Biodistribution and internal dosimetry of the 188Re-labelled humanized monoclonal antibody anti-epidemal growth factor receptor, nimotuzumab, in the locoregional treatment of malignant gliomas

OBJECTIVE: To evaluate the biodistribution, internal radiation dosimetry and safety of the 188Re-labelled humanized monoclonal antibody nimotuzumab in the locoregional treatment of malignant gliomas. METHODS: Single doses of 370 or 555 MBq of 188Re-labelled nimotuzumab were locoregionally administered to nine patients with recurrent high-grade gliomas, according to an approved dose-escalation study. SPECT, planar scintigraphy and magnetic resonance images were combined for dosimetric and pharmacokinetic studies. Blood and urine samples were collected to evaluate clinical laboratory parameters and for absorbed doses calculations. Biodistribution, internal dosimetry, human anti-mouse antibody response and toxicity were evaluated and reported. RESULTS: The 188Re-nimotuzumab showed a high retention in the surgically created resection cavity with a mean value of 85.5+/-10.3%ID 1 h post-injection. It produced mean absorbed doses in the tumour region of approximately 24.1+/-2.9 Gy in group I (patients receiving 370 MBq) and 31.1+/-6.4 Gy in group II (patients receiving 555 MBq); the normal organs receiving the highest absorbed doses were the kidneys, liver and urinary bladder. About 6.2+/-0.8%ID was excreted by the urinary pathway. The maximum tolerated dose was 370 MBq because two patients showed severe adverse effects after they received 555 MBq of 188Re-nimotuzumab. No patient developed human anti-mouse antibody response. CONCLUSIONS: A locoregional single dose of 188Re-labelled nimotuzumab of approximately 370 MBq could be used safely in the routine treatment of patients suffering with high-grade gliomas. The efficacy of this therapy needs to be evaluated in a phase II clinical trial.     

Usefulness of diffusion/perfusion-weighted MRI in patients with non-enhancing supratentorial brain gliomas: a valuable tool to predict tumour grading?

22 patients with non-enhancing supratentorial gliomas on contrast-enhanced MRI underwent both diffusion- and perfusion-weighted MRI (DWI/PWI) before surgical resection. 14 low-grade gliomas (WHO Grade I and II) and 8 anaplastic gliomas were verified histologically. Both apparent diffusion coefficient (ADC) values and relative cerebral blood volume (rCBV) ratios were calculated on the solid portion of the tumour, on peritumoural area, as well as on the contralateral normal white matter, respectively. The results showed that lower ADC values were present in the solid portions of anaplastic gliomas, but not in low grade (p < 0.01). All ADC values in peritumoural regions of tumours were decreased compared with the contralateral normal white matter. However, there was no significant difference between anaplastic gliomas and low-grade gliomas. Meanwhile, higher rCBV ratios were present in both solid portions and peritumoural regions of anaplastic gliomas, but not in low grade gliomas (p < 0.01). In conclusion, non-enhancing brain gliomas with lower ADC values in the solid portions and higher rCBV ratios in both solid portions and peritumoural regions of tumours are significantly correlated with anaplasia. Therefore, DWI and PWI should be integrated in the diagnostic work-up of non-enhancing gliomas in order to predict grading.     

Radiopeptide transmitted internal irradiation of non-iodophil thyroid cancer and conventionally untreatable medullary thyroid cancer using

AIM: Differentiated thyroid carcinomas (DTC) and medullary thyroid carcinomas (MTC) overexpress somatostatin receptor subtypes (sstr). The aim of this pilot study was to evaluate the tumour response of thyroid carcinomas to targeted irradiation with the radiolabelled somatostatin analogue [90Y]-1,4,7,10-tetra-azacyclododecan-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe1-Tyr3-octreotide ([90Y]-DOTA-D-Phe1-Tyr3-octreotide, or 90Y-DOTATOC) which has a high affinity to subtype 2 and a low affinity to subtype 5. It shows no affinity to sstr1, sstr3 and sstr4. PATIENTS AND METHODS: Twenty patients (mean age 58 years; 50% female, 50% male) with thyroid cancer were included (medullary thyroid cancer (MTC), 12 patients; differentiated thyroid cancer (DTC), seven patients; papillar carcinoma (PC), four patients; follicular carcinoma (FC), three patients; anaplastic carcinoma (AC), one patient). All patients had been therapy resistant and had progressive disease before 90Y-DOTATOC therapy. The dose applied was between totals of 1700 MBq x m(-2) to 7400 MBq x m(-2) 90Y-DOTATOC, administered in one to four injections at intervals of 6 weeks. In the case of tumour progression under therapy, treatment was terminated. RESULTS: The overall antitumour effect (objective response and stable disease) was 35%; in MTC 42%, in DTC 29%, and in AC 0%. The objective overall response rate was 0%. A stable disease was achieved in 35% (7/20), and progressive disease was found in 65% (13/20). The median time to progression was 8 months, with a median follow-up of 15 months. The treatment was very well tolerated. There were no grade III/IV haematological or renal toxicities. CONCLUSION: Targeted radiotherapy using 90Y-DOTATOC is able to stop tumour progression in a small number of patients and therefore may be an alternative treatment option for resistant disease. More significant tumour responses in thyroid and medullary thyroid cancer may be obtained by using radiopeptides with pan-somatostatin characteristics.     

Pre-operative grading of intracranial glioma.

AIM: To compare the accuracy of MR-determined cerebral blood volume (CBV) maps with SPECT imaging with thallium-201 in pre-operative grading of intracranial glioma. MATERIAL AND METHODS: Nineteen patients (7 female and 12 male, mean age 46.8 years) with intracranial gliomas were examined with MR perfusion imaging pre-operatively. Sixteen of these patients were also examined with SPECT imaging with thallium-201. The tumour to contralateral white matter NI (negative integral) and tracer uptake ratios were evaluated. The ratios in high-grade and low-grade tumours were compared. RESULTS: The maximum CBV ratios of grades I and II gliomas (2.958+/-2.217) were significantly lower than the maximum CBV ratio of grades III and IV (9.484+/-4.520), p<0.001. There was no statistical difference when CBV ratios of grades I and II (p=0.381), grades II and III (p=0.229) and grades III and IV (p=0.476) gliomas were compared. Thallium SPECT imaging showed no difference in tumour uptake ratio between low-grade and high-grade gliomas (p=0.299). CONCLUSION: MR-determined NI was useful for pre-operative grading of intracranial gliomas but SPECT thallium-201 imaging was not.     

111In-labelled bleomycin complex for the differentiation of high- and low-grade gliomas

The aim of this study was to evaluate 111In-labelled bleomycin complex (111In-BLMC) SPET in the differentiation of high- and low-grade gliomas. Nineteen glioma patients, 14 with high-grade and five with low-grade tumours, were studied 1, 4 and 24 h after the injection of 111In-BLMC. In the high-grade glioma group, there was significant uptake of 111In-BLMC in 12 patients and no uptake in two patients based on the visual classification of SPET images at 4 and 24 h. In the low-grade glioma group, one patient had low uptake at 4 and 24 h, but the other four patients showed no visible uptake. The mean tumour to extracerebral circulation activity ratio (T/Cr) at 4 h was 0.13 +/- 0.10 (n = 5) in low-grade gliomas and 1.7 +/- 1.0 (n = 14) in high-grade gliomas. At 24 h the T/Cr ratios were 0.56 +/- 0.21 and 3.4 +/- 1.7, respectively. The mean tumour to contralateral normal brain activity ratios (T/Br) were 5.0 +/- 3.9 (4 h) and 3.0 +/- 2.8 (24 h) in low-grade gliomas, and 37.2 +/- 37.3 (4 h) and 8.3 +/- 8.2 (24 h) in high-grade gliomas. These higher T/Br ratios did not, however, result in improved differentiation between the two groups of gliomas; at 4 h the T/Cr and T/Br ratios were of equal value, as two high-grade gliomas would have been misclassified as low-grade, but at 24 h the T/Br ratio resulted in more misclassifications. Our results show that 111In-BLMC can be used in the differentiation of high- and low-grade gliomas and that the selection of the reference area for calculating tumour to non-tumour ratios is important.     

Role of perfusion-weighted imaging at 3 Tesla in the assessment of malignancy of cerebral gliomas

PURPOSE: This study was performed to clarify the role of perfusion-weighted imaging (PWI) at 3 Tesla in the characterisation of haemodynamic heterogeneity within gliomas and surrounding tissues and in the differentiation of high-grade from low-grade gliomas. MATERIALS AND METHODS: We examined 36 patients with histologically verified gliomas (25 with high-grade and 11 with low-grade gliomas). PWI was performed by first-pass gadopentetate dimeglumine T2*-weighted echo-planar images, and cerebral blood volume (CBV) maps were computed with a nondiffusible tracer model. Relative CBV (rCBV) was calculated by dividing CBV in pathological areas by that in contralateral white matter. RESULTS: In high-grade gliomas, rCBV were markedly increased in mass [mean+/-standard deviation (SD), 4.3+/-1.2] and margins (4.0+/-1.1) and reduced in necrotic areas (0.3+/-0.3). Oedematous-appearing areas were divided in two groups according to signal intensity on T2-weighted images: tumour with lower (nearly isointense to grey matter) and oedema with higher (scarcely isointense to cerebrospinal fluid) signal intensity. Tumour showed significantly higher rCBV than did oedema (1.8+/-0.5 vs. 0.5+/-0.2; p<0.001) areas. In low-grade gliomas, mass (2.0+/-1.5) and margin (2.2+/-1.2) rCBV were significantly lower than in high-grade gliomas (p<0.001). CONCLUSIONS: Three-Tesla PWI helps to distinguish necrosis from tumour mass, infiltrating tumour from oedema and high-grade from low-grade gliomas. It enhances the magnetic resonance (MR) assessment of cerebral gliomas and provides useful information for planning surgical and radiation treatment.     

3-[123I]Iodo-alpha-methyl-L-tyrosine uptake in cerebral gliomas: relationship to histological grading and prognosis

3-[123I]Iodo-alpha-methyl-L-tyrosine (IMT) is employed clinically as a tracer of amino acid transport in brain tumours using single-photon emission tomography (SPET). This study investigates the role of IMT SPET in the non-invasive histological grading and prognostic evaluation of cerebral gliomas. The files of patients investigated by IMT SPET in our clinic between 1988 and 1996 were evaluated retrospectively. Complete follow-up was available for 58 patients with cerebral gliomas investigated by IMT SPET shortly after tumour diagnosis. Seventeen patients had low-grade gliomas (WHO grade II), 14 had anaplastic gliomas (WHO grade III) and 27 had glioblastomas (WHO grade IV). Thirty-six cases were primary tumours and 22 cases, recurrences. Maximal and mean tumour-to-brain (T/B) ratios of IMT uptake at the first IMT SPET investigation were related to histological grading and survival time. Patients with low-grade gliomas showed significantly longer survival than patients with high-grade (grade III or IV) tumours. Gliomas without contrast enhancement on computed tomography or magnetic resonance imaging scans were associated with longer patient survival than tumours with contrast enhancement. The T/B ratios of IMT SPET showed no differences in relation to histological grading [WHO grade II: 1.73+/-0.59; WHO grade III: 1.74+/-0.38; WHO grade IV: 1.59+/-0.35, (mean+/-SD, T/B ratios of mean tumour uptake)]. The median survival time of patients with a high T/B ratio on IMT SPET was not significantly different from that of patients with a low T/B ratio (T/B ratio <1.6, 14.8 months; T/B ratio > or =1.6, 13.0 months). Thus, no evidence could be found for a relationship between IMT uptake in cerebral gliomas and either histological grading or survival time. Nevertheless, IMT SPET constitutes a useful method for the detection of primary and recurrent gliomas, determination of tumour extent and individual follow-up.     

Correlation of myo-inositol levels and grading of cerebral astrocytomas

BACKGROUND AND PURPOSE: In a limited number of patients, the level of myo-inositol (MI), as seen by proton magnetic resonance spectroscopy (HMRS), has been shown to differ for gliomas of different histologic grades. We sought to determine if MI levels correlate with cerebral astrocytoma grade. METHODS: Five control subjects, 14 patients with low-grade astrocytoma, 10 patients with anaplastic astrocytoma, and 10 patients with glioblastoma multiforme (GBM) underwent single-volume HMRS with an echo time of 20 ms. Twenty-five patients had received surgery, chemotherapy, and/or radiation therapy previously. Using the curve-fitting program supplied by the manufacturer, peak areas for n-acetyl aspartate (NAA), choline (Cho), and MI were normalized with respect to the peak area of creatine (Cr). Ratios for MI/Cr, Cho/Cr, and NAA/Cr were obtained for each lesion and retrospectively compared with the histologic grade of the lesion. RESULTS: Levels of MI/Cr were higher (0.82 +/- 0.25) in patients with low-grade astrocytoma, intermediate (0.49 +/- 0.07) in control subjects, and lower in patients with anaplastic astrocytoma (0.33 +/- 0.16) and GBM (0.15 +/- 0.12). CONCLUSION: Our study shows a trend toward lower MI levels in the presence of anaplastic astrocytomas and GBMs compared with those of low-grade astrocytomas. MI levels may have implications in the grading of cerebral astrocytomas.     

Biokinetics and dosimetry in patients administered with (111)In-DOTA-Tyr(3)-octreotide: implications for internal radiotherapy with (90)Y-DOTATOC.

Recent advances in receptor-mediated tumour imaging have resulted in the development of a new somatostatin analogue, DOTA-dPhe(1)-Tyr(3)-octreotide. This new compound, named DOTATOC, has shown high affinity for somatostatin receptors, ease of labelling and stability with yttrium-90 and favourable biodistribution in animal models. The aim of this work was to evaluate the biodistribution and dosimetry of DOTATOC radiolabelled with indium-111, in anticipation of therapy trials with (90)Y-DOTATOC in patients. Eighteen patients were injected with DOTATOC (10 microg), labelled with 150-185 MBq of (111)In. Blood and urine samples were collected throughout the duration of the study (0-2 days). Planar and single-photon emission tomography images were acquired at 0.5, 3-4, 24 and 48 h and time-activity curves were obtained for organs and tumours. A compartmental model was used to determine the kinetic parameters for each organ. Dose calculations were performed according to the MIRD formalism. Specific activities of >37 GBq/ micromol were routinely achieved. Patients showed no acute or delayed adverse reactions. The residence time for (111)In-DOTATOC in blood was 0.9+/-0.4 h. The injected activity excreted in the urine in the first 24 h was 73%+/-11%. The agent localized primarily in spleen, kidneys and liver. The residence times in source organs were: 2.2+/-1.8 h in spleen, 1.7+/-1.2 h in kidneys, 2.4+/-1.9 h in liver, 1.5+/-0.3 h in urinary bladder and 9. 4+/-5.5 h in the remainder of the body; the mean residence time in tumour was 0.47 h (range: 0.03-6.50 h). Based on our findings, the predicted absorbed doses for (90)Y-DOTATOC would be 7.6+/-6.3 (spleen), 3.3+/-2.2 (kidneys), 0.7+/-0.6 (liver), 2.2+/-0.3 (bladder), 0.03+/-0.01 (red marrow) and 10.1 (range: 1.4-31.0) (tumour) mGy/MBq. These results indicate that high activities of (90)Y-DOTATOC can be administered with low risk of myelotoxicity, although with potentially high radiation doses to the spleen and kidneys. Tumour doses were high enough in most cases to make it likely that the desired therapeutic response desired would be obtained.     

Detection of tumour progression in the follow-up of irradiated low-grade astrocytomas: comparison of 3-[123I]iodo-alpha-methyl- L-tyrosine and 99mTc-MIBI SPET

Conventional MRI often fails to distinguish between progressive tumour and radiation injury, because both appear as mass lesions with unspecific Gd-DTPA enhancement. Furthermore, the sensitivity of FDG PET for the evaluation of malignant lesions in the brain is limited owing to high cortical uptake. The aim of this study was to assess the potential of alternative SPET tracers in the same group of patients. 35.2+/-20.1 months after stereotactic radiotherapy (59.3+/-4.2 Gy) of low-grade astrocytomas (median WHO II), 16 patients, presenting 25 Gd-DTPA-enhancing lesions on MRI, were examined by SPET. Lesions were classified as progressive tumour (PT, n=17) or non-PT (nPT, n=8) based on prospective follow-up (clinical examination, MRI, proton-MR spectroscopy) for 25.6+/-6.7 months after SPET. SPET scans were performed 15 and 60 min after injection of 694+/-67 MBq hexakis(2-methoxyisobutylisonitrile)(99m)Tc(I) (MIBI). 3-[(123)I]iodo-alpha-methyl- L-tyrosine (IMT) SPET was acquired 15 min after injection of 291+/-58 MBq IMT. Lesion-to-normal tissue ratios (l/n) for IMT (l/n(IMT)) and MIBI (l/n(MIBI)) were calculated using a reference region mirrored to the contralateral hemisphere. Using IMT, significantly higher ratios ( P<0.001) were found in PT (1.7+/-0.4) than in nPT (1.1+/-0.1). For MIBI, there was no statistically significant difference ( P=0.206) between PT (3.7+/-2.8) and nPT (1.8+/-1.8). Sensitivities for MIBI and IMT were 53% and 94%, and specificities 75% and 100%, respectively. Positive predictive values for MIBI and IMT respectively reached 80% and 100%, and negative predictive values were 46% and 90%. In conclusion, in contrast to MIBI, IMT showed almost no overlap between the PT and the nPT group. The sensitivity, specificity and predictive values of IMT SPET were obviously higher than those of MIBI SPET. IMT is considered to be a useful tracer for differentiating PT from nPT in the follow-up of irradiated low-grade astrocytomas.     

Treatment with 177Lu-DOTATOC of patients with relapse of neuroendocrine tumors after treatment with 90Y-DOTATOC.

Therapy with [(90)Y-DOTA(0), Tyr(3)]-octreotide (DOTATOC, where DOTA = tetraazacyclododecane tetraacetic acid and TOC = D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol)) is established for the treatment of metastatic neuroendocrine tumors. Nevertheless, many patients experience disease relapse, and further treatment may cause renal failure. Trials with (177)Lu-labeled somatostatin analogs showed less nephrotoxicity. We initiated a prospective study with (177)Lu-DOTATOC in patients with relapsed neuroendocrine tumors after (90)Y-DOTATOC treatment. METHODS: Twenty-seven patients, pretreated with (90)Y-DOTATOC, were included. The mean time between the last treatment with (90)Y-DOTATOC and (177)Lu-DOTATOC was 15.4 +/- 7.8 mo (SD). All patients were injected with 7,400 MBq of (177)Lu-DOTATOC. Restaging was performed after 8-12 wk. Hematotoxicity or renal toxicity of World Health Organization grade 1 or 2 was not an exclusion criterion. RESULTS: Creatinine levels increased significantly, from 66 +/- 14 micromol/L to 100 +/- 44 micromol/L (P < 0.0001), after (90)Y-DOTATOC therapy. The mean hemoglobin level dropped from 131 +/- 14 to 117 +/- 13 g/L (P < 0.0001) after (90)Y-DOTATOC therapy. (177)Lu-DOTATOC therapy was well tolerated. No serious adverse events occurred. The mean absorbed doses were 413 +/- 159 mGy for the whole body, 3.1 +/- 1.5 Gy for the kidneys, and 61 +/- 5 mGy for the red marrow. After restaging, we found a partial remission in 2 patients, a minor response in 5 patients, stable disease in 12 patients, and progressive disease in 8 patients. Mean hemoglobin and creatinine levels did not change significantly. CONCLUSION: (177)Lu-DOTATOC therapy in patients with relapse after (90)Y-DOTATOC treatment is feasible, safe, and efficacious. No serious adverse events occurred.     

Preliminary data on biodistribution and dosimetry for therapy planning of somatostatin receptor positive tumours: comparison of (86)Y-DOTATOC and (111)In-DTPA-octreotide.

The somatostatin analogue (90)Y-DOTATOC (yttrium-90 DOTA- D-Phe(1)-Tyr(3)-octreotide) is used for treatment of patients with neuroendocrine tumours. Accurate pretherapeutic dosimetry would allow for individual planning of the optimal therapeutic strategy. In this study, the biodistribution and resulting dosimetric calculation for therapeutic exposure of critical organs and tumour masses based on the positron emission tomography (PET) tracer (86)Y-DOTATOC, which is chemically identical to the therapeutic agent, were compared with results based on the tracer commonly used for somatostatin receptor scintigraphy, (111)In-DTPA-octreotide (indium-111 DTPA- D-Phe(1)-octreotide, OctreoScan). Three patients with metastatic carcinoid tumours were investigated. Dynamic and static PET studies with 77-186 MBq (86)Y-DOTATOC were performed up to 48 h after injection. Serum and urinary activity were measured simultaneously. Within 1 week, but not sooner than 5 days, patients were re-investigated by conventional scintigraphy with (111)In-DTPA-octreotide (110-187 MBq) using an equivalent protocol. Based on the regional tissue uptake kinetics, residence times were calculated and doses for potential therapy with (90)Y-DOTATOC were estimated. Serum kinetics and urinary excretion of both tracers showed no relevant differences. Estimated liver doses were similar for both tracers. Dose estimation for organs with the highest level of radiation exposure, the kidneys and spleen, showed differences of 10.5%-20.1% depending on the tracer. The largest discrepancies in dose estimation, ranging from 23.1% to 85.9%, were found in tumour masses. Furthermore, there was a wide inter-subject variability in the organ kinetics. Residence times (tau(organs)) for (90)Y-DOTATOC therapy were: tau(liver) 1.59-2.79 h; tau(spleen) 0.07-1.68 h; and tau(kidneys) 0.55-2.46 h (based on (86)Y-DOTATOC). These data suggest that dosimetry based on (86)Y-DOTATOC and (111)In-DTPA-octreotide yields similar organ doses, whereas there are relevant differences in estimated tumour doses. Individual pretherapeutic dosimetry for (90)Y-DOTATOC therapy appears necessary considering the large differences in organ doses between individual patients. If possible, the dosimetry should be performed with the chemically identical tracer (86)Y-DOTATOC.     

Minimum apparent diffusion coefficients in the evaluation of brain tumors

OBJECTIVE: To determine whether diffusion-weighted imaging by using minimum apparent diffusion coefficient (ADC(min)) values could differentiate various brain tumors including gliomas, metastases, and lymphomas. MATERIALS AND METHODS: We examined 65 patients with histologically or clinically diagnosed brain tumors (12 low-grade gliomas, 31 high-grade gliomas, 14 metastatic tumors, and 8 lymphomas) using a 1.5 T MR unit. On diffusion-weighted imaging, the ADC(min) values were measured within the tumors and mean values were evaluated regarding statistical differences between groups. RESULTS: The ADC(min) values of low-grade gliomas (1.09+/-0.20 x 10(-3)mm(2)/s) were significantly higher (p<.001) than those of other tumors. There were no statistical significant differences between glioblastomas (0.70+/-0.16 mm(2)/s), anaplastic astrocytomas (0.77+/-0.21 mm(2)/s), metastases (0.78+/-0.21 mm(2)/s), and lymphomas. But, lymphomas had lower mean ADC(min) values (0.54+/-0.10mm(2)/s) than high-grade gliomas and metastases. CONCLUSION: The ADC measurements may help to differentiate low-grade gliomas from high-grade gliomas, metastases, and lymphomas. Although there is no statistical difference, lymphomas seem to have marked restriction in diffusion coefficients.     

192Ir核素脑胶质瘤间质内放疗的研究及其临床应用

为观察用＾１９２Ｉｒ后装治疗脑胶质瘤间后内放疗的有效性及其并发症,用皮荷瘤鼠和脑荷瘤鼠模型行间质内放疗实验,证明在内照射后可抑制肿瘤生长及延长鼠的生存期的可靠基础上,对７２例脑胶质瘤采用＾１９２Ｉｒ后装机行瘤间后内近距离照射,取得良好疗效。手术无何严重并发症,无死亡。术后随访１－５年,生存率分别为９２％、８２％、７２％、５６％及３２％,表明生存期显著延长。结论脑深部胶质瘤用＾１９２Ｉｒ核素瘤间持     

Quantitative volumetric analysis of gliomas with sequential MRI and 11C-methionine PET assessment: patterns of integration in therapy planning

Purpose

The aim of the study was to evaluate the volumetric integration patterns of standard MRI and ¹¹C-methionine positron emission tomography (PET) images in the surgery planning of gliomas and their relationship to the histological grade.

Methods

We studied 23 patients with suspected or previously treated glioma who underwent preoperative ¹¹C-methionine PET because MRI was imprecise in defining the surgical target contour. Images were transferred to the treatment planning system, coregistered and fused (BrainLAB). Tumour delineation was performed by ¹¹C-methionine PET thresholding (vPET) and manual segmentation over MRI (vMRI). A 3-D volumetric study was conducted to evaluate the contribution of each modality to tumour target volume. All cases were surgically treated and histological classification was performed according to WHO grades. Additionally, several biopsy samples were taken according to the results derived either from PET or from MRI and analysed separately.

Results

Fifteen patients had high-grade tumours [ten glioblastoma multiforme (GBM) and five anaplastic), whereas eight patients had low-grade tumours. Biopsies from areas with high ¹¹C-methionine uptake without correspondence in MRI showed tumour proliferation, including infiltrative zones, distinguishing them from dysplasia and radionecrosis. Two main PET/MRI integration patterns emerged after analysis of volumetric data: pattern vMRI-in-vPET (11/23) and pattern vPET-in-vMRI (9/23). Besides, a possible third pattern with differences in both directions (vMRI-diff-vPET) could also be observed (3/23). There was a statistically significant association between the tumour classification and integration patterns described above (p?Conclusion The metabolically active tumour volume observed in ¹¹C-methionine PET differs from the volume of MRI by showing areas of infiltrative tumour and distinguishing from non-tumour lesions. Differences in ¹¹C-methionine PET/MRI integration patterns can be assigned to tumour grades according to the WHO classification. This finding may improve tumour delineation and therapy planning for gliomas.     

Cerebral gliomas: prospective comparison of multivoxel 2D chemical-shift imaging proton MR spectroscopy,echoplanar perfusion and diffusion-weighted MRI

Developments in MRI have made it possible to use diffusion-weighted MRI, perfusion MRI and proton MR spectroscopy (MRS) to study lesions in the brain. We evaluated whether these techniques provide useful, complementary information for grading gliomas, in comparison with conventional MRI. We studied 17 patients with histologically verified gliomas, adding multivoxel proton MRS, echoplanar diffusion and perfusion MRI the a routine MRI examination. The maximum relative cerebral blood volume (CBV), minimum apparent diffusion coefficient (ADC) and metabolic peak area ratios in proton MRS were calculated in solid parts of tumours on the same slice from each imaging data set. The mean minimum ADC of the 13 high-grade gliomas (0.92+/-0.27 x 10(-3) mm(2)/s) was lower than that of the four low-grade gliomas (1.28+/-0.15 x 10(-3) mm(2)/s) ( P<0.05). Means of maximum choline (Cho)/N-acetylaspartate (NAA), Cho/creatine (Cr), Cho/Cr in normal brain (Cr-n) and minimum NAA/Cr ratios were 5.90+/-2.62, 4.73+/-2.22, 2.66+/-0.68 and 0.40+/-0.06, respectively, in the high-grade gliomas, and 1.65+/-1.37, 1.84+/-1.20, 1.61+/-1.29 and 1.65+/-1.61, respectively, in the low-grade gliomas. Significant differences were found on spectroscopy between the high- and low-grade gliomas ( P<0.05). Mean maximum relative CBV in the high-grade gliomas (6.10+/-3.98) was higher than in the low-grade gliomas (1.74+/-0.57) ( P<0.05). Echoplanar diffusion, perfusion MRI and multivoxel proton MRS can offer diagnostic information, not available with conventional MRI, in the assessment of glioma grade.     

Grading of brain glioma with 1-11C-acetate PET: comparison with 18F-FDG PET

The objective of this study is to reevaluate the clinical significance of 1-11C-acetate (ACE) positron emission tomography (PET) in patients with brain glioma, in comparison with 18F-fluorodeoxyglucose (FDG) PET. METHODS: Ten patients with histologically proven glioma were included in this study. They underwent PET examination with both FDG and ACE on separate days. For ACE PET, 20-min data acquisition was performed just after the administration of 740 MBq of ACE; 10-20-min data were used for the analysis. FDG PET data acquisition for 10 min started 60 min postinjection of 370 MBq of FDG, approximately. Both reconstructed images were converted to standardized uptake value (SUV) images for patient body weight and injected dose. Regions of interest were placed on the tumor and the contralateral cerebral cortex, and SUV and tumor-to-cortex ratio (T/C) were calculated; these values were compared between high- and low-grade gliomas. RESULTS: SUV and T/C of ACE PET showed significant difference (SUV: 2.63+/-0.46 vs. 1.85+/-0.56, P=.03; T/C: 2.36+/-0.63 vs. 1.14+/-0.36, P=.02). In contrast, FDG PET revealed no significant difference in SUV or T/C between high- and low-grade gliomas (SUV: 7.13+/-4.31 vs. 4.71+/-1.27, P=.31; T/C: 0.98+/-0.55 vs. 0.62+/-0.09, P=.22). CONCLUSION: This preliminary study revealed that ACE PET is a promising tracer for the grading of brain glioma.     

Perfusion MR Imaging in Gliomas: Comparison with Histologic Tumor Grade

Objective

To determine the usefulness of perfusion MR imaging in assessing the histologic grade of cerebral gliomas.

Materials and Methods

In order to determine relative cerebral blood volume (rCBV), 22 patients with pathologically proven gliomas (9 glioblastomas, 9 anaplastic gliomas and 4 low-grade gliomas) underwent dynamic contrast-enhanced T2*-weighted and conventional T1- and T2-weighted imaging. rCBV maps were obtained by fitting a gamma-variate function to the contrast material concentration versus time curve. rCBV ratios between tumor and normal white matter (maximum rCBV of tumor / rCBV of contralateral white matter) were calculated and compared between glioblastomas, anaplastic gliomas and low-grade gliomas.

Results

Mean rCBV ratios were 4.90°±1.01 for glioblastomas, 3.97°±0.56 for anaplastic gliomas and 1.75°±1.51 for low-grade gliomas, and were thus significantly different; p < .05 between glioblastomas and anaplastic gliomas, p < .05 between anaplastic gliomas and low-grade gliomas, p < .01 between glioblastomas and low-grade gliomas. The rCBV ratio cutoff value which permitted discrimination between high-grade (glioblastomas and anaplastic gliomas) and low-grade gliomas was 2.60, and the sensitivity and specificity of this value were 100% and 75%, respectively.

Conclusion

Perfusion MR imaging is a useful and reliable technique for estimating the histologic grade of gliomas.     

Low-grade gliomas: dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging--prediction of patient clinical response

PURPOSE: To determine retrospectively whether relative cerebral blood volume (CBV) measurements can be used to predict clinical response in patients with low-grade gliomas. MATERIALS AND METHODS: Approval for this retrospective HIPAA-compliant study was obtained from the Institutional Board of Research Associates, with waiver of informed consent. Thirty-five patients (23 male and 12 female patients; median age, 39 years; range, 4-80 years) with histologically diagnosed low-grade gliomas (21 low-grade astrocytomas and 14 low-grade oligodendrogliomas and low-grade mixed oligoastrocytomas) were examined with dynamic susceptibility-weighted contrast material-enhanced perfusion magnetic resonance (MR) imaging. Wilcoxon tests were used to compare patients in different response categories (complete response, stable, progressive, death) with respect to baseline relative CBV. Kaplan-Meier survival curves, log-rank tests, and Weibull survival models were used to characterize and evaluate the association of baseline relative CBV with time to progression. Tumor volumes and relative CBV measurements were obtained at initial examination and follow-up. RESULTS: Lesions with relative CBV less than 1.75 had a median time to progression of 4620 days +/- 433 (standard deviation), and lesions with relative CBV more than 1.75 had a median time to progression of 245 days +/- 62. Patients who had an adverse event (either death or progression) had significantly higher (P = .003) relative CBV than did patients without adverse events (either complete response or stable disease). Lesions with low baseline relative CBV had stable tumor volumes at follow-up over time, whereas those with high baseline relative CBV (>1.75) had progressively increasing tumor volumes over time. CONCLUSION: Dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging can help to identify low-grade gliomas that will progress rapidly and a subset of low-grade gliomas that have a propensity for malignant transformation.     

Mapping of brain tumor metabolites with proton MR spectroscopic imaging: clinical relevance.

Brain tumor metabolism was studied with hydrogen-1 magnetic resonance spectroscopy and positron emission tomography with fluorine-18 fluorodeoxyglucose in 50 patients. N-acetylaspartate (NAA) was generally decreased in tumors and radiation necrosis but was somewhat preserved at neoplasm margins. Choline was increased in most solid tumors. Solid high-grade gliomas had higher normalized choline values than did solid low-grade gliomas (P < .02), but the normalized choline value was not a discriminator of tumor grade, since necrotic high-grade lesions had reduced choline values. Serial studies in one case showed an increase in choline as the glioma underwent malignant degeneration. Choline values were lower in chronic radiation necrosis than in solid anaplastic tumors (P < .001). In two cases studied before and after treatment, clinical improvement and a reduction in choline followed therapy. Lactate is more likely to be found in high-grade gliomas, but its presence is not a reliable indicator of malignancy.