Survival outcomes in elderly patients with glioblastoma.

AIMS: Many elderly glioblastoma patients are excluded from randomised trials due to age, comorbidity or poor functional status. The purpose of this study was to describe the survival outcomes in all elderly patients with glioblastoma managed at a tertiary cancer centre. MATERIALS AND METHODS: A retrospective chart review identified 235 elderly patients (age 65 years or over) with a histological diagnosis of glioblastoma between 1 December 2006 and 31 December 2013. The primary outcome of this study was overall survival by treatment type. Univariate and multivariate Cox proportional hazard models were used to explore significant prognostic variables associated with overall survival. RESULTS: The median survival for all patients was 6.5 months (95% confidence interval 5.3-7.7), with 1 year overall survival of 23.7% (95% confidence interval 18.8-30.0). The median survival for patients treated with radiation and chemotherapy was 11.1 months (95% confidence interval 8.1-13.7). Patients treated with radiation alone had a median survival of 6.8 months (95% confidence interval 5.6-7.9). For patients managed with comfort measures only, the median survival was 1.9 months (95% confidence interval 1.6-2.6). Univariate analysis revealed age, performance status, surgery type (biopsy, subtotal resection, gross total resection) and type of treatment received (comfort measures only, radiotherapy alone, radiotherapy and chemotherapy) to be statistically associated with overall survival. In the multivariate analysis, only two predictive factors (treatment received and surgery type) were significant. CONCLUSIONS: Elderly patients with glioblastoma selected for treatment (surgery followed by radiation alone or radiation and chemotherapy) survive longer than patients managed with comfort measures. Prospective randomised trials will help guide management for patients eligible for therapy. Elderly patients with glioblastoma who are deemed not eligible for active therapy have very short survival.

Factors influencing overall survival specific to adult low-grade astrocytoma: a population-based study.

AIMS: We report a population-based overall survival and prognostic factor analysis specific to adult patients diagnosed with low-grade astrocytoma (LGA). MATERIALS AND METHODS: All histologically confirmed cases of LGA diagnosed between 1992 and 1996 in the province of Ontario, Canada, were identified from the Ontario Cancer Registry and reviewed. RESULTS: In total, 182 patients were identified; the mean age was 50 years and the mean survival time was 4.1 years (standard deviation = 5.1 years). Fifty-four per cent of patients had a surgical excision and 46% were biopsied alone. Both univariate and multivariate analyses showed that patients aged <30 years were significantly more likely to undergo an excision as compared with a biopsy alone (odds ratio = 4.26, 95% confidence interval 1.54-11.77). For the entire cohort, we observed a significant relationship between decreasing survival as a function of increasing age at diagnosis. In the biopsy sub-group, relative to patient's age <30 years, the hazard of dying increased significantly according to age when stratified by decade. However, in those patients having had a primary surgical excision, the hazard of dying relative to patient's age <30 years was similar for those aged 30-49 years and then significantly greater as patient age surpassed 50 years. CONCLUSIONS: Age is a significant prognostic factor for LGA. Our analysis suggests that in those patients amenable to a primary tumour excision, a survival benefit may be confined to those under age 50 years.

Inducible expression of p57KIP2 inhibits glioma cell motility and invasion.

To examine the role of p57KIP2 in human malignant glioma cells, we studied its expression in a panel of human malignant glioma specimens by western blot and immunohistochemical analysis. To determine the effects of p57KIP2 expression on the phenotype of glioma cells, we analyzed two inducible stably transfected p57KIP2 expressing glioma cell lines. Expression of p57KIP2 was induced in U373 and U87 malignant glioma cells with doxycycline using the tetracycline repressor system. A phagokinetic track assay on gold particles was used to investigate differences in cell migration between p57KIP2 expressing and non-expressing control cells. The effects of the extracellular matrix (ECM) on U373 motility was determined in p57+ and p57-cells on surfaces coated with 5 microg/cm2 of fibronectin, laminin, type I and type IV collagens. The invasion of p57+ and p57- glioma cells across BD Biocoat Matrigel invasion chambers was then determined. p57KIP2 was weakly expressed in 4/6 glioblastoma (GBM) specimens by western blot. By immunohistochemistry, p57KIP2 immunoreactivity was positive in 8/40 GBMs, and was primarily nuclear in location. The motility of U373 glioma cells was significantly reduced after p57KIP2 induction. The presence of ECM proteins did not further alter the motility of p57+ and p57- glioma cells. The results of the invasion chamber assay showed that p57+ cells exhibited a 35% reduction in their invasive capacity as compared to p57- cells. These data suggest that p57KIP2 is expressed in at least some malignant gliomas. Inducible expression of 57KIP2 in cell lines deficient in this cyclin-dependent kinase inhibitor reduces their otility and invasiveness.

Advances in the treatment of pediatric brain tumors.

Brain tumors are a heterogeneous group of neoplasms with different origins, pathobiologies, treatments and prognoses. The collective contributions from the fields of neuro-oncology, neurosurgery, radiation oncology, neurology, neuropathology, neuroradiology and molecular biology have all led to significant advances in the treatment of certain brain tumors. Ideas from these fields, under the cooperative umbrella of clinical cancer trial consortia, have been tested in large-scale studies. As a result, patient survivals have increased markedly for these tumor types. Unfortunately, there are certain brain tumors in childhood, such as the diffuse intrinsic pontine glioma and atypical teratoid rhabdoid tumor, for which survival advantages have not been found. This review will discuss the current and possible future therapies of the most common pediatric brain tumors and highlight some of the novel imaging modalities that are used pre- and intraoperatively.

Tolterodine is equally effective in patients with mixed incontinence and those with urge incontinence alone.

OBJECTIVE: To examine the efficacy of tolterodine, an antimuscarinic agent with a bladder-selective profile, in patients with mixed incontinence (MI, stress and urge) compared with patients with urge incontinence (UI) alone. PATIENTS AND METHODS: The study included 239 patients with MI (urge predominating) and 755 with urge incontinence alone from a single-blind, multicentre trial of 1380 patients (80% female) with an overactive bladder. Those completing the trial were analysed 'per-protocol'. After a 7-day washout and a 3-day run-in to collect baseline information, patients were treated with tolterodine twice daily for 16 weeks. The two groups were compared for incontinence episodes/24 h, voiding frequency, nocturia episodes and pad usage after 16 weeks of treatment. RESULTS: After 16 weeks the median changes from baseline for all voiding variables were statistically significant for the MI and the UI groups (P < 0.001), with no apparent significant between-group differences. The median percentage reduction in incontinence episodes from baseline was 67% for the MI and 75% for the UI groups (P = 0.39). 'Dry' rates for the MI and UI groups at the end of the study were 39% (66/171) and 44% (243/552), respectively, whilst 24% of patients in each group (MI 40/170; UI 130/551) achieved a voiding pattern of < 8 voids/24 h. 'Cure' rates for nocturia and the reduction in the number of patients not using pads used were also similar between the groups. CONCLUSION: Tolterodine is as effective in reducing leakage and other symptoms of an overactive bladder in patients with MI as it is in patients with UI alone.

Long-term assessment of the incontinence ring pessary for the treatment of stress incontinence.

A prospective cohort of 38 women who presented with predominantly stress incontinence symptoms were fitted with an incontinence ring pessary. They had documented stress incontinence on multichannel urodynamic testing. Nine women (24%) were not leaking by subjective measures. Six women (16%) continued using the pessary. This group of women had no statistically identifiable parameters that distinguished them from women who had not wanted to continue using the pessary. There was a trend showing that successfully fitted women were younger (41 vs 52 years old), had less pelvic surgery and leaked less on semiquantitative pad testing (10.7 g vs 19.2 g). In women who chose to continue using the pessary there was a trend showing a decrease in the semiquantitative pad score (1.2 g from 10.7 g) and 7-day voiding diary (1.5 episodes from 4.1). In conclusion, the incontinence pessary was successful in a small proportion of women with stress incontinence.

Medulloblastoma in a child with Rubenstein-Taybi Syndrome: case report and review of the literature.

Although medulloblastoma is usually sporadic, there are a number of uncommon predisposing germline mutation syndromes, including: Gorlin's Syndrome, Turcot's Syndrome and Li-Fraumeni Syndrome. Patients with Rubenstein-Taybi Syndrome secondary to mutation/deletion of the CBP gene on chromosome 16 are predisposed to a variety of developmental anomalies as well as cancer. We report a child with Rubenstein-Taybi syndrome who developed a cerebellar medulloblastoma and review the literature on Rubenstein-Taybi Syndrome and pediatric medulloblastoma. As the product of the CBP gene functions in a variety of signaling pathways, we discuss the molecular implications of findings a medulloblastoma in a child with Rubenstein-Taybi Syndrome.

Hyaluronate receptors mediating glioma cell migration and proliferation.

The extracellular matrix (ECM) of the central nervous system (CNS) is enriched in hyaluronate (HA). Ubiquitous receptors for HA are CD44 and the Receptor for HA-Mediated Motility known as RHAMM. In the present study, we have investigated the potential role of CD44 and RHAMM in the migration and proliferation of human astrocytoma cells. HA-receptor expression in brain tumor cell lines and surgical specimens was determined by immunocytochemistry and western blot analyses. The ability of RHAMM to bind ligand was determined through cetylpyridinium chloride (CPC) precipitations of brain tumor lysates in HA-binding assays. The effects of HA, CD44 blocking antibodies, and RHAMM soluble peptide on astrocytoma cell growth and migration was determined using MTT and migration assays. Our results show that the expression of the HA-receptors, CD44, and RHAMM, is virtually ubiquitous amongst glioma cell lines, and glioma tumor specimens. There was a gradient of expression amongst gliomas with high grade gliomas expressing more RHAMM and CD44 than did lower grade lesions or did normal human astrocytes or non-neoplastic specimens of human brain. Specific RHAMM variants of 85- and 58-kDa size were shown to bind avidly to HA following CPC precipitations. RHAMM soluble peptide inhibited glioma cell line proliferation in a dose-dependent fashion. Finally, while anti-CD44 antibodies did not inhibit the migration of human glioma cells, soluble peptides directed at the HA-binding domain of RHAMM inhibited glioma migration both on and off an HA-based ECM. These data support the notion that HA-receptors contribute to brain tumor adhesion, proliferation, and migration, biological features which must be better understood before more effective treatment strategies for these tumors can be found.

Cip/Kip cell-cycle inhibitors: a neuro-oncological perspective.

The cell cycle is a precisely controlled cellular program that ensures normal cellular proliferation and development. The cyclin-dependant kinases (CDK) are molecules central to the continued progression through the cell-cycle checkpoints and as such are regulated by various mechanisms including cyclin levels, phosphorylation/dephosphorylation and cyclin-dependant kinase inhibitors (CKI). The CKIs are grouped into two families based on their structure and function, four lnk4 CKIs and three Cip/Kip CKIs. Abnormalities in these proteins can give rise to developmental defects and cancer. In this review, we will discuss the biochemistry and cell biology of the each of the Cip/Kip CKIs, their role in development as evidenced by targeted mutations in mice, and their role as possible tumor suppressor genes.

Molecular genetics of pineal region neoplasms.

A large variety of mass lesions have been reported in the region of the pineal gland. Pineal parenchymal tumors and germ cell tumors (GCTs) are especially characteristic of this region. Despite their rarity, a number of excellent studies on the cytogenetics and molecular genetics of pineal parenchymal tumors and pineal region GCTs have been published. These studies draw attention to a number of distinct genomic regions recurrently involved in the various subtypes of malignancies of the pineal gland. Outcomes for tumors in this location vary widely between patients and among differing histologies. Development of novel therapies for patients with poor prognoses will depend on the acquisition of a more detailed understanding of the molecular basis associated with the etiopathogenesis of these neoplasms. We review the literature on cytogenetics, familial syndromes, animal models and molecular genetics of pineal region neoplasms.

Molecular insight into medulloblastoma and central nervous system primitive neuroectodermal tumor biology from hereditary syndromes: a review.

Through the study of uncommon familial syndromes, physicians and scientists have been able to illuminate the underlying mechanisms of some of the more common sporadic diseases; this is illustrated best by studies of familial retinoblastoma. A number of rare familial syndromes have been described in which affected individuals are at increased risk of developing medulloblastoma and/or supratentorial primitive neuroectodermal tumors. The descriptions of many of these syndromes are based on patients observed by clinicians in their clinical practice. Determination of the underlying genetic defects in these patients with uncommon syndromes has led to identification of a number of genes subsequently found to be mutated in sporadic medulloblastomas (tumor suppressor genes). Associated genes in the same signaling pathways have also been found to be abnormal in sporadic medulloblastoma. Identification of patients with these rare syndromes is important, as they are often at increased risk for additional neoplasms, as are family members and future children. We review the published literature describing hereditary syndromes that have been associated with an increased incidence of medulloblastoma and/or central nervous system primitive neuroectodermal tumor. Review of the underlying molecular abnormalities in comparison to changes found in sporadic neoplasms suggests pathways important for tumorigenesis.

Molecular biology and neurosurgery in the third millennium.

The application of techniques in molecular biology to human neurosurgical conditions has led to an increased understanding of disease processes that affect the brain and to novel forms of therapy that favorably modify the natural history of many of these conditions. Molecular strategies are currently being either used or sought for brain tumors, stroke, neurodegenerative diseases, vascular malformations, spinal degenerative diseases, and congenital malformations of the central nervous system. Considering that the structure of deoxyribonucleic acid was ascertained by Watson and Crick as recently as 1953, the progress that has been made to implement molecular medicine in clinical practice has been meteoric. More than 2000 patients have been treated in approved gene therapy trials throughout the world. Many of these patients have been treated for neurological diseases for which conventional medical therapies have been of limited utility. As part of this continuing series on advances in neurosurgery in the third millennium, we first reflect on the history of the nascent field of molecular biology. We then describe the powerful techniques that have evolved from knowledge in this field and have been used in many publications in Neurosurgery, particularly within the past decade. These methods include commonly used techniques such as advanced cytogenetics, differential display, microarray technology, molecular cell imaging, yeast two-hybrid assays, gene therapy, and stem cell utilization. We conclude with a description of the rapidly growing field of bioinformatics. Because the Human Genome Project will be completed within 5 years, providing a virtual blueprint of the human race, the next frontier (and perhaps our greatest challenge) will involve the development of the field of "proteomics," in which protein structure and function are determined from the deoxyribonucleic acid blueprint. It is our conviction that neurosurgeons will continue to be at the forefront of the treatment of patients with neurological diseases using molecular strategies, by performing essential research leading to increased understanding of diseases, by conducting carefully controlled studies to test the effects of treatments on disease processes, and by directly administering (by neurosurgical, endovascular, endoscopic, or stereotactic means) the treatments to patients.

Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene.

We have identified a family afflicted over multiple generations with posterior fossa tumors of infancy, including central nervous system (CNS) malignant rhabdoid tumor (a subset of primitive neuroectodermal tumors, or PNET) and choroid plexus carcinoma. Various hereditary tumor syndromes, including Li-Fraumeni syndrome, Gorlin syndrome, and Turcot syndrome, have been linked to increased risk of developing CNS PNETs and choroid plexus tumors. Malignant rhabdoid tumors of the CNS and kidney show loss of heterozygosity at chromosome 22q11. The hSNF5 gene on chromosome 22q11 has recently been identified as a candidate tumor-suppressor gene in sporadic CNS and renal malignant rhabdoid tumors. We describe a family in which both affected and some unaffected family members were found to have a germline splice-site mutation of the hSNF5 gene, leading to exclusion of exon 7 from the mature cDNA and a subsequent frameshift. Tumor tissue shows loss of the wild-type hSNF5 allele, in keeping with a tumor-suppressor gene. These findings suggest that germline mutations in hSNF5 are associated with a novel autosomal dominant syndrome with incomplete penetrance that predisposes to malignant posterior fossa brain tumors in infancy.

Perspectives in pediatric neurosurgery.

The new millennium beckons for novel advances in the diagnosis and treatment of pediatric neurosurgical conditions. Almost every aspect of pediatric neurosurgery has changed over the last decade. Undoubtedly with the application of knowledge in molecular biology to human disease many aspects of neurosurgery, especially neuro-oncology and the field of neuro-developmental anomalies, will change appreciably over the next decade. Overall, the trend in surgery in general and neurosurgery in particular is toward less invasive procedures and possibly non-surgical interventions. This review will briefly cover many of the important areas of pediatric neurosurgery. We will describe the state-of-the-art of our subspecialty and discuss possible future directions.

June 1999--22 year old female with intraventricular mass.

A 22 year old female presented with a single seizure. CT scan and craniotomy demonstrated an intraventricular papillary tumor with histologic and immunohistochemical features indicative of a choroid plexus carcinoma. Even though the occurrence of this neoplasm is exceptional beyond childhood, pathologists should considered a malignant choroid plexus tumor when postulating the differential diagnosis of intraventricular papillary neoplasms in adults.

GABA concentrations in the striatum following repetitive cerebral ischemia.

GABAergic neurons in the striatum are very sensitive to the effects of ischemia. The progressive decline in striatal GABA following transient forebrain ischemia in gerbils may be secondary to either a decreased production or an increase in reuptake mechanisms or both. The current experiment was designed to evaluate release of GABA by stimulation with K+ or inhibition of its uptake with nipecotic acid or their combination (K+ nipecotic) after repetitive forebrain ischemia in gerbils by in-vivo microdialysis on Days 1, 3, 5, and 14 following the insult. Infusion of nipecotic acid or potassium chloride, resulted in a significant increase in extracellular GABA. This response was significantly decreased in the post-ischemic animals. The synergistic effect of increased GABA concentrations by the infusion of nipecotic acid + potassium chloride seem in the controls was not evident in the post-ischemic animals. In conclusion, though there is a reduction in the extracellular GABA concentrations in the first week following an ischemic insult, restorative mechanisms are operative in the second week as seen by the increasing GABA concentrations.

Progressive decrease in extracellular GABA concentrations in the post-ischemic period in the striatum: a microdialysis study.

Repetitive cerebral ischemia in gerbils produces delayed neuronal damage in the substantia nigra reticulata (SNr). This damage begins 4 to 5 days after the insult and is severe by day 7. The damage can be attenuated by GABA agonists. There is a prominent GABAergic striatal pathway to the SNr. Damage to this pathway leads to progressive loss of SNr neurons. This loss can be prevented by GABA agonists. We postulate that, ischemia-induced lack of GABAergic inhibitory input from the striatum to the SNr, may be responsible for this delayed neuronal damage. In the present experiment, we have measured striatal extracellular GABA concentrations with or without nipecotic acid, a GABA-reuptake inhibitor, in gerbils exposed to repetitive ischemia. GABA levels were measured on days 1, 3, 5, and 7 after the ischemic insult. Five control animals and a similar number of ischemic animals were monitored on each day. Extracellular fluid was collected using in vivo microdialysis and GABA levels were measured by electrochemical detection with HPLC. The extracellular striatal GABA levels were very low in the initial three specimens collected, both in the control and in the ischemic animals. However, addition of nipecotic acid resulted in an immediate increase of GABA in measurable range. In comparison to the controls, the increase in GABA on day 1 and 3 were significantly higher in animals with repetitive ischemia (two-way ANOVA with repeated measures). Subsequent measurements showed a gradual decrease in GABA levels when compared to controls. The increase in GABA with nipecotic acid was significantly lower on day 7 after the ischemic insults when compared to the controls. The increased GABA responsiveness immediately after the ischemic insults may reflect a protective effect against excitotoxicity. The subsequent decline in GABA levels after the insult may be secondary to progressive loss of striatal GABAergic neurons. This may contribute to the production of delayed neural damage in the SNr by a decrease in the inhibitory striatal input.

Characterization of the latency-related transcriptionally active region of the bovine herpesvirus 1 genome.

Approximate 5' and 3' ends of the bovine herpesvirus 1 (BHV-1) latency-related RNA (LR RNA) were mapped in rabbit trigeminal ganglia (TG) by in situ hybridization. The data provide a size estimate of 0.77 to 1.16 kb for the LR RNA. An LR RNA mapping to a similar location was also detected in TG of cattle latently infected with BHV-1. The BHV-1 LR region is transcriptionally active in bovine cell cultures lytically infected with BHV-1. A 1.15-kb transcript, present at early and late times postinfection, of the same sense and approximate size that seen in latently infected TG overlaps a 2.9-kb immediate-early and a 2.6-kb early and late transcription unit present on the complementary strand. Sequence analysis of the LR RNA sense strand indicates the presence of a potential polymerase II promoter in close proximity to the 5' terminus of the LR RNA and two open reading frames within its map positions. The complementary strand contains the 3' portion of a large open reading frame that almost completely overlaps the map position of the LR RNA present on the opposite strand.