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Brian T. Ragel and William T. Couldwell

Pituitary carcinomas, defined as distant metastases of a pituitary neoplasm, are rare; fewer than 140 reports exist in the English literature. The initial presenting pituitary tumor is usually a secreting, invasive macroadenoma, with adrenocorticotropic hormone (ACTH)– and prolactin (PRL)–secreting tumors being the most common. The latency period between the diagnosis of a pituitary tumor and the diagnosis of a pituitary carcinoma is 9.5 years for ACTH-producing lesions and 4.7 years for PRL-secreting tumors. Survival after documentation of metastatic disease is poor; 66% of patients die within 1 year. Treatment options include additional surgery, radiotherapy, and chemotherapy, all of which are associated with poor results. Future studies will focus on identifying those invasive pituitary tumors most likely to metastasize and treating them aggressively before they progress to pituitary carcinomas.

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Brian T. Ragel and Randy L. Jensen

In this article the authors provide a brief description of the current understanding of meningioma genetics. Chromosome 22 abnormalities, especially in the Neurofibromatosis Type 2 (NF2) gene, have been associated with meningioma development. Loss of heterozygosity of chromosome 22 occurs in approximately 60% of meningiomas; however, loss of NF2 gene function occurs in only one third of these lesions. This discrepancy supports the theory that a second tumor suppressor gene exists on chromosome 22, and the authors introduce several possible gene candidates, including BAM22, LARGE, INI1, and MN1 genes. Deletions of 1p have also been shown to correlate with meningioma progression. The genetic similarities and differences among sporadic, NF2-associated, pediatric, and radiation-induced meningiomas are discussed, with the observation that the nonsporadic meningiomas have a higher incidence of multiple chromosomal abnormalities at presentation. Ultimately, a better understanding of the molecular pathways of meningioma tumorigenesis will lead to new, successful treatments.

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Brian T. Ragel, Randy L. Jensen and William T. Couldwell

✓In this article the authors discuss the rationale and research supporting the hypothesis that meningioma tumorigenesis may, in part, be driven by overexpression of cyclooxygenase-2 (Cox-2) and that treatment with celecoxib, a selective Cox-2 inhibitor, may hold therapeutic promise. Because therapies for recurrent or aggressive meningiomas (atypical or malignant subtypes) such as chemotherapy and radiotherapy generally offer little therapeutic benefit, interest in targeting Cox-2 has grown. This rate-limiting enzyme of prostaglandin synthesis can be inhibited with nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and celecoxib. Treatment with NSAIDs has been shown to curb the tumorigenic properties of prostaglandins in several cancer models via both Cox-2-dependent and -independent mechanisms. In addition, celecoxib is well tolerated in humans, making its use as a chronic therapy for meningiomas attractive.

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Nathaniel Whitney, Ahmed M. Raslan and Brian T. Ragel

Severe traumatic brain injury (TBI) in pregnant women can result in devastating outcomes for both the mother and the fetus. Historically, there has been concern regarding the issues involved when the fetus is not yet viable outside the womb. Currently, the ability to treat severe TBI with aggressive management of intracranial pressure (ICP) has led to the possibility of sustaining maternal life until the fetus is of a viable age and can be delivered. The authors present the case of a young woman 21 weeks pregnant with a severe TBI (Glasgow Coma Scale Score 3) in whom safe medical ICP management became ineffective. A decompressive craniectomy was performed to obviate the need for aggressive medical management of elevated ICP using fetal-toxic medications, and thus providing the fetus the best chance of continued in utero development until a viable gestational age was reached.

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Brian T. Ragel, Samuel R. Browd and Richard H. Schmidt

Object

Infection represents the most common serious complication of shunt surgery, and typically its incidence ranges between 5 and 15%, despite the use of systemic antibiotic agents. Because systemic antibiotic medications generally penetrate the cerebrospinal fluid (CSF) poorly, the authors investigated, in a controlled study, whether the addition of intraventricular antibiotic treatment decreases the incidence of perioperative infection in adult patients.

Methods

Data pertaining to all CSF shunt procedures conducted at the authors’ institution during an 11-year period were reviewed. Perioperative infection was defined as culture-positive CSF and the clinical presence of infection-related symptoms occurring within 90 days of surgery. All patients underwent intraoperative systemic antistaphylococcal antibiotic therapy. Before May 16, 1999, the senior author (R.H.S.) also administered 4 mg of gentamicin intraventricularly at surgery (Group I); thereafter, 10 mg of vancomycin was additionally administered (Group II). Other neurosurgeons at this institution did not use intraventricular antibiotic therapy, and their patients served as additional controls in identical time periods (Groups III and IV).

A total of 802 shunt procedures were performed in 534 patients. Control infection rates were 5.4% (eight of 147) in Group I; 6.2% (nine of 145) in Group III; and 6.7% (18 of 267) in Group IV. With the combination of systemic antibiotic and intraventricular gentamicin and vancomycin (Group II), the infection rate fell significantly to 0.4% (one of 243). No complications were noted in association with intraventricular antibiotic administration.

Conclusions

The combination of intraventricular gentamicin and vancomycin with systemic antibiotic therapy significantly decreased the incidence of perioperative shunt infection. It is presumed that intraventricular antibiotic therapy extends prophylactic antibiotic coverage into the CSF and prevents bacterial seeding.

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Brian T. Ragel, William T. Couldwell, Robert D. Wurster and Randy L. Jensen

✓In this article, the authors review the research supporting the use of calcium channel antagonists (CCAs) in the treatment of recurrent or unresectable meningiomas. Calcium channel antagonists (for example, diltiazem and verapamil) are known to augment the effects of chemotherapy drugs (for example, vincristine) in multiple cancers. Although it was initially thought that this occurred by interference with calcium-dependent secondary messenger systems, it appears that other mechanisms account for this effect. The authors' initial work in this field was based on the then-emerging data that meningiomas are receptor positive for growth factor receptors (for example, platelet-derived growth factor [PDGF]), which are known to trigger calcium-dependent secondary messenger pathways. In fact, they were able to show that CCAs block the growth stimulatory effects of multiple growth factors, including PDGF, in vitro and augment the growth inhibitory effects of hydroxyurea and RU486 (mifepristone). The authors have shown similar in vivo growth inhibition by these agents. In addition, diltiazem- and verapamil-treated meningiomas are less vascular and smaller, with decreased cell proliferation and increased apoptosis. The use of CCAs is attractive as an adjunct treatment for unresectable or recurrent meningiomas because they are safe drugs with well-known side effect profiles that lend themselves to long-term chronic therapy.

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Brian T. Ragel, Randy L. Jensen, David L. Gillespie, Stephen M. Prescott and William T. Couldwell

Object

Meningiomas are the second most common symptomatic primary central nervous system tumor in adults. Findings of epidemiological studies link meningiomas with a history of head trauma, indicating a causal relationship between the inflammatory response and meningioma tumorigenesis. Cyclooxygenase-2 (COX-2), an inducible inflammatory enzyme, converts arachidonic acid to prostaglandins, which have angiogenic, cell-proliferative, and antiapoptotic effects. The authors investigated COX-2 expression in meningiomas and the effects of celecoxib, a COX-2 inhibitor, on meningioma cell growth in vitro.

Methods

Four meningioma surgical specimens were immunohistochemically stained and graded (0 to 4) for COX-2. In addition, a Western blot analysis was performed to detect the presence of COX-2. Human meningioma cells grown in cell culture were treated with vehicle or celecoxib (0.25–1 mM). An immunohistochemical analysis of COX-2, a methylthiotetrazole cell proliferation assay, a TUNEL apoptosis assay, and a Western blot analysis for the proapoptotic protein BAX were performed in vitro.

One hundred eleven (87%) of 128 benign meningiomas and six (86%) of seven atypical meningiomas displayed a high COX-2 immunoreactivity (Grade 4 staining). In the Western blot analysis all four surgical specimens (100%) stained positive for a 70-kD band consistent with COX-2. Celecoxib inhibited cell growth in a dose-dependent fashion and induced apoptosis by Day 2, with no change noted in the expression of the BAX protein.

Conclusions

The COX-2 enzyme is universally expressed in meningiomas. Celecoxib inhibits meningioma growth in vitro in a dose-dependent fashion, with evidence of apoptosis. Inhibitors of COX-2 may have a role in the treatment of recurrent meningiomas.

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Paul Klimo Jr., Brian T. Ragel, William H. Scott Jr. and Randall McCafferty

Object

Operation Enduring Freedom (OEF) is the current US military conflict against terrorist elements in Afghanistan. Deepening US involvement in this conflict and increasing coalition casualties prompted the establishment of continuous neurosurgical assets at Craig Joint Theater Hospital (CJTH) at Bagram Airfield, Afghanistan, in September 2007. As part of the military's medical mission, children with battlefield-related injuries and, on a selective case-by-case basis, non–war-related pathological conditions are treated at CJTH.

Methods

A prospectively maintained record was created in which all rotating neurosurgeons at CJTH recorded their personal procedures. From this record, the authors were able to extract all cases involving patients 18 years of age or younger. Variables recorded included: age, sex, and category of patient (for example, local national, enemy combatant), date, indication and description of the neurosurgical procedure, mechanism of injury, and in-hospital morbidity and mortality data.

Results

From September 2007 to October 2009, 296 neurosurgical procedures were performed at CJTH. Fifty-seven (19%) were performed in 43 pediatric patients (16 girls and 27 boys) with an average age of 7.5 years (range 11 days–18 years). Thirty-one of the 57 procedures (54%) were for battlefield-related trauma and 26 for humanitarian reasons (46%). The vast majority of cases were cranial (49/57, 86%) compared with spinal (7/54, 13%), with one peripheral nerve case. Craniotomies or craniectomies for penetrating brain injuries were the most common procedures. There were 5 complications (11.6%) and 4 in-hospital deaths (9.3%).

Conclusions

As in previous military conflicts, children are the unfortunate victims of the current Afghanistan campaign. Extremely limited pediatric neurosurgical service and care is rendered under challenging conditions and Air Force neurosurgeons provide valuable, life-saving pediatric treatment for both war-related injuries and humanitarian needs. As the conflict in Afghanistan continues, military neurosurgeons will continue to care for injured children to the best of their abilities.

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Paul Klimo Jr., Clinton J. Thompson, Brian T. Ragel and Frederick A. Boop

Object

Neurosurgeons are inundated with vast amounts of new clinical research on a daily basis, making it difficult and time-consuming to keep up with the latest literature. Meta-analysis is an extension of a systematic review that employs statistical techniques to pool the data from the literature in order to calculate a cumulative effect size. This is done to answer a clearly defined a priori question. Despite their increasing popularity in the neurosurgery literature, meta-analyses have not been scrutinized in terms of reporting and methodology.

Methods

The authors performed a literature search using PubMed/MEDLINE to locate all meta-analyses that have been published in the JNS Publishing Group journals (Journal of Neurosurgery, Journal of Neurosurgery: Pediatrics, Journal of Neurosurgery: Spine, and Neurosurgical Focus) or Neurosurgery. Accepted checklists for reporting (PRISMA) and methodology (AMSTAR) were applied to each meta-analysis, and the number of items within each checklist that were satisfactorily fulfilled was recorded. The authors sought to answer 4 specific questions: Are meta-analyses improving 1) with time; 2) when the study met their definition of a meta-analysis; 3) when clinicians collaborated with a potential expert in meta-analysis; and 4) when the meta-analysis was the only focus of the paper?

Results

Seventy-two meta-analyses were published in the JNS Publishing Group journals and Neurosurgery between 1990 and 2012. The number of published meta-analyses has increased dramatically in the last several years. The most common topics were vascular, and most were based on observational studies. Only 11 papers were prepared using an established checklist. The average AMSTAR and PRISMA scores (proportion of items satisfactorily fulfilled divided by the total number of eligible items in the respective instrument) were 31% and 55%, respectively. Major deficiencies were identified, including the lack of a comprehensive search strategy, study selection and data extraction, assessment of heterogeneity, publication bias, and study quality. Almost one-third of the papers did not meet our basic definition of a meta-analysis. The quality of reporting and methodology was better 1) when the study met our definition of a meta-analysis; 2) when one or more of the authors had experience or expertise in conducting a meta-analysis; 3) when the meta-analysis was not conducted alongside an evaluation of the authors' own data; and 4) in more recent studies.

Conclusions

Reporting and methodology of meta-analyses in the neurosurgery literature is excessively variable and overall poor. As these papers are being published with increasing frequency, neurosurgical journals need to adopt a clear definition of a meta-analysis and insist that they be created using checklists for both reporting and methodology. Standardization will ensure high-quality publications.