Giampiero Villavecchia

131I-metaiodobenzylguanidine (131I-MIBG) therapy for residual neuroblastoma: a mono-institutional experience with 43 patients

SummaryIncomplete response to therapy may compromise the outcome of children with advanced neuroblastoma. In an attempt to improve tumour response we incorporated 131I-metaiodobenzylguanidine (131I-MIBG) in the treatment regimens of selected stage 3 and stage 4 patients. Between 1986 and 1997, 43 neuroblastoma patients older than 1 year at diagnosis, 13 with stage 3 (group A) and 30 with stage 4 disease (group B) who had completed the first-line protocol without achieving complete response entered in this study. 131I-MIBG dose/course ranged from 2.5 to 5.5 Gbq (median, 3.7). The number of courses ranged from 1 to 5 (median 3) depending on the tumour response and toxicity. The most common acute side-effect was thrombocytopenia. Later side-effects included severe interstitial pneumonia in one patient, acute myeloid leukaemia in two, reduced thyroid reserve in 21. Complete response was documented in one stage 4 patient, partial response in 12 (two stage 3, 10 stage 4), mixed or no response in 25 (ten stage 3, 15 stage 4) and disease progression in five (one stage 3, four stage 4) Twenty-four patients (12/13 stage 3, 12/30 stage 4) are alive at 22–153 months (median, 59) from diagnosis. 131I-MIBG therapy may increase the cure rate of stage 3 and improve the response of stage 4 neuroblastoma patients with residual disease after first-line therapy. A larger number of patients should be treated to confirm these results but logistic problems hamper prospective and coordinated studies. Long-term toxicity can be severe.

Comparison of 18F-dopa PET/CT and 123I-MIBG scintigraphy in stage 3 and 4 neuroblastoma: a pilot study

Purpose18F-Dopa positron emission tomography (PET)/CT has proved a valuable tool for the assessment of neuroendocrine tumours. So far no data are available on 18F-dopa utilization in neuroblastoma (NB). Our aim was to evaluate the role of 18F-dopa PET/CT in NB and compare its diagnostic value with that of 123I-metaiodobenzylguanidine (MIBG) scintigraphy in patients affected by stage 3–4 NB.MethodsWe prospectively evaluated 28 paired 123I-MIBG and 18F-dopa PET/CT scans in 19 patients: 4 at the time of the NB diagnosis and 15 when NB relapse was suspected. For both imaging modalities we performed a scan-based and a lesion-based analysis and calculated sensitivity, specificity and accuracy. The standard of reference was based on clinical, imaging and histological data.ResultsNB localizations were confirmed in 17 of 19 patients. 18F-Dopa PET/CT and 123I-MIBG scintigraphy properly detected disease in 16 (94%) and 11 (65%), respectively. On scan-based analysis, 18F-dopa PET/CT showed a sensitivity and accuracy of 95 and 96%, respectively, while 123I-MIBG scanning showed a sensitivity and accuracy of 68 and 64%, respectively (p < 0.05). No significant difference in terms of specificity was found. In 9 of 28 paired scans (32%) PET/CT results influenced the patient management. We identified 156 NB localizations, 141 of which were correctly detected by 18F-dopa PET/CT and 88 by MIBG. On lesion-based analysis, 18F-dopa PET/CT showed a sensitivity and accuracy of 90% whereas 123I-MIBG scintigraphy showed a sensitivity and accuracy of 56 and 57%, respectively (p < 0.001). No significant difference in terms of specificity was found.ConclusionIn our NB population 18F-dopa PET/CT displayed higher overall accuracy than 123I-MIBG scintigraphy. Consequently, we suggest 18F-dopa PET/CT as a new opportunity for NB assessment.

Giant Cell Arteritis: A Systematic Review of the Qualitative and Semiquantitative Methods to Assess Vasculitis with 18F-Fluorodeoxyglucose Positron Emission Tomography

Giant cell arteritis (GCA) is the most common vasculitis affecting medium and large vessels. It shows a close clinical association with polymyalgia rheumatica (PMR), a musculoskeletal inflammatory disorder, which is clinically characterized by girdles pain and stiffness. 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is an effective tool for the diagnosis, grading, and follow-up of patients affected by GCA involving the aorta and its proximal branches, but the lack of a standardized method for the assessment of vascular inflammation remains a critical issue, potentially leading to misclassification. In our systematic review, including 19 original articles for a total of 442 GCA patients (with or without PMR symptoms) and 535 healthy controls, we described the different qualitative, semiquantitative and combined methods that have been proposed throughout the literature for assessing the presence and grading the severity of GCA-related vascular inflammation on 18F-FDG PET scans, focusing on the diagnostic performance and examining their respective advantages and limitations. The majority of the included studies adopted qualitative methods of PET image analysis, which are less sensitive but more specific than semiquantitative ones. Among the semiquantitative approaches, the aortic-to-blood pool uptake ratio of the aortic arch seems to be the most accurate method.

Megatherapy combining I131 metaiodobenzylguanidine and high-dose chemotherapy with haematopoietic progenitor cell rescue for neuroblastoma

Despite the use of aggressive chemotherapy, stage 4 high risk neuroblastoma still has very poor prognosis which is estimated at 25%. Metabolic radiotherapy with I131 MIBG appears a feasible option to enhance the effects of chemotherapy. Seventeen patients having MIBG-positive residual disease received 4.1–11.1 mCi/kg of I131 MIBG 7–10 days before initiating the high-dose chemotherapy cycle consisting of busulphan 16 mg/kg and melphalan 140 mg/m2 followed by PBSC infusion. We compared the toxicity in these patients to that seen in 15 control subjects with neuroblastoma who underwent a PBSC transplant without MIBG therapy. We observed greater toxic involvement of the gastrointestinal system in children treated with I131 MIBG: grade 2 or 3 mucositis developed in 13/17 patients treated with I131 MIBG and in 9/15 treated without it. Grade 1–2 gastrointestinal toxicity occurred in 12/17 children given MIBG and in 5/15 of the controls. One child receiving I131 MIBG developed transient interstitial pneumonia. Another child who also received I131 MIBG after PBSC rescue developed fatal pneumonia after the third course of metabolic radiotherapy. Our experience indicates that MIBG can be included in the high-dose chemotherapy regimens followed by PBSC rescue for children with residual neuroblastoma taking up MIBG. Attention should be paid to avoiding lung complications. Prospective studies are needed to demonstrate the real efficacy of this treatment. Bone Marrow Transplantation (2001) 27, 571–574.

18F-DOPA PET/CT in neuroblastoma: comparison of conventional imaging with CT/MR.

Aim: Role of 18F-DOPA PET/CT in neuroblastoma (NB) compared with CT/MR. Materials and Methods: In all, 21 patients (M:F = 14:7; mean age, 7.4 years) affected by advanced stage NB (III-IV) were prospectively enrolled. Overall, 37 paired 18F-DOPA PET and CT/MR scans were performed, and for each, we identified site and number of lesions. Standard of reference was based on a multidisciplinary assessment, including 123I-MIBG, selective biopsy, and clinical-instrumental monitoring. Both scan-based and a lesion-based analysis was performed, and for each modality, we calculated sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy. Results: On the scan-based analysis, 18F-DOPA PET and CT/MR showed the following rates: sensitivity, specificity, NPV, PPV, and accuracy were 100%, 92.3%, 100%, 96%, and 97.3% versus 91.7%, 61.5%, 80%, 81.5%, and 81.1%, respectively (P = 0.014). Overall 179 findings were reported at imaging, of which 139 (77.7%) resulted true sites of disease at final outcome. On the lesion-based analysis, the 2 imaging modalities showed the following sensitivity, specificity, NPV, PPV, and accuracy rates: 90.6%, 90%, 73.5%, 96.9%, and 90.5% versus 47.5%, 27.5%, 13.1%, 69.5%, and 43% (P < 0.00001). Conclusions: In our study, 18F-DOPA PET/CT results more accurate than CT/MR in advanced stage NB therefore should be taken into consideration for the diagnostic workup of these patients.

18F-NaF Uptake by Atherosclerotic Plaque on PET/CT Imaging: Inverse Correlation Between Calcification Density and Mineral Metabolic Activity

Several studies have highlighted the role of vascular 18F-NaF uptake as a marker of ongoing calcium deposition. However, accumulation of 18F-NaF is often inconsistent with localization of arterial plaque. Calcification activity and thus 18F-NaF uptake might prevail in the earlier plaque stages. To test this hypothesis, we evaluated 18F-NaF uptake in plaque of 3 different densities, using density as a marker of calcification progression. We also tested whether attenuation-weighted image reconstruction affects 18F-NaF uptake in the different plaque stages. Methods: Sixty-four oncologic patients (14 men and 50 women; mean age, 65.3 ± 8.2 y; range, 26–81 y) underwent 18F-NaF PET/CT. A volume of interest was drawn on each plaque within the infrarenal aorta to assess mean standardized uptake value and attenuation (in Hounsfield units [HU]). Plaque was then categorized as light (<210 HU), medium (211–510 HU), or heavy (>510 HU). Standardized uptake value was normalized for blood 18F-NaF activity to obtain the plaque target-to-background ratio (TBR). During this process, several focal, noncalcified areas of 18F-NaF were identified (hot spots). The TBR of the hot spots was computed after isocontour thresholding. The TBR of a noncalcified control region was also calculated. In 35 patients, the TBR of non–attenuation-corrected images was calculated. Results: The average TBR was highest in light plaque (2.21 ± 0.88), significantly lower in medium plaque (1.59 ± 0.63, P < 0.001), and lower still in heavy plaque (1.14 ± 0.37, P < 0.0001 with respect to both light and medium plaque). The TBR of the control region was not significantly different from that of heavy plaque but was significantly lower than that of light and medium plaque (P < 0.01). Hot spots had the highest absolute TBR (3.89 ± 1.87, P < 0.0001 vs. light plaque). TBRs originating from non–attenuation-corrected images did not significantly differ from those originating from attenuation-corrected images. Conclusion: Our results support the concept that 18F-NaF is a feasible option in imaging molecular calcium deposition in the early stages of plaque formation, when active uptake mechanisms are the main determinants of calcium presence, but that retention of 18F-NaF progressively decreases with increasing calcium deposition in the arterial wall. Our data suggest that non–attenuation-corrected reconstruction does not significantly affect evaluation of plaque of any thickness.

Divergent determinants of 18F–NaF uptake and visible calcium deposition in large arteries: relationship with Framingham risk score

To compare regional vascular distribution and biological determinants of visible calcium load, as assessed by computed tomography, as well as of molecular calcium deposition as assessed by 18F–NaF positron emission tomography. Eighty oncologic patients undergoing 18F–NaF PET/CT scan were included in the study. Cardiovascular-risk stratification was performed according to a simplified version of the Framingham model [including age, diabetes, smoking, systolic blood pressure and body mass index (BMI)]. Arterial 18F–NaF uptake was measured by drawing regions of interest comprising the arteries on each slice of the transaxial PET/CT and normalized to blood 18F–NaF activity to obtain the arterial target-to-background ratio (TBR). The degree of arterial calcification (AC) was measured using a software program providing Agatston-like scores. Differences in mean values and regression analysis were tested. Predictors of AC and TBR were evaluated by univariate and multivariate analysis. p value of 0.05 was considered statistically significant. No correlation was documented between regional calcium load and regional TBR in any of the studied arterial segments. Visible calcium deposition was found to be dependent upon age while it was not influenced by all the remaining determinants of cardiovascular risk. By contrast, 18F–NaF uptake was significantly correlated with all descriptors of cardiovascular risk, with the exception of BMI. Vascular 18F–NaF uptake displays a different regional distribution, as well as different biological predictors, when compared to macroscopic AC. The tight dependency of tracer retention upon ongoing biological determinants of vascular damage suggests that this tool might provide an unexplored window on plaque pathophysiology.

Detection of metastatic bone lesions in breast cancer patients: Fused 18F-Fluoride-PET/MDCT has higher accuracy than MDCT. Preliminary experience

PURPOSE So far, no studies comparing (18)F-Fluoride-PET/CT and MDCT for the detection of bone metastases are available. We compared the accuracy of (18)F-Fluoride-PET/CT (MDCT: 3.75 mm thickness-image-reconstruction), whole-body Multi-Detector-CT (MDCT: 1.25 mm thickness-image-reconstruction) and (18)F-Fluoride-PET/MDCT (MDCT: 1.25 mm thickness-image-reconstruction) in identifying bone metastases in breast cancer patients. METHODS We studied 39 breast cancer patients for bone metastases. Imaging was performed on an integrated PET/MDCT-system; CT images were reconstructed at 3.75 mm and 1.25 mm thickness. Two nuclear medicine physicians and one radiologist interpreted blindly (18)F-Fluoride-PET/CT, (18)F-Fluoride-PET/MDCT and MDCT. MDCT at 12 months served as the standard of reference. RESULTS Overall, 662 bone lesions were detected in our analysis. Of these, 542 were malignant and 120 were benign according to the standard of reference. (18)F-Fluoride-PET/CT detected 491 bone metastases, 114 (23%) of which displayed no clear morphological changes on MDCT, whereas MDCT detected 416 bone metastases, 39 (9.3%) of which showed no (18)F-Fluoride-PET uptake. Overall sensitivity and specificity were: 91% and 91%, respectively, for (18)F-Fluoride-PET/CT, and 77% and 93% for MDCT. The integrated assessment of (18)F-Fluoride-PET/MDCT yielded sensitivity and specificity values of 98% and 93%, respectively. CONCLUSIONS (18)F-Fluoride-PET/MDCT has higher diagnostic accuracy than (18)F-Fluoride-PET/CT and MDCT for the evaluation of bone metastases in breast cancer.

Bone and lymph node metastases from neuroblastoma detected by 18F-DOPA-PET/CT and confirmed by posttherapy 131I-MIBG but negative on diagnostic 123I-MIBG scan

We report the case of a 6-year-old child with stage 4 neuroblastoma, previously treated with chemotherapy, which relapsed in the right mandibular branch, right submandibular lymph nodes, and bone marrow. These sites of recurrence were detected on diagnostic (123)I-MIBG and confirmed by (18)F-DOPA-PET/CT, which revealed the following 2 additional sites of disease: in the skull base and the left supraclavicular lymph nodes. The patient was scheduled for radioiodine therapy and received a total dose of 7400 MBq (200 mCi) of (131)I-MIBG. The whole-body scan, acquired 72 hours later, revealed all sites of disease detected by (18)F-DOPA-PET/CT, including those negative on (123)I-MIBG scan.

Skeletal involvement in infants with neuroblastoma a quality control attempt

AIMS AND BACKGROUND In 1994, French authors hypothesized that positive skeletal mlBG spots in infants with stage 4 neuroblastoma were not prognostically unfavorable unless associated to abnormal standard X-ray or CT findings. In 1999, the European Infant Neuroblastoma Study adopted this definition, indeed reducing the number of patients candidate to chemotherapy. Such an approach requires high quality scans and standardized procedures. The present study critically reviewed and assessed the quality of mlBG scans performed in Italian patients enrolled in the European Infant Neuroblastoma Study. METHODS Three independent nuclear medicine specialists reviewed scans of 25 Italian patients enrolled in Trials 99.2, 99.3, and 99.4 of the European Infant Neuroblastoma Study between January 2000 and September 2002. An arbitrary quality score was attributed to each mlBG scintigraphy, ranging from 1 (less than adequate) to 3 (excellent). One radiologist and 2 oncologists reviewed the X-rays and CT scans and correlated the results with clinical assessment. RESULTS The quality of mlBG scans was rated from good to excellent in 15 of 25 cases, poor in 4, and inadequate for diagnostic evaluation in 6. X-rays confirmed the presence of metastases in 3 of 7 cases with mlBG bone uptake. CT scan confirmed skull metastases in 6 of 9 mlBG-positive cases. Discrepancies in scan interpretation, making trial and stage attribution questionable, were found in 2 patients and are discussed. CONCLUSIONS The quality of mlBG scans proved to be at least acceptable in most Italian pediatric oncology centers. Efforts should be made to further standardize evaluation of the scans. Additional techniques (99mTc scintigraphy, MRI, SPECT) might be useful to help understand the most complex cases.