Hannah Goldstein

A Secreted PTEN Phosphatase That Enters Cells to Alter Signaling and Survival

PTEN Variations The product of the tumor suppressor gene phosphate and tensin homolog on chromosome ten (PTEN) is a lipid and protein phosphatase that regulates important cellular processes, including growth, survival, and metabolism (see the Perspective by Leslie and Brunton). Though PTEN is best known for effects on the phosphatidylnositol 3-kinase (PI3K) signaling pathway, the PTEN protein is also found in the nucleus. Bassi et al. (p. 395) found that PTENs presence in the nucleus was regulated in response to covalent modification of the protein by SUMOylation and phosphorylation. Cells lacking nuclear PTEN showed increased sensitivity to DNA damage and underwent cell death if the PI3K pathway was also inhibited. Hopkins et al. (p. 399, published online 6 June) discovered an alternative translation start site in human PTEN messenger RNA that allowed expression of a protein, PTEN-Long, with about 170 extra amino acids. The unusual enzyme was released from cells and then taken up into other cells. In a mouse tumor model, uptake of the enzyme inhibited the PI3K pathway and inhibited tumor growth. An alternative translation start site produces an elongated PTEN that can enter tumor cells and kill them. [Also see Perspective by Leslie and Brunton] Phosphatase and tensin homolog on chromosome ten (PTEN) is a tumor suppressor and an antagonist of the phosphoinositide-3 kinase (PI3K) pathway. We identified a 576–amino acid translational variant of PTEN, termed PTEN-Long, that arises from an alternative translation start site 519 base pairs upstream of the ATG initiation sequence, adding 173 N-terminal amino acids to the normal PTEN open reading frame. PTEN-Long is a membrane-permeable lipid phosphatase that is secreted from cells and can enter other cells. As an exogenous agent, PTEN-Long antagonized PI3K signaling and induced tumor cell death in vitro and in vivo. By providing a means to restore a functional tumor-suppressor protein to tumor cells, PTEN-Long may have therapeutic uses.

Carotid-cavernous fistulas.

Carotid-cavernous fistulas (CCFs) are vascular shunts allowing blood to flow from the carotid artery into the cavernous sinus. The characteristic clinical features seen in patients with CCFs are the sequelae of hemodynamic dysfunction within the cavernous sinus. Once routinely treated with open surgical procedures, including carotid ligation or trapping and cavernous sinus exploration, endovascular therapy is now the treatment modality of choice in many cases. The authors provide a review of CCFs, detailing the current classification and clinical management of these lesions. Therapeutic options including conservative management, open surgery, endovascular intervention, and radiosurgical therapy are presented. The complications and treatment results as reported in the contemporary literature are also reviewed.

MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma.

Significance Molecular analysis of surgically resected glioblastomas (GBM) samples has uncovered phenotypically and clinically distinct tumor subtypes. However, little is known about the molecular features of the glioma margins that are left behind after surgery. To address this key issue, we performed RNA-sequencing (RNA-seq) and histological analysis on MRI-guided biopsies from the contrast-enhancing core and nonenhancing margins of GBM. Computational deconvolution of the RNA-seq data revealed that cellular composition, including nonneoplastic cells, is a major determinant of the expression patterns at the margins of GBM. The different GBM subtypes show distinct expression patterns that relate the contrast enhancing centers to the nonenhancing margins of tumors. Understanding these patterns may provide a means to infer the molecular and cellular features of residual disease. Glioblastomas (GBMs) diffusely infiltrate the brain, making complete removal by surgical resection impossible. The mixture of neoplastic and nonneoplastic cells that remain after surgery form the biological context for adjuvant therapeutic intervention and recurrence. We performed RNA-sequencing (RNA-seq) and histological analysis on radiographically guided biopsies taken from different regions of GBM and showed that the tissue contained within the contrast-enhancing (CE) core of tumors have different cellular and molecular compositions compared with tissue from the nonenhancing (NE) margins of tumors. Comparisons with the The Cancer Genome Atlas dataset showed that the samples from CE regions resembled the proneural, classical, or mesenchymal subtypes of GBM, whereas the samples from the NE regions predominantly resembled the neural subtype. Computational deconvolution of the RNA-seq data revealed that contributions from nonneoplastic brain cells significantly influence the expression pattern in the NE samples. Gene ontology analysis showed that the cell type-specific expression patterns were functionally distinct and highly enriched in genes associated with the corresponding cell phenotypes. Comparing the RNA-seq data from the GBM samples to that of nonneoplastic brain revealed that the differentially expressed genes are distributed across multiple cell types. Notably, the patterns of cell type-specific alterations varied between the different GBM subtypes: the NE regions of proneural tumors were enriched in oligodendrocyte progenitor genes, whereas the NE regions of mesenchymal GBM were enriched in astrocytic and microglial genes. These subtype-specific patterns provide new insights into molecular and cellular composition of the infiltrative margins of GBM.

Incidence, treatment and survival of patients with craniopharyngioma in the surveillance, epidemiology and end results program

Craniopharyngioma is a rare primary central nervous system neoplasm. Our objective was to determine factors associated with incidence, treatment, and survival of craniopharyngiomas in the United States. We used the surveillance, epidemiology and end results program (SEER) database to identify patients who received a diagnosis of craniopharyngioma during 2004-2008. We analyzed clinical and demographic information, including age, race, sex, tumor histology, and treatment. Age-adjusted incidence rates and age, sex, and race-adjusted expected survival rates were calculated. We used Cox proportional hazards models to determine the association between covariates and overall survival. We identified 644 patients with a diagnosis of craniopharyngioma. Black race was associated with an age-adjusted relative risk for craniopharyngioma of 1.26 (95% confidence interval [CI], 0.98-1.59), compared with white race. One- and 3-year survival rates of 91.5% (95% CI, 88.9%-93.5%), and 86.2% (95% CI, 82.7%-89.0%) were observed for the cohort; relative survival rates were 92.1% (95% CI, 89.5%-94.0%) and 87.6% (95% CI, 84.1%-90.4%) for 1- and 3-years, respectively. In the multivariable model, factors associated with prolonged survival included younger age, smaller tumor size, subtotal resection, and radiation therapy. Black race, on the other hand, was associated with worse overall survival in the final model. We demonstrated that >85% of patients survived 3 years after diagnosis and that subtotal resection and radiation therapy were associated with prolonged survival. We also noted a higher incidence rate and worse 1- and 3-year survival rates in the black population. Future investigations should examine these racial disparities and focus on evaluating the efficacy of emerging treatment paradigms.

The role for adjuvant radiotherapy in the treatment of hemangiopericytoma: a Surveillance, Epidemiology, and End Results analysis

OBJECT Central nervous system (CNS) hemangiopericytomas are relatively uncommon and unique among CNS tumors as they can originate from or develop metastases outside of the CNS. Significant difference of opinion exists in the management of these lesions, as current treatment paradigms are based on limited clinical experience and single-institution series. Given these limitations and the absence of prospective clinical trials within the literature, nationwide registries have the potential to provide unique insight into the efficacy of various therapies. METHODS The authors queried the Surveillance Epidemiology and End Results (SEER) database to investigate the clinical behavior and prognostic factors for hemangiopericytomas originating within the CNS during the years 2000-2009. The SEER survival data were adjusted for demographic factors including age, sex, and race. Univariate and multivariate analyses were performed to identify characteristics associated with overall survival. RESULTS The authors identified 227 patients with a diagnosis of CNS hemangiopericytoma. The median length of follow-up was 34 months (interquartile range 11-63 months). Median survival was not reached, but the 5-year survival rate was 83%. Univariate analysis showed that age and radiation therapy were significantly associated with survival. Moreover, young age and supratentorial location were significantly associated with survival on multivariate analysis. Most importantly, multivariate analysis using the Cox proportional hazards model showed a statistically significant survival benefit for patients treated with gross-total resection (GTR) in combination with adjuvant radiation treatment (HR 0.31 [95% CI 0.01-0.95], p = 0.04), an effect not appreciated with GTR alone. CONCLUSIONS The authors describe the epidemiology of CNS hemangiopericytomas in a large, national cancer database, evaluating the effectiveness of various treatment paradigms used in clinical practice. In this study, an overall survival benefit was found when GTR was accomplished and combined with radiation therapy. This finding has not been appreciated in previous series of patients with CNS hemangiopericytoma and warrants future investigations into the role of upfront adjuvant radiation therapy.

Causes and Timing of Unplanned Early Readmission After Neurosurgery.

BACKGROUND Reducing the rate of 30-day hospital readmission has become a priority in healthcare quality improvement policy, with a focus on better characterizing the reasons for unplanned readmission. In neurosurgery, however, peer-reviewed analyses describing the patterns of readmission have been limited in their number and generalizability. OBJECTIVE To determine the incidence, timing, and causes of 30-day readmission after neurosurgical procedures. METHODS We conducted a retrospective longitudinal study from 2009 to 2012 using the Statewide Planning And Research Cooperative System, which collects patient-level details for all admissions and discharges within New York. We identified patients readmitted within 30 days of initial discharge. The rate of, reasons for, and time to readmission were determined overall and within 4 subgroups: craniotomies, cranial surgery without craniotomy, spine, and neuroendovascular procedures. RESULTS There were 163 743 index admissions, of whom 14 791 (9.03%) were readmitted. The most common reasons for unplanned readmission were infection (29.52%) and medical complications (19.22%). Median time to readmission was 11 days, with hemorrhagic strokes and seizures occurring earlier, and medical complications and infections occurring later. Readmission rates were highest among patients undergoing cerebrospinal fluid shunt revision and malignant tumor resection (15.57%-22.60%). Spinal decompressions, however, accounted for the largest volume of readmissions (33.13%). CONCLUSION Many readmissions may be preventable and occur at predictable time intervals. The causes and timing of readmission vary significantly across neurosurgical subgroups. Future studies should focus on detecting specific complications in select cohorts at predefined time points, which may allow for interventions to lower costs and reduce patient morbidity. ABBREVIATIONS CSF, cerebrospinal fluidIQR, interquartile rangeSPARCS, Statewide Planning And Research Cooperative System.

Chronic subdural hematomas: perspective on current treatment paradigms.

C hronic subdural hematoma (CSDH) is a routine problem encountered in the field of neurosurgery, with an increasing incidence seen in the elderly population. Estimates for overall incidence rates range from 1–2 per 100,000 per year to up to 13.1 per 100,000 per year (24). The higher estimates reflect both an increase in diagnosis with better imaging techniques as well as an aging population. Despite its frequency, there is still no consensus on the optimal treatment for CSDH; novel therapeutic strategies are being tested to improve outcomes, and more importantly, prevent recurrence. Here we will discuss some basic principles of CSDH, providing context for the study by Singanallur et al. published in this issue of WORLD NEUROSURGERY, in which the authors have explored the use of subdural tissue plasminogen activator (t-PA) for the treatment of CSDH.

Letter to the Editor: Ventriculoiliac shunt: a single case experience

TO THE EDITOR: The recent article by Tubbs et al.1 assessing the feasibility of ventriculoiliac shunts prompted us to share our clinical experience and difficulties using a ventriculoiliac shunt in a pediatric patient (Tubbs RS, Tubbs I, Loukas M, et al: Ventriculoiliac shunt: a cadaveric feasibility study. J Neurosurg Pediatr 15:310–312, March 2015). We currently care for a 7-year-old boy who was born premature at 26 weeks and developed hydrocephalus of prematurity. His early years were complicated by multiple distal shunt revisions, largely due to infection and a subsequent abdominal pseudocyst. Subsequent distal sites for the shunt included several attempts in the peritoneum, atrium, pleura, gallbladder, and superior sagittal sinus. Bilateral jugular veins, subclavian veins, and femoral veins were utilized at different times to access the atrium until thrombus occluded all of these veins and the only venous return to the heart was through a dilated azygous system. At 5 years of age, after all intraoperative and interventional radiology attempts to access the atrium were ultimately unsuccessful, we placed the distal catheter in the iliac crest (Fig. 1). Unfortunately, the shunt failed after 10 days due to failure of absorption and leakage from the distal wound, and the shunt had to be placed directly in the atrium via a median sternotomy. From our limited experience with placement of a ventriculoiliac shunt in a single pediatric patient, two technical considerations are worth noting. First, we believe the shunt failed primarily due to the inability to maintain a tight seal between the distal catheter and the iliac crest. In our patient, a 2.5-cm deep channel into the iliac crest was made using a gear shift and a drill with a small bur. Distal tubing was cut precisely to fit into the channel and then was attached to a straight metal connector at the cortical margin of the iliac crest to be able to secure it tightly with 2-0 silk sutures and seal it with bone wax. Distal flow into the iliac crest was confirmed intraoperatively with a manometer. Despite these efforts, the shunt still failed distally after 10 days. We hypothesize that this was due to small movements of the catheter and loosening of the seal that occurs with clinical activity, with subsequent backflow of fluid along the catheter. Although this anatomical study nicely demonstrates that the ilium has enormous capacity to absorb spinal fluid (up to 30 L/hour), our clinical experience suggests that securing the distal catheter with only bone wax is unlikely to be successful. Second, we elected to tunnel the distal catheter into and then back out of the peritoneum before securing the end to the iliac crest. This allowed us to leave extra tubing in the peritoneum to allow for subsequent growth of the patient. In the artist’s rendition of the ventriculoiliac shunt included in this article, there appears to be no additional tubing to allow for growth and is likely to result in eventual pullout of the catheter and distal failure. We congratulate the authors of this study for scientifically assessing the feasibility of alternative sites for distal catheters and look forward to further modifications that will help make this technique successful clinically.

The Annual Neurosurgery Charity Softball Tournament: 15th Anniversary Commemorative Article. The creation, development, and establishment of a neurosurgical tradition

The Annual Neurosurgery Charity Softball Tournament (ANCST) represents one of largest events in organized neurosurgery, involving 40 programs from across the US, Canada, and Puerto Rico. For the past 15 years, on a Saturday in late spring or early summer, more than 600 neurosurgeons have come together in Central Park in Manhattan to compete in softball, represent their respective departments, and hopefully win the championship. The ANCST, however, represents much more than a softball tournament. The event is a demonstration of the teamwork, camaraderie, and friendship that exists in the neurosurgical profession as players bond with their department colleagues as well as players on competing teams. Moreover, the ANCST embodies a strong philanthropic drive in neurosurgery reflected in the tournament’s main mission of raising funds primarily for pediatric brain tumor research. With the 15th anniversary of the ANCST scheduled for June 9, 2018, this commemorative article reviews the tournament’s local origins in New York City, through its evolution into an international event and a neurosurgical tradition.

Identifying Factors Predictive of Atlantoaxial Fusion Failure in Pediatric Patients

Study Design. Multicenter retrospective cohort study with multivariate analysis. Objective. To determine factors predictive of posterior atlantoaxial fusion failure in pediatric patients. Summary of Background Data. Fusion rates for pediatric posterior atlantoaxial arthrodesis have been reported to be high in single-center studies; however, factors predictive of surgical non-union have not been identified by a multicenter study. Methods. Clinical and surgical details for all patients who underwent posterior atlantoaxial fusion at seven pediatric spine centers from 1995 to 2014 were retrospectively recorded. The primary outcome was surgical failure, defined as either instrumentation failure or fusion failure seen on either plain x-ray or computed tomography scan. Multiple logistic regression analysis was undertaken to identify clinical and technical factors predictive of surgical failure. Results. One hundred thirty-one patients met the inclusion criteria and were included in the analysis. Successful fusion was seen in 117 (89%) of the patients. Of the 14 (11%) patients with failed fusion, the cause was instrumentation failure in 3 patients (2%) and graft failure in 11 (8%). Multivariate analysis identified Down syndrome as the single factor predictive of fusion failure (odds ratio 14.6, 95% confidence interval [3.7–64.0]). Conclusion. This retrospective analysis of a multicenter cohort demonstrates that although posterior pediatric atlantoaxial fusion success rates are generally high, Down syndrome is a risk factor that significantly predicts the possibility of surgical failure. Level of Evidence: 3