients, and all patients were followed up postoperatively to assess for new neurological deficits or other surgical complications. RESULTS: The histopathological findings were as follows: 12 metastases, 5 glioblastomas, 3 cavernous malformations, and 1 hemangioblastoma. Total radiographically confirmed resection was achieved in 8 cases, near-total in 6 cases, and subtotal in 7 cases. There were no perioperative deaths. Complications included 1 infection and 1 pulmonary embolus. There were no postoperative hematomas, no postoperative seizures, and no worsened neurological deficits in the immediate postoperative period. CONCLUSIONS: Fully endoscopic resection may be a technically feasible method of resection for selected subcortical masses. Further experience with this technique will help to determine its applicability and safety.

Stereotactic-Guided Dilatable Endoscopic Port Surgery for Deep-Seated Brain Tumors: Technical Report with Comparative Case Series Analysis.

OBJECTIVE: Deep-seated brain tumors are often best treated by primary surgical excision. Traditional microsurgical techniques can cause retraction injury and require extensive brain dissection. To mitigate this risk, stereotactic-guided tubular retractors were developed; however, the risk of shear injury remains. We created a stereotactic-guided dilatable port system to create a corridor for deep brain tumor surgery along the trajectory of a brain needle to minimize iatrogenic brain injury. METHODS: Of the 8 included patients (6 colloid cysts, 1 metastasis, 1 intraventricular meningioma), 5 had undergone frameless and 3 frame-based stereotactic targeting. We used a tans-sulcal trajectory and a 2.6-mm stereotactic needle. At the target depth, the cannula was removed and the balloon inflated to 14 mm. The balloon was deflated and removed before placing the port. Pre- and 3-month postoperative magnetic resonance imaging scans were used to measure the T2-weighted signal change and residual cannulation defect. These patients were compared with a case-matched standard endoscopic port surgery cohort. RESULTS: All patients had undergone total lesional resection without new neurologic deficits. Patients undergoing dilatable endoscopic port surgery (DEPS) had significantly smaller residual cannulation defects (P < 0.05) but no significant differences in postoperative T2-weighted signal changes or diffusion restriction volumes at 3 months postoperatively (P > 0.05). CONCLUSIONS: DEPS might be a safe alternative to standard endoscopic port surgery or microsurgery for deep-seated brain tumors. The degree of iatrogenic injury using DEPS, as determined by magnetic resonance imaging analysis, might be equivalent to or less than that with standard port surgery techniques, although larger sample sizes are needed for validation.

Clinical and Molecular Recursive Partitioning Analysis of High-grade Glioma Treated With IMRT.

INTRODUCTION: Despite multimodal treatment for high-grade gliomas, prognosis remains grim. Prior Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) reports indicate based on pretreatment and treatment-related factors, a subset of patients experience a significantly improved survival. Since the development of the RTOG-RPA, high-grade gliomas have seen the widespread introduction of temozolomide and tumor oncogenetics. Here we aimed to determine whether the RTOG-RPA retained prognostic significance in the context of modern treatment, as well as generate an updated RPA incorporating both clinical and genetic variables. METHODS: Patients with histologically proven glioblastoma, gliosarcoma, anaplastic astrocytoma, and anaplastic oligodendroglioma treated with intensity-modulated radiation therapy (IMRT) between 2004 and 2017 were reviewed. The primary endpoint was overall survival from date of diagnosis. Primary analysis compared actual survival rates to that expected of corresponding RTOG-RPA class. Secondary analysis utilized the rpart function to recursively partition overall survival by numerous clinical and genetic pretreatment and treatment-related variables. A tertiary analysis recursively partitioned a subset of patients in which the status of all genetic markers were known. RESULTS: We identified 878 patients with histologically proven high-grade glioma treated with IMRT and 291 patients in our genetic subset. Median overall survival for the entire cohort was 14.2 months (95% confidence interval, 13.1-15.3). Applying the RTOG-RPA to our cohort validated the relative prognostic ordering of the survival classes except class II. Generating our new RPA created 7 significantly different survival classes (P<0.001, χ=584) with median survival ranging from 96.4 to 2.9 months based on age, histology, O6-methylguanine-DNA methyltransferase methylation status, radiation fractions, tumor location, radiation dose, temozolomide status, and resection status. Our second RPA of our genetic subset generated 5 significantly different survival classes (P<0.001, χ=166) with survival ranging from 65.3 to 5.6 months based on age, isocitrate dehydrogenase 1 mutation status, O6-methylguanine-DNA methyltransferase methylation status, neurological functional classification, hospitalization during IMRT, temozolomide status, and Karnofsky performance status. CONCLUSIONS: The RTOG-RPA retains partial prognostic significance, however, should be updated to reflect recent advancements. This series represents a large RPA analyzing both clinical and genetic factors and generated 7 distinct survival classes. Further assessment of patients with fully available genetic markers generated 5 distinct survival classes. These survival classifications need to be validated by a prospective data set and compared against the RTOG-RPA to determine whether they provide improved prognostic power.

Diffusion-weighted magnetic resonance imaging demonstrating intraventricular rupture of a cerebral abscess and subsequent therapeutic response.

BACKGROUND: The most feared complication of a pyogenic brain abscess is intraventricular rupture. Mortality for this event has been traditionally reported to be approximately 80%. Appreciation of the incidence of IVROBA has likely increased with the dawn of CT and MRI. In selected cases, a patient with IVROBA may demonstrate a functional survival with low morbidity, if therapy is initiated quickly and aggressively. CASE DESCRIPTION: The authors report the IVROBA in a 49-year-old patient despite appropriate abscess drainage and broad-spectrum intravenous antibiotic administration. Diffusion-weighted MRI was particularly useful in this case for the demonstration of not only the intraventricular rupture but also the subsequent resolution of the inflammatory response within the ventricular system in response to aggressive ventricular drainage and systemic antibiotic therapy. CONCLUSION: Diffusion-weighted MRI can be applicable both to the diagnosis of IVROBA as well as to the response to appropriate surgical therapy. With aggressive treatment, a good outcome is achievable in the setting of IVROBA.

The Utility of Early Postoperative Head Computed Tomography in Brain Tumor Surgery: A Retrospective Analysis of 755 Cases.

OBJECTIVE: Scheduled early postoperative computed tomography (EPOCT) after craniotomy for brain tumor resection is standard at many institutions. We analyzed utility of preplanned EPOCT after elective craniotomy for brain tumor resection. METHODS: We retrospectively analyzed 755 brain tumor resections for which EPOCT was performed within 4 hours of surgery. Postoperative clinical neurologic examination results were classified into expected (baseline or predicted postoperative examination), changed (from baseline examination), and unreliable (sedated or baseline comatose patient). Scans were analyzed for unexpected and/or worrisome findings (e.g., hemorrhagic or ischemic stroke). In cases of unexpected findings, management changes were correlated to patient's neurologic examination. Demographic information, tumor histology, and tumor location were analyzed to determine risk factors for unexpected findings. RESULTS: Rate of unexpected EPOCT findings was 4.1%. Patients with expected postoperative examinations were at significantly lower risk of abnormal findings (odds ratio [OR] = 0.074, P < 0.001). Patients with intraventricular tumors (OR = 5.7, P = 0.001) were at higher risk compared with patients with metastatic tumors (OR = 0.24, P = 0.06). No unexpected EPOCT findings led to management changes in patients with expected postoperative neurologic examinations. All unexpected EPOCT findings in patients with changed postoperative neurologic examinations led to management changes. Patients with nonreliable neurologic examinations were at significantly higher risk for unexpected findings on EPOCT (OR = 6.33, P < 0.001) and subsequent management changes. CONCLUSIONS: Routine EPOCT is not indicated for patients undergoing brain tumor resection if postoperative neurologic examination is unchanged, as imaging is unlikely to result in management changes. EPOCT should be obtained in all patients with worrisome changes in examination or nonreliable examinations, as both groups have high rates of unexpected findings on imaging that lead to management changes.

Assessing the Structural Footprint of Minimally Invasive Brain Cannulation on Cerebral White Matter: A Cadaveric Model.

BACKGROUND: All brain surgery requires some degree of iatrogenic trauma to healthy tissue. Minimally invasive approaches to brain tumors offer the potential of decreasing this trauma compared with conventional approaches. However, there are no validated radiologic models to examine axonal damage after minimally invasive entry into the brain. OBJECTIVE: To present a cadaveric model of brain cannulation using fractional anisotropy measurements obtained from diffusion tensor magnetic resonance imaging (MRI). Two different methods of access are compared. METHODS: Freshly harvested unfixed cadaveric brains were cannulated using both direct and indirect (i.e., dilation followed by cannulation) methods. Specimens were subjected to 68-direction diffusion tensor imaging scans and proton-density imaging. Fractional anisotropy (FA) data from a region of interest surrounding the entry zone was extracted from scans using imaging software and analyzed. RESULTS: FA values were significantly higher following indirect cannulation (less invasive method) than they were following direct cannulation. FA values for undisturbed brain were significantly higher than in either of the cannulated groups, suggesting an inverse relationship between FA values and brain injury. CONCLUSION: Axonal damage following brain cannulation can potentially be evaluated by FA analysis in a cadaveric model. These data may lead to an MRI-based model of iatrogenic brain injury following tumor surgery. Future studies will focus on histologic analysis and clinical validation in live tissues.

Cardioversion-Responsive Ventriculoatrial Shunt Malfunction Precipitated by Atrial Fibrillation.

BACKGROUND: Ventriculoatrial shunts are common alternatives for patients who cannot tolerate ventriculoperitoneal shunts. The majority of ventriculoatrial shunt malfunctions are related to mechanical problems. We report an interesting case of ventriculoatrial shunt malfunction due to elevated central venous pressure from new-onset atrial fibrillation. METHODS: After the patient was confirmed to have ventriculomegaly, he was taken to the operating room for exploration of his ventriculoatrial shunt; there were no obstructions. Subsequently, the patient was cardioverted to normal sinus rhythm for his new onset atrial fibrillation. RESULTS: The clinical syndrome and ventriculomegaly both resolved after the patient's atrial fibrillation was corrected with chemical cardioversion. CONCLUSIONS: The cause of this patient's VA shunt malfunction was likely associated with his new onset atrial fibrillation.

Long-Term Survivorship Following Stereotactic Radiosurgery Alone for Brain Metastases: Risk of Intracranial Failure and Implications for Surveillance and Counseling.

BACKGROUND: Historically, survival for even highly select cohorts of brain metastasis patients selected for SRS alone is <2 yr; thus, limited literature on risks of recurrence exists beyond 2 yr. OBJECTIVE: To investigate the possibility that for subsets of patients the risk of intracranial failure beyond 2 yr is less than the commonly quoted 50% to 60%, wherein less frequent screening may be appropriate. METHODS: As a part of our institutional radiosurgery database, we identified 132 patients treated initially with stereotactic radiosurgery (SRS) alone (± pre-SRS surgical resection) with at least 2 yr of survival and follow-up from SRS. Primary study endpoints were rates of actuarial intracranial progression beyond 2 yr, calculated using the Kaplan-Meier and Cox regression methods. RESULTS: The median follow-up from the first course of SRS was 3.5 yr. Significant predictors of intracranial failure beyond 2 yr included intracranial failure before 2 yr (52% vs 25%, P < .01) and total SRS tumor volume ≥5 cc (51% vs 25%, P < .01). On parsimonious multivariate analysis, failure before 2 yr (HR = 2.2, 95% CI: 1.2-4.3, P = .01) and total SRS tumor volume ≥5 cc (HR = 2.3, 95% CI: 1.2-4.3, P = .01) remained significant predictors of intracranial relapse beyond 2 yr. CONCLUSION: Relapse rates beyond 2 yr following SRS alone for brain metastases are low in patients who do not suffer intracranial relapse within the first 2 yr and with low-volume brain metastases, supporting a practice of less frequent screening beyond 2 yr. For remaining patients, frequent (every 3-4 mo) screening remains prudent, as the risk of intracranial failure after 2 yr remains high.

Stereotactic body radiation therapy for benign spine tumors: is dose de-escalation appropriate?

OBJECTIVE Akin to the nonoperative management of benign intracranial tumors, stereotactic body radiation therapy (SBRT) has emerged as a nonoperative treatment option for noninfiltrative primary spine tumors such as meningioma and schwannoma. The majority of initial series used higher doses of 16-24 Gy in 1-3 fractions. The authors hypothesized that lower doses (such as 12-13 Gy in 1 fraction) might provide an efficacy similar to that found with the dose de-escalation commonly used for intracranial radiosurgery to treat acoustic neuroma or meningioma and with a lower risk of toxicity. METHODS The authors identified 38 patients in a prospectively maintained institutional radiosurgery database who were treated with definitive SBRT for a total of 47 benign primary spine tumors between 2004 and 2016. SBRT consisted of 9-21 Gy in 1-3 fractions using the CyberKnife (n = 11 [23%]), Synergy S (n = 21 [45%]), or TrueBeam (n = 15 [32%]) radiosurgery platform. For a comparison of SBRT doses, patients were dichotomized into 1 of 2 groups (low-dose or high-dose SBRT) using a cutoff biologically effective dose (BED10Gy) of 30 Gy. Tumor control was calculated from the date of SBRT to the last follow-up using Kaplan-Meier survival analysis, with comparisons between groups completed using a log-rank method. To account for potential indication bias, a propensity score analysis was completed based on the conditional probabilities of SBRT dose selection. Toxicity was graded using Common Terminology Criteria for Adverse Events version 4.0 with a focus on grade 3+ toxicity and the incidence of pain flare. RESULTS For the 38 patients, the most common histological findings were meningioma (15 patients), schwannoma (13 patients), and hemangioblastoma (7 patients). The median age at SBRT was 58 years (range 25-91 years). The 47 treated lesions were located in the cervical (n = 18), thoracic (n = 19), or lumbosacral (n = 10) spine. Five (11%) lesions were lost to follow-up after SBRT. The median follow-up duration for the remaining 42 lesions was 54 months (range 1.2-133 months). Six (16%) patients (with a total of 8 lesions) experienced pain flare after SBRT; no significant predictor of pain flare was identified. No grade 3+ acute- or late-onset complication was noted. The 5-year local control rate was 76% (95% CI 61%-91%). No significant difference in local control according to dose, fractionation, previous radiation, surgery, tumor histology, age, treatment platform, planning target volume, or spine level treated was found. The 5-year local control rates for low- and high-dose treatments were 73% (95% CI 53%-93%) and 83% (95% CI 61%-100%) (p = 0.52). In propensity score-adjusted multivariable analysis, no difference in local control was identified (HR 0.30, 95% CI 0.02-5.40; p = 0.41). CONCLUSIONS Long-term follow-up of patients treated with SBRT for benign spinal lesions revealed no significant difference between low-dose (BED10Gy ≤ 30) and high-dose SBRT in local control, pain-flare rate, or long-term toxicity.

Long-Term Outcomes After Stereotactic Radiosurgery for Spine Metastases: Radiation Dose-Response for Late Toxicity.

PURPOSE: To document the 5- and 10-year rates of late toxicity and vertebral compression fracture (VCF) in long-term survivors after stereotactic radiosurgery for spine metastases. METHODS AND MATERIALS: A retrospective review was performed on 562 patients treated with SRS for spine metastases between April 2001 and July 2011. Selecting those with at least 5-year survival after SRS, included were 43 patients who collectively underwent 84 treatments at 54 spine sites. Most were treated with single-fraction stereotactic radiosurgery to a median dose of 16 Gy (range, 12-24 Gy), and 56% of sites had received prior external beam radiation therapy. Late toxicities and VCFs occurring in the absence of tumor progression were recorded. Binary logistic regression was used to identify predictors of late complications. RESULTS: Nine patients (17% of treatment sites) developed grade ≥2 late toxicities at a median time of 12.8 months (range, 4.2-59.0 months). Actuarial 5- and 10-year rates of grade ≥2 late toxicity were 17% and 17%, respectively. On multivariate analysis, only cumulative biologically effective dose (BED3) > 200 Gy (or EQD22Gy [2-Gy equivalent dose calculated using an α/ß ratio of 2] > 130 Gy) was associated with grade ≥2 late toxicity (P = .036). Maximum point BED3 > 110 Gy (or EQD22Gy > 70 Gy) to spinal cord or cauda equina was associated with grade ≥2 late neuropathy (P = .017). Nine VCFs (18%) occurred at a median time of 10.2 months (range, 3.2-57.2 months), with 5- and 10-year VCF rates of 17% and 17%, respectively. CONCLUSION: Stereotactic radiosurgery for primary treatment and reirradiation of spinal metastases is associated with a moderate risk of late toxicity with 10-year follow-up. Risk of late toxicity significantly increases with cumulative BED3 > 200 Gy and spinal cord or cauda equina point BED3 > 110 Gy. Patients remain at moderate risk of VCF up to 5 years after treatment, with a plateau in incidence thereafter up to 10 years.

Tip Design for Safety of Steerable Needles for Robot-Controlled Brain Insertion.

BACKGROUND: Current practice in neurosurgical needle insertion is limited by the straight trajectories inherent with rigid probes. One technique allowing curvilinear trajectories involves flexible bevel-tipped needles, which bend during insertion due to their asymmetry. In the brain, safety will require avoidance of the sharp tips often used in laboratory studies, in favor of a more rounded profile. Steering performance, on the other hand, requires maximal asymmetry. Design of safe bevel-tipped brain needles thus involves management of this tradeoff by adjusting needle gauge, bevel angle, and fillet (or tip) radius to arrive at a design that is suitably asymmetrical while producing strain, strain rate, and stress below the levels that would damage brain tissue. METHODS: Designs with a variety of values of needle radius, bevel angle, and fillet radius were evaluated in finite-element simulations of simultaneous insertion and rotation. Brain tissue was modeled as a hyperelastic, linear viscoelastic material. Based on the literature available, safety thresholds of 0.19 strain, 10 s-1 strain rate, and 120 kPa stress were used. Safe values of needle radius, bevel angle, and fillet radius were selected, along with an appropriate velocity envelope for safe operation. The resulting needle was fabricated and compared with a Sedan side-cutting brain biopsy needle in a study in the porcine model in vivo (N=3). RESULTS: The prototype needle selected was 1.66 mm in diameter, with bevel angle of 10° and fillet radius of 0.25 mm. Upon examination of postoperative CT and histological images, no differences in tissue trauma or hemorrhage were noted between the prototype needle and the Sedan needle. CONCLUSIONS: The study indicates a general design technique for safe bevel-tipped brain needles based on comparison with relevant damage thresholds for strain, strain rate, and stress. The full potential of the technique awaits the determination of more exact safety thresholds.

Alteration of the Ki-67 Proliferative Index following Surgical Resection with or without Radiation Therapy of Intracranial Meningiomas.

The Ki-67 proliferative index is a widely accepted assay for cycling cells within tumor specimens of multiple histological subtypes. While it is not a substitute for the World Health Organization (WHO) grading, the Ki-67 proliferative index is thought to correlate with the biological activity of selected tumors. In the case of intracranial meningiomas, many lesions may be resected multiple times, with radiation therapy juxtaposed between surgical procedures. A retrospective review of 3,900 consecutive patients undergoing intracranial surgical resection at the University of Pittsburgh Medical Center over a five year period was undertaken. Of these patients, 604 had multiple resections. Multiple Ki-67 index scores were available for 42 patients with WHO grade I and II meningiomas, who suffered a recurrence or progression after their initial resection. Evidence of radiation therapy in the interval between pathology reports was also recorded. Data was evaluated for significant differences (p<0.05). WHO grade II meningiomas were more likely to have a higher Ki-67 index score on second resection than WHO grade I tumors (p=0.051). Furthermore, radiation-treated meningiomas demonstrated similar first Ki-67 index scores and higher second Ki-67 index scores (p=0.057 and p=0.022). Male patients tended to have less change in proliferation rates than female patients between the first and second resections (p=0.083), with a greater proportion of female patient tumors demonstrating accelerating proliferation rates. Treatment with radiation was associated with diminishing changes in meningioma proliferation rates compared to non-treated patients for tumors showing both accelerating rates (p=0.067) and decelerating rates (p=0.081). Ki-67 proliferation indices of recurrent or progressive meningiomas indicate that there are potentially distinct types of growth patterns of meningiomas, consisting of accelerating and decelerating proliferation rates. Meningioma growth is related to WHO grade, patient gender, and treatment with radiation. Radiation treatment appears to stabilize or "inactivate" tumor proliferation and thus normalize changes in meningioma growth rates.

A First-in-Class TWIST1 Inhibitor with Activity in Oncogene-Driven Lung Cancer.

TWIST1, an epithelial-mesenchymal transition (EMT) transcription factor, is critical for oncogene-driven non-small cell lung cancer (NSCLC) tumorigenesis. Given the potential of TWIST1 as a therapeutic target, a chemical-bioinformatic approach using connectivity mapping (CMAP) analysis was used to identify TWIST1 inhibitors. Characterization of the top ranked candidates from the unbiased screen revealed that harmine, a harmala alkaloid, inhibited multiple TWIST1 functions, including single-cell dissemination, suppression of normal branching in 3D epithelial culture, and proliferation of oncogene driver-defined NSCLC cells. Harmine treatment phenocopied genetic loss of TWIST1 by inducing oncogene-induced senescence or apoptosis. Mechanistic investigation revealed that harmine targeted the TWIST1 pathway through its promotion of TWIST1 protein degradation. As dimerization is critical for TWIST1 function and stability, the effect of harmine on specific TWIST1 dimers was examined. TWIST1 and its dimer partners, the E2A proteins, which were found to be required for TWIST1-mediated functions, regulated the stability of the other heterodimeric partner posttranslationally. Harmine preferentially promoted degradation of the TWIST1-E2A heterodimer compared with the TWIST-TWIST1 homodimer, and targeting the TWIST1-E2A heterodimer was required for harmine cytotoxicity. Finally, harmine had activity in both transgenic and patient-derived xenograft mouse models of KRAS-mutant NSCLC. These studies identified harmine as a first-in-class TWIST1 inhibitor with marked anti-tumor activity in oncogene-driven NSCLC including EGFR mutant, KRAS mutant and MET altered NSCLC.Implications: TWIST1 is required for oncogene-driven NSCLC tumorigenesis and EMT; thus, harmine and its analogues/derivatives represent a novel therapeutic strategy to treat oncogene-driven NSCLC as well as other solid tumor malignancies. Mol Cancer Res; 15(12); 1764-76. ©2017 AACR.

Endoscopic third ventriculostomy as adjunctive therapy in the treatment of low-pressure hydrocephalus in adults.

BACKGROUND: Treatment of low-pressure hydrocephalus (LPH) may require prolonged external ventricular drainage (EVD) at sub-zero pressures to reverse ventriculomegaly. Endoscopic third ventriculostomy (ETV) has been used in the treatment of noncommunicating hydrocephalus; however, indications for ETV are expanding. METHODS: Patients with the diagnosis of LPH as defined by the Pang and Altschuler criteria who underwent sub-zero drainage treatment over an 8-year period were included. Patients were divided into two cohorts based on whether or not ETV was employed during their treatment. Time from EVD placement to internalization of shunt was recorded for both groups; time from ETV to placement of shunt was recorded for the patients undergoing ETV. RESULTS: Sixteen adult patients with LPH were managed with sub-zero drainage method. Ten (62.5%) patients did not undergo ETV and the average time from first ventriculostomy to shunting was 73 days (range 14-257 days). Six (37.5%) patients underwent ETV during the course of their treatment; average time from initial ventriculostomy to shunt was 114 days (range 0-236 days) (P = 0.16). Time from development of LPH to ETV ranged from 28 days to 6.5 months. In the ETV group, of the 4 patients who underwent shunting, the average time to shunting following ETV was 15.25 days. CONCLUSIONS: ETV can be used successfully in the management of refractory LPH to decrease the duration of EVD.