MicroRNAs and glioblastoma; the stem cell connection.

Recent data draw close parallels between cancer, including glial brain tumors, and the biology of stem and progenitor cells. At the same time, it has become clear that one of the major roles that microRNAs play is in the regulation of stem cell biology, differentiation, and cell 'identity'. For example, microRNAs have been increasingly implicated in the regulation of neural differentiation. Interestingly, initial studies in the incurable brain tumor glioblastoma multiforme strongly suggest that microRNAs involved in neural development play a role in this disease. This encourages the idea that certain miRs allow continued tumor growth through the suppression of differentiation and the maintenance of the stem cell-like properties of tumor cells. These concepts will be explored in this article.

Aggressive papillary glioneuronal tumor: case report and literature review.

Papillary glioneuronal tumors (PGNT) are a rare, recently described form of mixed neoplasm composed of glial and neuronal components. PGNT usually occur in children and young adults, and typically demonstrate low-grade pathology, with a low proliferative index of 1-3%. Here we describe a newly diagnosed case of PGNT with a more aggressive phenotype that required irradiation and chemotherapy. The patient was a 19-year-old female who developed progressive headaches and visual seizures. An MRI revealed a heterogeneously enhancing solid mass in the left temporo-occipital region, with significant surrounding edema and mass effect. The mass was resected under stealth guidance without complication. Postoperative MRI scans showed patchy enhancement and residual T2 and FLAIR abnormality. Pathology revealed a highly cellular neoplasm with papillary-like structures, containing cells with glial and neuronal differentiation. Regions of mitoses and focal necrosis were noted, along with a Ki-67 labeling index of 26%. The diagnosis was aggressive PGNT, and treatment consisted of conformal irradiation and concomitant temozolomide over 6 weeks. Postirradiation follow-up MRI scans demonstrated a reduction of residual enhancement and FLAIR abnormality. The patient continues standard-dose adjuvant temozolomide on a monthly basis, with further improvement on subsequent MRI scans and a stable neurologic exam. This patient demonstrates that PGNT may, in rare cases, display an aggressive clinicopathologic phenotype that requires a therapeutic approach more consistent with a high-grade glioma.

Neurological decompression illness and hematocrit: analysis of a consecutive series of 200 recreational scuba divers.

Neurological complications are common in recreational divers diagnosed with decompression illness (DCI). Prior reports suggest that hemoconcentration, with hematocrit values of 48 or greater, increase the risk for more severe and persistent neurological deficits in divers with DCI. Herein we describe our experience with neurological DCI and hematocrit values in a large series of consecutively treated divers. We performed a retrospective chart review of 200 consecutive recreational divers that received treatment for DCI. Standard statistical analyses were performed to determine if there were any significant relationships between diving-related or demographic parameters, neurological manifestations, and hematocrit. In 177 of the 200 divers (88.5%), at least one manifestation of neurological DCI (mild, moderate, or severe) was present. The median hematocrit value was 43, for both male and female divers, with a range of 30 to 61. Hematocrit values did not correlate with diver age or level of diving experience. In male divers, the hematocrit did not correlate with neurological symptoms, including the sub-group with values of 48 or greater. In contrast, female divers with hematocrit values of 48 or greater were significantly more likely to develop motor weakness (p=0.002, Fisher's exact test) and an increased number of severe sensory symptoms (p=0.001, Kendall's tau statistic). Neurological complications are common in recreational divers treated for DCI. Hematocrit values of 48 or higher were correlated with the presence of motor weakness and severity of sensory symptoms in female divers. The hematocrit did not correlate with neurological DCI in male divers.

Neurological manifestations of decompression illness in recreational divers - the Cozumel experience.

Neurological signs and symptoms are common in recreational divers with decompression illness (DCI). The spectrum of neurological manifestations, temporal profile, and laboratory findings are described in a large series of 200 consecutive recreational divers treated for DCI. The Hyperbaric Medicine Unit charts of 200 recreational divers treated for DCI were reviewed and analyzed. The cohort was mainly male, with a median age of 40 years, and quite experienced, with a median of 100 prior dives. In 44 divers (22%) a rapid ascent was documented. The median time to onset of neurological symptoms was 60 minutes after surfacing. One hundred seventy-seven of 200 divers (88.5%) had at least one symptom of neurological DCI at presentation. The most common neurological manifestations were paresthesia, dysesthesia, incoordination, motor weakness, and dizziness. Paresthesias were associated with significantly younger (p = 0.003) and less experienced (p = 0.03) divers. Similar but less significant correlations were noted for dysesthesias. Female divers were significantly more likely to experience painful skin symptoms (p < 0.001). Neurological manifestations are common in recreational divers treated for DCI. Neurological DCI and paresthesias are more likely to occur in younger and less experienced divers.

Prevalence and rupture rate of cerebral aneurysms discovered during intra-arterial chemotherapy of brain tumors.

BACKGROUND: During the administration of intra-arterial (IA) chemotherapy for the treatment of brain tumors (BTs), angiography may demonstrate asymptomatic, incidental cerebral aneurysms. The prevalence and complication rate of incidental aneurysms in patients undergoing IA chemotherapy remains unknown. It remains unclear whether the presence of an aneurysm represents an increased risk or a contraindication to this form of treatment. METHODS: We performed a chart and angiography review of BT patients receiving IA chemotherapy over the previous 16 months. Seventy-eight patients were identified with primary (39) and metastatic (39) BTs. RESULTS: The cohort consisted of 40 men and 38 women, with a mean age of 47.8 years (range, 22-80 years). During initial angiography, 8 patients (10.3%) were identified with incidental cerebral aneurysms. The aneurysms were saccular and varied in size from 2-4 mm (mean, 3 mm). Seven of the 8 patients continued IA chemotherapy after detection of the aneurysm, for a total of 35 IA procedures. Of these 7 patients, 5 expired from nonaneurysmal complications (mean survival, 5.4 months; range, 2-10 months); 4 from the primary tumor, and one from an infected craniotomy site. Two patients continue to survive; one remains in treatment, and the other has completed 12 months of IA therapy. There were no aneurysmal complications during or after IA treatment in any of the BT patients. CONCLUSION: Incidental aneurysms may be more common in patients with BTs than the general population. In our patient population, there was no indication that an incidental aneurysm was reason to preclude or delay the use of IA chemotherapy.

Weber's syndrome and sixth nerve palsy secondary to decompression illness: a case report.

We describe the first case of Weber's Syndrome to present as a manifestation of decompression illness in a recreational scuba diver. Weber's Syndrome is characterized by the presence of an oculomotor nerve palsy and contralateral hemiparesis. The patient was a 55 year-old male with a past medical history of a pulmonary cyst, in whom symptoms developed after a multilevel drift dive to a depth of 89 feet for 53 minutes, exceeding no-decompression limits. Symptom onset was within 30 minutes of surfacing and included the Weber's Syndrome, a sixth nerve palsy, dizziness, nausea, sensory loss, and ataxia. The patient received four U.S. Navy Treatment Tables with complete resolution of all neurological signs and symptoms. The mechanism of injury remains unclear, but may involve aspects of both air gas embolism and decompression sickness. Individuals with pre-existing pulmonary cysts may be at increased risk for dive-related complications.

Hydroxyurea chemotherapy for meningiomas: enlarged cohort with extended follow-up.

Meningiomas account for 18-20% of all intracranial tumours and often recur despite surgical resection. Hydroxyurea is under evaluation as adjuvant therapy of meningiomas. In the authors' initial report of 17 patients with meningioma, hydroxyurea demonstrated modest efficacy, with a median time to progression (TTP) of 80 weeks. In the current study, 21 patients with meningioma have been placed on hydroxyurea (20 mg/kg/day orally), with extended follow-up of the original cohort. Eighteen of 20 evaluable patients (90%) responded with stable disease ranging from 20 to 328 + weeks (median TTP 176 weeks; 11 patients censored). Five of the stabilized patients progressed after 20, 56, 36, 216 and 56 weeks, respectively. Two patients had progressive disease after 10 weeks. Toxicity was mainly haematological. Hydroxyurea has modest activity against meningiomas and should be considered for patients who are poor surgical candidates, have unresectable or large residual meningiomas, or have progressed after surgical resection or irradiation, or both.

Neurologic complications of scuba diving.

Recreational scuba diving has become a popular sport in the United States, with almost 9 million certified divers. When severe diving injury occurs, the nervous system is frequently involved. In dive-related barotrauma, compressed or expanding gas within the ears, sinuses and lungs causes various forms of neurologic injury. Otic barotrauma often induces pain, vertigo and hearing loss. In pulmonary barotrauma of ascent, lung damage can precipitate arterial gas embolism, causing blockage of cerebral blood vessels and alterations of consciousness, seizures and focal neurologic deficits. In patients with decompression sickness, the vestibular system, spinal cord and brain are affected by the formation of nitrogen bubbles. Common signs and symptoms include vertigo, thoracic myelopathy with leg weakness, confusion, headache and hemiparesis. Other diving-related neurologic complications include headache and oxygen toxicity.

Review of the molecular genetics and chemotherapeutic treatment of adult and paediatric medulloblastoma.

Medulloblastoma is the most common primary brain tumour in children and accounts for 25% of newly diagnosed cases. Recent advances in treatment have extended 5-year survival rates from 3 - > 70% during the past 50 years. These improvements in survival have resulted from a multi-modality approach that includes surgical resection, posterior fossa and craniospinal irradiation and chemotherapy for selected, high-risk patients. The literature regarding chemotherapy of adult and paediatric patients is reviewed in-depth. The most active agents include cisplatin, CCNU, cyclophosphamide, vincristine and carboplatin. Although patients are living longer with their disease, neurocognitive function and quality of life are often impaired following radiation therapy (RT) to the developing brain. To safely allow reductions in the dose of RT, the specificity and efficacy of chemotherapy must be improved. Recent advances in the molecular genetics of medulloblastoma transformation (e.g., myc, PTCH ) are reviewed and discussed. A thorough understanding of these pathways will be critical for the development of more specific, novel drugs. Further clinical trials will be needed to evaluate the activity of these new drugs and determine their role in the treatment plan of patients with medulloblastoma.

Brain metastases from fallopian tube carcinoma responsive to intra-arterial carboplatin and intravenous etoposide: a case report.

Fallopian tube carcinoma is the least common neoplasm of the female genital tract. Although rare, neurological complications such as brain metastases can develop. It remains unclear, however, what role chemotherapy has in the treatment of these patients and what route of administration is most effective. Intra-arterial (IA) regional administration of chemotherapy may increase intra-tumoral drug concentrations and improve efficacy. We report the case of a 47-year-old woman who developed bilateral fallopian tube cancer and multifocal brain metastases. After progression through radiation therapy and oral chemotherapy, she was placed on IA carboplatin (200 mg/m2/d x 2 days every 4 weeks) and intravenous etoposide (100 mg/m2/d x 2 days every 4 weeks). During treatment she had objective tumor shrinkage that has remained stable for more than 12 months. For patients with fallopian tube carcinoma that develop brain metastases and respond poorly to surgery and/or irradiation, multi-agent chemotherapy containing carboplatin should be considered. The effectiveness of carboplatin may be improved if administered by the IA route.

Novel chemotherapeutic agents for the treatment of brain cancer.

Brain cancer encompasses both primary and metastatic brain tumours and accounts for over 120,000 new patients each year. Despite aggressive therapy, the majority of patients with brain cancer have poor prognosis and have brief survival intervals. Current chemotherapy drugs, used alone or in combination, have minimal or only modest activity. Novel agents that have recently been applied to brain cancer include temozolomide, irinotecan and paclitaxel. Temozolomide is a DNA alkylating agent, irinotecan inhibits DNA topoisomerase I and paclitaxel binds to microtubules and induces polymerisation. Neoplastic angiogenesis and brain tumour invasion are also targets for therapeutic intervention with new agents such as thalidomide, suramin and marimastat. All of these agents have demonstrated activity against brain cancer in vitro. Several of the drugs, in particular temozolomide, paclitaxel and irinotecan, have entered preliminary clinical trials and have demonstrated some efficacy. However, chemotherapy for primary brain tumours remains rather non-specific and mostly ineffective. The use of chemotherapy may be more effective against selected metastatic brain tumours. Continued basic research is needed to further elucidate the genetic basis of transformation, tumour invasion and angiogenesis. It is hoped that this research will lead to new therapeutic targets for drug design and development. In addition, new strategies must be developed to overcome the problem of chemotherapy resistance.

Hydroxyurea chemotherapy for unresectable or residual meningioma.

Meningiomas represent 18-20% of all intracranial tumors and have a 10-year recurrence rate of 20-50%, despite aggressive surgery and irradiation. In addition, many tumors are not amenable to surgery due to their deep location or proximity to delicate structures. Chemotherapy is being explored as another potential treatment option for unresectable or refractory meningiomas. Hydroxyurea is an agent that inhibits ribonucleotide reductase and can induce apoptosis in meningioma cell cultures and animal models. We have placed 17 patients with unresectable or residual meningioma on hydroxyurea chemotherapy (20 mg/kg/d orally). The mean age of our cohort was 57.2 years; 13 patients were female. Eleven patients had actively growing tumors or neurological progression at the onset of chemotherapy. Sixteen patients were evaluable for response. Fourteen of the 16 patients (88%) responded with stable disease ranging from 20 to 144+ weeks (median 80 weeks; 10 patients still accruing time). Three of the responders progressed after 20, 36, and 56 weeks, respectively. Two patients had progressive disease after 10 weeks. Toxicity was hematologic in most patients; leukopenia was most common. Nine patients (53%) required dosage reductions (250-500 mg/d) secondary to hematologic toxicity. Hydroxyurea appears to have modest activity against meningiomas and should be considered in patients with unresectable tumors or large residual tumors following surgical resection.

Brain tumors: complications of cerebral angiography accompanied by intraarterial chemotherapy.

PURPOSE: To evaluate the rate of complications associated with diagnostic cerebral angiography accompanied by intraarterial chemotherapy for the treatment of primary and metastatic brain tumors. MATERIALS AND METHODS: Three hundred ninety-two consecutive transfemoral cerebral angiographic procedures accompanied by intraarterial chemotherapy were performed in 48 patients (28 men, 20 women), and complications were evaluated. RESULTS: The most common local complications were groin hematomas, which occurred in 10 (2.6%) of the 392 procedures and none of which required therapy. Two carotid arterial dissections (0.5%) were reported in two patients who were asymptomatic and did not require further treatment. Both improved at follow-up examinations. Only one patient required surgery for a delayed popliteal embolus. Systemic transient complications occurred five times (1.3%). There were seven (1.8%) transient neurologic events, which were paresis and visual disturbances. Six (1.5%) transient seizure events were recorded. There were no permanent neurologic complications. CONCLUSION: Intraarterial chemotherapy for brain tumors is a safe procedure with a low complication rate.

Clinical presentation, diagnosis, and pharmacotherapy of patients with primary brain tumors.

OBJECTIVE: To briefly review the clinical presentation and diagnosis of patients with primary brain tumors, followed by an in-depth survey of the pertinent pharmacotherapy. DATA SOURCES: A detailed search of the neurologic, neurosurgical, and oncologic literature for basic science research, clinical studies, and review articles related to chemotherapy and pharmacotherapy of primary brain tumors. STUDY SELECTION: Relevant studies on tissue culture systems, animals, and humans examining the mechanisms of action, pharmacokinetics, clinical pharmacology, and treatment results of chemotherapeutic agents for primary brain tumors. In addition, studies of pharmacologic agents administered for supportive care and symptom control are reviewed. DATA SYNTHESIS: Primary brain tumors derive from cells within the intracranial cavity and generally present with headache, seizure activity, cognitive changes, and weakness. They are diagnosed most efficiently with magnetic resonance imaging. After diagnosis, the most common supportive medications include corticosteroids, gastric acid inhibitors, and anticonvulsants. Chemotherapy is adjunctive treatment for patients with malignant tumors and selected recurrent or progressive benign neoplasms. In general, the most effective chemotherapeutic drugs are alkylating agents such as the nitrosoureas, procarbazine, cisplatin, and carboplatin. Other agents used include cyclophosphamide, methotrexate, vincristine, and etoposide. Angiogenesis inhibitors and gene therapy comprise some of the novel therapeutic strategies under investigation. CONCLUSIONS: The efficacy of chemotherapy for primary brain tumors remains modest. Novel agents must be discovered that are more specific and attack tumor cells at the molecular level of tumorigenesis. Furthermore, strategies must be developed to counteract the pervasive problem of brain tumor chemoresistance.

Neurologic complications of systemic cancer.

Neurologic complications occur frequently in patients with cancer. After routine chemotherapy, these complications are the most common reason for hospitalization of these patients. Brain metastases are the most prevalent complication, affecting 20 to 40 percent of cancer patients and typically presenting as headache, altered mental status or focal weakness. Other common metastatic complications are epidural spinal cord compression and leptomeningeal metastases. Cord compression can be a medical emergency, and the rapid institution of high-dose corticosteroid therapy, radiation therapy or surgical decompression is often necessary to preserve neurologic function. Leptomeningeal metastases should be suspected when a patient presents with neurologic dysfunction in more than one site. Metabolic encephalopathy is the common nonmetastatic cause of altered mental status in cancer patients. Cerebrovascular complications such as stroke or hemorrhage can occur in a variety of tumor-related conditions, including direct invasion, coagulation disorders, chemotherapy side effects and nonbacterial thrombotic endocarditis. Radiation therapy is the most commonly employed palliative measure for metastases. Chemotherapy or surgical removal of tumors is used in selected patients.

Ethical issues in neuro-oncology.

Ethical issues and dilemmas are common in patients with brain tumors and other neuro-oncologic diseases. Basic knowledge of ethical principles and theory is essential for the day-to-day care of these patients, which often involves life and death decisions. The most important ethical principles include respect for autonomy, justice, beneficience, and nonmaleficence. The application of these principles is important for resolving ethical questions related to neuro-oncology patients such as discussing diagnosis and prognosis, whether or not to initiate therapy (including clinical trials), quality of life during and after treatment, when it is appropriate to stop treatment, if hospice care should be implemented, and pain control. Frequent consideration of these basic ethical principles will assist physicians during the decision-making process and improve their ability to make sound choices.

Lhermitte's sign as a presenting symptom of primary spinal cord tumor.

We describe a previously healthy 29 year-old man who developed Lhermitte's sign, a shock-like or electric sensation, transmitted down the spine, which occurred during neck flexion or rotation. Evaluation demonstrated an intrinsic, fusiform mass extending from c5 to c7. At operation, the mass was completely removed and found to be a low-grade ependymoma. The sensory phenomena of Lhermitte's sign were most likely caused by tumor-induced distortion and demyelination of cervical dorsal column sensory axons. Lhermitte's sign is most prevalent in patients with multiple sclerosis, cervical spondylotic myelopathy, cisplatin neurotoxicity, cervical radiation injury, and neck trauma. Rarely, Lhermitte's sign occurs with spinal cord compression from epidural or subdural tumor. This patients is the first reported case of an intrinsic spinal cord tumor to present with Lhermitte's sign.

Extracranial plasma cell granuloma presenting as a diffuse meningeal and intraparenchymal mass.

Plasma cell granuloma (PCG) is uncommon, characterized by polyclonal proliferation of mature plasma cells, usually within systemic organs. Only four previous cases have involved the central nervous system (CNS).

Spinal cord tumors: review of etiology, diagnosis, and multidisciplinary approach to treatment.

Spinal cord tumors (SCT) are a diverse group of uncommon neoplasms that develop from tissues in and around the spinal canal. They often have an indolent onset and progression of signs and symptoms, which may include back pain, extremity weakness, sensory alterations, and bowel or bladder incontinence. The most common SCTs are located in the extramedullary space and include meningiomas and neurofibromas. Intramedullary SCTs, for example ependymomas and astrocytomas, occur less frequently. The most useful screening test for diagnosis of a SCT is enhanced magnetic resonance imaging; myelography and computed tomography also can be helpful. The majority of SCTs are amenable to surgical therapy and can be partially or completely resected. Radiation therapy is reserved for incompletely resected low-grade tumors, malignant tumors, and recurrent tumors. The rehabilitative process should be initiated early on following diagnosis, if possible, in patients with neurologic deficits to minimize long-term disability.

Progressive multifocal leukoencephalopathy presenting as multiple enhancing lesions on MRI: case report and literature review.

This report describes an immunocompetent patient with memory loss and motor abnormalities whose magnetic resonance images demonstrated multiple enhancing white matter lesions, including one that was cystic, suggestive of metastatic tumors or abscesses. Neuropathological evaluation at biopsy and subsequent autopsy revealed progressive multifocal leukoencephalopathy. Magnetic resonance evidence of enhancement and cystic changes are rare findings in progressive multifocal leukoencephalopathy, but should be considered in the differential diagnosis, especially in patients without evidence for primary malignancy or infection.