N. Scott Litofsky

Depression in patients with high-grade glioma: results of the Glioma Outcomes Project.

OBJECTIVETo study the incidence of depression among patients undergoing surgery for high-grade glioma, document factors associated with the presence of depression, and examine the relationship between depression and patient outcome. METHODSPhysician and patient reports of depression were analyzed immediately postoperatively and again 3 and 6 months after surgery for high-grade glioma. Physician-reported depression was defined according to the Diagnostic and Statistical Manual of Mental Disorders, ed 4. Patient self-assessment of depression was based on responses to questions contained in two validated functional status surveys. Concordance of physician- and patient-reported depression was examined, along with the extent of use of pharmacological treatment for depression. Additional outcomes examined included quality of life, survival, patient satisfaction, and posttreatment complications. RESULTSData from 598 patients were analyzed. In the early postoperative period, physicians reported depression in 15% of patients, whereas 93% of patients reported symptoms consistent with depression. The incidence of patient self-reported depression remained similar at 3- and 6-month follow-up, whereas physician reported depression increased from 15% in the early postoperative period to 22% at both 3- and 6-month follow-up. Concordance between physician recognition of depression and treatment of depression was low initially (33%) and increased at 3 and 6 months (51 and 60%, respectively). As compared with patients who were not depressed, survival was shorter and complications were more common among depressed patients. CONCLUSIONSymptoms of depression were common immediately after surgery for glioma, and they increased throughout the 6-month period after surgery. These findings support the hypothesis that clinically important depression is a common complication in patients with high-grade glioma. Concordance between physician recognition of depression and self-reports of depression by patients was low. Concordance between physician recognition of depression and initiation of pharmacological antidepressant therapy was fair in the early postoperative period and improved somewhat over the subsequent 6-month period; however, within the 6-month period after surgery for glioma, antidepressant therapy was provided for only 60% of patients in whom the physician recognized depressive symptoms and in only 15% of patients who self-reported symptoms of depression. Findings from this observational study suggest the need for a controlled trial that is designed to test the hypothesis that more attention to the identification of postoperative depression and aggressive treatment of depressive symptoms can improve the quality of life and survival of patients after surgery for high-grade glioma.

Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas.

The optimal treatment for elderly patients (defined as patients 70 years of age or older) with malignant gliomas (MG) remains controversial. Some physicians advocate withholding therapy following diagnosis based on the observation that elderly patients do not tolerate adjuvant radiotherapy. The availability of temozolomide (TMZ), a new alkylating agent with antiglioma efficacy, offers another potential therapeutic option for these patients. The drug can be administered orally at home with minimal morbidity.

PTEN in Neural Precursor Cells: Regulation of Migration, Apoptosis, and Proliferation

PTEN is a lipid phosphatase, and PTEN mutations are associated with gliomas, macrocephaly, and mental deficiencies. We have used PTEN +/- mice to assess PTENs role in subventricular zone (SVZ) precursor cells. For cultured SVZ neurosphere cells, haploinsufficiency for PTEN increases phosphorylation of Akt and forkhead transcription factor and slightly enhances proliferation. Based on a filter penetration assay, PTEN +/- cells are substantially more migratory and invasive than +/+ cells. The +/- cells also are more resistant to H(2)O(2)-induced apoptosis. Analysis of PTEN +/- and +/+ mice by BrdU labeling reveals no difference in the rate of cell proliferation in the SVZ. Exit of BrdU-labeled cells from the SVZ and radial migration to the outer layers of the olfactory bulb are more rapid for +/- cells. These observations indicate that PTEN regulates SVZ precursor cell function and is particularly important for migration and apoptosis in response to oxidative stress.

Temporal Bone Fractures: Otic Capsule Sparing versus Otic Capsule Violating Clinical and Radiographic Considerations

OBJECTIVE To assess the practicality and utility of the traditional classification system for temporal bone fracture (transverse vs. longitudinal) in the modern Level I trauma setting and to determine whether a newer system of designation (otic capsule sparing vs. otic capsule violating fracture) is practical from a clinical and radiographic standpoint. METHODS The University of Massachusetts Medical Center Trauma Registry was reviewed for the years 1995 to 1997. Patients identified as sustaining closed head injury were reviewed for basilar skull fracture and temporal bone fracture. Clinical and radiographic records were evaluated by using the two classification schemes. RESULTS A total of 2,977 patients were treated at the trauma center during this time. Ninety (3%) patients sustained a temporal bone fracture. The classic characterization of transverse versus longitudinal fracture (20% vs. 80%, respectively) was unable to be determined in this group; therefore, clinical correlation to complications using that paradigm was not possible. By using the otic capsule violating versus sparing designation, an important difference in clinical sequelae and intracranial complications became apparent. Compared with otic capsule sparing fractures, patients with otic capsule violating fractures were approximately two times more likely to develop facial paralysis, four times more likely to develop CSF leak, and seven times more likely to experience profound hearing loss, as well as more likely to sustain intracranial complications including epidural hematoma and subarachnoid hemorrhage. CONCLUSION The use of a classification system for temporal bone fractures that emphasizes violation or lack of violation of the otic capsule seems to offer the advantage of radiographic utility and stratification of clinical severity, including severity of Glasgow Coma Scale scores and intracranial complications such as subarachnoid hemorrhage and epidural hematoma.

The relationships between depression and brain tumors

Depression is a common complication/co-morbidity in patients with brain tumors. Better understanding of the relationships between brain tumors and depression should lead to improvement in patient care. This paper reviews these relationships in order to direct further study to improve patient care, and hopefully, outcome. Both anatomic and physiological perturbations in the brain are likely involved in the associations between depression and brain tumors. Tumor treatments are also associated with depression. Depression has a significant negative impact on outcome in brain tumor patients. The role of treatment of depression in brain tumor patients has been scantly studied. Further investigation directed to these areas of knowledge deficit should benefit depressed patients with brain tumors.

Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid.

One of the endogenous transformation products of tetrahydrocannabinol (THC) is THC-11-oic acid, and ajulemic acid (AJA; dimethylheptyl-THC-11-oic acid) is a side-chain synthetic analog of THC-11-oic acid. In preclinical studies, AJA has been found to be a potent anti-inflammatory agent without psychoactive properties. Based on recent reports suggesting antitumor effects of cannabinoids (CBs), we assessed the potential of AJA as an antitumor agent. AJA proved to be approximately one-half as potent as THC in inhibiting tumor growth in vitro against a variety of neoplastic cell lines. However, its in vitro effects lasted longer. The antitumor effect was stereospecific, suggesting receptor mediation. Unlike THC, however, whose effect was blocked by both CB(1) and CB(2) receptor antagonists, the effect of AJA was inhibited by only the CB(2) antagonist. Additionally, incubation of C6 glioma cells with AJA resulted in the formation of lipid droplets, the number of which increased over time; this effect was noted to a much greater extent after AJA than after THC and was not seen in WI-38 cells, a human normal fibroblast cell line. Analysis of incorporation of radiolabeled fatty acids revealed a marked accumulation of triglycerides in AJA-treated cells at concentrations that produced tumor growth inhibition. Finally, AJA, administered p.o. to nude mice at a dosage several orders of magnitude below that which produces toxicity, inhibited the growth of subcutaneously implanted U87 human glioma cells modestly but significantly. We conclude that AJA acts to produce significant antitumor activity and effects its actions primarily via CB(2) receptors. Its very favorable toxicity profile, including lack of psychoactivity, makes it suitable for chronic usage. Further studies are warranted to determine its optimal role as an antitumor agent.

Stem Cells as Vectors to Deliver HSV/tk Gene Therapy for Malignant Gliomas

The prognosis of patients diagnosed with malignant gliomas including glioblastoma multiforme (GBM) is poor and there is an urgent need to develop and translate novel therapies into the clinic. Neural stem cells display remarkable tropism toward GBMs and thus may provide a platform to deliver oncolytic agents to improve survival. First we provide a brief review of clinical trials that have used intra-tumoral herpes simplex virus thymidine kinase (HSV/tk) gene therapy to treat brain tumors. Then, we review recent evidence that neural stem cells can be used to deliver HSV/tk to GBMs in animal models. While previous clinical trials used viruses or non-migratory vector-producing cells to deliver HSV/tk, the latter approaches were not effective in humans, primarily because of satellite tumor cells that escaped surgical resection and survived due to low efficiency delivery of HSV/tk. To enhance delivery of HSV/tk to kill gliomas cells, recent animal studies have focused on the ability of neural stem cells, transduced with HSV/tk, to migrate efficiently and selectively to regions occupied by GBM cells. This approach holds the promise of targeting GBM cells that have infiltrated the brain well beyond the original site of the tumor epicenter.

Doublecortin is preferentially expressed in invasive human brain tumors

Doublecortin (DCX) is required for neuroblastic migration during the development of the cerebral cortex. DCX is a microtubule-associated protein that plays a role in cellular motility. These facts led us to hypothesize that DCX is increased in invasive brain tumors. DCX expression was assessed in 69 paraffin-embedded brain tumors of neuroepithelial origin. In addition, mouse brain sections of the subventricular zone and dentate gyrus were used as positive controls for immunostaining, and specificity of antibody staining was demonstrated by peptide neutralization. DCX was highly expressed in both high-grade invasive tumors (glioblastoma, n=11; anaplastic astrocytoma/oligoastrocytoma, n=7; and medulloblastoma/PNET, n=6) and low-grade invasive tumors (oligodendroglioma, n=3; and astrocytoma/oligoastrocytoma, n=5). However, DCX was less intensely expressed in the circumscribed group of tumors (pilocytic astrocytoma, n=6; ependymoma/subependymoma, n=7; dysembryoplastic neuroepithelial tumor, n=4; ganglioglioma, n=2; meningioma, n=9; and schwannoma, n=9). By the Cochran-Mantel-Haenszel statistical test, the circumscribed group was significantly different from both the high-grade invasive group (P<0.0001) and the low-grade invasive group (P<0.0001). We conclude that DCX is preferentially expressed in invasive brain tumors. In addition, DCX immunostaining was stronger at the margin of the tumor than at the center. For a subset of these tumors, we also detected DCX mRNA and protein by Northern and Western blotting. DCX mRNA and protein was detected in glioma cell lines by Northern blotting, immunofluorescence microscopy and Western blotting. Collectively, the immunohistochemistry, Western blots and Northern blots conclusively demonstrate expression of DCX by human brain tumors.

Safety and efficacy of early thromboembolism chemoprophylaxis after intracranial hemorrhage from traumatic brain injury

OBJECT Patients with traumatic brain injury (TBI) are at risk for development of thromboembolic disease. The use of chemoprophylaxis in this patient group has not fully been characterized. The authors hypothesize that early chemoprophylaxis in patients with TBI is safe and efficacious. METHODS In May 2009, a protocol was instituted for patients with TBI where chemoprophylaxis for thromboembolic disease (either 30 mg of Lovenox twice daily or 5000 U of heparin 3 times a day) was initiated 24 hours after an intracranial hemorrhage (ICH) was demonstrated as stable on head CT image. Two cohorts were evaluated: Cohort A included patients from May 2008 through April 2009 who had no routine administration of chemoprophylaxis, and Cohort B included patients from May 2009 through May 2010 after the protocol was instituted. The groups were compared, with the major outcomes being deep venous thrombosis (DVT), pulmonary embolism, and increase in size of ICH. RESULTS Of the 312 patients with TBI who were seen during the study course, 236 patients met criteria for inclusion in the study: 107 patients in Cohort A and 129 patients in Cohort B. The DVT rate was 6 occurrences (5.61%) in Cohort A and 0 occurrences (0%) in Cohort B, which was a statistically significant difference (p = 0.0080). Pulmonary embolism was found in 4 patients (3.74%) in Cohort A and 1 patient (0.78%) in Cohort B, a difference that did not reach statistical significance (p = 0.18). Three instances (2.8%) in Cohort A and 1 instance (0.7%) in Cohort B of increased ICH occurred after starting anticoagulation for chemoprophylaxis; this was not statistically different (p = 0.33). CONCLUSIONS Use of chemoprophylaxis in TBI 24 hours after stable head CT is safe and decreases the rate of DVT formation.

Isolation and characterization of a population of stem-like progenitor cells from an atypical meningioma

The majority of meningiomas are benign tumors associated with favorable outcomes; however, the less common aggressive variants with unfavorable outcomes often recur and may be due to subpopulations of less-differentiated cells residing within the tumor. These subpopulations of tumor cells have tumor-initiating properties and may be isolated from heterogeneous tumors when sorted or cultured in defined medium. We report the isolation and characterization of a population of tumor-initiating cells derived from an atypical meningioma. We identify a tumor-initiating population from an atypical meningioma, termed meningioma-initiating cells (MICs). These MICs self-renew, differentiate, and can recapitulate the histological characteristics of the parental tumor when transplanted at 1000 cells into the flank regions of athymic nude mice. Immunohistochemistry reveals stem-like protein expression patterns similar to neural stem and progenitor cells (NSPCs) while genomic profiling verified the isolation of cancer cells (with defined meningioma chromosomal aberrations) from the bulk tumor. Microarray and pathway analysis identifies biochemical processes and gene networks related to aberrant cell cycle progression, particularly the loss of heterozygosity of tumor suppressor genes CDKN2A (p16(INK4A)), p14(ARF), and CDKN2B (p15(INK4B)). Flow cytometric analysis revealed the expression of CD44 and activated leukocyte adhesion molecule (ALCAM/CD166); these may prove to be markers able to identify this cell type. The isolation and identification of a tumor-initiating cell population capable of forming meningiomas demonstrates a useful model for understanding meningioma development. This meningioma model may be used to study the cell hierarchy of meningioma tumorogenesis and provide increased understanding of malignant progression.