Chordoma of the skull base: predictors of tumor recurrence

2003 ◽  
Vol 98 (4) ◽  
pp. 812-822 ◽  
Author(s):  
Roberto Pallini ◽  
Giulio Maira ◽  
Francesco Pierconti ◽  
Maria Laura Falchetti ◽  
Ester Alvino ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Microsatellite Instability ◽  
Skull Base ◽  
Tumor Recurrence ◽  
Doubling Time ◽  
P53 Protein ◽  
Biological Behavior ◽  
Htert Mrna ◽  
Content Type ◽  
Fine Print

Object. Chordomas of the skull base are generally regarded as slow-growing tumors; however, approximately 20% of these lesions have been shown to recur as early as 1 year postsurgery. The classic pathological paradigms are poor predictors of outcome, and additional markers are needed to identify patients at risk for early tumor recurrence. In this study the authors describe such a marker. Methods. In a series of 26 patients with chordomas of the skull base, the authors investigated the relationship between the biological behavior of the tumor, which was determined according to the interval for its recurrence and volume doubling time, and several pathological and molecular features, which included the histological variant, proliferative activity, mutation of p53 protein, expression of human telomerase reverse transcriptase (hTERT) messenger (m)RNA, loss of heterozygosity (LOH), and microsatellite instability. The major finding in this study was that hTERT mRNA expression in chordoma cells identifies those tumors that exhibit unusually fast rates of growth. The expression of hTERT mRNA was frequently associated with mutation of p53 protein, indicating that telomerase dysfunction combines with abnormal p53 function to initiate the unrestrained clonal expansion of the tumor cells. In cases in which the tumor was partially removed, mutation of p53 protein and expression of hTERT mRNA predicted increased doubling time for residual tumor as well as the probability of tumor recurrence. Cell proliferation, as investigated using the Ki-67 method, was significantly related to the tumor doubling time; however, the authors found that the pattern of cell proliferation was not homogeneous throughout the chordoma tissue, and that the proliferative index might change by a factor as high as 8 among different regions of the same tumor. The LOH and microsatellite instability do not seem to affect the prognosis of skull base chordomas. Conclusions. Reactivation of telomerase in chordomas is a reliable predictor of outcome. The ability to predict the biological behavior of chordomas might have immediate implications in the management of this disease in patients who undergo surgery.

Evidence for telomerase involvement in the angiogenesis of astrocytic tumors: expression of human telomerase reverse transcriptase messenger RNA by vascular endothelial cells

2001 ◽  
Vol 94 (6) ◽  
pp. 961-971 ◽  
Author(s):  
Roberto Pallini ◽  
Francesco Pierconti ◽  
Maria Laura Falchetti ◽  
Daniela D'Arcangelo ◽  
Eduardo Fernandez ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Astrocytic Tumors ◽  
Htert Mrna ◽  
Content Type ◽  
Human Telomerase ◽  
Fine Print

Object. Evidence from recent in vitro studies indicates that reactivation of telomerase, the enzyme that synthesizes the telomere ends of chromosomes, is a crucial event in the unlimited clonal expansion of endothelial cells that precedes the neoplastic conversion of these cells. It is known that high-grade gliomas express telomerase and that, in these neoplasms, proliferating endothelial cells may undergo transformational changes with development of sarcomatous components within the primitive tumor. To assess whether telomerase is involved in the endothelial cell proliferation that characterizes brain tumor angiogenesis, the authors investigated at the single-cell level the expression of messenger (m)RNA for the human telomerase catalytic subunit human telomerase reverse transcriptase (hTERT) by vascular cells of astrocytic tumors. Methods. The in situ hybridization (ISH) method was performed by processing histological sections with specific riboprobes for hTERT and for c-myc, an oncogene that is known to upregulate hTERT. Results of the ISH studies were compared with proliferative activity, as estimated by Ki-67 immunostaining. The expression of hTERT mRNA by vascular endothelial cells was related to the histological grade of the tumor because it was detected in five (29%) of 17 low-grade astrocytomas, nine (56%) of 16 anaplastic astrocytomas, and 19 (100%) of 19 glioblastomas multiforme (GBMs). Expression of c-myc mRNA was strictly correlated with that of hTERT mRNA. In low-grade astrocytomas and anaplastic astrocytomas, a dissociation was noted between hTERT mRNA expression and the proliferation rate of endothelial cells. Conversely, GBMs displayed a significant correlation between the level of hTERT mRNA expression and endothelial cell proliferation. Data from an in vitro assay in which human umbilical vein endothelial cells were stimulated to proliferate by adding vascular endothelial growth factor and an ISH study of newly formed vessels surrounding brain infarcts confirmed that expression of hTERT mRNA does not merely reflect the proliferative status of endothelial cells but represents a specific feature of brain tumor neovascularization. Conclusions. The results of this study are consistent with a role of telomerase in the angiogenesis of astrocytic tumors. Expression of hTERT mRNA by tumor vascular cells is an early event during the progression of astrocytic tumors, which precedes endothelial cell proliferation and may represent a first sign of dedifferentiation. Other than elucidating the mechanisms of tumor angiogenesis, these results encourage research on antitelomerase drugs for the treatment of malignant gliomas.

Tumor recurrence and survival following gamma knife surgery for brain metastases

2005 ◽  
Vol 102 (Special_Supplement) ◽  
pp. 287-288 ◽  
Author(s):  
Thomas Mindermann
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Gamma Knife ◽  
Tumor Recurrence ◽  
Patient Survival ◽  
Gamma Knife Surgery ◽  
Recurrence Rates ◽  
Term Survival ◽  
Content Type ◽  
Fine Print

Object. The authors evaluated prognostic factors for tumor recurrence and patient survival following gamma knife surgery (GKS) for brain metastasis. Methods. A retrospective review of 101 patient charts was undertaken for those patients treated with GKS for brain metastases from 1994 to 2001. Recurrence rates of brain metastasis following GKS depended on the duration of patient survival. Long-term survival was associated with a higher risk of tumor recurrence and shorter-term survival was associated with a lower risk. The duration of survival following GKS for brain metastases seems to be characteristic of the primary disease rather than the cerebral disease. Conclusions. Recurrence rates of brain metastasis following GKS are related to duration of survival, which is in turn mostly dependent on the nature and course of the primary tumor.

Monstrous, crablike hypertrophy of the cerebellar vermis and its relationship with Lhermitte—Duclos disease

1996 ◽  
Vol 85 (1) ◽  
pp. 157-162 ◽  
Author(s):  
Guillermo A. de León ◽  
John A. Grant ◽  
Crystal F. Darling
Keyword(s):  
Surgical Resection ◽  
Basic Structure ◽  
Cerebellar Vermis ◽  
Biological Behavior ◽  
Content Type ◽  
Neuroepithelial Cells ◽  
Poorly Differentiated ◽  
New Interpretation ◽  
Fine Print

✓ The case of an infant with a peculiar tumorous malformation of the cerebellum is described. The tumor apparently developed as an exophytic, hypertrophic sprout of the inferior vermis. It had a monstrous appearance resembling a crab, with a metameric body and multiple pairs of limbs attached to the folia of both cerebellar hemispheres. Histologically, the lesion was formed by poorly differentiated neuroepithelial cells without any evidence of organization into nuclei, cortex, or fascicles. Clinically, the tumor behaved in an indolent manner and did not regrow after subtotal surgical resection. Because of its gross appearance and its biological behavior, this unusual hamartoblastomatous growth is readily distinguished from medulloblastoma. The morphology of the cerebellum in Lhermitte—Duclos disease is reviewed, and a new interpretation of its basic structure is proposed. This and other known types of cerebellar hypertrophy are different from the malformation in the present case.

Enhancement of radiosensitivity of wild-type p53 human glioma cells by adenovirus-mediated delivery of the p53 gene

1998 ◽  
Vol 89 (1) ◽  
pp. 125-132 ◽  
Author(s):  
Frederick F. Lang ◽  
W. K. Alfred Yung ◽  
Uma Raju ◽  
Floralyn Libunao ◽  
Nicholas H. A. Terry ◽  
...  
Keyword(s):  
Cell Line ◽  
Glioma Cell ◽  
Radiation Treatment ◽  
P53 Protein ◽  
Glioma Cells ◽  
Glioma Cell Line ◽  
Wild Type ◽  
Content Type ◽  
Infected Cells ◽  
Fine Print

Object. The authors sought to determine whether combining p53 gene transfer with radiation therapy would enhance the therapeutic killing of p53 wild-type glioma cells. It has been shown in several reports that adenovirus-mediated delivery of the p53 gene into p53 mutant gliomas results in dramatic apoptosis, but has little effect on gliomas containing wild-type p53 alleles. Therefore, p53 gene therapy alone may not be a clinically effective treatment for gliomas because most gliomas are composed of both p53 mutant and wild-type cell populations. One potential approach to overcome this problem is to exploit the role p53 plays as an important determinant in the cellular response to ionizing radiation. Methods. In vitro experiments were performed using the glioma cell line U87MG, which contains wild-type p53. Comparisons were made to the glioma cell line U251MG, which contains a mutant p53 allele. Monolayer cultures were infected with an adenovirus containing wild-type p53 (Ad5CMV-p53), a control vector (dl312), or Dulbecco's modified Eagle's medium (DMEM). Two days later, cultures were irradiated and colony-forming efficiency was determined. Transfection with p53 had only a minor effect on the plating efficiency of nonirradiated U87MG cells, reducing the plating efficiency from 0.23 ± 0.01 in DMEM to 0.22 ± 0.04 after addition of Ad5CMV-p53. However, p53 transfection significantly enhanced the radiosensitivity of these cells. The dose enhancement factor at a surviving fraction of 0.10 was 1.5, and the surviving fraction at 2 Gy was reduced from 0.61 in untransfected controls to 0.38 in p53-transfected cells. Transfection of the viral vector control (dl312) had no effect on U87MG radiosensitivity. In comparison, transfection of Ad5CMV-p53 into the p53 mutant cell line U251MG resulted in a significant decrease in the surviving fraction of these cells compared with controls, and no radiosensitization was detected. To determine whether Ad5CMV-p53—mediated radiosensitization of U87MG cells involved an increase in the propensity of these cells to undergo apoptosis, flow cytometric analysis of terminal deoxynucleotidyl transferase-mediated biotinylated-deoxyuridinetriphosphate nick-end labeling—stained cells was performed. Whereas the amount of radiation-induced apoptosis in uninfected and dl312-infected control cells was relatively small (2.1 ± 0.05% and 3.7 ± 0.5%, respectively), the combination of Ad5CMV-p53 infection and radiation treatment significantly increased the apoptotic frequency (18.6 ± 1.4%). To determine whether infection with Ad5CMV-p53 resulted in increased expression of functional exogenous p53 protein, Western blot analysis of p53 was performed on U87MG cells that were exposed to 9 Gy of radiation 2 days after exposure to Ad5CMV-p53, dl312, or DMEM. Infection with Ad5CMV-p53 alone increased p53 levels compared with DMEM- or dl312-treated cells. Irradiation of Ad5CMV-p53—infected cells resulted in a further increase in p53 that reached a maximum at 2 hours postirradiation. To determine whether exogenous p53 provided by Ad5CMV-p53 had transactivating activity, U87MG cells were treated as described earlier and p21 messenger RNA levels were determined. Infection of U87MG cells with Ad5CMV-p53 only resulted in an increase in p21 compared with DMEM- and dl312-treated cells. Irradiation of Ad5CMV-p53—infected cells resulted in an additional time-dependent increase in p21 expression. Conclusions. These data indicate that adenovirus-mediated delivery of p53 may enhance the radioresponse of brain tumor cells containing wild-type p53 and that this radiosensitization may involve converting from a clonogenic to the more sensitive apoptotic form of cell death. Although the mechanism underlying this enhanced apoptotic susceptibility is unknown, the Ad5CMV-p53—infected cells have a higher level of p53 protein, which increases further after irradiation, and this exogenous p53 is transcriptionally active. Thus, it is possible that the combination of Ad5CMV-p53 infection and radiation treatment increases p53 protein to a level that is sufficient to overcome at least partially the block in apoptosis existing in U87MG cells.

Use of the radial forearm microvascular free-flap graft for cranial base reconstruction

1999 ◽  
Vol 90 (4) ◽  
pp. 651-655 ◽  
Author(s):  
Marc S. Schwartz ◽  
James I. Cohen ◽  
Toby Meltzer ◽  
Michael J. Wheatley ◽  
Sean O. McMenomey ◽  
...  
Keyword(s):  
Skull Base ◽  
Free Flap ◽  
Cranial Base ◽  
Csf Leak ◽  
Content Type ◽  
Lateral Skull Base ◽  
Csf Leakage ◽  
Radial Forearm ◽  
Microvascular Free Flap ◽  
Fine Print

Object. Reconstruction of the cranial base after resection of complex lesions requires creation of both a vascularized barrier to cerebrospinal fluid (CSF) leakage and tailored filling of operative defects. The authors describe the use of radial forearm microvascular free-flap grafts to reconstruct skull base lesions, to fill small tissue defects, and to provide an excellent barrier against CSF leakage.Methods. Ten patients underwent 11 skull base procedures including placement of microvascular free-flap grafts harvested from the forearm and featuring the radial artery and its accompanying venae comitantes. Operations included six craniofacial, three lateral skull base, and two transoral procedures for various diseases. Excellent results were obtained, with no persistent CSF leaks, no flap failures, and no operative infections. One temporary CSF leak was easily repaired with flap repositioning, and at one flap donor site minor wound breakdown was observed. One patient underwent a second procedure for tumor recurrence and CSF leakage at a site distant from the original operation.Conclusions. Microvascular free tissue transfer reconstruction of skull base defects by using the radial forearm flap provides a safe, reliable, low-morbidity method for reconstructing the skull base and is ideally suited to “low-volume” defects.

Radiation necrosis or glioma recurrence: is computer-assisted stereotactic biopsy useful?

1995 ◽  
Vol 82 (3) ◽  
pp. 436-444 ◽  
Author(s):  
Peter A. Forsyth ◽  
Patrick J. Kelly ◽  
Terrence L. Cascino ◽  
Bernd W. Scheithauer ◽  
Edward G. Shaw ◽  
...  
Keyword(s):  
Disease Progression ◽  
Tumor Recurrence ◽  
Stereotactic Biopsy ◽  
Radiation Necrosis ◽  
Low Grade ◽  
Tumor Type ◽  
Content Type ◽  
Radiation Induced ◽  
Chondroblastic Osteosarcoma ◽  
Fine Print

✓ Fifty-one patients with supratentorial glioma treated with external beam radiotherapy (median dose 59.5 Gy) who then demonstrated clinical or radiographic evidence of disease progression underwent stereotactic biopsy to differentiate tumor recurrence from radiation necrosis. The original tumor histological type was diffuse or fibrillary astrocytoma in 21 patients (41%), oligodendroglioma in 13 (26%), and oligoastrocytoma in 17 (33%); 40 tumors (78%) were low-grade (Kernohan Grade 1 or 2). The median time to suspected disease progression was 28 months. Stereotactic biopsy showed tumor recurrence in 30 patients (59%), radiation necrosis in three (6%), and a mixture of both in 17 (33%); one patient (2%) had a parenchymal radiation-induced chondroblastic osteosarcoma. The tumor type at stereotactic biopsy was similar to the original tumor type and was astrocytoma in 24 patients (47%), oligodendroglioma in eight (16%), oligoastrocytoma in 16 (31%), unclassifiable in two (4%), and chondroblastic osteosarcoma in one patient (2%). At biopsy, however, only 19 tumors (37%) were low grade (Kernohan Grade 1 or 2). Subsequent surgery confirmed the stereotactic biopsy histological findings in eight patients. Follow-up examination showed 14 patients alive with a median survival of 1 year for the entire group. Median survival times after biopsy were 0.83 year for patients with tumor recurrence and 1.86 years for patients with both tumor recurrence and radionecrosis; these findings were significantly different (p = 0.008, log-rank test). No patient with radiation necrosis alone died. Other factors associated with reduced survival were a high proportion of residual tumor (p = 0.024), a low proportion of radionecrosis (p < 0.001), and a Kernohan Grade of × or 4 (p = 0.005). In conclusion, in patients with previously irradiated supratentorial gliomas in whom radionecrosis or tumor recurrence was clinically or radiographically suspected, results of stereotactic biopsy could be used to differentiate tumor recurrence, radiation necrosis, a mixture of both lesions, or radiation-induced neoplasm. In addition, biopsy results could predict survival rates.

The rationale and methodology for intra-arterial chemotherapy with BCNU as treatment for glioblastoma

1985 ◽  
Vol 63 (6) ◽  
pp. 876-880 ◽  
Author(s):  
Fred H. Hochberg ◽  
Amy A. Pruitt ◽  
Deborah O. Beck ◽  
Gerard DeBrun ◽  
Kenneth Davis
Keyword(s):  
Carotid Artery ◽  
Tumor Recurrence ◽  
Recurrent Glioblastoma ◽  
Current Therapy ◽  
Infusion Therapy ◽  
Ocular Complications ◽  
White Matter Changes ◽  
Content Type ◽  
Irradiation Therapy ◽  
Fine Print

✓ The rationale for, methodology of, and experience with intra-arterial BCNU infusion therapy of malignant glioma are described. This approach achieves tumor levels of drug four times greater than equal doses infused intravenously, and has been used to treat 79 patients over the course of 4 years. The drug was given in 192 infraophthalmic and 66 supraophthalmic carotid artery infusions. Patients who were treated via infraophthalmic carotid artery infusion following tumor recurrence (after both operation and irradiation) survived 54 additional weeks (92 weeks after initial diagnosis). Patients who were treated with BCNU immediately after initial irradiation therapy survived 64 weeks (infraophthalmic carotid artery infusion) and 49.5 weeks (supraophthalmic carotid artery infusion). The major ocular complications (pain and diminished visual acuity) associated with infraophthalmic carotid artery infusion are avoided by selective balloon-guided supraophthalmic carotid artery administration. However, both approaches were associated with white-matter changes, seen as diminished absorption on computerized tomography scans, in 20% of patients treated following irradiation therapy. This toxicity appears to preclude intra-arterial BCNU treatment in the immediate postirradiation period. Better results are being achieved with our current therapy, which involves four infusions of BCNU (400 mg every 4 weeks) into the infraophthalmic or supraophthalmic carotid artery in advance of irradiation. Cisplatin infusions (60 to 90 mg/sq m every 5 weeks) are offered for recurrent glioblastoma.

A multidisciplinary team approach to skull base chondrosarcomas

2001 ◽  
Vol 95 (2) ◽  
pp. 184-189 ◽  
Author(s):  
H. Alan Crockard ◽  
Anthony Cheeseman ◽  
Timothy Steel ◽  
Tamas Revesz ◽  
Janice L. Holton ◽  
...  
Keyword(s):  
Skull Base ◽  
Team Approach ◽  
Content Type ◽  
Mean Survival Time ◽  
Cranial Nerve Palsies ◽  
Slow Progression ◽  
The Mean ◽  
Skull Base Chordomas ◽  
Skull Base Chordoma ◽  
Fine Print

Object. The authors review their experience with treating skull base chondrosarcomas, which are much rarer than skull base chordomas and differ from them in prognosis and treatment. Methods. Seventeen patients (12 male and five female patients) with histologically verified chondrosarcomas were followed up prospectively over a 12-year period. The mean age at presentation was 35.9 years. Most patients presented with cranial nerve palsies. Seven had undergone surgery prior to referral to the authors' unit. All underwent maximum surgical cytoreduction by the most direct surgical approach; only the two patients harboring the mesenchymal variant underwent radiotherapy. Conclusions. One patient died of a pulmonary embolus; the patients harboring mesenchymal chondrosarcomas died at 20 and 36 months, respectively, after treatment. Of the remaining patients, 93% were alive 5 years postsurgery and had a projected 10-year survival rate of 84% (mean survival time 9.3 years). These data emphasize the very slow progression of this tumor compared with skull base chordoma.

A light and electron microscopic study of ectopic tendon and ligament formation induced by bone morphogenetic protein—13 adenoviral gene therapy

2001 ◽  
Vol 95 (2) ◽  
pp. 298-307 ◽  
Author(s):  
Gregory A. Helm ◽  
Jin Zhong Li ◽  
Tord D. Alden ◽  
Sarah B. Hudson ◽  
Elisa J. Beres ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Skeletal Development ◽  
Light And Electron Microscopy ◽  
Mesenchymal Cell ◽  
Ultrastructural Changes ◽  
Endochondral Bone Formation ◽  
Electron Microscopic ◽  
Content Type ◽  
Time Points ◽  
Fine Print

Object. Bone morphogenetic proteins (BMPs) are involved in the growth and development of many tissues, but it is their role in skeletal development and their unique ability to induce ectopic and orthotopic osteogenesis that have attracted the greatest interest. Expression of the BMP-13 gene is predominantly localized to hypertrophic chondrocytes in regions of endochondral bone formation during development, as well as in mature articular cartilage in the adult. In addition, the application of BMP-13 on a collagen carrier induces neotendon/neoligament formation when delivered subcutaneously or intramuscularly in rodents. The aim of the present study was to determine the histological and ultrastructural changes that occur after the intramuscular injection of a first-generation BMP-13 adenoviral vector. Methods. Athymic nude rats were injected with 3.75 × 1010 plaque-forming units of adenovirus (Ad)-BMP-13 or Ad-β-galactosidase in the thigh musculature, and the region was examined using light and electron microscopy at various time points between 2 days and 100 days postinjection. As early as 2 days after injection of Ad-BMP-13, progenitor cells were observed infiltrating between the transduced muscle fibers. These cells subsequently proliferated, differentiated, and secreted large amounts of collagenous extracellular matrix. By 100 days postinjection, the treated tissue displayed the histological and ultrastructural appearance of neotendon/neoligament, which was clearly demarcated from the surrounding muscle. Small foci of bone and fibrocartilage were also seen within the treated tissue. A short-term bromodeoxyuridine study also demonstrated rapid mesenchymal cell proliferation at the Ad-BMP-13 injection site as early as 48 hours postinjection. At all time points, the control AD-β-gal injection sites were found to contain only normal muscle, without evidence of inflammation or mesenchymal cell proliferation. Conclusions. The results of this study indicate that in the future the use of the BMP-13 gene may have therapeutic utility for the healing of tendon and ligament tears and avulsion injuries.

Multiple meningiomas: a long-term review

1983 ◽  
Vol 59 (1) ◽  
pp. 1-5 ◽  
Author(s):  
John P. Sheehy ◽  
H. Alan Crockard
Keyword(s):  
Tumor Recurrence ◽  
The Other ◽  
Von Recklinghausen’S Disease ◽  
Von Recklinghausen's Disease ◽  
Content Type ◽  
Multiple Meningiomas ◽  
Recklinghausen's Disease ◽  
Fine Print ◽  
Recklinghausen’S Disease

✓ Ten cases of multiple meningiomas seen over a 34-year period have been reviewed. The total case load from which these cases were selected was 566. The incidence of multiple meningiomas found prior to the introduction of computerized tomography (CT) in this series was 1.1%. The incidence since the introduction of CT was 8%. In eight cases all the tumors were found at the initial presentation and surgery; in the other two cases new tumors were discovered 1 and 4 years later. In only one case was von Recklinghausen's disease known to be present, and this patient developed new tumors. Six cases have been followed for 5 or more years, two for 16 years. Tumor recurrence has not been seen. All the patients were females. There was a higher proportion than usual of the whorling psammomatous type of tumor; papillary, angioblastic or malignant forms were not noted. The possibility of multiple meningiomas being a forme fruste of von Recklinghausen's disease is considered.

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