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Michael D. Taylor and Mark Bernstein

Object. Awake craniotomy was performed as the standard surgical approach to supratentorial intraaxial tumors, regardless of the involvement of eloquent cortex, in a prospective trial of 200 patients surgically treated by the same surgeon at a single institution.

Methods. Patient presentations, comorbid conditions, tumor locations, and the histological characteristics of lesions were recorded. Brain mapping was possible in 195 (97.5%) of 200 patients. The total number of patients sustaining complications was 33 for an overall complication rate of 16.5%. There were two deaths in this series, for a mortality rate of 1%. New postoperative neurological deficits were seen in 13% of the patients, but these were permanent in only 4.5% of them. Complication rates were higher in patients who had gliomas or preoperative neurological deficits and in those who had undergone prior radiation therapy or surgery. No patient who entered the operating room neurologically intact sustained a permanent neurological deficit postoperatively. Of the most recent 50 patients treated, three (6%) required a stay in the intensive care unit, and the median total hospital stay was 1 day.

Conclusions. Use of awake craniotomy can result in a considerable reduction in resource utilization without compromising patient care by minimizing intensive care time and total hospital stay. Awake craniotomy is a practical and effective standard surgical approach to supratentorial tumors with a low complication rate, and provides an excellent alternative to craniotomy performed with the patient in the state of general anesthesia because it allows the opportunity for brain mapping and avoids general anesthesia.

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Ian D. Kamaly-Asl, Navid Shams and Michael D. Taylor

Choroid plexus tumors consist of papillomas and carcinomas. A variety of germline and somatic genetic changes have been demonstrated for each of these subtypes. In this paper, the authors summarize the current knowledge of the genetic bases of these tumors.

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Paul A. Northcott, James T. Rutka and Michael D. Taylor

Advances in the field of genomics have recently enabled the unprecedented characterization of the cancer genome, providing novel insight into the molecular mechanisms underlying malignancies in humans. The application of high-resolution microarray platforms to the study of medulloblastoma has revealed new oncogenes and tumor suppressors and has implicated changes in DNA copy number, gene expression, and methylation state in its etiology. Additionally, the integration of medulloblastoma genomics with patient clinical data has confirmed molecular markers of prognostic significance and highlighted the potential utility of molecular disease stratification. The advent of next-generation sequencing technologies promises to greatly transform our understanding of medulloblastoma pathogenesis in the next few years, permitting comprehensive analyses of all aspects of the genome and increasing the likelihood that genomic medicine will become part of the routine diagnosis and treatment of medulloblastoma.

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Mustafa Nadi, Navid Khezri, Tahani Ahmad, Michael Ellis, Eric Bouffet, James T. Rutka and Michael D. Taylor

Medulloblastoma is a highly malignant brain tumor of childhood. Although craniospinal dissemination within the subarachnoid space is common, invasion of the dural sinuses is rare. Here, the authors report on a 15-year-old girl who presented with a right cerebellar mass, obstructive hydrocephalus, and radiographic evidence of tumor invasion into the right transverse–sigmoid sinus junction. The patient underwent posterior fossa craniotomy, gross-total resection of the intraparenchymal component of the right cerebellar tumor, and coagulation of the tumor invading the transverse sinus. After pathological confirmation of anaplastic medulloblastoma, the patient underwent craniospinal radiation therapy and high-dose chemotherapy. At 2 years posttreatment, the child was neurologically intact with no radiographic evidence of residual disease or recurrence. The implications for disease prognosis and management are discussed.

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Machiel van den Akker, Paul Northcott, Michael D. Taylor, William Halliday, Ute Bartels and Eric Bouffet

A 9-year-old boy with known Duchenne type muscular dystrophy (DMD) presented with signs of increased intracranial pressure. Radiological investigations revealed a lesion in the midline of the posterior fossa. Subtotal resection was performed. Pathology findings were consistent with the diagnosis of anaplastic medulloblastoma. The postoperative lumbar CSF was positive for malignant cells. Postoperatively, the patient showed severe neurological deterioration and lost his capacity to walk. He was treated with craniospinal radiation followed by nonintensive chemotherapy. At 30 months postsurgery, he was still in complete remission but had not recovered his walking ability. This is the second report of a malignant brain tumor in a boy with DMD. The possible link between the 2 conditions is discussed, as are ethical considerations regarding the management of medulloblastoma in children with DMD.

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Daniel W. Fults, Michael D. Taylor and Livia Garzia

Leptomeningeal dissemination (LMD) is the defining pattern of metastasis for medulloblastoma. Although LMD is responsible for virtually 100% of medulloblastoma deaths, it remains the least well-understood part of medulloblastoma pathogenesis. The fact that medulloblastomas rarely metastasize outside the CNS but rather spread almost exclusively to the spinal and intracranial leptomeninges has fostered the long-held belief that medulloblastoma cells spread directly through the CSF, not the bloodstream. In this paper the authors discuss selected molecules for which experimental evidence explains how the effects of each molecule on cell physiology contribute mechanistically to LMD. A model of medulloblastoma LMD is described, analogous to the invasion–metastasis cascade of hematogenous metastasis of carcinomas. The LMD cascade is based on the molecular themes that 1) transcription factors launch cell programs that mediate cell motility and invasiveness and maintain tumor cells in a stem-like state; 2) disseminating medulloblastoma cells escape multiple death threats by subverting apoptosis; and 3) inflammatory chemokine signaling promotes LMD by creating an oncogenic microenvironment. The authors also review recent experimental evidence that challenges the belief that CSF spread is the sole mechanism of LMD and reveal an alternative scheme in which medulloblastoma cells can enter the bloodstream and subsequently home to the leptomeninges.

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Michael J. Ellis, Samuel Cheshier, Sunjay Sharma, Derek Armstrong, Cynthia Hawkins, Eric Bouffet, James T. Rutka and Michael D. Taylor

Among the neoplastic conditions that affect patients with neurofibromatosis Type 1 (NF1) are malignant peripheral nerve sheath tumors (MPNSTs), which typically arise from peripheral nerves of the limbs, trunk, and lumbar and brachial plexuses. Ionizing radiation is an established risk factor for MPNST development, especially in susceptible patients such as those with NF1. Patients with NF1 are also at risk for intracranial aneurysms, which are increasingly being successfully managed with endovascular therapies. The authors describe the case of a 9-year-old, previously healthy girl who presented in extremis with a right frontal intracerebral hemorrhage resulting from a ruptured right middle cerebral artery (MCA) trifurcation aneurysm. Following urgent decompressive craniectomy, the patient underwent endovascular coil embolization of the MCA aneurysm without complication. Given her mother's history of NF1, the child underwent genetic testing, which disclosed signs positive for NF1. The patient recovered well, but follow-up MR imaging and MR angiography performed at 14 months demonstrated a large frontotemporal mass encasing the right MCA trifurcation. The patient underwent frontotemporal craniotomy and subtotal resection of the mass, which was histologically found to be an intracranial MPNST. The patient received chemotherapy and focal radiation therapy and remains alive at 6 months postresection. To the authors' knowledge, this represents the only known case of intracranial neoplasm arising in the region of an intracranial aneurysm repaired by endovascular coil embolization. While patients with NF1 represent a population with genetic susceptibility to radiation-induced tumors, the pathogenesis of intracerebral MPNSTs remains poorly understood.

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Sanjay Gupta, Shobhan Vachhrajani, Abhaya V. Kulkarni, Michael D. Taylor, Peter Dirks, James M. Drake and James T. Rutka

Object

Extraaxial infections of the CNS, including subdural empyema and epidural abscess, are rare but potentially life-threatening conditions. Symptoms are usually progressive, and early diagnosis is therefore important. Early intervention with appropriate treatment offers the best opportunity for eradicating the infection and promoting maximal neurological recovery.

Methods

The medical records of children with extraaxial CNS infection over the last 24 years at the Hospital for Sick Children were analyzed. Only those patients with radiological and/or operative confirmation of the diagnosis of subdural empyema or epidural abscess were included in the study. Demographic and clinical data were collected to determine the outcomes after such infections and factors that predict for such outcomes.

Results

The authors identified 70 children who fulfilled the inclusion criteria. Sinusitis was the most common etiology and was seen in 38 patients. All of these patients were older than 7 years of age at diagnosis. Subdural empyemas were diagnosed in 13 patients following bacterial meningitis, and they were found primarily in infants within the 1st year of life. Other etiological factors included otogenic infection (4 cases), postneurosurgical infection (7 cases), and hematogenous spread of infection (7 cases including 6 cases of spinal epidural abscess). Streptococcus anginosus and Staphylococcus aureus were the most common pathogens identified. Sixty-four patients (91.4%) underwent at least 1 neurosurgical procedure. Seizures and cerebral edema from cortical vein thrombosis were the most common complications.

Conclusions

Due to variable etiology, identification of the responsible microorganism through neurosurgical drainage followed by long-term intravenous antibiotics remains the mainstay in treating extraaxial CNS infections. Optimal outcome is achieved with early diagnosis and therapy.

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Chinatsu Kasuga, Yukiko Nakahara, Shigeo Ueda, Cynthia Hawkins, Michael D. Taylor, Christian A. Smith and James T. Rutka

Object

Cancer testis antigens (CTAs) were initially identified by their ability to elicit autologous T-cell–mediated immune responses in patients with melanoma. The CTA genes are widely expressed in a variety of human cancers, such as melanoma, breast cancer, lung cancer, esophageal cancer, and hepatocellular carcinoma; however, their expression in pediatric brain tumors, such as medulloblastoma (MB), has not been the subject of in-depth analysis. The MAGE proteins are members of the CTA family and have been shown to correlate with tumor development, aggressive clinical course, or resistance to chemotherapeutic agents. The authors undertook this study to examine the expression and role of MAGE proteins in human MB cell lines and specimens.

Methods

From a transcriptional profiling study in which 47,000 genes in MB cell lines were examined, the authors identified members of the MAGE and GAGE families as being highly expressed. A series of MB tumors was examined using both immunohistochemistry and Western blot analysis with antibodies to the MAGE-A family, MAGE-A1, and GAGE proteins.

Results

Western blot analysis showed expression of these 3 proteins (MAGE-A family, MAGE-A1, and GAGE) in 62, 46, and 84%, respectively, of MB specimens examined. In addition, a correlation was observed between the expression of MAGE and GAGE genes and resistance of MB cells to chemotherapeutic agents. The functional significance of this correlation was examined in MAGE knockdown studies, and increased drug-induced cytotoxicity was observed in UW426 MB cells following treatment with chemotherapeutic drugs. Cleaved caspase-3 was found in UW426/MAGE small interfering (si)RNA–inhibited cells treated with cisplatin, but not in UW426 cells treated with cisplatin alone at the same concentration.

Conclusions

These data show that MAGE and GAGE family members are expressed in MB cell lines and specimens, and that inhibition of MAGE and GAGE genes by siRNA increases apoptosis of MB cells and sensitizes them to certain chemotherapeutic agents such as cisplatin and etoposide.