Ethylene oxide gas sterilization: a simple technique for storing explanted skull bone. Technical note.

The authors evaluated the effectiveness of a simple technique using ethylene oxide (EtO) gas sterilization and room temperature storage of autologous bone grafts for reconstructive cranioplasty following decompressive craniectomy. The authors retrospectively analyzed data in 103 consecutive patients who underwent cranioplasty following decompressive craniectomy for any cause at the University of Illinois at Chicago between 1999 and 2005. Patients with a pre-existing intracranial infection prior to craniectomy or lost to follow-up before reconstruction were excluded. Autologous bone grafts were cleansed of soft tissue, hermetically sealed in sterilization pouches for EtO gas sterilization, and stored at room temperature until reconstructive cranioplasty was performed. Cranioplasties were performed an average of 4 months after decompressive craniectomy, and the follow-up after reconstruction averaged 14 months. Excellent aesthetic and functional results after single-stage reconstruction were achieved in 95 patients (92.2%) as confirmed on computed tomography. An infection of the bone flap occurred in eight patients (7.8%), and the skull defects were eventually reconstructed using polymethylmethacrylate with satisfactory results. The mean preservation interval was 3.8 months in patients with uninfected flaps and 6.4 months in those with infected flaps (p = 0.02). A preservation time beyond 10 months was associated with a significantly increased risk of flap infection postcranioplasty (odds ratio [OR] 10.8, p = 0.02). Additionally, patients who had undergone multiple craniotomies demonstrated a trend toward increased infection rates (OR 3.0, p = 0.13). Data in this analysis support the effectiveness of this method, which can be performed at any institution that provides EtO gas sterilization services. The findings also suggest that bone flaps preserved beyond 10 months using this technique should be discarded or resterilized prior to reconstruction.

Primary biliary B-cell lymphoma of the cystic duct causing obstructive jaundice.

A distinctive case of primary biliary lymphoma occurring in the cystic duct causing extrinsic compression of the porta hepatis in a 48-year-old woman is presented. Imaging studies revealed stricture of the common hepatic duct with a 2.5-cm nonhomogeneous mass at the porta hepatis, mimicking a Klatskin tumor. Exploratory laparotomy revealed a mass in the gallbladder neck with extension into the cystic duct akin to Mirizzi's syndrome. A soft, tan-yellow 1.0-cm mass was removed from the cystic duct, and infiltrating atypical lymphocytic nodules were identified with a final diagnosis of an anaplastic variant of diffuse large B-cell lymphoma.

Role of omega-3 fatty acid supplementation in inflammation and malignancy.

Omega-3 fatty acids (FAs), which include eicosapentaenoic acid (EPA) and docosahexaenoic acid, are found in fish oils and have long been investigated as components of therapy for various disease states. Population studies initially revealed the cardioprotective and anti-inflammatory effects of omega-3 FAs and EPA, with subsequent clinical studies supporting the therapeutic role of omega-3 FAs in cardiovascular and chronic inflammatory conditions. Prospective randomized placebo-controlled trials have also demonstrated the utility of omega-3 FA supplementation in malignancy and cancer cachexia. In recent years, in vitro and animal studies have elucidated some of the mechanistic explanations underlying the wide range of biological effects produced by omega-3 FAs and EPA, including their antiproliferative and anticachectic actions in malignancy. In this review, the authors discuss the recent progress made with omega-3 FAs, focusing on the advances in mechanistic understanding and the results of clinical trials.

Eicosapentaenoic acid supplementation reduces tumor volume and attenuates cachexia in a rat model of progressive non-metastasizing malignancy.

BACKGROUND: Eicosapentaenoic acid (EPA) has been shown to have anti-inflammatory and tumor growth inhibitory effects clinically and experimentally; evidence also supports the role of EPA in attenuating cancer-associated weight loss, but the mechanisms of these effects remain to be defined. As the liver plays a central role in modulating nutritional status and the cachexia syndrome, we examined the liver and nutritional parameters indicative of cachexia along with the tumor volume in response to oral EPA supplementation in a rat model of progressive non-metastasizing malignancy. METHODS: Fischer 344 rats implanted with the methylcholanthrene-induced fibrosarcoma (MCA) were trained to meal-feed with access to food from 8:00 PM to 8:00 AM and water ad libitum. On day 13, rats were randomly divided into 3 study groups: (1) 5.0 g/kg per day EPA plus 10 IU vitamin E/g fat, (2) 5.0 g/kg per day corn oil plus 10 IU vitamin E/g fat, and (3) 5.0 g/kg per day saline plus 10 IU vitamin E/g saline. The treatment was delivered via oral gavage twice daily. The animals were killed on day 29, and serum plus tissues (ie, liver and lung) were collected and frozen for analysis. Parameters evaluated include the following: tumor volume, weight loss, liver weight, total liver protein, liver lipid content, serum albumin content, and macrophage inflammatory protein-2 (MIP-2) levels. RESULTS: EPA-treated rats showed a reduction in tumor volume compared with corn oil (25% reduction, p < .01) and saline (33% reduction, p < .01) animals. EPA rats also demonstrated increased liver weight (p < .01) and total liver protein levels (p < .03) over saline-treated animals. EPA- and corn oil-treated rats received more calories than the saline group because of the dietary fat treatments (p < .01) and had elevated lipid content in their livers (p = .05 and p = .04, respectively) compared with saline rats. Serum albumin (a marker of liver function) and MIP-2 levels (a marker of the hepatic acute phase response) were not different between treatment groups. CONCLUSIONS: EPA supplementation resulted in a dramatic reduction of tumor volume and mild improvements in weight maintenance. In addition, EPA-treated animals demonstrated increased total liver protein and serum protein levels. Regression analyses showed that the weight and protein differences between treatment groups were not correlated with individual tumor volumes. The increase in liver and serum protein was not explained by differences in albumin or MIP-2. We conclude that the tumor growth inhibitory effects and anticachexiogenic effects of EPA are independent phenomena, and the effects on cachexia may be related to increased levels of undefined protein(s) in the liver and serum. To our knowledge, this is the first study to demonstrate the effects of EPA in the MCA fibrosarcoma model and is also novel in its evaluation of EPA as an anticachexiogenic therapy in progressive non-metastasizing malignancy. Further studies may identify the protein(s) elevated in the liver and the mechanisms for the development of EPA nutritional therapies for the treatment of progressive malignancies.

Modulation of the ubiquitin-proteasome proteolytic pathway by eicosapentaenoic acid supplementation in a model of progressive malignancy.

BACKGROUND: A benefit for eicosapentaenoic acid (EPA) supplementation for protein maintenance in cancer patients exists, although specific mechanisms are unknown. As the ubiquitin-proteasome proteolytic (UPP) pathway has been implicated in protein use in malignancy, we determined mRNA levels for UPP components in the liver and muscles from EPA-treated rats bearing the methylcholanthrene (MCA) fibrosarcoma. METHODS: Rats implanted with MCA tumor were divided into 3 groups on day 13: EPA (5 g/kg per day plus 10 IU vitamin E/g fat), corn oil (5 g/kg per day plus 10 IU vitamin E/g fat), and saline (5 g/kg per day plus 10 IU E/g saline). On day 29, tumor volume (TV) was determined; liver and quadriceps muscles were also excised to determine gene expression of C2, C3, E2(14k), and E3alpha by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: EPA-treated rats demonstrated a reduced TV of 21% compared with the 28% and 30% TV of corn oil- and saline-treated rats, respectively. Muscle mRNA levels of E2(14k) and E3alpha in EPA-treated animals were decreased compared with corn oil- and saline-treated animals. EPA treatment also decreased hepatic C2, C3, and E2(14k) mRNA levels compared with saline treatment. CONCLUSION: EPA supplement decreased skeletal muscle E2(14k), E3alpha, and hepatic C2 mRNA levels compared with the isocaloric, isonitrogenous corn oil supplement, supporting a treatment-specific effect. The decrease in hepatic C3 and E2(14k) mRNA levels induced by EPA were partly because of caloric benefit and partly attributable to a treatment-specific effect. Additionally, differences in the hepatic and muscle gene expressions of UPP components suggested an organ-specific effect for omega-3 fatty acid activity.

Simplified surgical placement and stabilization methods for intracerebroventricular cannulas in rat lateral ventricles.

Intracerebroventricular cannulation in rat models is an efficient tool for exploring the effects of substances directly injected into the CNS, bypassing the blood-brain barrier. Techniques for surgically securing the ICV cannula require a balance between ease of application and adequate stability. The authors tested several methods of lateral ventricle cannula stabilization, especially focusing on a comparison of cyanoacrylate gel to cranioplastic cement with an anchoring bone screw.

Pituitary apoplexy: large surgical series with grading system.

BACKGROUND: Pituitary apoplexy is an infrequent occurrence that can require timely treatment. The term "pituitary apoplexy" as used in the literature describes a heterogeneous spectrum. There is controversy about which subsets require urgent as opposed to elective surgical treatment or even medical treatment alone. We present a retrospective series of 109 consecutive cases of pituitary apoplexy from a single institution from 1992-2012 and develop a comprehensive classification system to analyze outcome. METHODS: Surgical and endocrine consult databases were reviewed to analyze patterns of presentation, imaging, treatment, and outcomes. RESULTS: Most of the patients in this series presented clinically with "classic" pituitary apoplexy (97%), had magnetic resonance imaging for evaluation (99%), underwent transsphenoidal surgery as their primary treatment (93%), and were found to have pituitary adenomas on histopathology (90%). We categorized patients into 5 grades based on clinical presentation. Tumor volume, cavernous sinus involvement, suprasellar extension, and need for ongoing endocrine replacement correlated with grade. Long-term endocrine replacement at follow-up was required in 62%-68% of patients with a higher grade compared with 0-23% of patients with a lower grade. Higher grade patients tended to undergo earlier surgery after symptom onset. Symptoms resolved or improved with treatment in 92%-100% of patients across all grades with good general outcomes for visual deficits and ocular motility problems, validating management decisions overall. CONCLUSIONS: We offer a simple yet comprehensive grading system to classify the clinical spectrum of pituitary apoplexy, which has implications for management, outcomes, and categorization for future studies.

Endoscopic burr hole evacuation of an acute subdural hematoma.

Acute subdural hematoma evacuations frequently necessitate large craniotomies with extended operative times and high relative blood loss, which can lead to additional morbidity for the patient. While endoscopic minimally invasive approaches to chronic subdural collections have been successfully demonstrated, this technique has not previously been applied to acute subdural hematomas. The authors report their experience with an 87-year-old patient presenting with a large acute right-sided subdural hematoma successfully evacuated via an endoscopic minimally invasive technique. The operative approach is outlined, and the literature on endoscopic subdural collection evacuation reviewed.

Concomitant presentation of a glioblastoma multiforme with superimposed abscess.

BACKGROUND: The coexistence of a primary brain tumor such as high-grade glioma and superimposed abscess is a rare entity and can present a diagnostic and therapeutic challenge. The concomitant abscess may not be recognized until surgery, and the overall course of treatment may require adjustment in the presence of a coinciding infection. In the present report we evaluate the diagnosis and treatment of a glioblastoma multiforme with an intratumoral abscess. METHODS: A patient was diagnosed with a glioblastoma multiforme with a concomitantly superimposed multimicrobial abscess containing coagulase-negative Staphylococcus, Acinetobacter iwofii, and Propionibacterium species. The suspected infectious source was a dental abscess with presumed secondary seeding. The patient underwent a left anterior temporal lobectomy with debulking of the lesion. Although the adjuvant therapy schedule was adjusted to accommodate the course of antibiotics, the existence of a concurrent abscess did not preclude adjuvant radiation and chemotherapy. RESULTS: The patient responded well to antibiotic treatment with no evidence of recurrent infection. He underwent a second operation for additional debulking of the lesion approximately half a year after his initial surgery. The patient died 2 years after the initial diagnosis. CONCLUSIONS: There are insufficient guidelines on the treatment of a primary brain tumor with intratumoral abscess. In this report we present our therapeutic decisions in this rare case.

Surgical treatment of a large fusiform distal anterior cerebral artery aneurysm with In Situ end-to-side A3-A3 bypass graft and aneurysm trapping: case report and review of the literature.

BACKGROUND AND IMPORTANCE: Large fusiform aneurysms of the distal anterior cerebral territory are extremely rare and can be particularly challenging to treat. The circumferential pathology of fusiform lesions renders stand-alone clip or coil ablation unsatisfactory, and the deep, narrow corridor augments the difficulty of surgical approaches. In this setting, bypass procedures may be used to both treat the aneurysm definitively and preserve distal parent artery flow. We report a rare case of a large fusiform A3 aneurysm treated with trapping and concomitant end-to-side A3:A3 bypass. CLINICAL PRESENTATION: A 52-year-old man was evaluated after losing consciousness and experiencing a fall. A noncontrast computed tomography scan revealed a focal area of hemorrhage above the body of the corpus callosum, and computed tomography angiography showed a fusiform aneurysm of the right A3 artery. To treat the aneurysm definitively and preserve distal vessel flow, the patient was taken to surgery in anticipation of aneurysm ablation and cerebrovascular bypass. A large, fusiform right A3 aneurysm was identified. Intraoperative flow measurement demonstrated poor collateral circulation. The aneurysm was trapped with clips, and a right-to-left A3:A3 end-to-side in situ bypass was performed. Aneurysm occlusion and preserved distal vessel flow were confirmed with intraoperative angiography. CONCLUSION: Large fusiform aneurysms in the distal anterior cerebral artery region are rare, and the anatomy of these lesions and their vascular location render stand-alone surgical management technically challenging. End-to-side A3:A3 bypass combined with aneurysm trapping represents a feasible treatment strategy for lesions in this location.

Modulation of lipopolysaccharide-stimulated macrophage tumor necrosis factor-alpha production by omega-3 fatty acid is associated with differential cyclooxygenase-2 protein expression and is independent of interleukin-10.

BACKGROUND: The role of omega-3 fatty acids (FA) as anti-inflammatory agents involves the inhibition of macrophage (Mphi) cytokine production, but the mechanisms involved are not well defined. The effects of omega-3 FA on the transcription and translation of cyclooxygenase-2 (COX-2), the production of prostaglandin E(2) (PGE(2)), and the production of interleukin-10 (IL-10) were investigated as potential mechanisms for the down-regulation of lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha production. METHODS: RAW 264.7 Mphi were incubated with Omegaven (10 mg% omega-3 FA), Lipovenos (10 mg% omega-6 FA), or DMEM for 4 h of pretreatment. The cells were then exposed to LPS (1 microg/ml) or medium alone for 3 h. COX-2 mRNA levels were determined by semi-quantitative reverse transcriptase polymerase chain reaction, and COX-2 protein levels were determined by Western blotting. The levels of PGE(2) and IL-10 proteins secreted into the medium were quantified using enzyme-linked immunosorbent assays. RESULTS: Pretreatment with omega-3 FA increased Mphi COX-2 protein expression levels without altering the levels of COX-2 mRNA in response to LPS stimulation. In addition, pretreatment with omega-3 FA dramatically decreased the PGE(2) and IL-10 production induced by LPS, whereas pretreatment with an equivalent dose of omega-6 FA only resulted in a modest increase in PGE(2) and a slight decrease in IL-10 production compared to controls. CONCLUSION: As COX-2 protein levels were increased without a change in COX-2 mRNA levels with omega-3 FA pretreatment, this suggested that omega-3 FA did not upregulate COX-2 at the transcriptional level. The omega-3 FA may instead posttranscriptionally stabilize existing COX-2 mRNA. The increased COX-2 expression may thus be explained by increased translation of COX-2 and/or decreased COX-2 degradation. The decreased PGE(2) production could be attributed to the replacement of Mphi membrane omega-6 FA substrates by omega-3 FA and the competitive inhibition of COX-2 enzyme by omega-3 FA. The reduction of active COX-2 product associated with an increase in COX-2 enzyme implies the existence of a negative feedback mechanism. Surprisingly, IL-10 production was decreased by omega-3 FA pretreatment, indicating that the reduced IL-10 inhibition of Mphi cytokine production was superceded by the other actions of omega-3 FA.

Ciliary neurotrophic factor upregulates ubiquitin-proteasome components in a rat model of neuronal injury.

Neuronal injury triggers the release of ciliary neurotrophic factor (CNTF), promoting local neuronal repair but producing systemic effects of anorexia and lean body weight loss. Due to the rapid rate of systemic protein loss stimulated by CNTF, we hypothesized involvement of the hepatic ubiquitin-proteasome proteolytic (UPP) pathway in CNTF-induced proteolysis. To assess the role of central CNTF in systemic UPP regulation, we measured hepatic UPP mRNA and proteasome activity in a rat model of neuronal injury and determined alterations induced by intracerebroventricular (ICV) administration of CNTF-neutralizing antibody or additional exogenous CNTF. We also assessed proteolytic parameters and nutritional status by measuring caloric intake, body weight, and protein levels. We produced neuronal injury by implanting a lateral ventricle cannula and giving daily ICV saline bolus injections, which increased hepatic 20S proteasome mRNA and enzymatic activity while reducing caloric intake, body weight, and protein levels compared to controls. Administration of ICV anti-CNTF antibodies (but not control antibodies) prevented these effects. Addition of exogenous CNTF augmented the weight loss along with the increases in 20S proteasome mRNA and proteolytic activity induced by neuronal injury. We conclude that CNTF decreases lean body weight through a combination of appetite inhibition and UPP pathway activation.

NF-kappa B inhibition by omega -3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcription.

Omega-3 fatty acid (FA) emulsions reduce LPS-stimulated murine macrophage TNF-alpha production, but the exact mechanism has yet to be defined. The purpose of this study was to determine the mechanism for omega-3 FA inhibition of macrophage TNF-alpha production following LPS stimulation. RAW 264.7 cells were pretreated with isocaloric emulsions of omega-3 FA (Omegaven), omega-6 FA (Lipovenos), or DMEM and subsequently exposed to LPS. IkappaB-alpha and phospho-IkappaB-alpha were determined by Western blotting. NF-kappaB binding was assessed using the electromobility shift assay, and activity was measured using a luciferase reporter vector. RT-PCR and ELISA quantified TNF-alpha mRNA and protein levels, respectively. Pretreatment with omega-3 FA inhibited IkappaB phosphorylation and significantly decreased NF-kappaB activity. Moreover, omega-3-treated cells demonstrated significant decreases in both TNF-alpha mRNA and protein expression by 47 and 46%, respectively. These experiments demonstrate that a mechanism for proinflammatory cytokine inhibition in murine macrophages by omega-3 FA is mediated, in part, through inactivation of the NF-kappaB signal transduction pathway secondary to inhibition of IkappaB phosphorylation.

E. coli pneumonia induces CD18-independent airway neutrophil migration in the absence of increased lung vascular permeability.

We examined the relationship between neutrophil [polymorphonuclear leukocyte (PMN)] influx and lung vascular injury in response to Escherichia coli pneumonia. We assessed lung tissue PMN uptake by measuring myeloperoxidase and transvascular PMN migration by determining PMN counts in lung interstitium and bronchoalveolar lavage fluid (BALF) in mice challenged intratracheally with E. coli. Lung vascular injury was quantified by determining microvessel filtration coefficient (Kf,c), a measure of vascular permeability. We addressed the role of CD18 integrin in the mechanism of PMN migration and lung vascular injury by inducing the expression of neutrophil inhibitory factor, a CD11/CD18 antagonist. In control animals, we observed a time-dependent sixfold increase in PMN uptake, a fivefold increase in airway PMN migration, and a 20-fold increase in interstitial PMN uptake at 6 h after challenge. Interestingly, Kf,c increased minimally during this period of PMN extravasation. CD11/CD18 blockade reduced lung tissue PMN uptake consistent with the role of CD18 in mediating PMN adhesion to the endothelium but failed to alter PMN migration in the tissue. Moreover, CD11/CD18 blockade did not affect Kf,c. Analysis of BALF leukocytes demonstrated diminished oxidative burst compared with leukocytes from bacteremic mice, suggesting a basis for lack of vascular injury. The massive CD11/CD18-independent airway PMN influx occurring in the absence of lung vascular injury is indicative of an efficient host-defense response elicited by E. coli pneumonia.