R. Leblanc

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.

THE USE OF HYPOFRACTIONATED INTENSITY-MODULATED IRRADIATION IN THE TREATMENT OF GLIOBLASTOMA MULTIFORME: PRELIMINARY RESULTS OF A PROSPECTIVE TRIAL

PURPOSEnDespite major advances in treatment modalities, the prognosis of patients with glioblastoma multiforme (GBM) remains poor. Exploring hypofractionated regimens to replace the standard 6-week radiotherapy schedule is an attractive strategy as an attempt to prevent accelerated tumor cell repopulation. There is equally interest in dose escalation to the gross tumor volume where the majority of failures occur. We report our preliminary results using hypofractionated intensity-modulated accelerated radiotherapy regimen in the treatment of patients with GBM.nnnMETHODS AND MATERIALSnBetween July 1998 and December 2001, 25 patients with histologically proven diagnosis of GBM, Karnofsky performance status > or =60, and a postoperative tumor volume < or =110 cm3 were treated with a hypofractionated accelerated course of radiotherapy. The gross tumor volume (GTV) was defined as the contrast-enhancing lesion on the postoperative MRI T1-weighted images with the latter fused with computed tomography images for treatment planning. The planning target volume was defined as GTV + 1.5-cm margin. Using forward-planning intensity modulation (step-and-shoot technique), 60 Gy in 20 daily fractions of 3 Gy each were given to the GTV, whereas the planning target volume received a minimum of 40 Gy in 20 fractions of 2 Gy each at its periphery. Treatments were delivered over a 4-week period using 5 daily fractions per week. Dose was prescribed at the isocenter (ICRU point). Three beam angles were used in all of the cases.nnnRESULTSnTreatments were well tolerated. Acute toxicity was limited to increased brain edema during radiotherapy in 2 patients who were on tapering doses of corticosteroids. This was corrected by increasing the steroid dose. At a median follow-up of 8.8 months, no late toxicity was observed. One patient experienced visual loss at 9 months after completion of treatment. MRI suggested nonspecific changes to the optic chiasm. On review of the treatment plan, the total dose to the optic chiasm was confirmed to be equal to or less than 40 Gy in 20 fractions. When Radiation Therapy Oncology Group recursive partitioning analysis was used, 10 patients were class III-IV, and 15 patients were class V-VI. To date, 21 patients have had clinical and/or radiologic evidence of disease progression, and 16 patients have died. The median survival was 9.5 months (range: 2.8-22.9 months), the 1-year survival rate was 40%, and the median progression-free survival was 5.2 months (range: 1.9-12.8 months).nnnCONCLUSIONnThis hypofractionated accelerated irradiation schedule using forward planning (step-and-shoot) hypofractionated, intensity-modulated accelerated radiotherapy is feasible and seems to be a safe treatment for patients with GBM. A 2-week reduction in the treatment time may be of valuable benefit for this group of patients. However, despite this accelerated regimen, no survival advantage has been observed.

Proton magnetic resonance spectroscopic imaging can predict length of survival in patients with supratentorial gliomas.

OBJECTIVEWe compared the ability of proton magnetic resonance spectroscopic imaging (1H-MRSI) measures with that of standard clinicopathological measures to predict length of survival in patients with supratentorial gliomas. METHODSWe developed two sets of leave-one-out logistic regression models based on either 1) intratumoral 1H-MRSI features, including maximum values of a) choline and b) lactate-lipid, c) number of 1H-MRSI voxels with low N-acetyl group values, and d) number of 1H-MRSI voxels with high lactate-lipid values, all (a–d) of which were normalized to creatine in normal-appearing brain, or 2) standard clinicopathological features, including a) tumor histopathological grade, b) patient age, c) performance of surgical debulking, and d) tumor diagnosis (i.e., oligodendroglioma, astrocytoma). We assessed the accuracy of these two models in predicting patient survival for 6, 12, 24, and 48 months by performing receiver operating characteristic curve analysis. Cox proportional hazards analysis was performed to assess the extent to which patient survival could be explained by the above predictors. We then performed a series of leave-one-out linear multiple regression analyses to determine how well patient survival could be predicted in a continuous fashion. RESULTSThe results of using the models based on 1H-MRSI and clinicopathological features were equally good, accounting for 81 and 64% of the variability (r2) in patients’ actual survival durations. All features except number of 1H-MRSI voxels with lactate-lipid/creatine values of at least 1 were significant predictors of survival in the 1H-MRSI model. Two features (tumor grade and debulking) were found to be significant predictors in the clinicopathological model. Survival as a continuous variable was predicted accurately on the basis of the 1H-MRSI data (r = 0.77, P < 0.001; median prediction error, 1.7 mo). CONCLUSIONOur results suggest that appropriate analysis of 1H-MRSI data can predict survival in patients with supratentorial gliomas at least as accurately as data derived from more invasive clinicopathological features.

Accelerated hypofractionated intensity-modulated radiotherapy with concurrent and adjuvant temozolomide for patients with glioblastoma multiforme: a safety and efficacy analysis.

PURPOSEnDespite multimodality treatments, the outcome of patients with glioblastoma multiforme remains poor. In an attempt to improve results, we have begun a program of accelerated hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concomitant and adjuvant temozolomide (TMZ).nnnMETHODS AND MATERIALSnBetween March 2004 and June 2006, 35 unselected patients with glioblastoma multiforme were treated with hypo-IMRT. During a 4-week period, using a concomitant boost technique, a dose of 60 Gy and 40 Gy were delivered in 20 fractions prescribed to the periphery of the gross tumor volume and planning target volume, respectively. TMZ was administered according to the regimen of Stupp et al.nnnRESULTSnThe median follow-up was 12.6 months. Of the 35 patients, 29 (82.8%) completed the combined modality treatment, and 25 (71.4%) received a median of four cycles of adjuvant TMZ. The median overall survival was 14.4 months, and the median disease-free survival was 7.7 months. The median survival time differed significantly between patients who underwent biopsy and those who underwent partial or total resection (7.1 vs. 16.1 months, p = 0.035). The median survival was also significantly different between patients with methylated vs. unmethylated 0-6-methylguanine-DNA methyltransferase promoters (14.4 vs. 8.7 months, p = 0.049). The pattern of failure was predominantly central, within 2 cm of the initial gross tumor volume. Grade 3-4 toxicity was limited to 1 patient with nausea and emesis during adjuvant TMZ administration.nnnCONCLUSIONnThe results of our study have shown that hypo-IMRT with concomitant and adjuvant TMZ is well tolerated with a useful 2-week shortening of radiotherapy. Despite a high number of patients with poor prognostic features (74.3% recursive partitioning analysis class V or VI), the median survival was comparable to that after standard radiotherapy fractionation schedules plus TMZ.

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.

Surgery of unruptured, asymptomatic aneurysms: a decision analysis

BACKGROUNDnAsymptomatic cerebral aneurysms are diagnosed more frequently since the advent of computed tomography and magnetic resonance imaging. Their management is currently empirical. We have used decision analysis to place it on a more analytical basis.nnnMETHODSnDecision analysis was used to determine the benefit in years of survival free of sequelae resulting from elective surgery of unruptured aneurysms over natural history. We took 2% as the annual rate of rupture (r), 73% as the risk of death or disability with rupture (M), and 6.5% for the average risk of elective surgery (S). Benefit was calculated from the equation L([1-(1-r)L]M/2-S) [1] for life expectancy (L) corresponding to each quinquennial age group from age 15 to 100 years. Sensitivity analysis was performed to take into account increasing risk of elective surgery based on the size, and accessibility of the aneurysm, and variable risks of rupture and outcome.nnnRESULTSnA gain of at least one year of survival free of neurological sequelae is achieved by surgery compared to natural history for patients whose life expectancy is 19.5 years, corresponding to age 63.5 years for males and 68 years for females. The life expectancy at which a benefit accrues is longer (the patient is younger) for larger, less accessible aneurysms, for lower rates of rupture, and for lesser risks of death or disability from rupture.nnnCONCLUSIONSnElective surgery of unruptured asymptomatic aneurysms achieves an increased survival over the natural history of at least one year free of neurological sequelae in patients whose life expectancy is 19.5 years or more, using our baseline assumptions. Using equation [1], the corresponding life expectancy producing this benefit can be calculated to account for the increased surgical risk of large, poorly accessible aneurysms and for factors affecting natural history.

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.

Cerebellar liponeurocytoma with high proliferation index: treatment options.

First described by Bechtel and collaborators1, cerebellar liponeurocytomas are posterior fossa lesions composed of densely packed neuronal cells admixed with foci of welldifferentiated adipocyte-like cells. Similar tumors have also been referred to as lipomatous medulloblastoma, lipidized medulloblastoma, medullocytoma, neurolipocytoma, lipomatous glioneurocytoma, or lipidized mature neuroectodermal tumor of the cerebellum2-8. These different appellations reflect the histopathological similarities between liponeurocytomas, medulloblastomas and central neurocytomas. However, cerebellar liponeurocytoma is genetically distinct from medulloblastoma and central neurocytoma9; it is now recognized as a separate entity by the World Health Organization10. Because of the small number of reported cases, the proper management of cerebellar liponeurocytoma, especially when subtotally resected, remains to be elucidated. We report the case of a patient with a hemispheric cerebellar liponeurocytoma in which the proliferation index contributed to the decision to use adjuvant radiotherapy after gross total resection.

Cushing, Penfield, and cortical stimulation

Harvey Cushing and Wilder Penfield enjoyed a unique professional and personal relationship. Shortly before his retirement from Harvard University in 1933, Cushing sent Penfield 8 sketches that he drew in 1902 and 1903 while he was at Johns Hopkins Hospital. The first series of 3 sketches illustrate the relationship between a cortical hemorrhagic lesion and the motor strip in a patient with focal motor seizures. The second series also comprises 3 sketches. These depict the operative findings in a patient in whom Cushing had electrically stimulated the precentral gyrus, before resecting the cortex subserving motility of the upper extremity to control painful dyskinetic movements. The third series consists of 2 sketches that illustrate the results of stimulation of the motor strip as an aid in the safe resection of an epileptogenic focus in a patient with Jacksonian seizures. These sketches are the subjects of this paper. They add to the relatively sparse record of Cushings activities in cortical stimulation and in the treatment of functional disorders.