Gamma knife radiosurgery as a lesioning technique in movement disorder surgery.

OBJECT: To increase knowledge of the safety and efficacy of the use of gamma knife radiosurgery in patients with movement disorders, the authors describe their own experience in this field and include blinded independent assessments of their results. METHODS: Fifty-five patients underwent radiosurgical placement of lesions either in the thalamus (27 patients) or globus pallidus (28 patients) for treatment of movement disorders. Patients were evaluated pre- and postoperatively by a team of observers skilled in the assessment of gait and movement disorders who were blinded to the procedure performed. The observers were not associated with the surgical team and concomitantly and blindly also assessed a group of 11 control patients with Parkinson's disease who did not undergo any surgical procedures. All stereotactic lesions were made with the Leksell gamma unit using the 4-mm secondary collimator helmet and a single isocenter with maximum doses from 120 to 160 Gy. Clinical follow-up evaluation indicated that 88% of patients who underwent thalamotomy became tremor free or nearly tremor free. Statistically significant improvements in performance were noted in the independent assessments of Unified Parkinson's Disease Rating Scale (UPDRS) scores in the patients undergoing thalamotomy. Of patients undergoing pallidotomy who had exhibited levodopainduced dyskinesias, 85.7% had total or near-total relief of that symptom. Clinical assessment indicated improvements in bradykinesia and rigidity in 64.3% of patients who underwent pallidotomy. Independent blinded assessments did not reveal statistically significant improvements in Hoehn and Yahr scores or UPDRS scores. On the other hand, 64.7% of patients showed improvements in subscores of the UPDRS, including activities of daily living (58%), total contralateral score (58%), and contralateral motor scores (47%). Total ipsilateral score and ipsilateral motor scores were both improved in 59% of patients. One (1.8%) of 55 patients experienced a homonymous hemianopsia 9 months after pallidotomy due to an unexpectedly large lesion. No other complications of any kind were seen. Neuropsychological test scores that were obtained for the combined pallidotomy and thalamotomy treatment groups preoperatively and at 6 months postoperatively demonstrated an absence of cognitive morbidity. Follow-up neuroimaging confirmed correct lesion location in all patients, with a mean maximum deviation from the planned target of 1 mm in the vertical axis. Measurements of lesions at regular intervals on postoperative magnetic resonance images demonstrated considerable variability in lesion volumes. The safety and efficacy of functional lesions made with the gamma knife appear to be similar to those made with the assistance of electrophysiological guidance with open functional stereotactic procedures. CONCLUSIONS: Functional lesions may be made safely and accurately using gamma knife radiosurgical techniques. The efficacy is equivalent to that reported for open techniques that use radiofrequency lesioning methods with electrophysiological guidance. Complications are very infrequent with the radiosurgical method. The use of functional radiosurgical lesioning to treat movement disorders is particularly attractive in older patients and in those with major systemic diseases or coagulopathies; its use in the general movement disorder population seems reasonable as well.

Application of the differential hybridization of Atlas Human expression arrays technique in the identification of differentially expressed genes in human glioblastoma multiforme tumor tissue.

BACKGROUND AND OBJECTIVES: Several molecular biology techniques are utilized to study changes in gene expression during the genesis of human tumors. Our objective was to identify genes that showed altered expression between normal brain tissue (NBT) and glioblastoma multiforme tumor tissue (GMTT). METHODS: The technique of differential hybridization of two Atlas Human cDNA expression array was used. In this technique, dCTP32-labeled complimentary DNA from NBT and GMTT was hybridized to two identical human cDNA expression array membranes containing 588 known genes. RESULTS: Autoradiographic analysis showed that of the 588 genes analyzed, 52 are overexpressed in GMTT and 57 in NBT. A gene-specific semiquantitative reverse transcription polymerase chain reaction (RT-PCR) method was used to confirm the expression pattern of seven known genes. RT-PCR results demonstrate that the expression pattern of a majority of genes agreed with the expression pattern observed on expression array. The known tumor suppressor genes retinoblastoma (RB) and p53 showed loss of expression in GMTT compared with NBT. CONCLUSIONS: We conclude that the differential hybridization technique of Atlas Human cDNA expression array can be a useful method in identifying genes that are differentially expressed either in NBT or GMTT.

Cell adhesion molecule Nr-CAM is over-expressed in human brain tumors.

Using the technique of differential display-polymerase chain reaction (DD-PCR), we isolated a cDNA fragment that is over-expressed in glioblastoma multiforme tissue as compared to normal brain tissue. Sequence analysis indicated that this sequence is identical to the previously isolated human neuron-glia-related cell adhesion molecule hNr-CAM. Gene-specific RT-PCR analysis indicated that hNr-CAM is over-expressed in high-grade astrocytomas, gliomas and glioblastoma tumor tissues as compared to normal brain tissue. High levels of hNr-CAM expression also were observed in cell lines derived from astrocytomas, gliomas and glioblastoma multiforme tumors. Low levels of hNr-CAM expression were observed in neuroblastoma, meningiomas, melanoma, normal breast and prostate tumor tissues. Northern blot analysis showed an alternatively spliced mRNA of 1.4 kb in several tumors as compared to the 7.5 kb transcript found in normal brain tissue. Genomic Southern blot analysis of DNA from 3 brain tumor cell lines showed that over-expression of hNr-CAM in brain tumors was not due to gene amplification. In situ hybridization analysis indicated that 11 of the 20 human brain tumor samples studied showed hNr-CAM over-expression. Our results suggest that hNr-CAM is over-expressed in malignant brain tumors and can serve as a novel marker for brain tumor detection and perhaps therapy.

Whole brain radiotherapy in the treatment of metastatic brain tumors.

Previous prospective and retrospective trials have failed to demonstrate the best treatment approach for patients with brain metastases. As a result, fractionated whole brain radiotherapy (WBRT) has been the mainstay of treatment for several decades. However, with improved surgical techniques and the advent of radiosurgical procedures to treat single and multiple metastases, the continued value of WBRT is in question. This is particularly true in the treatment of a favorable patient subset where the risks of long-term morbidity need to be addressed. This article reviews the trials of the Radiation Therapy Oncology Group (RTOG) and other select radiotherapy brain metastases trials, and compares their morbidities and outcomes to surgical and radiosurgical techniques. It is unfortunate that the inherent selection bias in most retrospective studies makes comparisons difficult. Therefore, to better understand the roles of WBRT, surgery, and radiosurgery in the treatment of brain metastases, additional randomized studies need to be conducted on homogeneous patient groups.

Cloning, sequence, and developmental expression analysis of C4-2, a potential brain tumor-suppressor gene.

BACKGROUND: Previously, we reported the isolation of C4-2 as a potential tumor suppressor gene in human brain tumors. To understand the function of this gene, we investigated its molecular characterization and expression during development. METHODS: Human fetal brain library screening and 5'RACE-PCR method was used to isolate the full-length cDNA. The coding region of C4-2 was used for in situ hybridization to study its expression during development. RESULTS: We report here the complete sequence of this gene. Sequence analysis indicated that C4-2 has a 94% sequence identity to a family of cAMP-regulated phosphoproteins (ARPP-16/19) in the coding region. C4-2 has a 3.1 Kb long 3'UTR with variable identity to ARPP-16 and ARPP-19. Northern blot analysis indicated that C4-2 is expressed at high levels in normal brain compared to other tissues. Zoo blot analysis demonstrated that the coding region of C4-2 is highly conserved among different animals. In situ hybridization using C4-2 coding region demonstrated that it follows a unique expression pattern during mouse brain development. High level of C4-2 expression was also observed in the spinal cord and somites of the developing embryo. CONCLUSION: Expression analysis during brain development strongly suggests that this family of proteins may play an important role not only in normal functioning of the brain, but also during brain development.

Isolation and characterization of a novel gene from human glioblastoma multiforme tumor tissue.

Using the technique of DD-PCR (differential display-polymerase chain reaction) we isolated a novel gene (D2-2) that is overexpressed in glioblastoma multiforme tissue (GMT) as compared to normal brain tissue (NBT). D2-2 is also highly expressed in recurrent glioma, colon tumor metastatic to brain, breast tumors, prostate tumors and a prostate tumor cell line (LNCaP). Northern blot analysis showed that D2-2 is highly expressed in several tumor cell lines (MOLT lymphoblastic leukemia, SW480 colorectal adrenocarcinoma, A549 lung carcinoma, HL-60 promyelocytic leukemia, S3 HeLa cells, K-562 chronic myelogeneous leukemia and G361 melanoma) as compared to NBT. Additionally, D2-2 is very highly expressed in cell lines derived from glioblastomas, grade IV astrocytomas, normal human fetal astrocytes (NHFA) and glioma. D2-2 is moderately expressed in neuroblastoma, neuroectodermal and medulloblastoma tumor cell lines. D2-2 expression is localized to the frontal lobe, occipital lobe and the cerebellum in the normal brain. Normal tissues such as thyroid, stomach, adrenal cortex, small intestine and pancreas show high expression of D2-2. We also show that D2-2 is expressed 28-fold higher in fetal brain (20 weeks) than in adult brain. Sequence analysis of a 2.0-kb fragment for D2-2 shows no homology to known sequences in the data base.

Gamma Knife radiosurgery for treatment of trigeminal neuralgia: idiopathic and tumor related.

Sixty patients with trigeminal neuralgia who did not have a response to pharmacologic treatment (including 22 who had no response to conventional surgical treatment) underwent stereotactic radiosurgical treatment with the Leksell Gamma Knife. A radiosurgical maximum dose of 70 Gy was delivered to the trigeminal nerve root adjacent to the pons via a 4-mm collimator helmet in 51 patients who presented with trigeminal neuralgia unrelated to tumors. In these patients, the root was localized by stereotactic MRI. Follow-up assessment of pain relief was accomplished by a third party not involved in the patients' clinical care. Within a latency period of 1 day to 4 months following the treatment, 38 of 51 patients (74.5%) were completely free of pain and eventually all medications were tapered off. An additional seven patients (13.7%) experienced reductions in pain from 50 to 90% and utilized little or no medications. Patients who had no prior surgical intervention fared much better than those who had previous surgery to relieve their facial pains. At last follow-up, a mean of 16.3 months (range 6-36 months) after treatment, 41 patients (80.4%) remained pain-free or had marked pain reduction. There were four patients with recurrent pain. All 26 patients with classical symptoms of trigeminal neuralgia with no atypical features who had no prior surgery, had complete or nearly complete pain relief, and none of these patients had recurrent pain. Nine patients with trigeminal neuralgia due to tumors received standard radiosurgical treatment directed at their tumors, and eight of nine (88.8%) had pain relief. Of the total of 60 patients treated for trigeminal neuralgia, 49 (81.7%) experienced complete or nearly complete relief of pain at last follow-up. Only one patient with pre-existing facial sensory loss due to a tumor had a mild increase in facial numbness. No other patient experienced either loss of facial sensation or any other complication. Gamma Knife radiosurgery appears to be a minimally invasive, safe, and effective therapy of trigeminal neuralgia.

Gamma knife radiosurgery as a lesioning technique in movement disorder surgery.

Fifty-five patients underwent radiosurgical placement of lesions either in the thalamus (27 patients) or globus pallidus (28 patients) for treatment of movement disorders. Patients were evaluated pre- and postoperatively by a team of observers skilled in the assessment of gait and movement disorders who were blinded to the procedure performed. They were not associated with the surgical team and concomitantly and blindly also assessed a group of 11 control patients with Parkinson's disease who did not undergo any surgical procedures. All stereotactic lesions were made with the Leksell gamma unit using the 4-mm secondary collimator helmet and a single isocenter with dose maximums from 120 to 160 Gy. Clinical follow-up evaluation indicated that 88% of patients who underwent thalamotomy became tremor free or nearly tremor free. Statistically significant improvements in performance were noted in the independent assessments of Unified Parkinson's Disease Rating Scale (UPDRS) scores in the patients undergoing thalamotomy. Eighty-five and seven-tenths percent of patients undergoing pallidotomy who had exhibited levodopa-induced dyskinesias had total or near-total relief of that symptom. Clinical assessment indicated improvement of bradykinesia and rigidity in 64.3% of patients who underwent pallidotomy. Independent blinded assessments did not reveal statistically significant improvements in Hoehn and Yahr scores or UPDRS scores. On the other hand, 64.7% of patients showed improvements in subscores of the UPDRS, including activities of daily living (58%), total contralateral score (58%), and contralateral motor scores (47%). Ipsilateral total UPDRS and ipsilateral motor scores were both improved in 59% of patients. One (1.8%) of 55 patients experienced a homonymous hemianopsia 9 months after pallidotomy due to an unexpectedly large lesion. No other complications of any kind were seen. Follow-up neuroimaging confirmed correct lesion location in all patients, with a mean maximum deviation from the planned target of 1 mm in the vertical axis. Measurements of lesions at regular interals on postoperative magnetic resonance images demonstrated considerable variability in lesion volumes. The safety and efficacy of functional lesions made with the gamma knife appear to be similar to those made with the assistance of electrophysiological guidance with open functional stereotactic procedures. Functional lesions may be made safely and accurately using gamma knife radiosurgical techniques. The efficacy is equivalent to that reported for open techniques that use radiofrequency lesioning methods with electrophysiological guidance. Complications are very infrequent with the radiosurgical method. The use of functional radiosurgical lesioning to treat movement disorders is particularly attractive in older patients and those with major systemic diseases or coagulopathies; its use in the general movement disorder population seems reasonable as well.

Characterization of C4-2 as a tumor-suppressor gene in human brain tumors.

BACKGROUND: Brain tumors claimed the lives of 13,300 people in 1995. Our objective was to isolate and characterize unique tumor-suppressor genes from human brain tumors derived from patients in the United States. METHODS: Differential display-polymerase chain reaction was used to isolate tumor suppressor genes. RESULTS: Clone C4-2 was isolated and is expressed in normal adult human brain, but not in brain tissue from glioblastoma multiforme tumors. C4-2 has 66% homology to the previously isolated ARPP-16 (cAMP-regulated phosphoprotein of Mr = 16,000) based on limited sequencing. C4-2 is expressed at high levels in normal brain and is not expressed or expressed at low levels in several brain tumor cell lines. Expression of C4-2 was also either not expressed or expressed at low levels in meningioma, B-cell lymphoma, recurrent glioma, LNCAP (prostate tumor cell line), breast tumor, or prostate tumor tissue. CONCLUSION: We conclude that C4-2 may function as a potential tumor-suppressor gene.

Electrophysiological target localization is not required for the treatment of functional disorders.

A total of 117 patients underwent 124 functional stereotactic procedures with the Leksell Gamma Knife to treat trigeminal neuralgia, movement disorders and chronic pain. Target identification was performed with stereotactic magnetic resonance imaging alone without electrophysiologic localization. Clinical observation of these patients over 1-41 months indicates that the efficacy of the procedure is comparable with that seen with open stereotactic procedures where electrophysiological localization is used. Using current techniques, the complications of functional neurosurgery with the Gamma Knife are nearly nonexistent. We believe that functional neurosurgery can be performed effectively and safely without electrophysiological localization, using the Leksell Gamma Knife.

An estimate of the margin required when defining blocks around the prostate.

The portal films of 54 consecutive patients treated for primary prostate cancer have been compared to the simulation films. The systematic and random uncertainty in the set-up, defined by the couch movement required to move the patient to the simulated position, was determined to be 1.6 mm UP (SD 3.3 mm), 0.3 mm RT (SD 2.6 mm) and 1.3 mm IN (SD 2.4 mm). The area of fields defined on simulation films was compared with that on portal films to determine the error in block production which was -0.7 mm (SD = 0.9 mm). Five sources of uncertainty in the radiotherapy have been identified, three occur before and two during the course of treatment. A method for combining these uncertainties is proposed and used on the data obtained in this study. This provides estimates of the margin required when drawing blocks so that the minimum dose to the target is 95% of the prescription in 95% of treatments. The block margins are not uniform and range from 21 mm, when drawing the block outline to the posterior on a lateral film, to 13 m when drawing laterally on an anterior film.

Technique of stereotactic medial thalamotomy with the Leksell Gamma Knife for treatment of chronic pain.

Nineteen patients underwent a total of 24 medial thalamic lesions made with the Leksell Gamma Knife for the treatment of chronic intractable pain after extensive prior medical and surgical intervention had failed to provide pain relief. The lesion locations were based on prior experience with open radiofrequency medial thalamotomies for the treatment of pain and were directed at the intralaminar, mediodorsal, centromedian, and parafascicular nuclei. All lesions were made with the 4 mm collimator helmet at radiosurgical doses from 140-180 Gray. Follow-up MRI scans indicated anatomically distinct lesions which developed 3-6 weeks after the procedure and were fully formed by 8-12 weeks. The lesion volumes averaged 300-400 mm3 for a single isocentre, 600-900 mm3 for two isocentres, and 900-1100 mm3 for three isocentres. One patient developed a lesion 5500 mm3 in volume after a two isocentre lesion at 160 Gray. Of 15 patients who have been followed for more than 3 months (average follow-up 12 months) four patients (27%) are virtually pain free and functioning normally, whereas five other patients (33%) achieved greater than 50% pain relief. Thus 9/15 patients (60%) have had worthwhile benefit from medial thalamotomy with the Gamma Knife. Medial thalamotomy with the Gamma Knife produces thalamic lesions which are reliable in size, shape and location with a low complication rate and offers a minimally invasive, cost effective treatment for certain selected patients with chronic intractable pain.

Gamma Knife thalamotomy for the treatment of persistent pain.

Twenty patients who suffered persistent intractable pain from a variety of disorders underwent medial thalamotomy with the Leksell Gamma Knife. The lesions were directed at the intralaminar nuclei, the lateral portion of the medial dorsal nucleus, the centromedian and the parafascicular nuclei. Lesions were made with radiation doses from 140 to 180 Gy using a 4-mm beam collimator helmet and either a single isocenter (1 patient), two isocenters (17 patients) or three isocenters (2 patients). Two thirds of the patients experienced either excellent or good pain relief in a follow-up period between 1 and 22 months. One patient showed temporary complications which resolved, and 2 other patients also suffered complications which currently are improving. One patient died due to radiation necrosis following a bilateral thalamotomy. Gamma Knife thalamotomy may offer a potentially safe and effective alternative for the treatment of certain difficult persistent pain problems.

A frameless method for stereotactic radiotherapy.

A frameless method for stereotactic multiple arc radiotherapy (SMART) is described. Three short gold wires are implanted in the scalp approximately 100 mm apart. These are localized in a computed tomographic or angiographic study along with the target. Subsequently the gold markers are localized on beam films and the target position calculated using a computer program ISOLOC. This program provides the couch movements required to move the target to the isocentre and a micropositioner attached to the couch is used to make the adjustment. Beam films are repeated until the movements required are less than 1 mm in any direction. It is shown that the simple procedures of implanting the markers subcutaneously do not provide a stable reference system in about 25% of patients and the markers are now screwed into the cranium. The precision of the method is evaluated by phantom studies and measurements taken during several hundred treatments.