Sandra Vermeulen

Gamma knife for glioma: Selection factors and survival

PURPOSE To determine factors associated with survival differences in patients treated with radiosurgery for glioma. METHODS AND MATERIALS We analyzed 189 patients treated with Gamma Knife radiosurgery for primary or recurrent glioma World Health Organization (WHO) Grades 1-4. RESULTS CONCLUSION The median minimum tumor dose was 16 Gy (8-30 Gy) and the median tumor volume was 5.9 cc (1.3-52 cc). Brachytherapy selection criteria were satisfied in 65% of patients. Median follow-up of all surviving patients was 65 weeks after radiosurgery. For primary glioblastoma patients, median survival from the date of pathologic diagnosis was 86 weeks if brachytherapy criteria were satisfied and 40 weeks if they were not (p = 0.01), indicating that selection factors strongly influence survival. Multivariate analysis showed that increased survival was associated with five variables: lower pathologic grade, younger age, increased Karnofsky performance status (KPS), smaller tumor volume, and unifocal tumor. Survival was not found to be significantly related to radiosurgical technical parameters (dose, number of isocenters, prescription isodose percent, inhomogeneity) or extent of preradiosurgery surgery. We developed a hazard ratio model that is independent of the technical details of radiosurgery and applied it to reported radiosurgery and brachytherapy series, demonstrating a significant correlation between survival and hazard ratio. CONCLUSIONS Survival after radiosurgery for glioma is strongly related to five selection variables. Much of the variation in survival reported in previous series can be attributed to differences in distributions of these variables. These variables should be considered in selecting patients for radiosurgery and in the design of future studies.

Gamma Knife thalamotomy for treatment of essential tremor: long-term results

OBJECT The goal of this report was to describe the safety and effectiveness of nucleus ventralis intermedius (VIM) thalamotomy performed with the Leksell Gamma Knife (GK) for the treatment of essential tremor (ET). METHODS One hundred seventy-two patients underwent a total of 214 VIM thalamotomy procedures with the Leksell GK between February 1994 and March 2007 for treatment of disabling ET. Eleven patients were lost to follow-up less than 1 year after the procedures, so that in this report the authors describe the results in 161 patients who underwent a total of 203 thalamotomies (119 unilateral and 42 bilateral). RESULTS There were statistically significant decreases (p < 0.0001) in tremor scores for both writing and drawing. The mean postoperative follow-up duration for all patients was 44 +/- 33 months. Fifty-four patients have been followed for more than 60 months posttreatment. There were 14 patients who suffered neurological side effects that were temporary (6) or permanent (8), which accounted for 6.9% of the 203 treatments. All complications were related to lesions that grew larger than expected. CONCLUSIONS A VIM thalamotomy with the Leksell GK offers a safe and effective alternative for surgical treatment of ET. It is particularly applicable to patients who are not ideal candidates for deep brain stimulation but can be offered to all patients who are considering surgical intervention for ET.

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).

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.

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. Int. J. Cancer 76:451–458, 1998.© 1998 Wiley‐Liss, Inc.

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, 53 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. Int. J. Cancer 71:565‐572, 1997.

Accelerated Partial Breast Irradiation: Using the CyberKnife as the Radiation Delivery Platform in the Treatment of Early Breast Cancer.

We evaluate the CyberKnife (Accuray Incorporated, Sunnyvale, CA, USA) for non-invasive delivery of accelerated partial breast irradiation (APBI) in early breast cancer patients. Between 6/2009 and 5/2011, nine patients were treated with CyberKnife APBI. Normal tissue constraints were imposed as outlined in the National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Therapy Oncology Group 0413 (NSABP/RTOG) Protocol (Vicini and White, 2007). Patients received a total dose of 30 Gy in five fractions (group 1, n = 2) or 34 Gy in 10 fractions (group 2, n = 7) delivered to the planning treatment volume (PTV) defined as the clinical target volume (CTV) +2 mm. The CTV was defined as either the lumpectomy cavity plus 10 mm (n = 2) or 15 mm (n = 7). The cavity was defined by a T2-weighted non-contrast breast MRI fused to a planning non-contrast thoracic CT. The CyberKnife Synchrony system tracked gold fiducials sutured into the cavity wall during lumpectomy. Treatments started 4–5 weeks after lumpectomy. The mean PTV was 100 cm3 (range, 92–108 cm3) and 105 cm3 (range, 49–241 cm3) and the mean PTV isodose prescription line was 70% for groups 1 and 2, respectively. The mean percent of whole breast reference volume receiving 100 and 50% of the dose (V100 and V50) for group 1 was 11% (range, 8–13%) and 23% (range, 16–30%) and for group 2 was 11% (range, 7–14%) and 26% (range, 21–35.0%), respectively. At a median 7 months follow-up (range, 4–26 months), no acute toxicities were seen. Acute cosmetic outcomes were excellent or good in all patients; for those patients with more than 12 months follow-up the late cosmesis outcomes were excellent or good. In conclusion, the lack of observable acute side effects and current excellent/good cosmetic outcomes is promising. We believe this suggests the CyberKnife is a suitable non-invasive radiation platform for delivering APBI with achievable normal tissue constraints.

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

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.

A non-contacting intraoperative electron cone apparatus.

Aluminum tubes, 20 cm long, of various diameter and face angle have been used to collimate electron beams for intraoperative radiotherapy. The tubes placed in a body cavity are clamped to the treatment couch. A thin rod is fixed coaxially to a disc which is placed on the entrance face of the tube. A stepwise procedure involving couch translation, rotation, and gantry rotation is used to align the central axis of the beam with the axis of the cone. Further collimation is provided by an aperture mounted in an assembly which slides into the standard accessory holder of the machine and is separated by a 10 cm air gap from the tube in the patient. Careful adjustment of this aperture diameter results in a relatively uniform dose across the treated area. The use of 3 mm wall thickness aluminum tube provides for minimal leakage outside of the cone. A camera has been mounted to a plate that also mounts in the standard accessory holder and is used to document the area treated.

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

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.