Jean-Guy Villemure

Using pattern analysis of in vivo proton MRSI data to improve the diagnosis and surgical management of patients with brain tumors.

We have used pattern analysis of proton magnetic resonance spectroscopic imaging (1H MRSI) data in a variety of situations related to the clinical management of patients with brain tumors and other cerebral space‐occupying lesions (SOLs). Here, we review how ‘leave‐one‐out’ linear discriminant analyses (LDAs) of in vivo 1H MRSI spectral patterns have enabled us to quickly, accurately, and non‐invasively: (1) discriminate amongst tissue arising from the five most common types of supratentorial tumors found in adults, and (2) use the metabolic heterogeneity of cerebral SOLs to predict certain pathological characteristics that are useful in guiding stereotaxic biopsy and selective tumor resection. These findings suggest that pattern analysis of 1H MRSI data can significantly improve the diagnostic specificity and surgical management of patients with certain cerebral SOLs.

Fractionated stereotactic radiation therapy for intracranial tumors.

In stereotactic radio surgery, a single, large dose of radiation is delivered to a small, well‐defined, stereotactically localized intracranial lesion. In contrast to conventional radiation therapy, in radio surgery no attempt is made to spare normal cells within the target volume by fractionating the tumor dose. In 1987, the authors began a program of fractionated stereotactic radiation therapy for selected tumors involving sensitive brain structures. Their objective was to improve the therapeutic index and study the feasibility of the fractionated technique. Fifteen patients were treated with a multifraction regimen typically consisting of six fractions of 700 cGy each, given on alternate days for 2 weeks (total tumor dose, 4200 cGy). All patients were treated with the dynamic stereotactic radio surgical technique. A head ring (“halo frame”) was used for immobilization and setup during radiation treatments. At a median follow‐up time of 27 months, the symptoms of the majority of the patients improved clinically; this improvement usually occurred within a few weeks after completion of the treatment. The radiologic response was much slower. Currently, only two patients have had complete radiologic disappearance of their lesions; the majority of the patients have only had a decrease in tumor size. The treatments were well tolerated by the patients and no acute complications were observed. One patient who had a vasogenic edema 11 months after treatment fully recovered after steroid therapy. Fractionated stereotactic radiation therapy is a feasible treatment technique and may prove to be useful for selected patients with intracranial tumors. Although the preliminary data are encouraging, this technique should still be considered experimental. A larger number of patients and a longer follow‐up time are necessary to determine whether the results of this technique are actually better than those of conventional radiation therapy. Cancer 68:2101–2108.

Low-grade pure and mixed cerebral astrocytomas treated in the CT scan era

SummaryFrom 1974 to 1992, 63 patients diagnosed with low-grade pure or mixed oligo-astrocytoma were seen and treated at our institution. All patients underwent CT scan pre-operatively. There were 20 female and 43 males ranging in age from 12 to 73 years (median age of 33 years). 15 patients had a stereotactic biopsy as the only surgical procedure. 34 had a partial tumor resection and 14 a gross total tumor resection.43 patients were treated with post-operative radiotherapy whereas 20 patients underwent surgery only as part of the initial management. 50 to 60 Gy (median 59.4 Gy) were given with daily fractions of 1.8 to 2 Gy. Tumor volume ranged from 3.4 to 441 cm3. Median tumor volume was larger for radiotherapy treated patients.Median follow-up was 54 months (range of 4 to 240 months). The overall 10 and 15 actuarial survival rates were 37% and 25% respectively. The 5 year survival rate for patients treated at initial diagnosis with surgery alone was 66% and it was 67.3% for patients treated with radiation therapy (P = NS). Prognostic factors having independant significant impact on survival were: extent of surgery, age, gender and tumor volume.As well, survival for patients with low-grade astrocytoma in the CT scan era appears to be improved compared to historical controls in the literature.

Radiosurgery and accelerated radiotherapy for patients with glioblastoma

OBJECTIVEnTo assess the feasibility, toxicity, and local control of stereotactic radiosurgery followed by accelerated external beam radiotherapy (AEBR) for patients with glioblastoma multiforme.nnnMATERIALS AND METHODSnSix males and eight females, with a median age of 67.5 years (range 45-78 years), entered the study. Karnofsky performance status was 90 for five, 80 for six, and 60 for three patients. Following surgery, the patients were left with a residual mass 4 cm. Radiosurgery was delivered with a single dose of 20 Gy to the 90% isodose surface corresponding to the contrast-enhancing edge of the tumour. A total AEBR dose of 60 Gy in 30 fractions was delivered using a concomitant boost technique over four weeks.nnnRESULTSnMedian survival time was 40 weeks (range 17-80 weeks). Actuarial survivals at 12 and 18 months were 43% and 14%, respectively. The median time to progression was 25 weeks (range 2-77 weeks). One patient developed a seizure on the day of stereotactic radiosurgery. Two patients experienced somnolence at 47 and 67 days post-radiotherapy. Eight patients remained steroid-dependent. Radiological evidence of leukoencephalopathy was observed in one patient, and brain necrosis in two additional patients at 30 and 63 weeks. One of these two patients with brain necrosis developed complete loss of vision in one eye, and decreased vision in the contralateral eye at 63 weeks.nnnCONCLUSIONnStereotactic radiosurgery followed by AEBR was feasible but was associated with late complications. The use of such radiosurgical boost for patients with glioblastoma multiforme should be reserved for those patients entering controlled clinical trials.

Early and Late Complications Following Dynamic Stereotactic Radiosurgery and Fractionated Stereotactic Radiotherapy

Between December 1986 and June 1990, 112 patients (116 lesions), underwent treatment with dynamic stereotactic radiosurgery at McGill University. Of the treated lesions, 59 were arteriovenous malformations and 53 were a variety of other neoplastic conditions. In 86 lesions, the treatment was delivered in a single fraction and the treatment of the remaining 30 lesions was fractionated. Complications attributed to treatment developed in seven of the 112 patients (6.3%). No relationship was found between complications and prescribed dose, fractionation, collimator diameter, type and anatomical region of the lesion that was treated, or previous irradiation. Although extensive clinical experience will be necessary to determine optimal total doses, the potential role of fractionated treatment, and the tolerance of critical structures to radiosurgery, the relatively low incidence of complications in our series allows us to conclude that radiosurgery is well tolerated by the vast majority of patients.

Prospective serial proton MR spectroscopic assessment of response to tamoxifen for recurrent malignant glioma

Objective Early prediction of imminent failure during chemotherapy for malignant glioma has the potential to guide proactive alterations in treatment before frank tumor progression. We prospectively followed patients with recurrent malignant glioma receiving tamoxifen chemotherapy using proton magnetic resonance spectroscopic imaging (1H-MRSI) to identify intratumoral metabolic changes preceding clinical and radiological failure. Methods We performed serial 1H-MRSI examinations to assess intratumoral metabolite intensities in 16 patients receiving high-dose oral tamoxifen monotherapy for recurrent malignant glioma (WHO grade III or IV) as part of a phase II clinical trial. Patients were followed until treatment failure, death, or trial termination. Results Patients were officially classified as responders (7 patients) or non-responders (9 patients) 8xa0weeks into treatment. At 8xa0weeks, responders and non-responders had different intratumoral intensities across all measured metabolites except choline. Beyond 8xa0weeks, metabolite intensities remained stable in all responders, but changed again with approaching disease progression. Choline, lipid, choline/NAA, and lactate/NAA were significantly elevated (Pxa0<xa00.02), while creatine (Pxa0<xa00.04) was significantly reduced, compared to stabilized levels on average 4xa0weeks prior to failure. Lactate was significantly elevated (Pxa0=xa00.036) fully 8xa0weeks prior to failure. In one patient who was still responding to tamoxifen at the conclusion of the trial, metabolite intensities never deviated from 8-week levels for the duration of follow-up. Conclusions Characteristic global intratumoral metabolic changes, detectable on serial 1H-MRSI studies, occur in response to chemotherapy for malignant glioma and may predict imminent treatment failure before actual clinical and radiological disease progression.

Malignant glioma-derived soluble factors regulate proliferation of normal adult human astrocytes

Malignant gliomas are characteristically surrounded by marked gliosis. To assess whether glioma-derived products contribute to the proliferation of astrocytes, a feature of the gliosis response, we evaluated the influence of culture supernatants from malignant human glioma lines and tumor cyst fluids collected from two patients with glioblastoma multiforme on the proliferation of non-transformed adult human astrocytes. Both the culture supernatants and cyst fluids significantly increased DNA synthesis in astrocytes as assessed by a double immunofluorescence glial fibrillary acidic protein-bromodeoxyuridine technique. The net proliferative effect mediated by glioma cell line supernatants was tumor growth phase-dependent, being preferentially expressed during the logarithmic phase of glioma cell growth. Specific growth factor molecules and cytokines known to be secreted by gliomas (epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor-ß, interleukin-6, and tumor necrosis factor-a) could not reproduce the mitogenic effects of the glioma-derived soluble factors. Cytokines which can induce DNA synthesis by adult human astrocytes in vitro, gamma-interferon and interleukin-1, were not detected in the culture supernatant of glioma lines used in this study. In conjunction with the documented effects of glioma products on endothclial and lymphoid cells, the current study suggests that soluble glioma products can contribute to the production of surrounding gliosis observed in vivo.

T Cell-mediated Cytotoxicity of Human Gliomas

Cellular immune effector mechanisms are implicated as potential therapies for malignant gliomas. We have examined the potential for anti-CD3-activated human peripheral blood-derived CD4+ and CD8+ T cells to induce lysis of human glioma cell lines in vitro, the mechanism of action of these cells, and the capacity of the glioma to inhibit the effect. We found that activated CD4+ and CD8+ T cell preparations containing less than 5% natural killer cells could induce significant lysis of the glioma cell line U251, as measured by an 18-hour, but not 5-hour, chromium-51 or lactate dehydrogenase release assay. This effect was not reproduced using recombinant tumor necrosis factor or inhibited with antitumor necrosis factor antibody. Anti-lymphocyte functional antigen-1 and anti-intercellular adhesion molecule antibodies also did not inhibit the effect. Glioma-derived supernatant could inhibit the proliferation of the T cells but not the cytotoxic effect. Human fetal astrocytes were also susceptible to the cytotoxic effect of the activated T cells. These results indicate that activated T cells can induce glioma cytotoxicity via a mechanism independent of tumor necrosis factor. The therapeutic potential of this effector mechanism will depend on its capacity to deliver these cells or their specific effector molecules to the tumor site or to augment the activity of such cells, which accumulate naturally in gliomas.

Metástase cerebral: tratamento paliativo com radiocirurgia

This is a retrospective review of 52 patients with metastatic brain disease who underwent stereotactic radiosurgery at McGill University in Montreal. The radiosurgical treatment was performed with the dynamic rotation technique in which there is continuous and simultaneous movement of treatment couch and machine gantry of a 10 MV linac. All patients were treated with a single isocenter and a median dose of 1800 cGy was delivered. In 88% of the cases radiosurgery was given after failure from whole brain conventional irradiation. All 52 cases were assessed with brain CT post radiosurgery. The median follow up time was 6 months (range 1 -37 months) and the response rate (partial or complete) was 64%. Only 4 patientes (7%) developed late complications related to the treatment. These findings are similar to the literature. Stereotactic radiosurgery is a well tolerated, effective and minimally invasive treatment technique which has a high response rate in selected patients with small, well delineated metastatic brain lesion. Its definitive value as a single therapy or combined with whole brain conventional radiotherapy is being studied in prospective and randomized trials.