[18F]FDG PET/CT-Avid Discordant Volume as a Biomarker in Patients with Gastroenteropancreatic Neuroendocrine Neoplasms: A Multicenter Study.

[18F]FDG PET/CT and [68Ga]Ga-DOTATATE PET/CT are both used to predict tumor biology in neuroendocrine neoplasms. Although the presence of discordant ([18F]FDG-avid/non-[68Ga]Ga-DOTATATE-avid) disease predicts poor prognosis, the significance of the volume of such discordant disease remains undetermined. The aim of this study is to investigate discordant tumor volume as a potential biomarker in patients with advanced gastroenteropancreatic neuroendocrine neoplasms (GEPNENs). Methods: A multicenter retrospective study in patients with advanced GEPNENs and paired [18F]FDG and [68Ga]Ga-DOTATATE PET/CT no more than 85 d apart was conducted. Patients with discordant disease were identified by the NETPET score, and discordant lesions were contoured with a flat [18F]FDG SUV cutoff of 4. The primary variable of interest was the total discordant volume (TDV), which was the sum of the volumes of discordant lesions. Patients were dichotomized into high- and low-TDV cohorts by the median value. The primary endpoint was overall survival. Results: In total, 44 patients were included (50% men; median age, 60 y), with primary cancers in the pancreas (45%), small bowel (23%), colon (20%), and other (12%). Of the patients, 5% had grade 1 disease, 48% had grade 2 disease, and 48% had grade 3 disease (24% well differentiated, 67% poorly differentiated, 10% unknown within the grade 3 cohort). The overall median survival was 14.1 mo. Overall survival was longer in the low-TDV cohort than in the high-TDV cohort (median volume, 43.7 cm3; survival time, 23.8 mo vs. 9.4 mo; hazard ratio, 0.466 [95% CI, 0.229-0.948]; P = 0.0221). Patients with no more than 2 discordant intrahepatic lesions survived longer than those with 2 or more lesions (31.8 mo vs. 10.2 mo, respectively; hazard ratio, 0.389 [95% CI, 0.194-0.779]; P = 0.0049). Conclusion: TDV is a potential prognostic biomarker in GEPNENs and should be investigated in future neuroendocrine neoplasm trials.

Prediction of 177Lu-DOTATATE PRRT Outcome Using Multimodality Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors: Results from a Prospective Phase II LUMEN Study.

Our objective was to predict the outcome of peptide receptor radionuclide therapy (PRRT) using multimodality imaging and tumor dosimetry on gastroenteropancreatic neuroendocrine tumor (GEP-NET) lesions and patients. Methods: This prospective study included patients with progressive GEP-NETs. Treatment consisted of 4 cycles of 7.4 GBq of 177Lu-DOTATATE. Imaging parameters were measured on 68Ga-DOTATATE PET/CT (SUVmax/mean, somatostatin receptor [SSTR] tumor volume [TV], total lesion SSTR expression, and tumor-to-blood and tumor-to-spleen ratios), 18F-FDG PET/CT (SUVmax/mean, metabolically active TV, and total lesion glycolysis), and diffusion-weighted MRI (apparent diffusion coefficient) in a maximum of 5 target lesions per patient at approximately 10 wk after each injection. Tumor dosimetry was performed using SPECT/CT at 3 time points for every cycle. Baseline imaging parameters, their relative changes after PRRT cycle 1 (C1), and the tumor-absorbed dose at C1 were correlated with lesion morphologic outcome. The average values of the imaging parameters and the minimal, maximal, and mean C1 tumor-absorbed dose in each patient were tested for association with progression-free survival (PFS) and best objective response (RECIST 1.1). Results: In the 37 patients, the median PFS was 28 mo. Eleven of the 37 (30%) achieved a partial response (RECIST 1.1). After a median follow-up of 57 mo, the median time to lesion progression had not been reached in 84 morphologically evaluable lesions, with only 12 (14%) progressing (size increase ≥ 20% from baseline). Patients receiving a minimal C1 dose of 35 Gy in all target lesions exhibited a significantly longer PFS (48.1 vs. 26.2 mo; hazard ratio, 0.37; 95% CI, 0.17-0.82; P = 0.02). Volumetric 68Ga-DOTATATE PET parameters correlated with lesion and patient outcome: patients with an SSTR TV decrease of more than 10% after C1 had a longer PFS (51.3 vs. 22.8 mo; hazard ratio, 0.35; 95% CI, 0.16-0.75; P = 0.003). There was no statistical evidence of an association between other dosimetric or imaging parameters and the lesion or patient outcome. Conclusion: Minimal tumor-absorbed dose at C1 is predictive of outcome in patients with GEP-NETs treated with PRRT, providing a basis for personalized dosimetry-guided treatment strategies. An SSTR TV decrease after C1 could be used for early therapy response assessment as a predictor of PRRT outcome.

Quantitative 177Lu SPECT/CT imaging for personalized dosimetry using a ring-shaped CZT-based camera.

BACKGROUND: Dosimetry after radiopharmaceutical therapy with 177Lu (177Lu-RPT) relies on quantitative SPECT/CT imaging, for which suitable reconstruction protocols are required. In this study, we characterized for the first time the quantitative performance of a ring-shaped CZT-based camera using two different reconstruction algorithms: an ordered subset expectation maximization (OSEM) and a block sequential regularized expectation maximization (BSREM) combined with noise reduction regularization. This study lays the foundations for the definition of a reconstruction protocol enabling accurate dosimetry for patients treated with 177Lu-RPT. METHODS: A series of 177Lu-filled phantoms were acquired on a StarGuide™ (GE HealthCare), with energy and scatter windows centred at 208 (± 6%) keV and 185 (± 5%) keV, respectively. Images were reconstructed with the manufacturer implementations of OSEM (GE-OSEM) and BSREM (Q.Clear) algorithms, and various combinations of iterations and subsets. Additionally, the manufacturer-recommended Q.Clear-based reconstruction protocol was evaluated. Quantification accuracy, measured as the difference between the SPECT-based and the radionuclide calibrator-based activity, and noise were evaluated in a large cylinder. Recovery coefficients (RCs) and spatial resolution were assessed in a NEMA IEC phantom with sphere inserts. The reconstruction protocols considered suitable for clinical applications were tested on a cohort of patients treated with [177Lu]Lu-PSMA-I&T. RESULTS: The accuracy of the activity from the cylinder, although affected by septal penetration, was < 10% for all reconstructions. Both algorithms featured improved spatial resolution and higher RCs with increasing updates at the cost of noise build-up, but Q.Clear outperformed GE-OSEM in reducing noise accumulation. When the reconstruction parameters were carefully selected, similar values for noise (~0.15), spatial resolution (~1 cm) and RCs were found, irrespective of the reconstruction algorithm. Analogue results were found in patients. CONCLUSIONS: Accurate activity quantification is possible when imaging 177Lu with StarGuide™. However, the impact of septal penetration requires further investigations. GE-OSEM is a valid alternative to the recommended Q.Clear reconstruction algorithm, featuring comparable performances assessed on phantoms and patients.

Dual [68Ga]DOTATATE and [18F]FDG PET/CT in patients with metastatic gastroenteropancreatic neuroendocrine neoplasms: a multicentre validation of the NETPET score.

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEPNENs) are heterogeneous in clinical course, biology, and outcomes. The NETPET score predicts survival by scoring uptake on dual [68Ga]DOTATATE and [18F]FDG PET/CT scans. We aimed to validate previous single-centre findings in a multicentre, international study. METHODS: Dual scans were assigned a NETPET score of P1 (DOTATATE positive/FDG negative), P2-4 (DOTATATE positive/FDG positive), or P5 (DOTATATE negative/FDG positive). NETPET score, histological grade, age at diagnosis, and presence/absence of extrahepatic disease were compared to overall survival/time to progression on univariate and multivariate analysis. RESULTS: 319 metastatic/unresectable GEPNEN patients were included. The NETPET score was significantly associated with overall survival and time to progression on univariate and multivariate analysis (all p < 0.01). Median overall survival/time to progression was 101.8/25.5 months for P1, 46.5/16.7 months for P2-4, and 11.5/6.6 months for P5. Histological grade correlated with overall survival and time to progression on univariate and multivariate analysis (all p < 0.01), while presence/absence of extrahepatic disease did not. Age at diagnosis correlated with overall survival on univariate and multivariate analysis (p < 0.01). The NETPET score also correlated with histological grade (p < 0.001). CONCLUSION: This study validates the NETPET score as a prognostic biomarker in metastatic GEPNENs, capturing the complexity of dual PET imaging.

Combined quality and dose-volume histograms for assessing the predictive value of 99mTc-MAA SPECT/CT simulation for personalizing radioembolization treatment in liver metastatic colorectal cancer.

BACKGROUND: The relationship between the mean absorbed dose delivered to the tumour and the outcome in liver metastases from colorectal cancer patients treated with radioembolization has already been presented in several studies. The optimization of the personalized therapeutic activity to be administered is still an open challenge. In this context, how well the 99mTc-MAA SPECT/CT predicts the absorbed dose delivered by radioembolization is essential. This work aimed to analyse the differences between predictive 99mTc-MAA-SPECT/CT and post-treatment 90Y-microsphere PET/CT dosimetry at different levels. Dose heterogeneity was compared voxel-to-voxel using the quality-volume histograms, subsequently used to demonstrate how it could be used to identify potential clinical parameters that are responsible for quantitative discrepancies between predictive and post-treatment dosimetry. RESULTS: We analysed 130 lesions delineated in twenty-six patients. Dose-volume histograms were computed from predictive and post-treatment dosimetry for all volumes: individual lesion, whole tumoural liver (TL) and non-tumoural liver (NTL). For all dose-volume histograms, the following indices were extracted: D90, D70, D50, Dmean and D20. The results showed mostly no statistical differences between predictive and post-treatment dosimetries across all volumes and for all indices. Notably, the analysis showed no difference in terms of Dmean, confirming the results from previous studies. Quality factors representing the spread of the quality-volume histogram (QVH) curve around 0 (ideal QF = 0) were determined for lesions, TL and NTL. QVHs were classified into good (QF < 0.18), acceptable (0.18 ≤ QF < 0.3) and poor (QF ≥ 0.3) correspondence. For lesions and TL, dose- and quality-volume histograms are mostly concordant: 69% of lesions had a QF within good/acceptable categories (40% good) and 65% of TL had a QF within good/acceptable categories (23% good). For NTL, the results showed mixed results with 48% QF within the poor concordance category. Finally, it was demonstrated how QVH analysis could be used to define the parameters that predict the significant differences between predictive and post-treatment dose distributions. CONCLUSION: It was shown that the use of the QVH is feasible in assessing the predictive value of 99mTc-MAA SPECT/CT dosimetry and in estimating the absorbed dose delivered to liver metastases from colorectal cancer via 90Y-microspheres. QVH analyses could be used in combination with DVH to enhance the predictive value of 99mTc-MAA SPECT/CT dosimetry and to assist personalized activity prescription.

Personalised radioembolization improves outcomes in refractory intra-hepatic cholangiocarcinoma: a multicenter study.

PURPOSE: Reported outcomes of patients with intra-hepatic cholangiocarcinoma (IH-CCA) treated with radioembolization are highly variable, which indicates differences in included patients' characteristics and/or procedure-related variables. This study aimed to identify patient- and treatment-related variables predictive for radioembolization outcome. METHODS: This retrospective multicenter study enrolled 58 patients with unresectable and chemorefractory IH-CCA treated with resin 90Y-microspheres. Clinicopathologic data were collected from patient records. Metabolic parameters of liver tumor(s) and presence of lymph node metastasis were measured on baseline 18F-FDG-PET/CT. 99mTc-MAA tumor to liver uptake ratio (TLRMAA) was computed for each lesion on the SPECT-CT. Activity prescription using body-surface-area (BSA) or more personalized partition-model was recorded. The study endpoint was overall survival (OS) starting from date of radioembolization. Statistical analysis was performed by the log-rank test and multivariate Cox's proportional hazards model. RESULTS: Median OS (mOS) post-radioembolization of the entire cohort was 10.3 months. Variables associated with significant differences in terms of OS were serum albumin (hazard ratio (HR) = 2.78, 95%CI:1.29-5.98, p = 0.002), total bilirubin (HR = 2.17, 95%CI:1.14-4.12, p = 0.009), aspartate aminotransferase (HR = 2.96, 95%CI:1.50-5.84, p < 0.001), alanine aminotransferase (HR = 2.02, 95%CI:1.05-3.90, p = 0.01) and γ-GT (HR = 2.61, 95%CI:1.31-5.22, p < 0.001). The presence of lymph node metastasis as well as a TLRMAA < 1.9 were associated with shorter mOS: HR = 2.35, 95%CI:1.08-5.11, p = 0.008 and HR = 2.92, 95%CI:1.01-8.44, p = 0.009, respectively. Finally, mOS was significantly shorter in patients treated according to the BSA method compared to the partition-model: mOS of 5.5 vs 14.9 months (HR = 2.52, 95%CI:1.23-5.16, p < 0.001). Multivariate analysis indicated that the only variable that increased outcome prediction above the clinical variables was the activity prescription method with HR of 2.26 (95%CI:1.09-4.70, p = 0.03). The average mean radiation dose to tumors was significantly higher with the partition-model (86Gy) versus BSA (38Gy). CONCLUSION: Radioembolization efficacy in patients with unresectable recurrent and/or chemorefractory IH-CCA strongly depends on the tumor radiation dose. Personalized activity prescription should be performed.

A dosimetry procedure for organs-at-risk in 177Lu peptide receptor radionuclide therapy of patients with neuroendocrine tumours.

PURPOSE: Peptide receptor radionuclide therapy with 177Lu-DOTATATE has become a standard treatment modality in neuroendocrine tumours (NETs). No consensus has yet been reached however regarding the absorbed dose threshold for lesion response, the absorbed dose limit to organs-at-risk, and the optimal fractionation and activity to be administered. This is partly due to a lack of uniform and comparable dosimetry protocols. The present article details the development of an organ-at-risk dosimetry procedure, which could be implemented and used routinely in a clinical context. METHODS: Forty-seven patients with NETs underwent 177Lu-DOTATATE therapy. Three SPECT/CT images were acquired at 4, 24 and 144-192 h post-injection. Three blood samples were obtained together with the SPECT/CT acquisitions and 2 additional samples were obtained around 30 min and 1 h post-injection. A bi-exponential fit was used to compute the source organ time-integrated activity coefficients. Coefficients were introduced into OLINDA/EXM software to compute organ-at-risk absorbed doses. Median values for all patients were computed for absorbed dose coefficient D/A0 and for late effective half-life T1/2eff for kidneys, spleen and red marrow. RESULTS: Dosimetry resulted in a median[interquartile range] of 0.78[0.35], 1.07[0.58] and 0.028[0.010] Gy/GBq for D/A0 and of 55[9], 71[9] and 52[18] h for T1/2eff for kidneys, spleen and red marrow respectively. CONCLUSIONS: A dosimetry procedure for organs-at-risk in 177Lu-DOTATATE therapy based on serial SPECT/CT images and blood samples can be implemented routinely in a clinical context with limited patient burden. The results obtained were in accordance with those of other centres.

90Y-PET/CT-based dosimetry after selective internal radiation therapy predicts outcome in patients with liver metastases from colorectal cancer.

BACKGROUND: The aim of this work was to confirm that post-selective internal radiation therapy (SIRT) 90Y-PET/CT-based dosimetry correlates with lesion metabolic response and to determine its correlation with overall survival (OS) in liver-only metastases from colorectal cancer (mCRC) patients treated with SIRT. Twenty-four mCRC patients underwent pre/post-SIRT FDG-PET/CT and post-SIRT 90Y-PET/CT. Lesions delineated on pre/post-SIRT FDG-PET/CT were classified as non-metabolic responders (total lesion glycolysis (TLG)-decrease < 15%) and high-metabolic responders (TLG-decrease ≥ 50%). Lesion delineations were projected on the anatomically registered 90Y-PET/CT. Voxel-based 3D dosimetrywas performed on the 90Y-PET/CT and lesions' mean absorbed dose (Dmean) was measured. The coefficient of correlation between Dmean and TLG-decrease was calculated. The ability of lesion Dmean to predict non-metabolic response and high-metabolic response was tested and two cutoff values (Dmean-under-treated and Dmean-well-treated) were determined using ROC analysis. Patients were dichotomised in the "treated" group (all the lesions received a Dmean > Dmean-under-treated) and in the "under-treated" group (at least one lesion received a Dmean < Dmean-under-treated). Kaplan-Meier product limit method was used to describe OS curves. RESULTS: Fifty-seven evaluable mCRC lesions were included. The coefficient of correlation between Dmean and TLG-decrease was 0.82. Two lesion Dmean cutoffs of 39 Gy (sensitivity 80%, specificity 95%, predictive-positive-value 86% and negative-predictive-value 92%) and 60 Gy (sensitivity 70%, specificity 95%, predictive positive-value 96% and negative-predictive-value 63%) were defined to predict non-metabolic response and high-metabolic response respectively. Patients with all lesions Dmean> 39 Gy had a significantly longer OS (13 months) than patients with at least one lesion Dmean < 39 Gy (OS = 5 months) (p = 0.012;hazard-ratio, 2.6 (95% CI 0.98-7.00)). CONCLUSIONS: In chemorefractory mCRC patients treated with SIRT, lesion Dmean determined on post-SIRT 90Y-PET/CT correlates with metabolic response and higher lesion Dmean is associated with prolonged OS.

Selective internal radiation therapy (SIRT) before partial hepatectomy or radiofrequency destruction for treatment of hepatocellular carcinoma in cirrhotic patients: a feasibility and safety pilot study.

BACKGROUND/PURPOSE: Preoperative selective internal radiation therapy (SIRT) may improve the results of partial hepatectomy (PH) or radiofrequency destruction (RF) for hepatocellular carcinoma (HCC) in patients with cirrhosis. The aim of this study was to evaluate the feasibility and safety of this combined approach. METHODS: Patients with cirrhosis and HCC selected for PH or RF were prospectively included and systematically proposed for preoperative SIRT. Feasibility and safety of SIRT and post-SIRT PH or RF were assessed. RESULTS: Thirty patients were included. SIRT was contraindicated in seven, due to lack of access to tumour artery or to hepato-pulmonary shunts. SIRT was performed in 23 patients without significant complications. Post-SIRT, surgery was refuted in seven patients, due to tumour progression or the patient's deteriorating condition. After surgery, major complications were observed in 2/16 patients (12.5%) and one patient died 52 days post-surgery. A major tumour pathological response was seen in most patients who underwent surgery after SIRT. CONCLUSIONS: On intention-to-treat basis, the overall feasibility of combining preoperative SIRT and surgery was limited. Preoperative SIRT did not increase expected operative morbidity, but post-SIRT, a third of patients were refuted for surgery. Accurate selection criteria and potential long-term oncological benefit of this approach remains to be determined. ClinicalTrials.gov NCT01686880.

N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89Zr-Trastuzumab and 18F-FDG PET imaging.

Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4.

Accuracy and precision assessment for activity quantification in individualized dosimetry of 177Lu-DOTATATE therapy.

BACKGROUND: In order to obtain a reliable 177Lu-DOTATATE therapy dosimetry, it is crucial to acquire accurate and precise activity measurements with the radionuclide calibrator, the SPECT/CT camera, and the NaI(Tl) well counter. The aim of this study was to determine, in a clinical context, the accuracy and the precision of their activity quantification over a range of activities and time. Ninety-three 177Lu sources from the manufacturer were measured in the radionuclide calibrator over 2.5 years to evaluate its calibration accuracy and precision compared to the manufacturer's value. A NEMA 2012/IEC 2008 phantom was filled with a 177Lu activity concentration sphere-to-background ratio of five. It was acquired with the SPECT/CT camera to determine the reconstruction parameters offering the best compromise between partial volume effect and signal-to-noise ratio. The calibration factor was computed accordingly. The calibration quality was monitored over 2.5 years with 33 phantom acquisitions with activities ranging from 7040 to 0.6 MBq. Home-made sources were used to calibrate the well counter. Its reliability was evaluated with activities ranging from 150 to 0.2 kBq measured 34 times over 2.5 years. RESULTS: For the radionuclide calibrator, median [interquartile range] for the error on activity measurement was -0.99 [1.31] %. The optimal SPECT reconstruction parameters were obtained with 16 iterations, 16 subsets and a 12-mm Gaussian post-filter. The calibration factor was 9.87 cps/MBq with an error of -1.05 [2.12] %. The well counter was calibrated with 31.5 cps/kBq, and the error was evaluated to -12.89 [16.55] %. CONCLUSIONS: The accuracy and the precision of activity quantification using dedicated quality control were found to be sufficient for use in dosimetry implemented in clinical routine. The proposed methodology could be implemented in other centres to obtain reproducible 177Lu-based treatment dosimetry.

Radioembolisation and portal vein embolization before resection of large hepatocellular carcinoma.

Resectability of hepatocellular carcinoma in patients with chronic liver disease is dramatically limited by the need to preserve sufficient remnant liver in order to avoid postoperative liver insufficiency. Preoperative treatments aimed at downsizing the tumor and promoting hypertrophy of the future remnant liver may improve resectability and reduce operative morbidity. Here we report the case of a patient with a large hepatocellular carcinoma arising from chronic liver disease. Preoperative treatment, including tumor downsizing with transarterial radioembolization and induction of future remnant liver hypertrophy with right portal vein embolization, resulted in a 53% reduction in tumor volume and compensatory hypertrophy in the contralateral liver. The patient subsequently underwent extended right hepatectomy with no postoperative signs of liver decompensation. Pathological examination demonstrated a margin-free resection and major tumor response. This new therapeutic sequence, combining efficient tumor targeting and subsequent portal vein embolization, could improve the feasibility and safety of major liver resection for hepatocellular carcinoma in patients with liver injury.

Y90 radioembolization of colorectal cancer liver metastases: response assessment by contrast-enhanced computed tomography with or without PET-CT guidance.

PURPOSE: To compare various computed tomography (CT) parameters to the positron emission tomography with computed tomography (PET-CT) response, with or without PET guidance for the response assessment of colorectal cancer (CRC) metastases treated by Y90 radioembolization. METHODS: Thirty-six CRC metastases were retrospectively evaluated on 18F-Fluoro-Deoxy-Glucose PET-CT and contrast-enhanced computed tomography (CECT) performed at baseline and 2-3 months after Y90 radioembolization. RESULTS: Median SUVmax values decreased from 11.39 to 6.71 after radioembolization (P<.001), and 23/36 (64%) metastases were categorized metabolic responses according to European Organisation for Research and Treatment of Cancer criteria. Only a decrease of the mean attenuation in the structural (P<.001) and metabolic active volume (P<.001) was observed. The change in these criteria was correlated with the change of SUVmax.

Tumour targeting and radiation dose of radioimmunotherapy with (90)Y-rituximab in CD20+ B-cell lymphoma as predicted by (89)Zr-rituximab immuno-PET: impact of preloading with unlabelled rituximab.

PURPOSE: To compare using immuno-PET/CT the distribution of (89)Zr-labelled rituximab without and with a preload of unlabelled rituximab to assess the impact of preloading with unlabelled rituximab on tumour targeting and radiation dose of subsequent radioimmunotherapy with (90)Y-labelled rituximab in CD20+ B-cell lymphoma. METHODS: Five patients with CD20+ B-cell lymphoma and progressive disease were prospectively enrolled. All patients underwent three study phases: initial dosimetric phase with baseline (89)Zr-rituximab PET/CT imaging without a cold preload, followed 3 weeks later by a second dosimetric phase with administration of a standard preload (250 mg/m(2)) of unlabelled rituximab followed by injection of (89)Zr-rituximab, and a therapeutic phase 1 week later with administration of unlabelled rituximab followed by (90)Y-rituximab. PET/CT imaging and tracer uptake by organs and lesions were assessed. RESULTS: With a cold rituximab preload, the calculated whole-body dose of (90)Y-rituximab was similar (mean 0.87 mSv/MBq, range 0.82-0.99 mSv/MBq) in all patients. Without a preload, an increase in whole-body dose of 59% and 87% was noted in two patients with preserved circulating CD20+ B cells. This increase in radiation dose was primarily due to a 12.4-fold to 15-fold higher dose to the spleen without a preload. No significant change in whole-body dose was noted in the three other patients with B-cell depletion. Without a preload, consistently higher tumour uptake was noticed in patients with B-cell depletion. CONCLUSION: Administration of the standard preload of unlabelled rituximab impairs radioconjugate tumour targeting in the majority of patients eligible for radioimmunotherapy, that is patients previously treated with rituximab-containing therapeutic regimens. This common practice may need to be reconsidered and further evaluated as the rationale for this high preload has its origin in the "prerituximab era". Clinical Trial Application: CTA 2011-005474-38 TRIAL REGISTRY: EudraCT.

Tumor texture analysis in 18F-FDG PET: relationships between texture parameters, histogram indices, standardized uptake values, metabolic volumes, and total lesion glycolysis.

UNLABELLED: Texture indices are of growing interest for tumor characterization in (18)F-FDG PET. Yet, on the basis of results published in the literature so far, it is unclear which indices should be used, what they represent, and how they relate to conventional indices such as standardized uptake values (SUVs), metabolic volume (MV), and total lesion glycolysis (TLG). We investigated in detail 31 texture indices, 5 first-order statistics (histogram indices) derived from the gray-level histogram of the tumor region, and their relationship with SUV, MV, and TLG in 3 different tumor types. METHODS: Three patient groups corresponding to 3 cancer types at baseline were studied independently: patients with metastatic colorectal cancer (72 lesions), non-small cell lung cancer (24 lesions), and breast cancer (54 lesions). Thirty-one texture indices were studied in addition to SUVs, MV, and TLG, and 5 indices extracted from histogram analysis were also investigated. The relationships between indices were studied as well as the robustness of the various texture indices with respect to the parameters involved in the calculation method (sampling schemes and tumor volume of interest). RESULTS: Regardless of the patient group, many indices were highly correlated (Pearson correlation coefficient |r| ≥ 0.80), making it desirable to focus on only a few uncorrelated indices. Three histogram indices were highly correlated with SUVs (|r| ≥ 0.84). Four texture indices were highly correlated with MV, and none was highly correlated with SUVs (|r| ≤ 0.55). The resampling formula used to calculate texture indices had a substantial impact, and resampling using at least 32 discrete values should be used for texture indices calculation. The texture indices change as a function of the segmentation method was higher than that of peak and maximum SUVs but less than mean SUV for 5 texture indices and was larger than that of MV for 14 texture indices and for the 5 histogram indices. All these results were extremely consistent across the 3 tumor types and explained many of the observations reported in the literature so far. CONCLUSION: None of the histogram indices and only 17 of 31 texture indices were robust with respect to the tumor-segmentation method. An appropriate resampling formula with at least 32 gray levels should be used to avoid introducing a misleading relationship between texture indices and SUV. Some texture indices are highly correlated or strongly correlate with MV whatever the tumor type. Such correlation should be accounted for when interpreting the usefulness of texture indices for tumor characterization, which might call for systematic multivariate analyses.

Multicenter harmonization of 89Zr PET/CT performance.

UNLABELLED: This study investigated the feasibility of quantitative accuracy and harmonized image quality in (89)Zr-PET/CT multicenter studies. METHODS: Five PET/CT scanners from 3 vendors were included. (89)Zr activity was measured in a central dose calibrator before delivery. Local activity assays were based on volume as well as on the local dose calibrator. Accuracy and image noise were determined from a cross calibration experiment. Image quality was assessed from recovery coefficients derived from different volume-of-interest (VOI) methods (VOI A 50%, based on a 3-dimensional isocontour at 50% of the maximum voxel value with local background correction; VOI Max, based on the voxel with the highest uptake; and VOI 3Dpeak, based on a spheric VOI of 1.2-cm diameter positioned so as to maximize the enclosed average). PET images were analyzed before and after postreconstruction smoothing, applied to match image noise. RESULTS: PET/CT accuracy and image noise ranged from -3% to 10% and from 13% to 22%, respectively. VOI 3Dpeak produced the most reproducible recovery coefficients. After calibration of the local dose calibrator to the central dose calibrator, differences between the local activity assays were within 6%. CONCLUSION: This study showed that quantitative accuracy and harmonized image quality can be reached in (89)Zr PET/CT multicenter studies.

Radioembolization of the spleen: a revisited approach for the treatment of malignant lymphomatous splenomegaly.

Intraarterial administration of (90)Y microspheres to the spleen in patients with malignant lymphoma was mentioned once in the literature in 1973. This case study illustrates the potential indication of selective internal radiotherapy in a heavily pretreated patient with highly refractory disease with a marginal zone lymphoma in leukemic phase and symptomatic splenomegaly. We describe the clinical course of disease; the biological and clinical response to the treatment after radioembolization; and simulation and dosimetry by multimodal imaging via single-photon emission computed tomography and computed tomography. The advantages of radioembolization for the management of lymphomatous splenomegaly are discussed.