Left ventricle function assessment using gated first-pass 18F-FDG PET: Validation against equilibrium radionuclide angiography.

PURPOSE: We appraised the feasibility of left ventricle (LV) function assessment using gated first-pass 18F-FDG PET, and assessed the concordance of the produced measurements with equilibrium radionuclide angiography (ERNA). MATERIALS AND METHODS: Twenty-four oncologic patients benefited from 99mTc-labeled red-blood-cell ERNA, in planar mode (all patients) and using SPECT (22 patients). All patients underwent gated first-pass 18F-FDG cardiac PET. Gated dynamic PET images were reconstructed over 1 minute during tracer first-pass inside the LV and post-processed using in-house software (TomPool). After re-orientation into cardiac canonical axes and adjustment of the valves plane using a phase image, pseudo-planar PET images obtained by re-projection were automatically segmented using thresholded region growing and gradient-based delineation to produce an LV ejection fraction (EF) estimate. PET images were also post-processed in fully-tomographic mode to produce LV end diastole volume (EDV), end systole volume (ESV), and EF estimates. Concordance was assessed using Lin's concordance (ccc) and Bland-Altman analysis. Reproducibility was assessed using the coefficient of variation (CoV) and intra-class correlation (ICC). RESULTS: Pseudo-planar PET EF estimates were concordant with planar ERNA (ccc = 0.81, P < .001) with a bias of 0% (95% CI [- 2%; 3%], limits of agreement [- 11%; 12%]). Reproducibility was excellent and similar for both methods (CoV = 2 ± 1% and 3 ± 2%, P = NS; ICC = 0.97 and 0.92, for PET and ERNA, respectively). Measurements obtained in fully-tomographic mode were concordant with SPECT ERNA: ccc = 0.83 and bias = - 3 mL for LV EDV, ccc = 0.92 and bias = 0 mL for LV ESV, ccc = 0.89 and bias = - 1% for LV EF (all P values < .001 for ccc, all biases not significant). CONCLUSIONS: Gated first-pass 18F-FDG PET might stand as a relevant alternative to ERNA for LV function assessment, enabling a joint evaluation of both therapeutic response and cardiac toxicity in oncologic patients receiving cardiotoxic chemotherapy.

Drugs That Modify Cholesterol Metabolism Alter the p38/JNK-Mediated Targeted and Nontargeted Response to Alpha and Auger Radioimmunotherapy.

PURPOSE: For the development of new anticancer therapeutic radiopharmaceuticals, including alpha particle emitters, it is important to determine the contribution of targeted effects in irradiated cells, and also of nontargeted effects in nonirradiated neighboring cells, because they may affect the therapeutic efficacy and contribute to side effects. EXPERIMENTAL DESIGN: Here, we investigated the contribution of nontargeted cytotoxic and genotoxic effects in vitro and in vivo (in xenografted mice) during alpha (212Pb/212Bi, 213Bi) and Auger (125I) radioimmunotherapy (RIT). RESULTS: Between 67% and 94% (alpha RIT) and 8% and 15% (Auger RIT) of cancer cells were killed by targeted effects, whereas 7% to 36% (alpha RIT) and 27% to 29% (Auger RIT) of cells were killed by nontargeted effects. We then demonstrated that the nontargeted cell response to alpha and Auger RIT was partly driven by lipid raft-mediated activation of p38 kinase and JNK. Reactive oxygen species also played a significant role in these nontargeted effects, as demonstrated by NF-κB activation and the inhibitory effects of antioxidant enzymes and radical scavengers. Compared with RIT alone, the use of RIT with ASMase inhibitor (imipramine) or with a lipid raft disruptor (e.g., methyl-beta-cyclodextrin or filipin) led to an increase in clonogenic cell survival in vitro and to larger tumors and less tissue DNA damage in vivo. These results were supported by an inhibitory effect of pravastatin on Auger RIT. CONCLUSIONS: Cell membrane-mediated nontargeted effects play a significant role during Auger and alpha RIT, and drugs that modulate cholesterol level, such as statins, could interfere with RIT efficacy.

Radiolabeled Antibodies Against Müllerian-Inhibiting Substance Receptor, Type II: New Tools for a Theranostic Approach in Ovarian Cancer.

We have developed the 16F12 mouse monoclonal antibody (mAb), which targets the Müllerian-inhibiting substance receptor, type II (MISRII), expressed by ovarian tumors. Here, we assessed in preclinical models the possibility of using radiolabeled 16F12 in a theranostic approach for small-volume ovarian peritoneal carcinomatosis, such as after cytoreductive surgery. Methods: DOTA-, DTPA- or deferoxamine mesylate-conjugated 16F12 mAb was radiolabeled with ß-particle (177Lu) or α-particle (213Bi) emitters for therapeutic use and with 89Zr for PET imaging. On the 13th postxenograft day, mice bearing intraperitoneal MISRII-positive AN3CA endometrial carcinoma cell xenografts were treated by conventional intraperitoneal radioimmunotherapy (IP-RIT) with 10 MBq of 177Lu-16F12 or 12.9 MBq of 213Bi-16F12 or by brief intraperitoneal radioimmunotherapy (BIP-RIT) using 50 MBq of 177Lu-16F12 or 37 MBq of 213Bi-16F12. For BIP-RIT, 30 min after injection of the radiolabeled mAbs, the peritoneal cavity was washed to remove the unbound radioactivity. The biodistribution of 177Lu- and 213Bi-16F12 mAbs was determined and then used for dose assessment. Hematologic toxicity was also monitored. Results: The 16F12 mAb was satisfactorily radiolabeled for both therapy and imaging. IP-RIT with 177Lu-16F12 was slightly more efficient in delaying tumor growth than IP-RIT with 213Bi-16F12. Conversely, 213Bi-16F12 was more efficient than 177Lu-16F12 in BIP-RIT. The biodistribution analysis showed that the tumor-to-blood uptake ratio was significantly higher with BIP-RIT than with IP-RIT for both 213Bi- and 177Lu-16F12. Hematologic toxicity was more pronounced with 177Lu-16F12 than with 213Bi-16F12. SPECT/CT images (after BIP-RIT with 177Lu-16F12) and PET/CT images (after injection of 89Zr-16F12 in the tail vein) showed focal uptake at the tumor site. Conclusion: Radiolabeled 16F12 could represent a new theranostic tool for small-volume ovarian peritoneal carcinomatosis. Specifically, 213Bi-16F12-based BIP-RIT could be proposed to selected patients as an alternative adjuvant treatment immediately after cytoreductive surgery. An anti-MISRII mAb is currently being used in a first-in-human study, thus making radiolabeled anti-MISRII mAbs a realistic theranostic option for the clinic.