Long-Term Survival after Primary Ewing's Sarcoma of the Skull with Intracranial Extension.

BACKGROUND AND OBJECTIVE: Primary Ewing's sarcoma of the skull is a very rare malignant neoplasm, predominantly occurring in children and adolescents. We describe here the clinical, neuroradiologic, and histopathologic features of a patient with primary Ewing's sarcoma of the skull and discuss the standards of therapy for this type of tumor. CLINICAL PRESENTATION: This 18-year-old male patient presented with a primary Ewing's sarcoma of the skull, involving the dura of the frontal and parietal lobes of the left cerebral hemisphere. He was treated with gross total surgical excision of tumor, skull reconstruction, chemotherapy, and irradiation. Twelve years after the surgery, the patient has no evidence of local recurrence or distant metastases. Radical surgical excision of the primary tumor with safety margins is thought to play a role in the favorable clinical course. CONCLUSION: The presented case is the longest surviving patient after treatment of primary Ewing's sarcoma of the skull bone. This rare type of tumor may allow better survival rates under adequate management than sarcoma elsewhere in the body.

A Novel Endoscopic Technique for Biopsy and Tissue Diagnosis for a Paraspinal Thoracic Tumor in a Pediatric Patient: A Case Report.

BACKGROUND: Conventional approaches to the thoracic spine can require extensive tissue dissection, bony disruption, and instability that may warrant the need for instrumentation and fusion. Furthermore, anterior approaches may require the involvement of various surgeons from multiple disciplines to ensure a successful operation and mitigate complications. Currently, available minimally invasive approaches still require bony removal and usually rely heavily on computed tomography (CT)-guided imaging without direct gross visualization. Endoscopic spinal procedures have provided an ultra-minimally invasive alternative to access many areas in and around the spinal column. METHODS: We present a 12-year-old boy with a right-sided 2.0 × 3.2-cm paravertebral lesion at the level of T5. The patient successfully underwent an endoscopic approach to the lesion with minimal tissue and bony disruption for tissue diagnosis and tumor resection. RESULTS: At initial and 6-month follow-up, the patient remained asymptomatic and without issues. CONCLUSIONS: We demonstrate here the feasibility and suggest the safety of a posterior ultra-minimally invasive endoscopic spinal approach to obtain a tissue biopsy of an incidentally found ventrolateral paraspinal tumor in the thoracic region in a pediatric patient. This minimal approach can prove to achieve similar results as other approaches that may otherwise necessitate more extensive or transthoracic procedures.

Triangular titanium implants for sacroiliac joint fusion.

BACKGROUND: Sacroiliac joint (SIJ) dysfunction is an underdiagnosed condition. Several published cohorts have reported favorable midterm outcomes after SIJ fusion using titanium implants placed across the SIJ. Herein, we report 12-month follow-up from SIJ fusion in a standard clinic setting. METHODS: A carefully selected group of 160 consecutive patients with painful SIJ dysfunction were diagnosed at a single center and underwent unilateral or staged bilateral SIJ fusion using triangular titanium implants. Patients were routinely seen in clinic for follow-up every 3 months where they completed visual analog scale (0-10 range) pain ratings and Oswestry Disability Index (ODI). Follow-up CT scan was performed at 1 year. RESULTS: Mean patient age was 58 years, and 68% were women. 30% underwent staged bilateral SIJ fusion. By month 12, SIJ pain decreased from 8.0 to 2.5 (p < 0.0001) and disability (ODI) decreased from 45.3 to 16.4 (p < 0.0001). The proportion with clinically significant improvements in SIJ pain and ODI was high (> 95%). Perioperative adverse events were mild and decreased with increasing surgical experience with the procedure. Subgroup analysis showed slightly smaller improvements in those undergoing bilateral surgery and those with a spinal cord stimulator in place. CT scan at 1 year showed reabsorption along one or more implants in 16% of cases, but there were no breakages or implant removals. CONCLUSIONS: In standard clinical practice, SIJ fusion with triangular titanium implants produces significant improvement in pain and disability related to SIJ dysfunction. These slides can be retrieved under Electronic Supplementary Material.

Increased expression of ABCB6 enhances protoporphyrin IX accumulation and photodynamic effect in human glioma.

BACKGROUND: Glioma recurrence usually occurs close to the tumor resection margins as a result of residual infiltrating glioma cells. 5-aminolevulinic acid (ALA) fluorescence-guided resection of gliomas has been demonstrated to enhance discrimination of tumor tissue and to improve survival. ALA-based photodynamic therapy is an effective albeit still experimental adjuvant treatment option for gliomas. However, insufficient protoporphyrin IX (PpIX) accumulation may limit the benefits of fluorescence-guided resection and photodynamic therapy. METHODS: We investigated the expression of the ATP-binding cassette transporter ABCB6, which regulates porphyrin synthesis, in surgical specimens from human gliomas and manipulated ABCB6 in human glioma cell lines. RESULTS: Our findings demonstrated that expression levels of ABCB6 were greatly elevated in human gliomas compared with normal brain tissues and correlated with World Health Organization histologic grade. A previously undescribed finding was that ABCB6 mRNA expression in solidly fluorescing tumor tissues was higher than that in vaguely fluorescing tumors, suggesting that ABCB6 may be at least in part responsible for PpIX accumulation in glioma cells. Accordingly, ABCB6 overexpression in glioma cell lines caused a marked increase in intracellular levels of PpIX, and was more sensitive to ALA-induced photodynamic therapy-events that could be prevented by silencing ABCB6 via siRNA treatment. CONCLUSIONS: Our findings indicate a crucial role of ABCB6 in ALA metabolism and accumulation of PpIX in glioma. ABCB6 overexpression is a potential approach to enhance accumulation of PpIX for optimizing the subjective discrimination of vague fluorescence and improving the efficacy of ALA-based photodynamic therapy.

Stathmin expression in glioma-derived microvascular endothelial cells: a novel therapeutic target.

The purpose of this study was to investigate stathmin expression and its mechanisms of action in GDMEC. Microvascular endothelial cells were isolated from human gliomas (n=68) and normal brain specimans (n=20), and purified by magnetic beads coated with anti-CD105 antibody. The expression of stathmin mRNA and protein were detected by RT-PCR and western blotting, respectively. Stathmin expression was silenced by application of specific siRNA in high grade GDMEC. The proliferation, apoptosis and invasion behavior of GDMEC were investigated. The stathmin positive rate of endothelial cells in normal brain, grade I-II glioma and grade III-IV glioma was 20, 66 and 95.5%, respectively (P<0.05). When cells were treated with siRNA to silence stathmin, cell viability was reduced, the apoptosis rate increased and the migration of vascular endothelial cells was suppressed significantly (P<0.05). Down-regulation of stathmin suppressed neoangiogenesis of glioma and provides a potential target for glioma treatment.

Targeted biological therapies for pain.

INTRODUCTION: Chronic pain is often resistant to currently used drugs. The effect of these is frequently self-limiting, with increasing level of side effects caused by increased doses. Biological pain therapies provide a means to target molecules to specific types of neural cells in spatially limited areas. Targeted biological therapies utilize agents acting at specific sites, or virus or cell vectors allowing expression and secretion of transgenic substances in small anatomical compartments. Biological approaches to treatment of chronic pain may be able to provide greater analgesic efficacy, avoiding many of the limitations associated with current analgesics. AREAS COVERED: The most important targets and tools for biological therapy of pain. Basic approaches, preclinical trials and the clinical studies successfully completed. The rationale and tools for biological therapies. EXPERT OPINION: Biological therapy of pain holds great promise and is rapidly developing. Despite the significant numbers of preclinical studies in the last two decades only a single biological agent, the cone snail toxin ziconotide, has been advanced through all stages and licensed for clinical use. Biological therapy of pain is thus here to stay, but will need more substantial proof of efficacy and safety before being widely accepted and routinely used.

MiR-106a inhibits glioma cell growth by targeting E2F1 independent of p53 status.

MicroRNAs are single-stranded small non-coding RNA molecules which regulate mammalian cell growth, differentiation, and apoptosis by altering the expression of other genes and play a role in tumor genesis and progression. MiR-106a is upregulated in several types of malignancies and provides a pro-tumorigenic effect. However, its role in glioma is largely unknown. Our findings demonstrate that the low expression of miR-106a in human glioma specimens is significantly correlated with high levels of E2F1 protein and high-grade glioma. Here, we present the first evidence that miR-106a provides a tumor-suppressive effect via suppressing proliferation of and inducing apoptosis in human glioma cells. We further show that E2F1 is a direct functional target of miR-106a, suggesting that the effect of miR-106a on the glioma suppressive effect may result from inhibition of E2F1 via post-transcriptional regulation. In addition, our results reveal that miR-106a can increase p53 expression via E2F1 inhibition, whereas the effect of miR-106a on the proliferation of glioma cells is independent of p53 status. Further investigations will focus on the therapeutic use of miR-106a-mediated antitumor effects in glioma.

Clinical development of experimental virus-mediated gene therapy for malignant glioma.

Advances in medical and surgical treatments in the last decades have resulted in quantum leaps in the overall survival of patients with many types of malignant disease, while survival of patients with malignant gliomas (WHO histological grades 3 and 4) has been only moderately improved. Maximum surgical resection, external fractionated radiotherapy, and oral chemotherapy during and after irradiation currently represent the pillars of malignant glioma therapy. Novel and experimental modalities aimed at a more selective and more effective treatment are however being increasingly developed and tested in clinical studies. Improved understanding of the fundamental mechanisms of glioma growth, resistance, and recurrence has resulted in the introduction of biologically and molecularly targeted therapies such as virus-mediated gene therapy, often in combination with spatially defined delivery methods specifically designed to be used in the local environment of the brain, such as convection-enhanced delivery. This review summarizes the key findings of the most important phase I and II clinical studies employing gene therapy with naturally occurring or genetically modified non-replicating or conditionally replicating (oncolytic) viruses, such as retrovirus, adenovirus, herpes-simplex-virus, Newcastle disease virus, or reovirus, in patients with primary or recurrent malignant gliomas. In addition, the two phase III gene therapy studies carried out to date in glioma patients and employing retrovirus or adenovirus vectors are presented in detail and critically discussed. Areas of necessary improvements and possible future developments of viruses and delivery methods are outlined.

Clinical development of experimental therapies for malignant glioma.

Advances in medical and surgical treatments in the last two to three decades have resulted in quantum leaps in the overall survival of patients with many types of non-central nervous system (CNS) malignant disease, while survival of patients with malignant gliomas (WHO grades 3 and 4) has only moderately improved. Surgical resection, external fractionated radiotherapy and oral chemotherapy, during and after irradiation, remain the pillars of malignant glioma therapy and have shown significant benefits. However, numerous clinical trials with adjuvant agents, most of them administered systemically and causing serious complications and side effects, have not achieved a noteworthy extension of survival, or only with considerable deterioration in patients' quality of life. Significant attention was focussed in the last decades on the cell biology and molecular genetics of gliomas. Improved understanding of the fundamental features of tumour cells has resulted in the introduction and increasing clinical use of local therapies, which employ spatially defined delivery methods and tumour-selective agents specifically designed to be used in the environment of a glioma-invaded brain. This review summarises the key findings of some of the most recent and important clinical studies of locally administered novel treatments for malignant glioma. Several such therapies have shown considerable anti-tumour activity and a favourable profile of local and systemic side effects. These include biodegradable polymers for interstitial chemotherapy, targeted toxins administered by convection enhanced delivery, and intra- and peritumourally injected genetically modified viruses conferring glioma-selective toxicity. Areas of possible improvement of these therapies and essential future developments are also outlined.

Selective inhibition of PDGFR by imatinib elicits the sustained activation of ERK and downstream receptor signaling in malignant glioma cells.

Clinical studies using the tyrosine kinase inhibitor, imatinib mesylate (Gleevec®), in glioblastoma, have shown no major inhibition of tumor growth or extension of survival for patients, unlike those in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. The molecular mechanisms of action of imatinib in glioblastoma cells are still not well understood. In this study, we investigated the effects of imatinib on the platelet derived growth factor receptor (PDGFR) downstream signaling pathways as well as on other cellular functions in human glioblastoma cells. NIH3T3 fibroblast and K562 CML cells were used for comparison. Western blot analysis demonstrated that imatinib was more effective in inhibiting the activated rather than the quiescent forms of the target proteins. Furthermore, the imatinib treatment induced the sustained activation of extracellular signal-regulated kinase (ERK 1/2) signaling as well as components of other downstream signaling pathways, such as PI3K/Akt, STAT3 and p38MAPK. Prior stimulation of the malignant cells with exogenous PDGF-BB partially abrogated this activation. Further analysis indicated that the activation of ERK induced by the imatinib treatment was related to the S-phase re-entry of the cell cycle in one of the three glioma cells. Imatinib significantly inhibited cell migration but not cell growth. The combination treatment of imatinib with a MEK or PI3K inhibitor resulted in significant growth inhibition but did not inhibit cell migration beyond the inhibition achieved with the imatinib treatment alone. The treatment of glioma cells with small interfering RNA inhibiting PDGFRB, however, evoked enhanced Akt signaling. These results indicate that the imatinib treatment of malignant glioma does not result in significant inhibitory effects and should be used with caution.

Overall survival in patients with malignant glioma may be significantly longer with tumors located in deep grey matter.

BACKGROUND: The aim of this study was to assess the correlation of overall survival with tumor location (lobar vs. deep grey matter) and with other clinical and imaging variables in a cohort of patients with high grade gliomas. METHODS: Adult patients with newly diagnosed supratentorial WHO grade 3 and 4 gliomas were evaluated. Clinical data included demographics, symptoms at presentation, treatment variables, and overall survival. Radiological data included tumor side, site (deep vs. lobar) and size, extent of peritumoral edema, and presence of midline shift. Biostatistics were carried out using log rank tests and univariate and multivariate Cox regression models. RESULTS: A total of 121 patients were investigated, 23 (19.0%) with WHO grade 3 and 98 (81.0%) with WHO grade 4 gliomas. Tumors had lobar location in 96 cases (79.3%) and deep grey matter location in 25 cases (20.7%). Median survival time for all patients was 26 weeks (IQR: 14-53). Patients with deep tumors survived significantly longer than those with lobar gliomas (log rank test, p=0.0083). Extensive brain edema significantly shortened survival (log rank test, p=0.0003). Presence of midline shift (>1 cm) was a statistically significant risk factor for shorter survival (log rank test, p<0.0001). The univariate Cox regression model demonstrated statistical significance for the variables age, side, site and size of tumor, presence of extensive edema, and presence of mass effect (>1 cm). In the multivariate Cox models, tumor grade, site and size showed statistical significance. CONCLUSIONS: This study suggests that patients with deep grey matter gliomas may survive significantly longer after the initial diagnosis than those with tumors in a lobar location. This is a potentially novel finding, which may corroborate the theory of differential invasion of glioma cells in different microenvironments of the brain, but remains to be confirmed in future prospective studies.

Autoantibodies to the inhibitor of apoptosis protein survivin in patients with brain tumors.

Survivin is a member of the inhibitor of apoptosis protein (IAP) family and is frequently expressed in cancers, including meningiomas and gliomas. Survivin may be associated with tumor progression and poor prognosis of patients with brain tumors. Using ELISA and immunoblot analysis we asked whether survivin is capable of eliciting a humoral immune response in patients with meningiomas and gliomas. Survivin-specific antibodies were detected in 5 of 42 (11.9%) patients with meningiomas and 3 of 35 (8.6%) patients with malignant gliomas of the WHO grades 3 and 4, but not in healthy controls. Tumors of patients with detectable anti-survivin antibodies demonstrated survivin expression in at least 20% of the tumor cells as assessed by immunohistochemistry. We conclude that patients with meningiomas and malignant gliomas can mount a high-titer IgG immune response against the 'universal' tumor-associated antigen survivin. Anti-survivin antibodies may represent attractive tools for diagnosis and follow-up of brain tumors.

Receptor tyrosine kinases as therapeutic targets in malignant glioma.

Malignant gliomas have retained their dismal prognosis despite aggressive multimodal conventional therapeutic approaches, illustrating the need for novel therapeutic strategies. Recent advances in the cellular and molecular biology of gliomas have enhanced our understanding of the role of receptor tyrosine kinases (RTK) and RTK-mediated signal transduction pathways in tumor initiation, maintenance, angiogenesis, and vascular proliferation. Special attention has been focused on targets such as epidermal growth factor receptors (EGFR), platelet-derived growth factor receptors (PDGFR), vascular endothelial growth factor receptors (VEGFR), and on pathways such as the Ras/Raf/mitogen-activated protein (MAP)-kinase and phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways. Novel targeted drugs known as small molecule inhibitors have been shown to modify the activity of these receptors and signaling pathways. Thus far, however, small molecule RTK inhibitor development has concentrated on a few RTK only, and drug activity has been comprehensively evaluated only in a limited number of different malignancies. One of the limiting factors for novel drug design and development is the incomplete knowledge of RTK functions in malignant glioma. This review summarizes current basic and clinical knowledge on the role of RTK in malignant glioma and on their importance as targets for new forms of therapy.

Novel therapies for malignant gliomas: a local affair?

Advances in medical and surgical treatments in the last few decades have resulted in quantum leaps in the overall survival of patients with malignant disease outside the central nervous system, whereas survival of patients with malignant gliomas (World Health Organization Grades III and IV) has remained essentially unchanged. Resection and external-beam fractionated radiotherapy remain the pillars of therapy for malignant gliomas and have shown significant beneficial effects on outcome in many clinical studies. On the other hand, numerous human trials with adjuvant agents, most of them administered systemically and causing serious complications and side effects, have not succeeded in achieving a noteworthy additional extension of survival duration, or have done so only with a considerable deterioration in the quality of life of the treated patients. The concept of local invasiveness of gliomas is not new, but only in the last one to two decades has significant attention been focused on the cell biology and molecular genetics of gliomas. Improved understanding of the fundamental features of tumor cells has resulted in the introduction and increasing clinical use of local therapies in which practitioners opt for spatially defined delivery methods and tumor-selective agents specifically designed to be used in the environment of a brain invaded by glioma. In this review, the authors summarize the key findings in some of the most important clinical studies of locally administered treatments for malignant glioma. A few such therapies have emerged in the last decade, and have shown considerable antitumor activity and a favorable profile of local and systemic side effects. These include biodegradable polymers for interstitial chemotherapy, targeted toxins administered by convection-enhanced delivery, and intra- and peritumorally injected genetically modified viruses conferring glioma-selective toxicity. In addition, areas of possible improvement of these therapies and essential further developments are outlined.

Clinical studies with targeted toxins in malignant glioma.

Targeted toxins represent a new class of agents with high specificity for tumor cells. Toxins in current clinical use for the treatment of brain tumors are mostly recombinant polypeptides consisting of a tumor-selective ligand coupled to a peptide toxin of bacterial origin. Targeted toxins are highly potent - one single molecule of toxin is enough to cause cell death. Toxins are able to kill tumor cells independent of any malignancy-associated genetic alterations and/or mutations. The blood-brain barrier has been a major obstacle for using targeted toxins for treatment of malignant glioma. Convection-enhanced delivery (CED), a method for delivery of large molecules to brain tissue via continuous interstitial microinfusion, has permitted direct administration of toxins to brain tumors or to surrounding brain tissue infiltrated by tumor cells. Four targeted toxins advanced to at least phase II clinical trials and are being used for treatment of adult or pediatric patients with recurrent or progressive malignant glioma. These are IL4-P. aeruginosa exotoxin (IL4-PE, NBI-3001), tumor growth factor (TGF)alpha-P. aeruginosa exotoxin (TP-38), IL13-P. aeruginosa exotoxin (IL13-PE38), and transferrin-C. diphtheriae toxin (TransMID(trade mark), Tf-CRM107). All of these toxins have shown an acceptable profile of toxicity and safety in phase I and II clinical studies and have demonstrated some evidence for tumor response. Current phase I and II clinical protocols are exploring several parameters, such as placement of catheters for CED either intratumorally or in the brain tissue surrounding a tumor, surgical resection of tumor before or after toxin infusion, and single vs. repeated infusion. Two large randomized and controlled phase III multicenter studies using IL13-PE38 or TransMID(trade mark) are currently enrolling patients. This review summarizes the study protocols and key findings of all previously completed and currently ongoing clinical studies with targeted toxins for malignant glioma. It offers in addition an outlook into future areas of development of targeted toxins, such as improved delivery modes and non-invasive in vivo imaging of intracerebral and intratumoral distribution of toxin in patients.

Technology evaluation: TransMID, KS Biomedix/Nycomed/Sosei/PharmaEngine.

KS Biomedix (formerly Avicenna Medica; now a subsidiary of the Xenova group) and Nycomed, together with Japanese licensee Sosei and Chinese licensee PharmaEngine, are developing TransMID, a transferrin-mediated diphtheria toxin delivery system for the potential treatment of adult, recurrent, inoperable, high-grade glioma (as TransMID-107R). It is also under investigation for other forms of brain cancer, including early brain cancer (as TransMID-107N), metastatic brain cancer (as TransMID-107M) and pediatric brain cancer (as TransMID-107P). TransMID is currently undergoing phase III clinical trials.

Predisposing conditions and risk factors for development of symptomatic meningioma in adults.

BACKGROUND: Risk factors and predisposing factors for the development of symptomatic meningioma during adult life are not well known. METHODS: Data from 306 consecutive patients with primary meningioma were collected retrospectively in a hypothesis-generating study. Factors studied included localisation of tumours, blood group typing, and risk factors, such as diabetes mellitus, coronary arterial disease, hypertension, rheumatoid arthritis, bronchial asthma, smoking, obesity, and second primary tumour. Case-control analysis of putative risk factors was carried out using a control data set from the German East-West Health Survey (n=7466, age range 25-69 years). Patients and controls were matched for age, gender, geographic area, and time of data collection. RESULTS: Rh(D) positive cases were significantly less frequent in the patient group compared to controls (p=0.01). Pre-existing diabetes was associated with meningioma in middle-aged (40-69 years) patients (odds ratio, OR 13.94-4.30, p=0.001-0.05). In female patients, arterial hypertension was significantly associated with occurrence of meningioma in the age group 60-69 years (OR=2.23, p=0.041). Rheumatoid arthritis had a negative association with meningioma in both males and females in the age groups above 50 years (OR 0.19-0.27, p=0.02-0.034). Bronchial asthma, smoking, and obesity were not significantly associated with meningioma. A second primary tumour was present in 12 cases. The most frequent combination was meningioma and breast cancer (5/12). CONCLUSIONS: This study shows statistically significant association of some co-morbidities with symptomatic meningioma in adults. Areas of interest have been identified where further research would be necessary.

Self-inflicted penetrating head injury in a patient with manic-depressive disorder.

A 32-year-old Caucasian male with a history of repeated self-injury drilled a hole in his skull using a power tool and subsequently introduced intracerebrally a binding wire from a sketch pad. An emergency craniotomy was performed around the site of cranial injury, and the foreign body was carefully extracted. The wire was located partially in the subdural space and partially in the right hemisphere of the brain. The patient made an excellent recovery and was referred to a psychiatrist for further treatment. This is a rare case of unusual and complex repetitive self-destructive behavior without apparent suicidal intent. The pertinent literature is reviewed and the surgical and psychiatric implications of such injuries are discussed.