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.

An exponential-Gompertzian description of LoVo cell tumor growth from in vivo and in vitro data.

The data of nine monolayer cultures, 48 multicellular spheroids, and 19 s.c. xenografts of LoVo cells were fitted, on an individual basis, by exponential and Gompertzian equations, respectively. The mean growth parameters alpha 0 (initial growth rate) and beta (retardation factor) of the three experimental systems presented a strong linear correlation alpha 0 = 6.88 beta + 0.56, r = 0.9843. This implies that, at the particular tumor size of 155 microns in diameter (mean +/- SD = 50-310 microns), the tumor growths described by Gompertzian curves (from spheroids as well as from s.c. xenografts) have the same growth rate as monolayer cultures. This occurrence strongly supports an exponential-Gompertzian growth model, where an exponential monolayer-like phase changes to a Gompertzian growth, controlled by environmental conditions, when the tumor size has reached a critical value.

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.

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.

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.

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.

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.

Chronobiological variations of prolactin (PRL) in chronic renal failure (CRF).

During a 24-hour period, the serum levels of prolactin (PRL) were determined in 89 subjects, including 24 controls and 65 with chronic renal failure (CRF), divided into groups according to sex, age and serum creatinine. In mild CRF, both in males and females, PRL level proved to be higher than controls while its circadian rhythm of secretion disappeared. The MANOVA analysis (multivariate analysis of variance) showed that all 3 considered factors (sex, age, creatinine) have a systematic effect on PRL values, that of creatinine being the most prominent. With the progression of renal failure, the physiological PRL oscillations tended to diminish. In general, increasing creatinine levels progressively shifted the acrophase (that is the time-distance between a given hour and the maximum peak of the function) to the morning, with hemodialysis patients showing acrophases between 12 p.m. and 1 a.m. It is possible that in CRF the PRL feedback system could no longer function.

Effect of aging on the body composition of dialyzed subjects. Comparison with normal subjects.

A bioimpedance analyzer (BIA-CHIP; Akern RJL System) was applied to 366 normal subjects (171 men and 195 women). Each gender group was divided into eight groups, according to age: 20-29 years; 30-39 years; 40-49 years; 50-59 years; 60-69 years; 70-79 years; 80-89 years; and 90-95 years. The same was done with 44 hemodialysis patients (22 men, 22 women), each being evaluated 15 times over a period of 5 years: these were divided into seven groups (seven, because no patient was older than 89) using the same criteria. For each subject, 23 parameters were determined: 5 directly measured (height, weight, resistance, reactance, phase angle) and the others (fat and lean mass, body water, body cell mass, extra and intracellular water, etc.) from appropriate equations. Twenty-four thousand data points were collected and served to form a data bank. Men and women on hemodialysis showed different effects of aging: women normalized their BC at an age > 70 years, whereas men continued to have a muscle mass lower than that of normal subjects until the age of 80. A computerized program (Nutritio) permits fast and reliable evaluation of the nutritional status of hemodialysis patients, each subject being compared with both the similarly aged population (dialyzed or not) or with his or her own data, obtained over time.

Intermittent venovenous hemofiltration as a chronic treatment for refractory and intractable heart failure.

Chronic heart failure (HF) is considered to be refractory when persisting despite an intensive drug regimen, or intractable when requiring "artificial" supports. Among them, hemofiltration (HE) has been used frequently, but only on an "acute" basis, to induce fast and safe water removal. Since 1985 the authors have treated refractory and intractable HF first by means of acute CAVH (continuous arteriovenous HE: 11 patients) and then (1988-1992) with IVVH (intermittent venovenous HE), initially done on an "acute" basis (13 patients) and then an a chronic basis (CIVVH): 8 subjects (6M, 2F; mean age, 60.8 years), 3 with RCHF and 5 with ICHF. This report deals with our experience in CIVVH. All patients were in severe failure. During a follow-up period of 63 months (range, 1-17/patient), 82 IVVH treatments (10.2/patient) were carried out, using this schedule: permanent Tesio catheter in superior vena cava, 0.6 m2 filter, double blood pump (blood flow = 80-250 ml/min); transmembrane pressure = 50-150 mmHg; mean ultrafiltration = 19 ml/min; replacement fluid = 8.6 ml/min; and session time = 340 +/- 88 min, according to individual dry weight (bioimpedance system). Six patients died (1-13 months after IVVH began); four of six had ICHF and two of six had RCHF; five of eight patients showed a significant amelioration of functional state, changing from fourth to third, to second and first degree failure, but this was after heart transplantation. In all cases a marked reduction in the drug regimen and in hospitalization was the rule.

The exponential-Gompertzian tumor growth model: data from six tumor cell lines in vitro and in vivo. Estimate of the transition point from exponential to Gompertzian growth and potential clinical implications.

The published growth data were examined for six tumor cell lines (FSA, Line 1, MCA-11, EMT6/RO, MGH-U1, MLS) grown in vivo and in vitro as monolayer cultures and as multicell spheroids cultured under different experimental conditions. Serial estimates of tumor sizes were fitted by Gompertzian equations obtained with a non-linear computerized program. When the growth equations of the same tumor growing in different experimental conditions were compared, the Gompertzian parameters alpha 0 (initial specific growth rate) and beta (retardation factor) showed a strong linear correlation in all the examined lines, with no exception. This occurrence supports the exponential-Gompertzian growth model, where an early exponential phase (which is virtually not influenced by exogenous factors) is followed by a Gompertzian phase, the characteristics of which are greatly dependent on environmental conditions. The transition between the two phases was estimated to occur when tumor size reached 10(2)-10(4) cells, depending on the cell line. This kinetic change in tumor growth may be clinically relevant as regards cytotoxic treatments. It could explain some consequences of delays in adjuvant (postoperative) chemotherapy observed in clinical trials on primary breast cancer.

Relative role of host and tumor in the growth pattern of murine and human neoplasms following subcutaneous transplantation in mice.

The growth patterns of two murine and eight human tumors, bilaterally implanted into subcutaneous tissue of groups of recipient mice, were studied. A Gompertz equation was fitted to experimental data for each individual implant and the Gompertz parameters were utilized as quantitative growth characteristics. The relative roles of the tumor-implanted flank (right versus left), of the individual host and of the tumor were analyzed by the paired t-test, simple linear regression model, one-way and two-way analysis of variance. Sixty pairs of Gompertz curves were obtained in seventy animals. Heterogeneity was the main characteristic of the growth pattern in all tumors under study, with a wide variability among the Gompertz parameters. Statistical analysis of experimental data showed that only the tumor systematically influenced the growth characteristics, whereas neither the tumor-implanted flank nor the individual host played a significant role. These results have both theoretical and practical implications.

Influence of tumor growth kinetics on response to doxorubicin treatment of C3H mammary carcinoma.

The influence of tumor growth kinetics on response to doxorubicin treatment of C3H mammary carcinoma was investigated. Gompertzian growth curves were obtained for the tumor mass of each mouse by a computerized best fit program. The response was assessed by evaluating: a) the total clonogenic cell reduction as a fraction of the initial tumor volume or the tumor volume that should result at the end of treatment in a free growth condition, and b) the partial clonogenic cell reduction at each drug administration, assuming a first order cell kill hypothesis. Slowly growing tumors at each dose level showed a significantly poorer response than rapidly growing tumors. Each response index exhibited a linear correlation with the specific instantaneous growth rate at the time of treatment. Data also suggested a dose-response dependence.

Pharmacologic data and technical feasibility of intraperitoneal doxorubicin administration.

Seventy intraperitoneal administrations of doxorubicin were performed in 12 patients with malignant disease in the abdominopelvic space. Peritoneal and hematologic drug levels were measured by fluorimetric assay. A first-order decline in the peritoneal level was determined (T 1/2 96 +/- 18 min), with a mean drug absorption of 84% in 4 h (range 40-96%) and a mean ratio of a peak dialysate/peak serum level of 111 (range 12-390). Gastrointestinal toxicity was common and peritoneal phlogosis occurred twice. The doxorubicin level and the time of peritoneal exposure seem to be critical factors for major local toxicity. At a moderate concentration doxorubicin can be intraperitoneally administered, but its usefulness is probably confined to patients with minimal abdominal disease.

New compartmental model approach to dialysis.

Compartmental models are used for solving the problem of the control of dialysis therapy. The inadequacy of the existing monocompartmental model is faced, first with a careful analysis of the physiology of the system, then with a method focused on the construction of a new multicompartmental model. Moreover, impedance techniques allow us to solve the problem of measuring the total body water for each patient.

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.

Simultaneous relapse of liver cell carcinoma and non-Hodgkin's lymphoma in the liver. Report of a case with diagnosis by ultrasonically guided fine needle aspiration biopsy.

A 50-year-old man was diagnosed with non-Hodgkin's lymphoma (NHL) in 1980; he was treated with chemotherapy and achieved complete remission. Six years later he reported upper abdominal pain. Ultrasound (US) showed a 3-cm mass in the right lobe of the liver. Needle aspiration showed hepatocellular carcinoma (HCC). The patient was treated with radical resection of the tumor. Three years later (June 1989), abdominal US showed two lesions in the right lobe of the liver. Needle aspiration and tissue core biopsy showed NHL in one lesion and HCC in the other. The lymphomatous lesion resolved after chemotherapy. The patient died 30 months later (January 1992) from a gastrointestinal hemorrhage; the NHL was in complete remission. This case of the simultaneous presence of HCC and hepatic lymphoma is, to our knowledge, the first diagnosed in vivo.

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.