Are Dynamic Arterial Spin-Labeling MRA and Time-Resolved Contrast-Enhanced MRA Suited for Confirmation of Obliteration following Gamma Knife Radiosurgery of Brain Arteriovenous Malformations?

BACKGROUND AND PURPOSE: Intra-arterial DSA has been traditionally used for confirmation of cure following gamma knife radiosurgery for AVMs. Our aim was to evaluate whether 4D arterial spin-labeling MRA and contrast-enhanced time-resolved MRA in combination can be an alternative to DSA for confirmation of AVM obliteration following gamma knife radiosurgery. MATERIALS AND METHODS: In this prospective study, 30 patients undergoing DSA for confirmation of obliteration following gamma knife radiosurgery for AVMs (criterion standard) also underwent MRA, including arterial spin-labeling MRA and contrast-enhanced time-resolved MRA. One dataset was technically unsatisfactory, and the case was excluded. The DSA and MRA datasets of 29 patients were independently and blindly evaluated by 2 observers regarding the presence/absence of residual AVMs. RESULTS: The mean time between gamma knife radiosurgery and follow-up DSA/MRA was 53 months (95% CI, 42-64 months; range, 22-168 months). MRA total scanning time was 9 minutes and 17 seconds. Residual AVMs were detected on DSA in 9 subjects (obliteration rate = 69%). All residual AVMs were detected on at least 1 MRA sequence. Arterial spin-labeling MRA and contrast-enhanced time-resolved MRA showed excellent specificity and positive predictive values individually (100%). However, their sensitivity and negative predictive values were suboptimal due to 1 false-negative with arterial spin-labeling MRA and 2 with contrast-enhanced time-resolved MRA (sensitivity = 88% and 77%, negative predictive values = 95% and 90%, respectively). Both sensitivity and negative predictive values increased to 100% if a composite assessment of both MRA sequences was performed. Diagnostic accuracy (receiver operating characteristic) and agreement (κ) are maximized using arterial spin-labeling MRA and contrast-enhanced time-resolved MRA in combination (area under receiver operating characteristic curve = 1, P < .001; κ = 1, P < .001, respectively). CONCLUSIONS: Combining arterial spin-labeling MRA with contrast-enhanced time-resolved MRA holds promise as an alternative to DSA for confirmation of obliteration following gamma knife radiosurgery for brain AVMs, having provided 100% sensitivity and specificity in the study. Their combined use also enables reliable characterization of residual lesions.

Diffusion tensor tracking of callosal fibers several years after callosotomy.

Diffusion tensor imaging (DTI) can provide more detailed in vivo information on the structural preservation of transected white matter tracts than conventional imaging methods. Here we show for the first time tracks of severed callosal fibers up to 17 years from resection. Five patients subjected to complete or partial callosotomy several years before the study were examined with DTI and compared to a normal control. Transected fibers were traced in all patients and were more clearly visible in the anterior and posterior parts than in the middle of the commissure. These findings suggest that microstructural changes persist for many years in the severed fibers, as also reflected by fractional anisotropy and apparent diffusion coefficient values, enabling a reconstruction of the longitudinal organization of severed central tracts that could not be achieved with previous techniques.

Software for hepatic vessel classification: feasibility study for virtual surgery.

PURPOSE: The detection and classification of hepatic vessels in diagnostic images are essential for hepatic pre-surgery planning. Our team has developed a tool for classification, analysis, and 3D reconstruction of the hepatic and portal systems. METHODS: Our software first extracts a graphic representation of a set of connected voxels, representing both systems. It then calculates two binary volumes representing the main part of the two venous systems. Finally, it combines these results to obtain the correct vessel classification. RESULTS: Segmentation steps are semi-automatic and require about 40 min to complete. Schematization and classification steps are automatic and require about 17 min for results. CONCLUSION: The software provides a correct and detailed reconstruction even where pathologies have caused morphological and geometrical variations in the vessels. The time required for the entire procedure is compatible with clinical requirements, providing an efficient tool for diagnosis and surgical planning.

Gamma knife radiosurgery in brain metastases from testicular tumors.

To our knowledge, there are no published reports on the effectiveness of radiosurgery in the management of brain metastases from testicular nonseminomatous germ cell tumor. The authors evaluate the results of gamma knife (GK) treatment in three patients with these unusual intracranial lesions. Between April 1995 and July 2001, three patients with brain metastasis from testicular nonseminomatous germ cell tumor underwent adjuvant radiosurgery at our department. The primary tumor had been surgically removed in all cases. At diagnosis, one patient was stage IB and two were stage III poor risk. Chemotherapy and whole brain radiotherapy were administered before radiosurgery in all cases. Pre-GK radiotherapy was administered with a daily fraction dosage of 1.8-2.0 Gy. The indications for radiosurgery were tumor volume <20 cm3, microsurgery too risky, refusal of surgery. All the lesions were located in eloquent brain areas. Post-GK high-dose chemotherapy with autologous peripheral-blood stem-cell rescue was administered in two cases due to systemic recurrence of the disease. All patients are still alive with a median and mean follow-up period after radiosurgery of 63 and 68.3 mo, respectively. They had no neurological deficits at the latest examination. Neuroradiological follow-up invariably showed tumor growth control (complete response in two cases and partial response in one) with typically delayed post-radiosurgical imaging changes (transient in two cases and long-lasting in one). In conclusion, GK seems to be highly effective and safe in brain metastases from testicular nonseminomatous germ cell tumor. In cases with diffuse metastatic brain involvement, the whole brain radiotherapy preceding radiosurgery should be delivered with 1.8 Gy daily fraction to prevent the risk of long-lasting post-radiosurgical imaging changes.

Gamma knife radiosurgery in skull base meningiomas: a possible relationship between somatostatin receptor decrease and early neurological improvement without tumour shrinkage at short-term imaging follow-up.

BACKGROUND: This study investigates a possible relationship between the effects of gamma knife (GK) on meningioma somatostatin receptors (SRs) and the high rate of early neurological improvement without tumour reduction at short-term imaging follow-up. METHODS: From December 1997 to December 2002, somatostatin receptor scintigraphy (SRS) using an 111Indium-labelled somatostatin analogue, Octreotide, was performed both before and 7-12 months after radiosurgery in 20 patients with intracranial meningiomas. Semiquantitative data were calculated as an SRS index. FINDINGS: The pre-GK SRS index was always > 1, averaging 4.44 +/- 3.20. There were no statistically significant differences between the pre-GK average values of primary (4.80 +/- 3.65) and residual (3.75 +/- 1.93) meningiomas. At the first clinical/MRI follow-up, the neurological examination had improved in 15/20 (75%) and had not changed in 5/20 patients. A corresponding slight tumour shrinkage on high-resolution MRI was documented in 3/20 cases only. The post-GK average SRS index was lower than pre-GK values both in primary (3.87 +/- 3.19) and in adjuvant (2.52 +/- 1.14) treatments, but the differences were not significant. However, the subgroup of patients with early neurological improvement showed a higher pre-GK average SRS index (5.21 +/- 3.33) and a more substantial post-GK average SRS index decrease (3.86 +/- 3.00) than the patients whose clinical condition remained stable (2.10 +/- 0.59 and 1.99 +/- 0.55, respectively). The difference between the two subgroups of patients proved to be statistically significant (P < 0.05). CONCLUSIONS: Our preliminary findings suggest a possible relationship between a decrease in the concentration of SRs on meningioma cells at short-term functional imaging follow-up after radiosurgery and early neurological improvement.

Multimodality stereotactic approach to the treatment of cystic craniopharyngiomas.

OBJECTIVES: To present the therapeutic reliability of a multimodality stereotactic approach (MSA) to cystic craniopharyngiomas (CPs), combining neuroendoscopy, intracavitary bleomycin and gamma knife (GK) radiosurgery. METHODS: 8 patients with mono- or multicystic CP (7/8 regrowths/recurrence) underwent stereotactic neuroendoscopy and subsequently treatment with intracavitary bleomycin and GK. They were clinically characterized by hypopituitarism (7 cases), visual impairment (7), endocranial hypertension (7), cognitive and behavioral disturbances (3), and cranial nerve deficits or focal signs (3). Concomitant hydrocephalus was observed in 3/8 patients. According to Backlund's classification, the treated CPs were classified as type A (3 cases), type Cc (4 cases) and type Dc (1 case). In all 8 patients, neuroendoscopy allowed evacuation of the cyst and, in multi-cystic CPs, fenestration of the interposed septa so as to create a single communicating cavity. Thus, a single catheter and Ommaya reservoir system was sufficient both for subsequent aspirations and for bleomycin injection (doses of 1.5-3 mg, usually repeated every 7-8 days, with total doses ranging from 3-35 mg). GK radiosurgery was carried out at a later stage on the collapsed cyst in type A forms, while in types Cc and Dc, it was used on the solid nodule on the same day as the neuroendoscopy. RESULTS: The median follow-up period was 42.5 months. Neurological improvement was observed in 8/8 patients. A complete response (reduction of the entire tumor volume > 90 %) was observed in 3/8 cases (type A), a subtotal response (reduction > 50 %) in 4/8 cases (types Cc and Dc), and a partial response (reduction < 50 %) in 1/8 cases (type Cc). Treatment of CP alone led to normalization of the ventricular morphology in the 3 patients with associated hydrocephalus. Transient GK-related visual worsening was recorded in one case only. One patient died because of ventriculitis after repeated shunt replacements. CONCLUSIONS: This MSA seems to be an effective and safe treatment alternative to microsurgery, above all in patients with regrowing/recurrent cystic CPs.

Gamma knife radiosurgery in the management of arteriovenous malformations of the Basal Ganglia region of the brain.

OBJECTIVES: The authors report the results of gamma knife (GK) radiosurgery on a clinical series of selected patients with basal ganglia arteriovenous malformations (BGAVMs) in the brain. Clinical, epidemiological, anatomical and functional characteristics of BGAVMs and of supratentorial cortical AVMs are comparatively analyzed, and their influence on radiosurgical outcome is discussed. METHODS: At our Department, 33 BGAVMs (21 with FU > 2 years) and 209 cortical AVMs (110 with FU > 2 years) with a radiosurgical volume

Gamma knife radiosurgery in meningiomas of the posterior fossa. Experience with 62 treated lesions.

OBJECTIVES: This study was undertaken to assess the role of the gamma knife (GK) in the treatment of meningiomas of the posterior cranial fossa (PCF) and to statistically analyze the predictability of arbitrarily-selected prognostic factors in such treatment. METHODS: From February 1993 to November 1998, 57 patients underwent GK treatment for 62 meningiomas of the PCF (19 M/38 F; average age, 57.5 years, ranging from 25 - 82 years). Tumor sites included: foramen jugular-petrous bone (26/62), petroclival (23/62), cerebellar convexity (6/62), tentorium (6/62), and foramen magnum (1/62). Single lesions were treated in 44/62 cases while meningiomatosis was treated in the remaining 18. Post-operative residual or recurrent tumor was found in 27/62 patients and, in 7/27, histology documented characteristics of biological aggressiveness (GII/III). Indications for radiosurgery included: advanced age, high operative risk, tumor volume < 20 ml, inoperable or refused for additional surgery. The prognostic factors statistically analyzed included: meningiomatosis (yes/no), radiosurgery as primary or adjuvant treatment, GI vs. GII/III histology, and tumor volume (< or = 5 ml vs. > 5 ml). RESULTS: The observation periods varied from 6 to 64.3 months (median 28.7 months). At the end of the study, 53/57 patients were alive and reported to be in stable or improved neurological condition. The cause of death for the remaining 4 patients included: 2 deaths associated with tumor progression, while 2 died due to causes unrelated to the disease. Neuroradiological evaluation documented the disappearance or reduction of the meningioma mass in 34/62 (55 %) cases, a stable imaging picture in 25/62 (40 %), and a progression only in 3/62 (5 %). To date, there have been no reported cases of post-GK permanent morbidity or mortality. Side effects observed were of a transient nature due to post-radiosurgical edema (6.5 %). With regard to statistical analysis, the only factor to appear to significantly influence efficacy of radiosurgery for tumor growth control (TGC) was the biological nature of the meningioma (chi(2) = 2.708). The presence of meningiomatosis, SR as a primary or adjuvant treatment nor tumor volume were shown to statistically influence tumor behavior after GK. CONCLUSIONS: The excellent results obtained for TGC with minimal associated side effects suggest that GK is an effective therapeutic tool also for treatment of PCF meningiomas.

An objective method for detecting time-dependent effects in graft survival.

The proportional hazards model has become increasingly important in the analysis of censored survival data after transplantation. Neverthless, in clinical transplantation it is still undefined how the influence of covariates changes over time. The additive regression model is an alternative (or extension) to the Cox model. It results in plots (Aalen plots) that may give information on the effect of covariates over time by way of the cumulative regression function plots. A total of 386 primary cadaveric kidney transplants performed between 1984 and 1996 were included in our analysis. The follow-up period ranged from 24 to 156 months. According to Aalen, an additive regression model was used and plots for the detection of time-dependent effects of covariates were determined. Patients dying with functioning grafts were classed as graft failures. Factors potentially affecting graft outcome, such as sex, donor and recipient's age, HLA A-B match, cold ischaemia time (CIT), delayed graft function (DGF), serum creatinine at 1 month (Cr1), rejection episodes within 3 months (R3), and type of brain death (BD), were considered. The slopes of the plots by donor age, DGF, HLA A-B match, R3, Cr1 and BD appear to have a significant influence throughout the observation period, with different time-dependent effects on graft survival. Slopes for DGF, Cr1, and age of donor are positive (increased hazard), while slopes for HLA match and BD are negative (decreased hazard). Estimated regression functions for DGF, donor age and Cr1 show a prompt slope (within 3 months); the covariate R3 has a clear influence for about 5 years, and then seems to disappear; and BD appears to have a consistent effect over the entire period. The additive regression model with Aalen plots represents a useful technique in the analysis of survival data after kidney transplantation. Some covariates, such as R3, may often lose their effects on graft survival, with a relevant clinical impact. Others have a clear and additive influence over the entire period (BD), while the effects of donor age, DGF and CR1 each appear to have a prompt effect in the outcome.

Forecasting the growth of multicell tumour spheroids: implications for the dynamic growth of solid tumours.

The growth dynamics of multicell tumour spheroids (MTS) were analysed by means of mathematical techniques derived from signal processing theory. Volume vs. time trajectories of individual spheroids were fitted with the Gompertz growth equation and the residuals (i.e. experimental volume determinations minus calculated values by fitting) were analysed by fast fourier transform and power spectrum. Residuals were not randomly distributed around calculated growth trajectories demonstrating that the Gompertz model partially approximates the growth kinetics of three-dimensional tumour cell aggregates. Power spectra decreased with increasing frequency following a 1/f(delta) power-law. Our findings suggest the existence of a source of 'internal' variability driving the time-evolution of MTS growth. Based on these observations, a new stochastic Gompertzian-like mathematical model was developed which allowed us to forecast the growth of MTS. In this model, white noise is additively superimposed to the trend described by the Gompertz growth equation and integrated to mimic the observed intrinsic variability of MTS growth. A correlation was found between the intensity of the added noise and the particular upper limit of volume size reached by each spheroid within two MTS populations obtained with two different cell lines. The dynamic forces generating the growth variability of three-dimensional tumour cell aggregates also determine the fate of spheroid growth with a strong predictive significance. These findings suggest a new approach to measure tumour growth potential.

New dosimetric approach for multidimensional dose evaluation in gamma knife radiosurgery. Technical note.

During the past two decades, the progress in computerized treatment planning systems has led to more accurate imaging and therapy by using the gamma knife, especially with the smallest collimators (4 mm). However, the ionization chambers that have been used to calibrate the gamma knife are not useful with the smallest collimators because the chambers are too big compared with the irradiated volume. Therefore, it is important to develop more suitable dosimeters. This study proposes a new dosimeter method. The FriXyGel method proposed here is based on a phantom dosimeter, an acquisition chain, and dedicated software. This dosimeter uses an agarose gel into which a ferrous sulphate solution (Fricke solution) and a metal ion indicator (xylenol orange) are incorporated. The absorbed dose is detected through measurements of visible light transmission, imaged by means of a charge-coupled device camera provided with a suitable optical filter. Gel layers are imaged before and after irradiation, and the differences in light absorption are related to the absorbed dose. By choosing convenient thickness of gel layers and by building up a phantom with different gel slices, it is possible to obtain a three-dimensional (3D) representation of the absorbed dose. The final 3D representation is reached after several mathematical processes have been applied to the images. The first step identifies and reduces all factors that could alter the original data, such as nonuniformity in illumination. Then, after calibration procedures, it is possible to obtain absorbed dose values and to discover their 3D representation. This goal has been reached by developing appropriate software that performs all the calculations necessary for spatial representation routines and prompt comparison with theoretical calculations.

Oscillating growth patterns of multicellular tumour spheroids.

The growth kinetics of 9L (rat glioblastoma cell line) and U118 (human glioblastoma cell line) multicellular tumour spheroids (MTS) have been investigated by non-linear least square fitting of individual growth curves with the Gompertz growth equation and power spectrum analysis of residuals. Residuals were not randomly distributed around calculated growth trajectories. At least one main frequency was found for all analysed MTS growth curves, demonstrating the existence of time-dependent periodic fluctuations of MTS volume dimensions. Similar periodic oscillations of MTS volume dimensions were also observed for MTS generated using cloned 9L cells. However, we found significant differences in the growth kinetics of MTS obtained with cloned cells if compared to the growth kinetics of MTS obtained with polyclonal cells. Our findings demonstrate that the growth patterns of three-dimensional tumour cell cultures are more complex than has been previously predicted using traditional continuous growth models.

A non-parametric method for the analysis of experimental tumour growth data.

Analysis of tumour growth is required to investigate the biology of tumours and to determine the effects of new anti-tumour therapies. A non-parametric mathematical method for the analysis of a set of experimental tumour growth data is described. The method is based on the similarity between time series of tumour size measurements (e.g. tumour volume), similarity being defined as the Euclidean distance between data measured for each tumour at the same time. Subsets of similar time series are found for a given population of tumours. A biologically meaningful parameter H has been derived which is a measure of the scattering of experimental volume samples. The method has been applied to the analysis of the growth of (i) untreated multicellular tumour spheroids obtained with different cell lines and (ii) spheroids treated with cytotoxic drugs (immunotoxins). Results are compared with those previously obtained by applying the classical Gompertz growth model to the analysis of treated and untreated spheroids.

Shape recovery and volume calculation from biplane angiography in the stereotactic radiosurgical treatment of arteriovenous malformations.

PURPOSE: A model for calculating the three-dimensional volume of arteriovenous malformations from biplane angiography. METHODS AND MATERIAL: Three-dimensional (3D) volume reconstruction is easily feasible with axial, coronal, or sagittal computer tomography (CT) and nuclear magnetic resonance (NMR) scans. On the other hand, radiosurgical treatment of arteriovenous malformations (AVM) is exclusively based on two orthogonal stereotactic projections, obtained with angiographic procedures. Most commonly, AVM volumes have been calculated by assimilating the nidus volume to a prolate ellipsoid. We present an algorithm dedicated to 3D structure reconstruction starting from two orthogonal stereotactic projections. This has been achieved using a heuristic approach, which has been widely adopted in the artificial intelligence domain. RESULTS: Tests on phantom of different complexity have shown excellent results. CONCLUSION: The importance of the algorithm is considerable. As a matter of fact: (a) it allows calculations of complex structures far away from regular ellipsoid; (b) it permits shape recovery; (c) it provides AVM visualization on axial planes.

Digital subtraction angiography for arteriovenous malformations in stereotactic radiosurgery.

Images coming from digital subtraction angiography (DSA) are affected by a perspective distortion due to the use of image intensifiers. As a result, DSA cannot be used for the accurate definition of stereotactic coordinates. A correction method has been developed to enable the use of DSA for the radiosurgery of arteriovnous malformations. A software program and a special phantom tool were employed. The phantom is made by a computer-controlled drilling machine which makes holes in a Plexiglas plate. It has 865 calibration steel spheres with coordinates determined with a precision of 0.01 mm. A calibration image is acquired by a personal computer, and the software calculates the transformation algorithm to superimpose the image on the known positions of the phantom. This algorithm is saved and then recalled to transform the diagnostic images.

Gamma Knife radiosurgery in skull base meningiomas. Preliminary experience with 50 cases.

Gamma Knife radiosurgery was performed on 50 patients (10 males and 40 females) with skull base meningiomas (SBMs) between February 1993 and September 1995. The patients ranged in age from 25 to 78 years (mean age 56 years). The location of the tumors was anterior fossa (n = 4), sphenoorbital (n = 2), sellar region (n = 5), cavernous sinus (n = 26), petroclival (n = 12), and occipital foramen (n = 1). The tumor volume ranged from 0.6 to 20 cm3 (mean 8.6 cm3). The mean values for dose planning were edge isodose (EI) 46.7%, edge dose (ED) 18.0 Gy, maximum dose 39.8 Gy, average dose (AD) 25.4 Gy, and average number of isocentres 5.7. The patients were analyzed for five parameters: tumor volume (< 7.5 vs. > or = 7.5 cm3); EI (< 50 vs. > or = 50%); ED (< 18 vs. > or = 18 Gy); AD (< 25 vs. > or = 25 Gy), and primary versus residual or recurrent tumors. The overall frequency of tumor growth control (TGC) was 98%, with 1- and 2-year TGC rates of 97% and 100%, respectively. The most favorable neurological results were obtained with a tumor volume < 7.5 cm3 (p < 0.05), EI > or = 50% (NS), ED > or = 18 Gy (NS) and with primary SBMs (p < 0.01). A favorable TGC was demonstrated at follow-up imaging examinations when the tumor volume was > or = 7.5 cm3 (100% TGC rate), EI < 50% (100%), ED > or = 18 Gy (100%), AD > 25 Gy (100%), in both primary SBMs (100%) and residual or recurrent SBMs (96.5%). To date, only 3 (6%) of the 50 patients have presented signs of neurological worsening related to the Gamma Knife radiosurgery. While no early complications were noted, neuroradiological follow-up did show delayed transient imaging complications (3 edema and 1 radionecrosis; 8% of all patients). In conclusion, our preliminary results seem to confirm that Gamma Knife radiosurgery is an effective and safe adjuvant or a feasible alternative primary treatment in controlling or preventing SBM progression.

Gamma Knife radiosurgery for intracranial metastases: from local tumor control to increased survival.

We have analyzed a series of 225 patients with intracranial metastases (343 lesions), treated in our department by Gamma Knife radiosurgery over a 30-month period. We have used a modified Pittsburgh protocol and performed 242 procedures on 164 single/78 multiple lesions. Primary tumors were mostly carcinomas of the lung (52%) and breast (11.6%). Neuroradiological localization of the target was usually performed by stereotactic computed tomography. Magnetic resonance imaging was only used in special circumstances. Routine dose planning was assisted by three-dimensional reconstruction programs. Mean tumor volume was larger than expected (5.7 ml). Mean prescription dose and average dose were 21.1 and 29.9 Gy, respectively. Middle- and long-term results were evaluated in a subset of 152 patients (236 lesions) with adequate (> 4 months) follow-up. Mean follow-up was 53.1 weeks with 61/152 patients still living. There was a predominance of retrospectively classified 'not fully eligible cases' among the survivors, mainly because of uncontrolled primary tumor. The 1-year local tumor control rate was 88.2%. Treatment-related radiological (3.9%) and clinical (1.6%) sequelae were minimal. Overall mean survival in these patients (40 weeks) turned out to be higher than that commonly reported after conventional surgical-radiation treatments. It was encouraging that the mean survival of 'fully' eligible patients was 51 weeks. Karnofsky performance status and neurological (Order Grading) performance scores were consistently high for most of the follow-up period. Functional Independence and the Palliative Index were not far from the value of mean survival. The main cause of death remains uncontrolled systemic disease (64.8%). On the other hand, the relative incidence of intracranial tumor progression was considerably decreased. This indicated that these patients should perhaps be treated more aggressively and underlines the need for randomized trials to determine the optimal treatment.