Treatment of a Pial Arterial Venous Fistula in a Newborn: 2-Dimensional Operative Video.

Pial arterial venous fistulas (PAVFs) are rare vascular entities that occur with direct high-flow connections between pial arterial feeders and large veins without an intervening nidus.1-5 These vascular abnormalities can present in the pediatric population with high output heart failure.1 PAVFs can be treated with endovascular intervention, microvascular ligation, or a combination depending on the clinical scenario.4 Here, we present a case in which a newborn presented in high output heart failure because of a large left-sided middle cerebral artery fed PAVF. We performed a craniotomy for ligation of the PAVF to obliterate the arteriovenous shunting to improve her cardiac status and diminish her intracranial venous hypertension. Throughout the ligation, we used indocyanine green to localize the next appropriate vessels to ligate, allowing us to safely obliterate the anomalous vasculature and improve the patient's cardiac function. Postoperatively, the patient did well neurologically with improvements in cardiac function and near normalization of intracranial vasculature. The patient's guardians consented to the procedure and to the publication of her image.

Flow diverter stenting for intracranial aneurysms in the pediatric population: Two case reports and literature review.

The Pipeline Embolization Device (PED) is a flow-diverting intraluminal device that is approved for use in adults 18 years or older with internal carotid artery aneurysms. However, it can also be used off-label in pediatric patients with aneurysms that cannot be resolved with traditional endovascular treatments. Herein, we present two cases of flow diversion in the pediatric population with complete obliteration of the aneurysm and excellent outcomes. Flow diversion has been shown to be a safe endovascular option in treating complex aneurysms in children. Larger-sized, multicenter trials are encouraged to compare outcomes between flow diversion and other aneurysm treatment options given the rarity of pediatric aneurysms.

Role of Advanced MR Imaging in Diagnosis of Neurological Malignancies: Current Status and Future Perspective.

Lesions of the central nervous system (CNS) can present with numerous and overlapping radiographical and clinical features that make diagnosis difficult based exclusively on history, physical examination, and traditional imaging modalities. Given that there are significant differences in optimal treatment protocols for these various CNS lesions, rapid and non-invasive diagnosis could lead to improved patient care. Recently, various advanced magnetic resonance imaging (MRI) techniques showed promising methods to differentiate between various tumors and lesions that conventional MRI cannot define by comparing their physiologic characteristics, such as vascularity, permeability, oxygenation, and metabolism. These advanced MRI techniques include dynamic susceptibility contrast MRI (DSC), diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE) MRI, Golden-Angle Radial Sparse Parallel imaging (GRASP), Blood oxygen level-dependent functional MRI (BOLD fMRI), and arterial spin labeling (ASL) MRI. In this article, a narrative review is used to discuss the current trends in advanced MRI techniques and potential future applications in identifying difficult-to-distinguish CNS lesions. Advanced MRI techniques were found to be promising non-invasive modalities to differentiate between paraganglioma, schwannoma, and meningioma. They are also considered promising methods to differentiate gliomas from lymphoma, post-radiation changes, pseudoprogression, demyelination, and metastasis. Advanced MRI techniques allow clinicians to take advantage of intrinsic biological differences in CNS lesions to better identify the etiology of these lesions, potentially leading to more effective patient care and a decrease in unnecessary invasive procedures. More clinical studies with larger sample sizes should be encouraged to assess the significance of each advanced MRI technique and the specificity and sensitivity of each radiologic parameter.

Cisternostomy as a Surgical Treatment for Traumatic Brain Injury-Related Prolonged and Delayed Intracranial Pressure Elevation: A Case Report.

Traumatic brain injury (TBI) can be classified into primary, due to the effect of the initial trauma, or secondary, due to increased intracranial pressure (ICP). Increased ICP may cause brain herniation and also decreases cerebral blood perfusion leading to ischemia. Recently, a few studies showed that cisternostomy with decompressive craniectomy (DC) has better outcomes than DC alone in patients with TBI. This can be explained by the recent advances indicating that cisternal cerebrospinal fluid (CSF) communicates with cerebral interstitial fluid (IF) through Virchow-Robin spaces. Theoretically, opening cisterns to atmospheric pressure may induce IF drainage and subsequently decrease ICP. A 55-year-old man presented to the emergency department with subdural hematomas, hemorrhagic contusions, and subarachnoid hemorrhage after falling off a moving truck. ICP elevation was refractory despite increased sedation, initiation of paralysis with Cisatracurium, esophageal cooling, multiple doses of 23.4 % saline and mannitol, and DC. Lumbar drain (LD) placement was performed with beneficial results. Unfortunately, the LD stopped functioning multiple times and each time this occurred, he developed increased ventricular size with elevated ICP. The patient underwent cisternostomy and lamina terminalis fenestration. No further increased ICPs were observed after cisternostomy at a one-month follow-up. Cisternostomy is a potential surgical treatment for patients with TBI-related prolonged ICP elevation.

Analysis of reported adverse events of pipeline stents for intracranial aneurysms using the FDA MAUDE database.

OBJECTIVE: Flow diverting stents (FDS) are a validated device in the treatment of intracranial aneurysms, allowing for minimally invasive intervention. However, after its approval for use in the United States in 2011, post-market surveillance of adverse events is limited. This study aims to address this critical knowledge gap by analyzing the FDA Manufacturer and User Facility Device Experience (MAUDE) database for patient and device related (PR and DR) reports of adverse events and malfunctions. METHODS: Using post-market surveillance data from the MAUDE database, PR and DR reports from January 2012-December 2021 were extracted, compiled, and analyzed with R-Studio version 2021.09.2. PR and DR reports with insufficient information were excluded. Raw information was organized, and further author generated classifications were created for both PR and DR reports. RESULTS: A total of 2203 PR and 4017 DR events were recorded. The most frequently reported PR adverse event categories were cerebrovascular (60%), death (11%), and neurological (8%). The most frequent PR adverse event reports were death (11%), thrombosis/thrombus (9%) cerebral infarction (8%), decreased therapeutic response (7%), stroke/cerebrovascular accident (6%), intracranial hemorrhage (5%), aneurysm (4%), occlusion (4%), headache (4%), neurological deficit/dysfunction (3%). The most frequent DR reports were activation/positioning/separation problems (52%), break (9%), device operates differently than expected (4%), difficult to open or close (4%), material deformation (3%), migration or expulsion of device (3%), detachment of device or device component (2%). CONCLUSIONS: Post-market surveillance is important to guide patient counselling and identify adverse events and device problems that were not identified in initial trials. We present frequent reports of several types of cerebrovascular and neurological adverse events as well as the most common device shortcomings that should be explored by manufacturers and future studies. Although inherent limitations to the MAUDE database are present, our results highlight important PR and DR complications that can help optimize patient counseling and device development.

Cisternotomy and Liliequist's Membrane Fenestration as a Surgical Treatment for Idiopathic Intracranial Hypertension (Pseudotumor Cerebri): A Case Report.

Subarachnoid basal cistern opening (cisternotomy) is used during many microsurgical operations to relax the brain by removing or diverting cerebrospinal fluid (CSF). Recently, cisternotomy has been used in patients with traumatic brain injury to improve outcomes due to its ability to decrease intracranial pressure (ICP) and brain edema by diverting CSF. Theoretically, another condition that can benefit from cisternotomy is idiopathic intracranial hypertension (IIH) as it presents with manifestations of increased ICP, such as headache, vomiting, and papilledema. Here, we discuss the case of a 39-year-old woman with IIH who presented with headache, nausea, and papilledema in the setting of maximally tolerated medical management after five months of shunt removal due to infection. The patient did not want to proceed with the replacement of her shunt and therefore underwent a right eyebrow craniotomy for cisternotomy, lamina terminals fenestration, and Liliequist's membrane opening. Postoperatively, her symptoms improved completely. She was off acetazolamide altogether at the three-month follow-up and no longer had pseudotumor cerebri headaches. This case report demonstrates the use of cisternotomy to relieve the manifestations of increased ICP and its potential as a surgical option for patients with IIH.

Lead toxicity due to retained intracranial bullet fragments: illustrative case.

BACKGROUND: Lead toxicity (plumbism) secondary to retained lead bullet fragments is a rare complication in patients with gunshot wounds. To the authors' knowledge, there has been no definitive case reported of lead toxicity due to retained intracranial bullet fragments. OBSERVATIONS: The authors reported the case of a 23-year-old man who presented after being found down. Computed tomography scanning of the head revealed bullet fragments within the calvaria adjacent to the left transverse sinus. During follow-up, he developed symptoms of plumbism with paresthesias in his bilateral hands and thighs, abdominal cramping, labile mood, and intermittent psychosis. Plumbism was confirmed with sequentially elevated blood lead levels (BLLs). The patient opted for surgical removal of the bullet fragments, which led to reduction in BLLs and resolution of his symptoms. LESSONS: Although rare, lead toxicity from retained intracranial bullet fragments should be considered in patients who have suffered a gunshot wound to the head and have symptoms of lead toxicity with elevated BLLs. For safe and accessible intracranial bullet fragments in patients with plumbism, surgical intervention may be indicated.

Basilar artery incarceration secondary to a longitudinal clivus fracture: A rare and favorable outcome of an often devastating injury.

Background: Clival fractures are a rare traumatic finding and are often the result of high-impact craniofacial trauma. Rarely, longitudinal clival fractures can be associated with incarceration of the basilar artery within the fracture and/or the sphenoid sinus. Of the 12 reported cases of basilar incarceration, 11 of these injuries have proved to be fatal due to pontine infarction. We present a patient with basilar artery incarceration without any neurologic deficits. Case Description: The case reported is a 17-year-old male who presented after a motor vehicle collision with a linear and longitudinal clival fracture with entrapment of the basilar artery within the sphenoid sinus. Diagnostic subtraction angiography showed a small intimal tear with possible intraluminal thrombus. The patient was started on aspirin and at 3-month post injury had no neurologic deficits. Conclusion: Basilar artery incarceration is an injury often associated with pontine infarction secondary to basilar artery dissection and/or thrombus developing at the site of entrapment. Our case illustrates a favorable outcome after this injury. Based on these results, antiplatelet therapy may be a viable option for prevention of brainstem infarcts in patients with this injury; however, further prospective studies must be done to assess the overall efficacy and validity of this treatment. There are no established treatment guidelines for this condition. Further research on this topic should also be tailored toward early identification of this pathology and prevention of thromboembolic sequelae of this injury.

Reversal of cognitive, behavioral, and language impairments after the left frontal arachnoid cyst fenestration in a pediatric patient.

BACKGROUND: Arachnoid cysts (ACs) are cerebrospinal fluid-containing cysts located between the surface of the brain or spinal cord and arachnoid layer of the leptomeninges. ACs have been known to cause cognitive, language, and behavioral deficits and currently there is no standard treatment paradigm. Surgical indications include papilledema, increasing growth with mass effect causing neurological deficit, or rapid head growth, however, cognitive symptoms related to mass effect may not always be considered. CASE DESCRIPTION: We present a 3-year-old male with an AC of the left anterior fossa causing frontal lobe compression with resultant behavioral, language, and cognitive deficits. CONCLUSION: Surgical intervention for AC decompression may be indicated when there are cognitive, behavioral, or language delays related to the mass effect and location of the AC. Neuropsychiatric testing or more advanced imaging studies may further support surgical treatment. After craniotomy for fenestration of the left frontal AC, there was drastic improvement in cognitive, language, and behavioral symptoms in our pediatric patient.

Pediatric middle meningeal artery embolization for chronic subdural hematoma: A case report.

BACKGROUND: The most common neuroradiological finding in pediatric nonaccidental trauma (NAT) is subdural hematoma (SDH). Management options for pediatric SDH range from conservative clinical surveillance to craniotomy or decompressive craniectomy. The middle meningeal artery (MMA) indirectly feeds the hematoma; thus, MMA embolization is an alternative or adjunct to current surgical treatments in adults. Herein, we present, to the best of our knowledge, the first reported case of successful MMA embolization in a pediatric patient as an adjunct to current standard treatment for chronic SDH (cSDH). CASE DESCRIPTION: An 18-month-old male with a history of NAT presented at 5 months of age with an acute right parietal skull fracture and bilateral SDH treated with burr hole drainage. He was lost to follow-up until 15 months of age with an increased head circumference and new dysconjugate gaze. Imaging revealed a right-sided cSDH and underwent craniotomy. Six-week follow-up revealed significant improvement in the SDH but cSDH remained at the periphery of the craniotomy's reach. The patient symptoms continued. The right-sided MMA embolization was offered as option to avoid repeat craniotomy. Follow-up CTs at 2 weeks, 3 months, and 6 months postprocedure revealed decrease of cSDH size and density. At 8-month follow-up, the patient continued to meet developmental milestones with near resolution of his dysconjugate gaze. CONCLUSION: This case report details the first successful use of MMA embolization in the treatment of pediatric cSDH as an adjunct to standard treatment. Further investigation of MMA embolization in pediatrics should be made to expand options available for cSDH in this patient population.

Investigation of a Valve-Agnostic Cranial Implant for Adult Hydrocephalus Patients Requiring Ventriculoperitoneal Shunting.

INTRODUCTION: Currently, the most effective treatment strategy for adults with hydrocephalus involves cerebrospinal fluid diversion by means of a shunt system, most commonly ventriculoperitoneal shunts (VPS). Ventriculoperitoneal shunting is associated with high complication and/or revision rates, in part due to the high-profile programmable valve designs. Thus, the valve-agnostic cranial implant (VACI) was designed and investigated as a safe and effective method of reducing the valve's high profile and is currently undergoing clinical trials. As such, the objective of this study was to collate preliminary, multi-institutional data of early outcomes using a VACI approach for patients requiring VPS by way of an Institutional Review Board approved registry. METHODS: A total of 25 adult patients across 4 institutions and 6 surgeons underwent VACI placement for VPS based on preoperative evaluation and perceived benefit. Patient demographics, operative details, and preliminary outcomes are presented here. RESULTS: Valve-agnostic cranial implant placement via a limited size craniectomy at time of shunt revision was performed with no adverse events. Over an average follow-up period of 1 year (394 ±â€Š178 days), 92% of patients experienced no major shunt-related or scalp-related complications. There were 2 cases with a major complication requiring reoperation: 1 shunt tubing extrusion and 1 case of meningitis. The most frequent postsurgical intervention seen in this study was related to adjustment of drainage: a non-invasively performed valve reprogramming after initial shunt placement when proper flow rate is being established. Of the 8 cases of drainage adjustment, all but 1 (88%) were receiving a VPS for the first time, with the exception undergoing a fourth shunt revision. All instances of improper flow were treated non-surgically and remediated effectively via shunt reprogramming in clinic. Removal of the VACI was not indicated in any treatment course. In this way, all complications as they relate to the shunt valve were minor and required nonsurgical intervention, and no complications reported were directly or indirectly caused by using the VACI. CONCLUSION: Preliminary findings from this multicenter trial suggest promising outcomes with a low complication rate for patients with hydrocephalus undergoing VACI placement during VPS. Ongoing research will continue to provide a more robust clinical picture of VACI in hydrocephalus management as more data becomes available.

Case report: vertebral osteomyelitis secondary to a dental abscess.

BACKGROUND: Vertebral osteomyelitis can be attributed to many factors including immunosuppression, diabetes, malignancy, collagen disease, periodontal disease, open fractures, and endoscopic procedures. Anaerobic bacteria, such as Veillonella species, are found in the oral cavity and are rarely implicated in the infection. This report describes vertebral osteomyelitis secondary to a dental abscess with positive Veillonella cultures. CASE DESCRIPTION: A 76-year-old man presented to the hospital due to back pain with a four-day history of fever and chills. CT scans revealed several abscesses in the lumbar region as well as indications of vertebral osteomyelitis. After a psoas drain, the patient began antibiotics with a combination of ampicillin-sulbactam, metronidazole, and levofloxacin, but due to the patient's penicillin allergy, he was initially desensitized to this antibiotic for a significant period of time. Laminectomies, foraminotomies, and facetectomies were performed, but the infection spread to vertebral levels. The patient was then switched to a combination of vancomycin, metronidazole, and levofloxacin which eliminated the infection. Final laminectomy was performed with posterior segmental instrumentation and arthrodesis. Post-operatively, there were no signs of infection. The patient recovered well and regained mobility. Deeper examination of the patient's medical history revealed a severe tooth abscess immediately before the onset of bacteremia. CONCLUSION: We believe that a delay in the onset of antibiotic treatment is what led to the initial bacteremia that ultimately took root in the lower lumbar vertebrae. To the best of our ability, we could identify only one other case that linked vertebral osteomyelitis to the oral cavity.

Innovations in Care Delivery of Stroke from Emergency Medical Services to the Neurointerventional Operating Room.

Acute ischemic stroke (AIS) and its care is currently one of the most dynamic and evolving illnesses across the globe. Among the most crucial factors in providing the best care to patients are the expedient delivery of thrombolytics and endovascular intervention when indicated. Here, we review our unique model of efficient care centered in our innovative Neurological Emergency Department (Neuro ED). The Neuro ED acts as our hub for EMS communication, imaging, administration of intravenous alteplase, and transition to the Neurointerventional OR. Our structure with its enabling of shortened IV alteplase delivery times and faster door-to-needle (DTN) times may serve as an international model for stroke centers.

Carotid Stenosis: Utility of Diagnostic Angiography.

OBJECTIVE: Carotid artery stenosis is frequently diagnosed through screening tests with noninvasive imaging. Because of differences noted between the various modalities, we sought to investigate our experience comparing noninvasive imaging (ultrasound, computed tomography angiography, magnetic resonance angiography) with invasive imaging (digital subtraction angiography). METHODS: In a multicenter retrospective analysis, 249 carotid vessels were reviewed based on angiography with the associated noninvasive imaging. RESULTS: Overall, medical or surgical decision management was changed in 43% (107/243) of cases investigated with digital subtraction angiography owing to a discrepancy between the measured percentage stenosis. In patients with potentially treatable carotid stenosis, angiography revealed nonsignificant stenosis 25.7% of the time. CONCLUSIONS: Angiography should be considered the confirmatory test for degree of stenosis in certain patients before definitive surgical treatment.

Trevo 2000: Results of a Large Real-World Registry for Stent Retriever for Acute Ischemic Stroke.

Background Recent randomized controlled trials show benefit of thrombectomy for large vessel occlusion in stroke. Real-world data aid in assessing reproducibility of outcomes outside of clinical trials. The Trevo Retriever Registry is a multicenter, international, prospective study designed to assess outcomes in a large cohort of patients. Methods and Results The Trevo Registry is a prospective database of patients with large vessel occlusion treated with the Trevo device as the first device. The primary end point is revascularization based on modified Thrombolysis in Cerebral Infarction score and secondary end points include 90-day modified Rankin Scale, 90-day mortality, neurological deterioration at 24 hours, and device/procedure related adverse events. Year 2008 patients were enrolled at 76 centers in 12 countries. Median admission National Institutes of Health Stroke Scale was 16 (interquartile range, 11-20). Occlusion sites were internal carotid artery (17.8%), middle cerebral artery (73.5%), posterior circulation (7.1%), and distal vascular locations (1.6%). A modified Thrombolysis in Cerebral Infarction 2b or 3 was achieved in 92.8% (95% CI, 91.6, 93.9) of procedures, with 55.3% (95% CI, 53.1, 57.5) of patients achieving modified Rankin Scale ≤2 at 3 months. Patients meeting revised 2015 American Heart Association criteria for thrombectomy had a 59.7% (95% CI , 56.0; 63.4) modified Rankin Scale 0 to 2 at 3 months, whereas 51.4% treated outside of American Heart Association criteria had modified Rankin Scale 0 to 2. 51.4% (95% CI , 49.6, 55.4). Symptomatic intracranial hemorrhage rate was 1.7% (95% CI , 1.2, 2.4). Conclusions The Trevo Retriever Registry represents real-world data with stent retriever. The registry demonstrates similar reperfusion rates and outcomes in the community compared with rigorous centrally adjudicated clinical trials. Future subgroup analysis of this cohort will assist in identifying areas of future research. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02040259.

Intrawound Vancomycin Decreases the Risk of Surgical Site Infection After Posterior Spine Surgery: A Multicenter Analysis.

STUDY DESIGN: Secondary analysis of data from a prospective multicenter observational study. OBJECTIVE: The aim of this study was to evaluate the occurrence of surgical site infection (SSI) in patients with and without intrawound vancomycin application controlling for confounding factors associated with higher SSI after elective spine surgery. SUMMARY OF BACKGROUND DATA: SSI is a morbid and expensive complication associated with spine surgery. The application of intrawound vancomycin is rapidly emerging as a solution to reduce SSI following spine surgery. The impact of intrawound vancomycin has not been systematically studied in a well-designed multicenter study. METHODS: Patients undergoing elective spine surgery over a period of 4 years at seven spine surgery centers across the United States were included in the study. Patients were dichotomized on the basis of whether intrawound vancomycin was applied. Outcomes were occurrence of SSI within postoperative 30 days and SSI that required return to the operating room (OR). Multivariable random-effect log-binomial regression analyses were conducted to determine the relative risk of having an SSI and an SSI with return to OR. RESULTS: .: A total of 2056 patients were included in the analysis. Intrawound vancomycin was utilized in 47% (n = 966) of patients. The prevalence of SSI was higher in patients with no vancomycin use (5.1%) than those with use of intrawound vancomycin (2.2%). The risk of SSI was higher in patients in whom intrawound vancomycin was not used (relative risk (RR) -2.5, P < 0.001), increased number of levels exposed (RR -1.1, P = 0.01), and those admitted postoperatively to intensive care unit (ICU) (RR -2.1, P = 0.005). Patients in whom intrawound vancomycin was not used (RR -5.9, P < 0.001), increased number of levels were exposed (RR-1.1, P = 0.001), and postoperative ICU admission (RR -3.3, P < 0.001) were significant risk factors for SSI requiring a return to the OR. CONCLUSION: The intrawound application of vancomycin after posterior approach spine surgery was associated with a reduced risk of SSI and return to OR associated with SSI. LEVEL OF EVIDENCE: 2.

Awake Craniotomy for the Treatment of a Cortical Pseudoaneurysm in a Pregnant Patient.

Neurosurgical pathologies presenting during pregnancy are uncommon. If present, the situation creates a unique diagnostic, observational, and therapeutic challenge as both lives are placed at potential risk. Surgical procedures during pregnancy are approached carefully as physiological stressors associated with surgery and anesthesia may cause fetal or maternal compromise. We present the only known case of a pseudoaneurysm treated with an awake craniotomy, allowing us to abate the risks associated with general anesthesia in pregnancy. A female suffered a superficially penetrating gunshot wound to the head for which she underwent a craniotomy with complete neurological recovery. She had complaints of intermittent headaches, dizziness, and tingling of her hands five months thereafter. The cerebral angiogram demonstrated an 8 mm pseudoaneurysm under her craniotomy site. A surgical repair of this aneurysm was undertaken in the 23rd week of pregnancy via an awake craniotomy with regional scalp block. The aneurysm was resected without complication, and the patient tolerated the procedure without neurological deficit during or subsequent to the operation. Cerebrovascular pathology in pregnant patients remains a difficult situation that poses challenges associated with the pathology itself as well as the anesthetic implications inherent with operative management. The neurosurgical literature demonstrates that surgical management of cerebrovascular pathology is well-tolerated in pregnancy, and our case further demonstrates the capability of utilizing an awake craniotomy for the treatment of this type of lesion without causing a residual deficit.

Anchor technique: Use of stent retrievers as an anchor to advance thrombectomy catheters in internal carotid artery occlusions.

In three recent cases of acute complete internal artery occlusions, we used stent retriever deployed through the mechanical aspiration/distal access catheters to achieve recanalization. In all cases the stent retriever was used as an anchor and supplemented mechanical thrombectomy. This report describes the technical details of the procedure and presents an alternative plan of action in difficult cases when standard thrombectomy techniques do not work.

Endothelial expression of TNF receptor-1 generates a proapoptotic signal inhibited by integrin α6ß1 in glioblastoma.

Activation of TNF receptor 1 (TNF-R1) can generate signals that promote either apoptosis or survival. In this study, we show that these signals can be determined by the character of the extracellular matrix in the tumor microenvironment. Specifically, through studies of glioblastoma, we showed that TNFα stimulation induced apoptosis of primary brain endothelial cells (EC) attached to collagen or fibronectin (which engage integrins α2ß1/α3ß1 and α5ß1, respectively), but did not induce apoptosis of ECs attached to laminin (which engages integrins α6ß1 and α3ß1). TNF-R1 expression was significantly higher in ECs in glioblastoma (GBM) tumors compared with ECs in normal brain specimens. TNFα was also expressed in GBM tumor-associated ECs, which was associated with longer patient survival. ECs plated on anti-integrin α2 or α3 antibody were susceptible to TNFα-induced apoptosis, whereas those plated on anti-integrin α6 antibody were not. Moreover, the ECs plated on laminin, but not collagen, expressed cellular FLICE inhibitory protein (cFLIP) and TNFα stimulation of laminin-attached cells in which cFLIP had been downregulated resulted in the induction of apoptosis. In contrast, attachment to laminin did not induce cFLIP expression in GBM tumor stem cells. Together, our findings indicate that the laminin receptor integrin α6ß1 promotes the survival of brain ECs by inhibiting prodeath signaling by TNF-R1, in part by inducing cFLIP expression.

Tumor-associated alterations in caspase-14 expression in epithelial malignancies.

PURPOSE: Caspase-14 is unique among caspase family proteases in that its proteolytic processing has been principally associated with epithelial cell differentiation rather than apoptosis or inflammation. We investigated caspase-14 expression in several types of human epithelial malignancy by immunohistochemistry, correlating results with stage, histologic grade, and patient survival. EXPERIMENTAL DESIGN: Tumor-associated alterations in caspase-14 expression were observed for cervical, ovarian, breast, gastric, and colon cancers. RESULTS: In cervical (n = 445), ovarian (n = 91), and colon (n = 106) specimens, expression of caspase-14 was significantly reduced in cancers compared with normal epithelium. Decreases in caspase-14 immunopositivity correlated with the histologic progression of cervical cancer (P < 0.0001, ANOVA). In localized gastric cancers, caspase-14 immunostaining was significantly lower in poorly differentiated tumors compared with well-differentiated tumors (P = 0.02, Pearson's chi(2) analysis). Lower caspase-14 expression was associated with advanced clinical stage in ovarian cancer (P = 0.04, ANOVA) and with shorter overall survival among ovarian cancer patients with serous tumors (n = 62) in both univariate (P = 0.005) and multivariate (P = 0.03) analysis. Lower caspase-14 expression correlated with shorter overall survival among patients with T(3)N(0)M(0) stage gastric cancers (n = 94; P = 0.006, log-rank test). In contrast to cervical, ovarian, and colon cancers, caspase-14 expression was increased in ductal carcinoma in situ and invasive cancers compared with normal mammary epithelium (P = 0.001, t test). CONCLUSIONS: The findings reveal tumor-specific alterations in caspase-14 expression and suggest that differences in its expression may define subsets of epithelial cancers with distinct clinical behaviors.