Brain Tumor Response Research Articles

Kinetic analysis of 2-[11C]thymidine PET imaging studies of malignant brain tumors: preliminary patient results.

2-[11C]Thymidine (TdR), a PET tracer for cellular proliferation, may be advantageous for monitoring brain tumor progression and response to therapy. Kinetic analysis of dynamic TdR images was performed to estimate the rate of thymidine transport (K1t) and thymidine flux (KTdR) into brain tumors and normal brain. These estimates were compared to MRI and pathologic results. Twenty patients underwent sequential [11C]CO2 (major TdR metabolite) and TdR PET studies with arterial blood sampling and metabolite analysis. The data were fitted using the five-compartment model described in the companion article. Comparison of model estimates with clinical and pathologic data shows that K1t is higher for MRI contrast enhancing tumors (p < .001), and KTdR increases with tumor grade (p < .02). On average, TdR retention was lower after treatment in high-grade tumors. The model was able to distinguish between increased thymidine transport due to blood-brain barrier breakdown and increased tracer retention associated with tumor cell proliferation. Initial analysis of model estimates of thymidine retention and transport show good agreement with the clinical and pathological features of a wide range of brain tumors. Ongoing studies will evaluate its role in measuring response to treatment and predicting outcome.

Kinetic analysis of 2-[11C]thymidine PET imaging studies of malignant brain tumors: compartmental model investigation and mathematical analysis.

2-[11C]Thymidine (TdR), a PET tracer for cellular proliferation, may be advantageous for monitoring brain tumor progression and response to therapy. We previously described and validated a five-compartment model for thymidine incorporation into DNA in somatic tissues, but the effect of the blood-brain barrier on the transport of TdR and its metabolites necessitated further validation before it could be applied to brain tumors. We investigated the behavior of the model under conditions experienced in the normal brain and brain tumors, performed sensitivity and identifiability analysis to determine the ability of the model to estirmine whether it can distinguish between thymidine transport and retention. Sensitivity and identifiability analysis suggested that the non-CO2 metabolite parameters could be fixed without significantly affecting thymidine parameter estimation. Simulations showed that K1t and KTdR could be estimated accurately (r = .97 and .98 for estimated vs. true parameters) with standard errors < 15%. The model was able to separate increased transport from increased retention associated with tumor proliferation. Our model adequately describes normal brain and brain tumor kinetics for thymidine and its metabolites, and it can provide an estimate of the rate of cellular proliferation in brain tumors.

Kinetic Analysis of 2-[&lt;SUP&gt;11&lt;/SUP&gt;C]Thymidine PET Imaging Studies of Malignant Brain Tumors: Compartmental Model Investigation and Mathematical Analysis

2-[11C]Thymidine (TdR), a PET tracer for cellular proliferation, may be advantageous for monitoring brain tumor progression and response to therapy. We previously described and validated a five-compartment model for thymidine incorporation into DNA in somatic tissues, but the effect of the blood-brain barrier on the transport of TdR and its metabolites necessitated further validation before it could be applied to brain tumors. We investigated the behavior of the model under conditions experienced in the normal brain and brain tumors, performed sensitivity and identifiability analysis to determine the ability of the model to estirmine whether it can distinguish between thymidine transport and retention. Sensitivity and identifiability analysis suggested that the non-CO2 metabolite parameters could be fixed without significantly affecting thymidine parameter estimation. Simulations showed that K1t and KTdR could be estimated accurately (r = .97 and .98 for estimated vs. true parameters) with standard errors < 15%. The model was able to separate increased transport from increased retention associated with tumor proliferation. Our model adequately describes normal brain and brain tumor kinetics for thymidine and its metabolites, and it can provide an estimate of the rate of cellular proliferation in brain tumors.

Kinetic Analysis of 2-[&lt;SUP&gt;11&lt;/SUP&gt;C]Thymidine PET Imaging Studies of Malignant Brain Tumors: Preliminary Patient Results

2-[11C]Thymidine (TdR), a PET tracer for cellular proliferation, may be advantageous for monitoring brain tumor progression and response to therapy. Kinetic analysis of dynamic TdR images was performed to estimate the rate of thymidine transport (K1t) and thymidine flux (KTdR) into brain tumors and normal brain. These estimates were compared to MRI and pathologic results. Twenty patients underwent sequential [11C]CO2 (major TdR metabolite) and TdR PET studies with arterial blood sampling and metabolite analysis. The data were fitted using the five-compartment model described in the companion article. Comparison of model estimates with clinical and pathologic data shows that K1t is higher for MRI contrast enhancing tumors (p < .001), and KTdR increases with tumor grade (p < .02). On average, TdR retention was lower after treatment in high-grade tumors. The model was able to distinguish between increased thymidine transport due to blood-brain barrier breakdown and increased tracer retention associated with tumor cell proliferation. Initial analysis of model estimates of thymidine retention and transport show good agreement with the clinical and pathological features of a wide range of brain tumors. Ongoing studies will evaluate its role in measuring response to treatment and predicting outcome.

Applications of nuclear medicine in pediatric oncology.

Nuclear medicine is important in the diagnosis, staging, and long-term surveillance of a number of pediatric cancers. Skeletal scintigraphy is used to evaluate primary skeletal cancers, such as osteosarcoma and Ewing sarcoma, and nonskeletal cancers such as neuroblastoma, lymphoma, medulloblastoma, rhabdomyosarcoma, and retinoblastoma. Metaiodobenzylguanidine scintigraphy is valuable in examinations of children with neuroblastoma. The therapeutic response of primary bone and brain tumors can be assessed using Tl-201 and Tc-99m MIBI scintigraphy. Imaging strategies for staging and monitoring the therapeutic response of Hodgkin's lymphoma include Ga-67 citrate scintigraphy. Pediatric oncologic applications of positron emission tomography are being investigated extensively.

Early non-invasive detection of brain tumor response to radiation using diffusion weighted MRI

patient ranged from 0.5cm to 2.6 cm, with a median of 1.6 cm. This difference was not related to patient’s AP and right-left dimensions. The lateral distances from the anterior midline are: 3.5 ,-0.4; 2.9 ,-0.4; 2.5 ,-0.4; 2.9 ,-2.7;, and 2.7 ,-0.7 cm, at the 1st, 2nd, 3rd, 4th, and 5th intercostal spaces respectively. Although the IM lateral positions varied from patient to patient, they were relatively consistent in respect to the lateral border of sternum, all located maximally less than 1 cm laterally at 2nd, 3rd, 4th, and 5th intercostal spaces, and 0.5 cm medially of the 1st intercostal space. Distances from the most lateral border of AXN and the most medial border of HH were -2.1 ,-1.3, 0.7 ,-0.5, and 2.9 ,-1.5 cm at levels of HH head, coracoid process and lateral end of clavicle respectively (negative value indicates overlapping). AXN frequently overlapped HH anteriorly when the arm was angled more than 90 degree, but did not when the arm is placed 90 degree or less. The gantry angle of the SCV port also effected HH sparing. The larger the angle, the less HH could be spared. DVHs of IMC, AXN, and HH at different conventional beam settings were also analyzed and showed significant variation of node coverage and HH sparing.

Early non-invasive detection of brain tumor response to radiation therapy using diffusion weighted MRI

Early non-invasive detection of brain tumor response to radiation therapy using diffusion weighted MRI

Stereotactic guided laser-induced interstitial thermotherapy (SLITT) in gliomas with intraoperative morphologic monitoring in an open MR-unit.

Stereotactic guided laser-induced interstitial thermotherapy (SLITT) represents a minimal invasive method to produce necrosis in cerebral tumor tissue by local heating. The dose/response relationship relies on experimental studies and few clinical data performed in high field MR systems. A better understanding of the energy-dose/tissue response in human brain tumors is important to optimize this treatment modality. Twenty-four patients with gliomas were treated with SLITT, with a total of 30 laser procedures performed. Under local anesthesia 600 microns laser-fibers were inserted by stereotactic-guided technique into the center of the tumor. In a low field open MR system (0.2 T) the denaturation of the tumor using a neodymium YAG laser (1064 nm) was monitored by 3D-turbo FLASH T1-weighted sequences. Laser energy was applied in steps of 400 to 1200 Joules. Development of necrosis at a mean total energy dose of 2979 Joules could be monitored in all procedures. Two different thermal lesion architectures were observed. First signal changes were monitored after a mean of 1108 Joules and 1393 Joules, respectively. Mean max. total lesion size was 21.2 mm. The higher the total energy the larger was the thermolesion, but no linear relationship could be seen. Tumor tissue response showed no dependency on tumor grading. Monitoring of stereotactic guided laser-induced thermolesions in the low-power MR OPEN is feasible and safe. Although lesion size basically is energy dependent, it should be applied individually, since the thermal response in brain tumors varies due to different optical properties, even in the same tumor gradings.

Proton magnetic spectroscopic imaging of the child's brain: the response of tumors to treatment

Our aim was to determine and/or predict response to treatment of brain tumors in children using proton magnetic resonance spectro-scopic imaging (MRSI). We studied 24 patients aged 10 months to 24 years, using MRI and point-resolved spectroscopy (PRESS; TR 2000 TE 65 ms) with volume preselection and phase-encoding in two dimensions on a 1.5 T imager. Multiple logistic regression was used to establish independent predictors of active tumor growth. Biologically vital cell metabolites, such as N-acetyl aspartate and choline-containing compounds (Cho), were significantly different between tumor and control tissues (P < 0.001). The eight brain tumors which responded to radiation or chemotherapy, exhibited lower Cho (P = 0.05), higher total creatine (tCr) (P = 0.02) and lower lactate and lipid (L) (P = 0.04) than 16 tumors which were not treated (except by surgery) or did not respond to treatment. The only significant independent predictor of active tumor growth was tCr (P < 0.01). We suggest that tCr is useful in assessing response of brain tumors to treatment.

Experimental Gliosarcoma Induces Chemokine Receptor Expression in Rat Brain

Macrophage/microglial infiltration is a characteristic feature of brain tumors. The functional role(s) of these cells is complex and could include both trophic and suppressive effects on tumors. Information has recently emerged about the molecular signals that regulate the accumulation and function of monocytes in pathological disorders. Recent data indicate that the chemokine, monocyte chemoattractant protein-1 (MCP-1), a potent monocyte activating and chemotactic factor, is a primary regulator of the macrophage response in brain tumors. We hypothesized that if MCP-1 regulates macrophage/microglial infiltration, then expression of the specific MCP-1 receptor, CCR2, will be induced in peritumoral tissue and/or within brain tumors. Identification of a specific receptor that is preferentially expressed in brain tumors could be important both in terms of tumor biology and as a potential therapeutic target. We used an established experimental gliosarcoma model, induced by intracranial transplantation of cultured 9L cells into adult rat brain, to test this hypothesis. RT-PCR analysis showed high levels of both MCP-1 and CCR2 mRNA and Western blot analysis demonstrated increased CCR2 protein in tumor extracts. Immunocytochemistry showed CCR2 immunoreactive microglia in peritumoral tissue and, unexpectedly, that intrinsic tumor cells, rather than monocytes, were the predominant source of CCR2. These results demonstrate that CCR2 expression is markedly upregulated in this brain tumor model.

Examination of low-incidence brain tumor responses in F344 rats following chemical exposures in National Toxicology Program carcinogenicity studies.

Neoplasms in the brain are uncommon in control Fischer 344 (F344) rats; they occur at a rate of less than 1% in 2-yr toxicity/carcinogenicity studies. Furthermore, only 10 of nearly 500 studies conducted by the National Toxicology Program (NTP) showed any evidence of chemically related neoplastic effects in the brain. Generally, the brain tumor responses were considered equivocal, because the characteristics of potential neurocarcinogenic agents (such as statistically significant increased incidences, decreased latency and/or survival, and demonstration of dose-response relationships) were not observed. A thorough examination, including comparisons with a well-established historical database, is often critical in evaluating rare brain tumors. Chemicals that gave equivocal evidence of brain tumor responses were generally associated with carcinogenicity at other sites, and many chemicals were mutagenic when incubated with metabolic activating enzymes. Other factors that were supportive of the theory that marginal increases in brain tumor incidence were related to chemical exposure were that (a) some of the tumors were malignant, (b) no brain neoplasms were observed in concurrent controls from some studies, and/or (c) brain tumors were also seen following exposure to structurally related chemicals. In 2-yr studies in F344 rats (studies conducted by the NTP), equivocal evidence of carcinogenicity was observed for the following 9 chemicals: isoprene, bromoethane, chloroethane, 3,3'-dimethylbenzidine dihydrochloride, 3,3'-dimethoxybenzidine dihydrochloride, furosemide, C.I. direct blue 15, diphenhydramine hydrochloride, and 1-H-benzotriazole. Glycidol was the only chemical evaluated by the NTP with which there was clear evidence of brain tumor induction in F344 rats. Clarification of the potential neurocarcinogenic risks of chemicals that produce equivocal evidence of a brain tumor response in conventional 2-yr rodent studies may be aided by the use of transgenic mouse models that exhibit genetic alterations that reflect those present in human brain tumors as well as by the use of in utero exposures.

Review and evaluation of MRI nonuniformity corrections for brain tumor response measurements.

Current MRI nonuniformity correction techniques are reviewed and investigated. Many approaches are used to remedy this artifact, but it is not clear which method is the most appropriate in a given situation, as the applications have been with different MRI coils and different clinical applications. In this work four widely used nonuniformity correction techniques are investigated in order to assess the effect on tumor response measurements (change in tumor volume over time): a phantom correction method, an image smoothing technique, homomorphic filtering, and surface fitting approach. Six brain tumor cases with baseline and follow-up MRIs after treatment with varying degrees of difficulty of segmentation were analyzed without and with each of the nonuniformity corrections. Different methods give significantly different correction images, indicating that rf nonuniformity correction is not yet well understood. No improvement in tumor segmentation or in tumor growth/shrinkage assessment was achieved using any of the evaluated corrections.

MRI Measurement of Brain Tumor Response: Comparison of Visual Metric and Automatic Segmentation

An automatic magnetic resonance imaging (MRI) multispectral segmentation method and a visual metric are compared for their effectiveness to measure tumor response to therapy. Automatic response measurements are important for multicenter clinical trials. A visual metric such as the product of the largest diameter and the largest perpendicular diameter of the tumor is a standard approach, and is currently used in the Radiation Treatment Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (EGOG) clinical trials. In the standard approach, the tumor response is based on the percentage change in the visual metric and is categorized into cure, partial response, stable disease, or progression. Both visual and automatic methods are applied to six brain tumor cases (gliomas) of varying levels of segmentation difficulty. The analyzed data were serial multispectral MR images, collected using MR contrast enhancement. A fully automatic knowledge guided method (KG) was applied to the MRI multispectral data, while the visual metric was taken from the MRI films using the T 1 gadolinium enhanced image, with repeat measurements done by two radiologists and two residents. Tumor measurements from both visual and automatic methods are compared to “ground truth,” (GT) i.e., manually segmented tumor. The KG method was found to slightly overestimate tumor volume, but in a consistent manner, and the estimated tumor response compared very well to hand-drawn ground truth with a correlation coefficient of 0.96. In contrast, the visually estimated metric had a large variation between observers, particularly for difficult cases, where the tumor margins are not well delineated. The inter-observer variation for the measurement of the visual metric was only 16%, i.e., observers generally agreed on the lengths of the diameters. However, in 30% of the studied cases no consensus was found for the categorical tumor response measurement, indicating that the categories are very sensitive to variations in the diameter measurements. Moreover, the method failed to correctly identify the response in half of the cases. The data demonstrate that automatic 3D methods are clearly necessary for objective and clinically meaningful assessment of tumor volume in single or multicenter clinical trials.

Perfusion Magnetic Resonance Imaging to Assess Brain Tumor Responses to New Therapies.

BACKGROUND: Although magnetic resonance imaging (MRI) is effective in detecting the location of intracranial tumors, new imaging techniques have been studied that may enhance the specificity for the prediction of histologic grade of tumor and for the distinction between recurrence and tumor necrosis associated with cancer therapy. METHODS: The authors review their experience and that of others on the use of perfusion magnetic resonance imaging to evaluate responses of brain tumors to new therapies. RESULTS: Functional imaging techniques that can distinguish tumor from normal brain tissue using physiological parameters. These new approaches provide maps of tumor perfusion to monitor the effects of novel compounds that restrict tumor angiogenesis. CONCLUSIONS: Perfusion MRI not only may be as effective as radionuclide-based techniques in sensitivity and specificity in assessing brain tumor responses to new therapies, but also may offer higher resolution and convenient co-registration with conventional MRI, as well as time- and cost-effectiveness. Further study is needed to determine the role of perfusion MRI in assessing brain tumor responses to new therapies.

Monitoring brain tumor response to therapy using MRI segmentation

The performance evaluation of a semi-supervised fuzzy c-means (SFCM) clustering method for monitoring brain tumor volume changes during the course of routine clinical radiation-therapeutic and chemo-therapeutic regimens is presented. The tumor volume determined using the SFCM method was compared with the volume estimates obtained using three other methods: (a) a k nearest neighbor (kNN) classifier, b) a grey level thresholding and seed growing (ISG-SG) method and c) a manual pixel labeling (GT) method for ground truth estimation. The SFCM and kNN methods are applied to the multispectral, contrast enhanced T 1, proton density, and T 2 weighted, magnetic resonance images (MRI) whereas the ISG-SG and GT methods are applied only to the contrast enhanced T 1 weighted image. Estimations of tumor volume were made on eight patient cases with follow-up MRI scans performed over a 32 week interval during treatment. The tumor cases studied include one meningioma, two brain metastases and five gliomas. Comparisons with manually labeled ground truth estimations showed that there is a limited agreement between the segmentation methods for absolute tumor volume measurements when using images of patients after treatment. The average intraobserver reproducibility for the SFCM, kNN and ISG-SG methods was found to be 5.8%, 6.6% and 8.9%, respectively. The average of the interobserver reproducibility of these methods was found to be 5.5%, 6.5% and 11.4%, respectively. For the measurement of relative change of tumor volume as required for the response assessment, the multi-spectral methods kNN and SFCM are therefore preferred over the seedgrowing method.

Interaction of drugs with P-glycoprotein in brain capillaries

P-glycoprotein (P-gp) is expressed at high levels in a variety of non-cancerous tissues such as the endothelial cells of the blood-brain barrier (BBB) capillaries. These thin capillaries tightly regulate the movement of substrates from the circulating blood into the brain. P-gp may be involved in the exclusion of various drugs from the capillary endothelial cells, blocking their entry into the brain. However, interactions of drugs with P-gp expressed in brain capillaries remain to be characterized. We have performed photoaffinity labeling studies using [ 125I]arylazidoprazosin (IAAP) to evaluate the inhibitory efficiency of various compounds. Cyclosporin A (CsA) and its derivative PSC 833 (PSC) were the most effective inhibitors of IAAP binding among the drugs tested. The magnitude of inhibition was: PSC > CsA > quinidine > vinblastine > verapamil > actinomycin D > colchicine > reserpine > bilirubin > doxorubicin > progesterone. Cremophor El, the vehicle used to administer CsA and PSC intravenously, was also able to inhibit IAAP photolabeling of P-gp. Labeling experiments were also performed using a photoactivatable [ 3H]CsA derivative. Photolabeling of P-gp with this compound was abolished almost completely by CsA and PSC. In vivo studies were also performed by treating rats with CsA [10 mg/(kg · day) for 10 days]. Following this treatment, no alteration in the level of P-gp expression in brain capillaries was; observed. These results suggest that, at the proper dosage, administration of CsA to cancer patients could help to enhance the response of brain tumors to chemotherapeutic agents without modifying the intrinsic level of P-gp expression in this tissue.

Endothelial differentiation in intracerebral and subcutaneous experimental gliomas

Blood-brain barrier (BBB) properties of endothelial cells have on impact on brain tumor behavior, diagnosis, and response to therapy. Biochemical BBB properties are expressed by endothelial cells within intracerebral (IC) gliomas but little is known regarding the expression of BBB-associated proteins within gliomas established subcutaneously (SC), a site that is frequently used in experimental glioma models. We compared the expression of two BBB proteins, glucose transporter type-1 (Glut1) and endothelial barrier antigen (EBA), in IC and SC rat 9L and F98 gliomas. The percentage of microvessels with immunohistochemically-detectable Glut1 and EBA in IC 9L tumors (31–98%) contrasted with that found in SC 9L tumors (0–3.9%) ( P < 0.0001). Likewise, the percentage of immunohistochemically-positive vessels in IC F98 tumors (35–66%) differed markedly from that in SC F98 tumors (0%) ( P < 0.00001). These differences were not explained by effects of tumor location on vessel density or tumor histology. These findings demonstrate that the peritumoral environment influences endothelial differentiation within glial tumors and suggest that glioma cells maintain but do not induce the expression of barrier properties in vessels that infiltrate tumor from surrounding tissue.

Effect of steroids on iopamidol blood-brain transfer constant and plasma volume in brain tumors measured with X-ray computed tomography.

Tumor blood-brain transfer constant of iopamidol (K) and plasma volume (Vp) were measured in 10 patients with primary brain tumors before and after 7 days of dexamethasone treatment (4 x 4 mg per oral per day) using X-ray computed tomography. Both K and Vp decreased significantly after dexamethasone treatment with p < 0.01 and 0.09 respectively according to one-tail paired t-test. The mean percentage decrease in K and Vp was 32% and 10% respectively. Functional images of the two parameters before and after treatment were generated and showed clearly the effect of steroids on the reduction of K in brain tumors. In contrast, when before and after treatment contrast enhanced CT scans were compared, no difference was observed in the enhancement in 8 out of 10 cases. The result obtained support the conclusion that: (1) corticosteroids reduce the blood-brain permeability to small hydrophilic molecules; (2) the X-ray computed tomography method we have developed can be used to measure the K and Vp response of brain tumors to steroid therapy; and, (3) ordinary contrast enhanced CT scans at one fixed time or multiple times after contrast injection are not sensitive in detecting the reduction of K due to steroids.

Expression and modulation of major histocompatibility antigens on murine primary brain tumor in vitro

Lysis of tumor cells by activated cytotoxic lymphocytes requires their recognition of antigens associated with major histocompatibility complex molecules. The authors studied the constitutive expression of Class I and Class II major histocompatibility complex antigens on mouse brain-tumor cells and the capacity of different cytokines and cytokine combinations to alter this expression in vitro. Cells from the murine glioma 26 (GL26), glioma 261 (GL261), and ependymoblastoma A (EpA) cell lines were established in monolayer culture and treated for 48 hours with either alpha interferon, gamma interferon, tumor necrosis factor alpha, tumor necrosis factor alpha plus gamma interferon, or interleukin-2. They were then analyzed by flow cytometry for baseline and cytokine-altered major histocompatibility complex expression. All cell lines had a similar constitutive major histocompatibility complex pattern with low Class I antigen expression and no detectable Class II antigen expression. Alpha interferon substantially induced and up-regulated Class I antigen expression, but had no effect on Class II antigen expression. Gamma interferon also stimulated up-regulation of Class I antigen expression, generally doubling the anti-Class I antigen fluorescence of treated cells. Its effect on Class II antigen expression was more extensive. In the GL26 and GL261 cell lines the expression of Class II antigen determinants increased to 12 x and 14 x control values and as many as 75% of cells that had no detectable constitutive expression of Class II antigen expressed this antigen after priming with gamma interferon. The addition of tumor necrosis factor alpha to gamma interferon further increased Class II antigen expression on EpA tumor cells only. Interleukin-2 and tumor necrosis factor alpha alone had no effect on Class I or Class II antigen expression of any cell lines. It is concluded that Class I and Class II antigen expression in mouse glioma cell lines is induced and enhanced after treatment with certain cytokines in vitro. Use of these cell lines to create in situ primary brain tumors in C57BL/6 mice should provide an excellent animal system to study major histocompatibility complex modulation in brain tumor cells and to examine the potential impact of major histocompatibility complex up-regulation on the response of brain tumors to immunotherapy.

Stereotactic radiation: Evaluation of brain tumor response

Stereotactic radiation: Evaluation of brain tumor response