Ilyas M. Eli

Reconstitution of Helicobacter pylori VacA toxin from purified components

Helicobacter pylori VacA is a pore-forming toxin that causes multiple alterations in human cells and contributes to the pathogenesis of peptic ulcer disease and gastric cancer. The toxin is secreted by H. pylori as an 88 kDa monomer (p88) consisting of two domains (p33 and p55). While an X-ray crystal structure for p55 exists and p88 oligomers have been visualized by cryo-electron microscopy, a detailed analysis of p33 has been hindered by an inability to purify this domain in an active form. In this study, we expressed and purified a recombinant form of p33 under denaturing conditions and optimized conditions for the refolding of the soluble protein. We show that refolded p33 can be added to purified p55 in trans to cause vacuolation of HeLa cells and inhibition of IL-2 production by Jurkat cells, effects identical to those produced by the p88 toxin from H. pylori. The p33 protein markedly enhances the cell binding properties of p55. Size exclusion chromatography experiments suggest that p33 and p55 assemble into a complex consistent with the size of a p88 monomer. Electron microscopy of these p33/p55 complexes reveals small rod-shaped structures that can convert to oligomeric flower-shaped structures in the presence of detergent. We propose that the oligomerization observed in these experiments mimics the process by which VacA oligomerizes when in contact with membranes of host cells.

A prospective analysis of hypovitaminosis D and mortality in 400 patients in the neurocritical care setting

OBJECTIVE Hypovitaminosis D is highly prevalent among the general population. Studies have shown an association between hypovitaminosis D and multiple negative outcomes in critical care patients, but there has been no prospective evaluation of vitamin D in the neurological critical care population. The authors examined the impact of vitamin D deficiency on in-hospital mortality and a variety of secondary outcomes. METHODS The authors prospectively collected 25-hydroxy vitamin D levels of all patients admitted to the neurocritical care unit (NCCU) of a quaternary-care center over a 3-month period. Demographic data, illness acuity, in-hospital mortality, infection, and length of hospitalization were collected. Univariate and multivariable logistic regression were used to examine the effects of vitamin D deficiency. RESULTS Four hundred fifteen patients met the inclusion criteria. In-hospital mortality was slightly worse (9.3% vs 4.5%; p = 0.059) among patients with deficient vitamin D (≤ 20 ng/dl). There was also a higher rate of urinary tract infection in patients with vitamin D deficiency (12.4% vs 4.2%; p = 0.002). For patients admitted to the NCCU on an emergency basis (n = 285), higher Simplified Acute Physiology Score II (OR 13.8, 95% CI 1.7-110.8; p = 0.014), and vitamin D deficiency (OR 3.0, 95% CI 1.0-8.6; p = 0.042) were significantly associated with increased in-hospital mortality after adjusting for other factors. CONCLUSIONS In the subset of patients admitted to the NCCU on an emergency basis, vitamin D deficiency is significantly associated with higher in-hospital mortality. Larger studies are needed to confirm these findings and to investigate the role of vitamin D supplementation in these patients.

Primary Intracranial Epidermoid Carcinoma with Diffuse Leptomeningeal Carcinomatosis: Report of Two Cases.

BACKGROUND Malignant degeneration of epidermoid cyst (EC) with accompanying leptomeningeal carcinomatosis (LC) at presentation is extremely rare. We add two cases to the literature, including the first case of primary brainstem involvement with simultaneous diffuse LC, and discuss clinical and radiological cues to differentiate benign and malignant epidermoid tumors for early diagnosis. CASE DESCRIPTION The first patient in this report was a 54-year-old woman with recurrent aseptic meningitis and hydrocephalus. Imaging revealed a prepontine and parapontine extra-axial EC with an intra-axial brainstem ring-enhancing cystic lesion, diffuse leptomeningeal enhancement, and intradural extramedullary nodular deposits throughout the spine. Surgical decompression of the cysts confirmed the diagnosis of invasive primary squamous cell carcinoma of the brainstem and benign epidermoid tumor of the cerebellopontine cistern. The second patient was a 37-year-old woman with extensive left-sided cranial neuropathies. Imaging revealed prepontine and parapontine enhancing and nonenhancing deposits along multiple cranial nerves and diffuse leptomeningeal nodular enhancement in the thoracolumbar spine. A biopsy confirmed the diagnosis of infiltrative, poorly differentiated carcinoma adjacent to a benign EC. Both patients underwent systemic screening to rule out metastatic disease. CONCLUSIONS These cases illustrate that a high index of clinical suspicion is necessary for early diagnosis of disseminated disease in cases of recurrent episodes of aseptic meningitis. In cases of primary benign EC, aggressive resection should be attempted to reduce the risk of malignant degeneration. A separate biopsy specimen from the enhancing portion of the tumor is used to rule out an underlying coexisting malignancy. Multimodal management carries the best prognosis for primary intracranial squamous cell carcinoma with LC.

Primary osseous tumors of the pediatric spinal column: review of pathology and surgical decision making

Spinal column tumors are rare in children and young adults, accounting for only 1% of all spine and spinal cord tumors combined. They often present diagnostic and therapeutic challenges. In this article, the authors review the current management of primary osseous tumors of the pediatric spinal column and highlight diagnosis, management, and surgical decision making.

Novel technologies in the treatment of intracranial aneurysms

Abstract The treatment of intracranial aneurysms has undergone precipitous expansion since the first detachable coils were used less than two decades ago. With rapidly expanding technology comes the need to keep all involved parties informed. The objective of our review is to provide a comprehensive, succinct overview of novel paradigms and devices used to treat intracranial aneurysms. We have divided these new technologies into: (1) coils, (2) flow diverters, (3) adjunctive balloon devices, and (4) stents.

Clinical Outcomes with Transcranial Resection of the Tuberculum Sellae Meningioma

BACKGROUND The tuberculum sellae is a relatively common location for meningiomas. We assessed our experience with the use of transcranial resection, which, although criticized for its more invasive nature compared with endonasal approaches, may be the ideal approach in selected patients with tuberculum sellae meningiomas (TSMs). METHODS We retrospectively reviewed the charts of patients with TSMs treated by frontotemporal or bifrontal open cranial resection. Clinical, radiographic, and surgical variables were analyzed. RESULTS Forty-nine patients with a TSM treated by frontotemporal or bifrontal open cranial resection were identified. The mean patient age was 53.2 ± 14.0 years, and the mean duration of follow-up was 42.3 ± 45.4 months. The mean tumor volume was 12.4 ± 18.0 cm3. Optic canal invasion was seen in 46.9% of the patients, and 91.8% presented with visual deficits. Gross total resection (GTR) was achieved in 42 patients (85.7%), and near-total resection was performed in 7 patients (14.3%). Postoperatively, visual outcomes improved in 17 patients (34.7%), remained stable in 22 (44.9%), were intact in 6 (12.2%), and worsened in 1 (2.0%). Good outcome (Glasgow Outcome Scale [GOS] ≥4) was achieved by 46 of 49 patients (93%) at discharge and by 39 of 41 patients (95.1%) at 6 months. A total of 16 manageable and self-limiting complications occurred in 16 patients. CONCLUSIONS In most patients undergoing a frontotemporal approach, a GTR/Simpson grade I resection with manageable and self-limiting surgical complications, a good 6-month GOS in most patients, and improved to stable vision were seen at follow-up. Various treatment approaches can be considered for TSM resection, but the ability to decompress the optic canal and achieve a GTR makes the frontotemporal approach attractive in many cases.

Sellar Wegener Granulomatosis Masquerading as Cabergoline-Resistant Prolactinoma.

BACKGROUND Pituitary manifestation of Wegener granulomatosis (WG) is extremely rare. When there is pituitary involvement, the granulomatous inflammatory lesions involving the pituitary gland may appear several months to years after the primary diagnosis. CASE DESCRIPTION We present a case of a 32-year-old woman who presented with galactorrhea, amenorrhea, and elevated serum prolactin levels. Imaging demonstrated a sellar lesion with characteristics of a pituitary macroadenoma. Treatment with cabergoline was initiated, but the tumor continued to grow during a 6-month period. Subsequent surgical exploration revealed a chronic inflammatory lesion; the patient subsequently was diagnosed with WG based on laboratory evaluation and further systemic manifestations. She had a favorable clinical and radiologic response with immunosuppressive doses of glucocorticoids and rituximab. CONCLUSIONS This case appears to be the first reported of a patient with unknown WG in whom the diagnosis was established after she presented with a sellar lesion mimicking a prolactin-secreting pituitary adenoma on initial presentation requiring surgical resection. The only endocrine abnormality discovered was moderate hyperprolactinemia. Sellar lesions with only moderate elevations in serum prolactin, particularly those that are refractory to medical management with a dopamine agonist, should prompt further investigation to confirm the diagnosis. WG should be part of the differential diagnosis of inflammatory lesions in the sella, the identification of which can facilitate early diagnosis and treatment of this systemic disease for optimal outcome.

327 A Prospective Analysis of Hypovitaminosis D and Mortality in 400 Patients in the Neurocritical Care Setting.

INTRODUCTION Hypovitaminosis D is highly prevalent among the general population. Studies have shown an association between hypovitaminosis D and multiple negative outcomes in critical care patients, but there has been no prospective evaluation of hypovitaminosis D in the neurological critical care population. The authors examined the impact of vitamin D deficiency on in-hospital mortality and a variety of secondary outcomes in the neurocritical care unit. METHODS The authors prospectively collected 25-hydroxy vitamin D levels on all patients admitted to the neurocritical care unit of a quaternary-care center over a 3-month period. Demographic data, illness acuity, in-hospital mortality, infection, and length of hospitalization were collected. Univariate and multivariable logistic regression were used to examine the effects of vitamin D deficiency. RESULTS Four hundred sixty-one patients met the inclusion criteria. In-hospital mortality was slightly worse (9.3% vs 4.5%, P = .059) among patients with deficient vitamin D (≤20 ng/dL). There was also a higher rate of urinary tract infection in patients with vitamin D deficiency (12.4% vs 4.2%, P = .002). For patients admitted to the neurocritical care unit emergently (n = 285), higher SAPS II score (odds ratio [OR], 13.33; 95% confidence interval [CI], 1.69-100; P = .014) and vitamin D deficiency (OR, 3.03; 95% CI, 1.14-8.06; P = .027) were significantly associated with increased in-hospital mortality on multivariable analysis. CONCLUSION In the subset of patients admitted to the neurocritical care unit emergently, vitamin D deficiency is significantly associated with higher in-hospital mortality. Larger studies are needed to confirm these findings and to investigate the role of vitamin D supplementation in these patients.

Analysis of cerebrovascular aneurysm treatment cost: retrospective cohort comparison of clipping, coiling, and flow diversion

OBJECTIVE With the continuous rise of health care costs, hospitals and health care providers must find ways to reduce costs while maintaining high-quality care. Comparing surgical and endovascular treatment of intracranial aneurysms may offer direction in reducing health care costs. The Value-Driven Outcomes (VDO) database at the University of Utah identifies cost drivers and tracks changes over time. In this study, the authors evaluate specific cost drivers for surgical clipping and endovascular management (i.e., coil embolization and flow diversion) of both ruptured and unruptured intracranial aneurysms using the VDO system. METHODS The authors retrospectively reviewed surgical and endovascular treatment of ruptured and unruptured intracranial aneurysms from July 2011 to January 2017. Total cost (as a percentage of each patients cost to the system), subcategory costs, and potential cost drivers were evaluated and analyzed. RESULTS A total of 514 aneurysms in 469 patients were treated; 273 aneurysms were surgically clipped, 102 were repaired with coiling, and 139 were addressed with flow diverter placements. Middle cerebral artery aneurysms accounted for the largest portion of cases in the clipping group (29.7%), whereas anterior communicating artery aneurysms were most frequently involved in the coiling group (30.4%) and internal carotid artery aneurysms were the majority in the flow diverter group (63.3%). Coiling (mean total cost 0.25% ± 0.20%) had a higher cost than flow diversion (mean 0.20% ± 0.16%) and clipping (mean 0.17 ± 0.14%; p = 0.0001, 1-way ANOVA). Coiling cases cost 1.5 times as much as clipping and flow diversion costs 1.2 times as much as clipping. Facility costs were the most significant contributor to intracranial clipping costs (60.2%), followed by supplies (18.3%). Supplies were the greatest cost contributor to coiling costs (43.2%), followed by facility (40.0%); similarly, supplies were the greatest portion of costs in flow diversion (57.5%), followed by facility (28.5%). Cost differences for aneurysm location, rupture status, American Society of Anesthesiologists (ASA) grade, and discharge disposition could be identified, with variability depending on surgical procedure. A multivariate analysis showed that rupture status, surgical procedure type, ASA status, discharge disposition, and year of surgery all significantly affected cost (p < 0.0001). CONCLUSIONS Facility utilization and supplies constitute the majority of total costs in aneurysm treatment strategies, but significant variation exists depending on surgical approach, rupture status, and patient discharge disposition. Developing and implementing approaches and protocols to improve resource utilization are important in reducing costs while maintaining high-quality patient care.

Clinical potential of meningioma genomic insights: a practical review for neurosurgeons

Meningiomas are among the most common intracranial pathological conditions, accounting for 36% of intracranial lesions treated by neurosurgeons. Although the majority of these lesions are benign, the classical categorization of tumors by histological type or World Health Organization (WHO) grade has not fully captured the potential for meningioma progression and recurrence. Many targeted treatments have failed to generate a long-lasting effect on these tumors. Recently, several seminal studies evaluating the genomics of intracranial meningiomas have rapidly changed the understanding of the disease. The importance of NF2 (neurofibromin 2), TRAF7 (tumor necrosis factor [TNF] receptor-associated factor 7), KLF4 (Kruppel-like factor 4), AKT1, SMO (smoothened), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), and POLR2 (RNA polymerase II subunit A) demonstrates that there are at least 6 distinct mutational classes of meningiomas. In addition, 6 methylation classes of meningioma have been appreciated, enabling improved prediction of prognosis compared with traditional WHO grades. Genomic studies have shed light on the nature of recurrent meningioma, distinct intracranial locations and mutational patterns, and a potential embryonic cancer stem cell-like origin. However, despite these exciting findings, the clinical relevance of these findings remains elusive. The authors review the key findings from recent genomic studies in meningiomas, specifically focusing on how these findings relate to clinical insights for the practicing neurosurgeon.