Caius Mihail Constantinescu

Prognostic implications of total hemispheric glucose metabolism ratio in cerebro-cerebellar diaschisis

Diaschisis denotes brain dysfunction remote from a focal brain lesion. We have quantified diaschisis and investigated its prognostic value in glioma. Methods: We compared 50 18F-FDG PET/CT studies collected prospectively from 14 patients with supratentorial glioma (5 men and 9 women; age range, 35–77 y) with 10 single scans from healthy controls (age range, 43–75 y). Dedicated 3-dimensional segmentation software was used to obtain total hemispheric glucose metabolic ratios (THGr) by dividing total hemispheric 18F-FDG uptake in each diaschitic hemisphere—that is, the ipsilateral cerebral hemisphere (THGr(Ce)) and the contralateral cerebellar hemisphere (THGr(Cb))—by its respective contralateral side. Receiver-operating-characteristic (ROC) analysis was performed to determine optimal cut-offs for combinations of THGr(Ce) and THGr(Cb). Two independent observers obtained data for reproducibility analysis, and THGr values were compared with qualitative assessment of diaschisis performed by a PET neuroimaging specialist. Results: Qualitative analysis confirmed cerebrocerebellar diaschisis in all glioblastoma PET studies performed within 1 y of death. Healthy subjects had significantly higher THGr(Ce) values (P = 0.0007) and THGr(Cb) values (P = 0.02) than glioblastoma patients. ROC analysis yielded diaschisis thresholds of 0.62 for THGr(Ce) and 0.84 for THGr (Cb). Qualitative assessment demonstrated cerebral diaschisis in 16 of 17 (94%) cases with THGr(Ce) below the determined threshold and cerebellar diaschisis in 25 of 26 (96%) cases with THGr(Cb) below the determined threshold. When both THGr(Ce) and THGr(Cb) were below the ROC threshold, the combined diaschisis measures had a positive predictive value for survival below 1 y of 100%. When one parameter was below the threshold, it had a positive predictive value of 75%, and when both parameters exceeded thresholds, the negative predictive value for survival above 1 y was 79%. Median interrater variability was 3.3% and 5.9% for THGr(Ce) and THGr(Cb), respectively. Conclusion: The THGr measures demonstrated diaschisis in the cerebrum and cerebellum of patients with glioma. Combined cerebrocerebellar diaschisis ratios with ROC thresholds for both forebrain and hindbrain had high negative and positive predictive values for survival for less than a year. The THGr method allows comparison of data obtained at different institutions and is now open for further validation in gliomas and other cerebral diseases.

The Role of PET in Evaluating Atherosclerosis: A Critical Review

Atherosclerosis is a common age-related disorder and is the major cause of morbidity and mortality in the developed countries. Structural imaging techniques, such as CT and MRI, have been of limited value in early detection of atherosclerotic plaques, and therefore, there is a dire need for techniques that are highly sensitive and specific for this purpose. Over the past decade, PET imaging with FDG and NaF has been tested for detection and characterization of atherosclerotic plaques in the major coronary arteries. While FDG uptake reflects inflammation in the plaques, NaF uptake is related to micro-calcification at the site. Recent data have revealed higher sensitivity for NaF compared to that of FDG-PET imaging for assessing this age-related disorder. Therefore, it is conceivable that detection of micro-calcification by NaF may become the study of choice in the future. Also, small volume of plaques even in the major arteries poses a significant challenge for optimal visualization and quantification of the disease process. Based on animal and human data, it has become apparent that global assessment of disease activity may overcome the physical limitations of PET imaging for optimal quantification of plaque burden in the arteries. The role of other tracers for detection of atherosclerosis is limited at this time and it is unlikely that other compounds will play a role in assessing plaques in the near future.

FDG-PET/CT for evaluation of inflammation in the lumbar spine following surgery for lumbar disc herniation

European Journal of Nuclear Medicine and Molecular Imaging Volume 44, Supplement 2 10.1007/s00259-017-3822-1 This supplement was not sponsored by outside commercial interests. It was funded entirely by the association’s own resources DOI 10.1007/s00259-017-3822-1 S119 Eur J Nucl Med Mol Imaging (2017) 44 (Suppl 2):S119–S956

Diagnostic implications of total hemi-spheric glucose metabolism ratio in Mild cognitive impairment and Alzheimer´s disease

European Journal of Nuclear Medicine and Molecular Imaging Volume 44, Supplement 2 10.1007/s00259-017-3822-1 This supplement was not sponsored by outside commercial interests. It was funded entirely by the association’s own resources DOI 10.1007/s00259-017-3822-1 S119 Eur J Nucl Med Mol Imaging (2017) 44 (Suppl 2):S119–S956

Decline with age in normal cerebral and cerebellar glucose metabolism in women and men determined by FDG PET/CT

European Journal of Nuclear Medicine and Molecular Imaging Volume 44, Supplement 2 10.1007/s00259-017-3822-1 This supplement was not sponsored by outside commercial interests. It was funded entirely by the association’s own resources DOI 10.1007/s00259-017-3822-1 S119 Eur J Nucl Med Mol Imaging (2017) 44 (Suppl 2):S119–S956

Total hemispheric glycolysis ratio by FDG-PET/CT in gliomas; Evaluating diaschisis and potential prognostic information

Hypothesis: We assessed in in vitro and in vivo models of ovarian cancer the therapeutic efficacy of 16F12 mAbs directed against Mullerian Inhibiting Substance type II receptor (MISRII) radiolabeled with 213Bi Methods: In vitro, both direct and bystander cytotoxic effects were measured using clonogenic assay and standard medium transfer protocol. Typically, Clonogenic survival was assessed in SK-OV-3 donor cells expressing MISRII and exposed for 90 min to 0.06-0.5MBq/mL of 16F12 213Bi-mAbs. Bystander cytotoxicity was measured in recipient cells grown in non-radioactive culture medium preconditioned for 2 hours in the presence of donor cells. DNA double strand breaks (DSBs) were measured in both donor and recipients cells using immunofluorescent detection of gamma-H2AX and of 53BP1. In vivo we explored in athymic nude mice bearing intraperitoneal (IP) MISRII-expressing AN3CA tumor the therapeutic efficacy of brief-intraperitoneal radioimmunotherapy (BIP-RIT, 12.95 37 MBq; 37MBq/mg) or of intraperitoneal RIT (IP-RIT; 2.96-12.95 MBq; 37MBq/mg) using 213Bi-16F12. BIP-RIT mimics hyperthermic intraperitoneal chemotherapy as used in clinic. It consists of intraperitoneal injection of high activities of radiolabeled mAbs followed 30 min later by wash of the peritoneal cavity with saline solution to remove unbound radioactivity. The biodistribution of radiolabeled antibodies following IP-RIT (12.95 MBq; 37MBq/mg) or BIP-RIT (37 MBq; 37MBq/mg) was assessed. Results: In vitro we showed in donor cells a strong direct cytotoxicity of 16F12 213Bi-mAbs. A significant bystander cytotoxicity was also measured in recipient cells. Genotoxic effects were also demonstrated as measured by the formation of DNA DSBs in both donor and recipient cells. In vivo, results of biodistribution indicated that tumour uptake of 213Bi-16F12 during BIP RIT was higher than after IP RIT. The tumour-to-blood uptake ratio was 9 versus 3, respectively, one hour post RIT while it decreased down to 3 and 1, respectively, three hours post-RIT. Finally, a similar delay in tumor growth was observed in mice treated with 12.95 MBq of 213Bi-16F12 following IP-RIT or treated with 37 MBq using BIP-RIT. Conclusions: We confirmed in vitro the therapeutic efficacy of newly developed 16F12 213Bi-mAbs. in vivo results indicate that similar therapeutic efficacy and lower toxicity could be obtained with BIP-RIT compared with IP-RIT. BIP-RIT could be a new tool in the therapy of peritoneal carcinomatosis. URI: Authors: LADJOHOUNLOU Riad PICHARD Alexandre DEHAYES E BOUDOUSQ Vincent BRUCHERTSEIFER Frank MORGENSTERN Alfred NAVARRO-TEULON Isabelle POUGET Jean-Pierre Publication Year: 2016 Science Areas: Health and consumer protection [1]European Journal of Nuclear Medicine and Molecular Imaging Volume 43, Supplement 1 10.1007/s00259-016-3484-4 This supplement was not sponsored by outside commercial interests. It was funded entirely by the association’s own resources. ABSTRACT DOI 10.1007/s00259-016-3484-4 Eur J Nucl Med Mol Imaging (2016) 43 (Suppl 1):S1–S734Background: In the context of the EORTC LungTech trial, a QA procedure including a PET/CT credentialing has been developed. This procedure will ultimately allow us to pool data from 23 institutions with the overall goal of investigating the impact of tumour motion on quantification. As no standardized procedure exists under respiratory conditions, we investigated the variability of 14 SUV metrics to assess their robustness over respiratory noise. Methods: The customized CIRS-008A phantom was scanned at 13 institutions. This phantom consists of a 18 cm long body, a rod attached to a motion actuator, and a sphere of either 1.5 or 2.5cm diameters. Body, rods and spheres were filled with homogeneous 18FDG solutions representative of activity concentrations in mediastinum, lung and tumour for a 70kg patient. Three respiratory patterns with peak-to-peak amplitudes and periods of 15mm/3sec, 15mm/6sec and 25mm/4sec were tested. Prior to scanning in respiratory condition, a 3D static PET/CT was acquired as reference. During motion, images were acquired using 3D or 4D gated PET(average image) according to institutional settings. 14 SUV(mean) metrics were obtained per acquisition varying VOI/ ROI shape and location. Three ROIs and three VOIs with respective radii of 0.5, 0.6 and 0.8cm were investigated. These ROIs/VOIs were first centred on the maximum activity voxel; a second analysis was made changing the location from the voxel to the region (ROI5voxels) or the volume (VOI7voxels) with the maximum value. Two additional VOIs were defined as 3D isocontours respectively at 70% and 50% of the maximum voxel value. The SUV metrics were normalized by the corresponding 3D static SUV. Converting to recovery coefficients (RC) allowed us to pool data from all institutions, while maintaining focus solely on motion. For each RC from each motion setting we calculated the mean over institutions, we then looked at the standard deviation (Sd) and spread of each averaged RC over each motion setting (formula [1], [2], Figure1). Results: For the institutions visited we found that RCVOI70% and RCVOI50%, yielded over the 14 metrics the lowest variability to motion with Sd of 0.04 and 0.03 respectively. The RCs based on ROIs/VOIs centered on a single voxel were less impacted by motion (Sd: 0.08) compared to region RCs (Sd: 0.14). The averaged Sd over the RCs based on VOIs and ROIs was 0.12 and 0.11 respectively. Conclusion: Quantification over breathing types depends on ROI/VOI definition. Variables based on SUV max thresholds were found the most robust against respiratory noise.

Inter-observer variability of total hemispheric glycolysis ratio obtained at 1-hour and 3-hour FDG-PET/CT imaging in glioma patients

Hypothesis: We assessed in in vitro and in vivo models of ovarian cancer the therapeutic efficacy of 16F12 mAbs directed against Mullerian Inhibiting Substance type II receptor (MISRII) radiolabeled with 213Bi Methods: In vitro, both direct and bystander cytotoxic effects were measured using clonogenic assay and standard medium transfer protocol. Typically, Clonogenic survival was assessed in SK-OV-3 donor cells expressing MISRII and exposed for 90 min to 0.06-0.5MBq/mL of 16F12 213Bi-mAbs. Bystander cytotoxicity was measured in recipient cells grown in non-radioactive culture medium preconditioned for 2 hours in the presence of donor cells. DNA double strand breaks (DSBs) were measured in both donor and recipients cells using immunofluorescent detection of gamma-H2AX and of 53BP1. In vivo we explored in athymic nude mice bearing intraperitoneal (IP) MISRII-expressing AN3CA tumor the therapeutic efficacy of brief-intraperitoneal radioimmunotherapy (BIP-RIT, 12.95 37 MBq; 37MBq/mg) or of intraperitoneal RIT (IP-RIT; 2.96-12.95 MBq; 37MBq/mg) using 213Bi-16F12. BIP-RIT mimics hyperthermic intraperitoneal chemotherapy as used in clinic. It consists of intraperitoneal injection of high activities of radiolabeled mAbs followed 30 min later by wash of the peritoneal cavity with saline solution to remove unbound radioactivity. The biodistribution of radiolabeled antibodies following IP-RIT (12.95 MBq; 37MBq/mg) or BIP-RIT (37 MBq; 37MBq/mg) was assessed. Results: In vitro we showed in donor cells a strong direct cytotoxicity of 16F12 213Bi-mAbs. A significant bystander cytotoxicity was also measured in recipient cells. Genotoxic effects were also demonstrated as measured by the formation of DNA DSBs in both donor and recipient cells. In vivo, results of biodistribution indicated that tumour uptake of 213Bi-16F12 during BIP RIT was higher than after IP RIT. The tumour-to-blood uptake ratio was 9 versus 3, respectively, one hour post RIT while it decreased down to 3 and 1, respectively, three hours post-RIT. Finally, a similar delay in tumor growth was observed in mice treated with 12.95 MBq of 213Bi-16F12 following IP-RIT or treated with 37 MBq using BIP-RIT. Conclusions: We confirmed in vitro the therapeutic efficacy of newly developed 16F12 213Bi-mAbs. in vivo results indicate that similar therapeutic efficacy and lower toxicity could be obtained with BIP-RIT compared with IP-RIT. BIP-RIT could be a new tool in the therapy of peritoneal carcinomatosis. URI: Authors: LADJOHOUNLOU Riad PICHARD Alexandre DEHAYES E BOUDOUSQ Vincent BRUCHERTSEIFER Frank MORGENSTERN Alfred NAVARRO-TEULON Isabelle POUGET Jean-Pierre Publication Year: 2016 Science Areas: Health and consumer protection [1]European Journal of Nuclear Medicine and Molecular Imaging Volume 43, Supplement 1 10.1007/s00259-016-3484-4 This supplement was not sponsored by outside commercial interests. It was funded entirely by the association’s own resources. ABSTRACT DOI 10.1007/s00259-016-3484-4 Eur J Nucl Med Mol Imaging (2016) 43 (Suppl 1):S1–S734Background: In the context of the EORTC LungTech trial, a QA procedure including a PET/CT credentialing has been developed. This procedure will ultimately allow us to pool data from 23 institutions with the overall goal of investigating the impact of tumour motion on quantification. As no standardized procedure exists under respiratory conditions, we investigated the variability of 14 SUV metrics to assess their robustness over respiratory noise. Methods: The customized CIRS-008A phantom was scanned at 13 institutions. This phantom consists of a 18 cm long body, a rod attached to a motion actuator, and a sphere of either 1.5 or 2.5cm diameters. Body, rods and spheres were filled with homogeneous 18FDG solutions representative of activity concentrations in mediastinum, lung and tumour for a 70kg patient. Three respiratory patterns with peak-to-peak amplitudes and periods of 15mm/3sec, 15mm/6sec and 25mm/4sec were tested. Prior to scanning in respiratory condition, a 3D static PET/CT was acquired as reference. During motion, images were acquired using 3D or 4D gated PET(average image) according to institutional settings. 14 SUV(mean) metrics were obtained per acquisition varying VOI/ ROI shape and location. Three ROIs and three VOIs with respective radii of 0.5, 0.6 and 0.8cm were investigated. These ROIs/VOIs were first centred on the maximum activity voxel; a second analysis was made changing the location from the voxel to the region (ROI5voxels) or the volume (VOI7voxels) with the maximum value. Two additional VOIs were defined as 3D isocontours respectively at 70% and 50% of the maximum voxel value. The SUV metrics were normalized by the corresponding 3D static SUV. Converting to recovery coefficients (RC) allowed us to pool data from all institutions, while maintaining focus solely on motion. For each RC from each motion setting we calculated the mean over institutions, we then looked at the standard deviation (Sd) and spread of each averaged RC over each motion setting (formula [1], [2], Figure1). Results: For the institutions visited we found that RCVOI70% and RCVOI50%, yielded over the 14 metrics the lowest variability to motion with Sd of 0.04 and 0.03 respectively. The RCs based on ROIs/VOIs centered on a single voxel were less impacted by motion (Sd: 0.08) compared to region RCs (Sd: 0.14). The averaged Sd over the RCs based on VOIs and ROIs was 0.12 and 0.11 respectively. Conclusion: Quantification over breathing types depends on ROI/VOI definition. Variables based on SUV max thresholds were found the most robust against respiratory noise.