Thomas Guiot

New Imaging Techniques for 90Y Microsphere Radioembolization

Adequate patient selection and treatment planning is crucial for a safe and cost-effective administration of selective internal radiotherapy (SIRT) of malignant liver disease using 90 Y-labelled microspheres. It requires the implementation of multimodality imaging, integrating metabolic, functional and structural characteristics. A multidisciplinary approach is a prerequisite for SIRT, bringing together the knowhow and expertise of radiologists, nuclear medicine physicians, medical physicists, imaging engineers, and radiotherapists. This review discusses the available radiologic (CT/MRI) and nuclear (SPECT/PET) imaging modalities and their specific utility in the different diagnostic phases related to SIRT: wholebody and intrahepatic pre-treatment disease staging, CT and MRI-based angiography, liver-lung shunt assessment, treatment simulation, predictive dosimetry, post-treatment imaging, and SIRT response assessment.

The Prognostic Significance of Metabolic Response Heterogeneity in Metastatic Colorectal Cancer

Background Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC). Methods Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m²/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions. Results Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8–10.5) and 4.2 months (95% CI: 3.4–4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21–0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36–0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS. Conclusion The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC. Trial Registration ClinicalTrials.gov NCT01290926

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

Regorafenib assessment in refractory advanced colorectal cancer: RegARd-C study protocol.

Introduction Regorafenib was recently approved for patients with pretreated advanced colorectal cancer (aCRC), despite a moderate improvement of the patients’ outcome, and significant toxicities. Based on previous studies showing that early fluorodeoxyglucose-positron emission tomography (FDG-PET)-based metabolic response assessment (MRA) might adequately select patients unlikely to benefit from treatment, the RegARd-C trial uses early MRA to identify likely non-responders to regorafenib in a population of patients with aCRC and guide a comprehensive evaluation of genomic and epigenetic determinants of resistance to treatment. Methods and analysis RegARd-C is a multicentric prospective study. Its primary objective is to identify non-benefitters from regorafenib given at 160 mg/day, 3 weeks out of 4 in a population of patients with pretreated aCRC. Baseline PET is repeated at day 14 of the first treatment course. MRA is blinded for the investigators. Overall survival (OS) is the primary end point and will be correlated with metabolic parameters and (epi)genetic alterations assessed from tumour and serial blood samples. A target sample size of 105 evaluable patients (70 as derivation set and 35 as validation set), is considered as sufficient to validate an expected HR for OS of metabolic responders compared to metabolic non-responders significantly <1 (with 80% power and 1-sided 5% α in case of a true HR≤0.59 and a responders rate of 47%). Ethics and dissemination The study was approved by the Institut Jules Bordets competent ethics committee and complies with the Helsinki declaration or the Belgian laws and regulations, whichever provides the greatest protection for the patient, and follows the International Conference on Harmonisation E 6 (R1) Guideline for Good Clinical Practice, reference number CPMP/ICH/135/95. The protocol and the trials results, even inconclusive, will be presented at international oncology congresses, and published in peer-reviewed journals. Genomic and epigenetic data will be made available in public open data sets. Trial registration numbers EudraCT number: 2012-005655-16; ClinicalTrials.gov number: NCT01929616.

Metabolic Active Tumor Volume and Total Lesion Glycolysis by18F-FDG PET/CT Validated as Prognostic Imaging Biomarkers in Chemorefractory Metastatic Colorectal Cancer

This study aimed to validate the prognostic value of baseline whole-body metabolically active tumor volume (WB-MATV) and total lesion glycolysis (WB-TLG) measured with 18F-FDG PET/CT in a large cohort of chemorefractory metastatic colorectal cancer (mCRC) patients treated with multikinase inhibitors. The secondary objective of this study was to compare WB-MATV and WB-TLG respective prognostic values with commonly used clinical prognostic factors. Methods: Of 238 patients pooled from 2 successive prospective multicenter trials investigating multikinase inhibitors in chemorefractory mCRC, 224 were considered suitable for analysis. The patients were retrospectively randomly assigned to a development set (n = 155 patients) or a validation set (n = 69 patients). WB-MATV and WB-TLG optimal cutoffs for prediction of overall survival (OS) were determined by Contal and O’Quigley’s method. Univariate analyses were performed to assess the prognostic values of WB-MATV and WB-TLG. Multivariate analyses were performed for WB-MATV and WB-TLG along with clinical factors to identify the independent prognostic factors of OS. The prognostic weight for each parameter was obtained from the Cox model. Results: WB-MATV and WB-TLG optimal cutoffs for OS prediction were 100 cm3 and 500 g, respectively. Univariate analyses showed that WB-MATV and WB-TLG parameters were strongly related to outcome in both the development and the validation sets. In the validation set, the median OS was 5.2 mo versus 12.8 mo for high versus low WB-MATV (hazard ratio [HR], 3.12; P < 0.001) and 4.7 mo versus 13.9 mo for high versus low WB-TLG (HR, 3.67; P < 0.001). The multivariate analyses found that both high WB-MATV and high WB-TLG were independent negative prognostic parameters for OS, having the highest prognostic weight among the well-known clinical prognostic factors (HR, 2.46 and 2.23, respectively; P < 0.001). Conclusion: Baseline WB-MATV and WB-TLG parameters were validated as strong prognosticators of outcome in a large cohort of chemorefractory mCRC patients treated with multikinase inhibitors. These parameters were identified as independent prognostic imaging biomarkers with the highest prognostic values among the commonly used clinical factors. These biomarkers should therefore be used to support the optimal therapeutic strategy.

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

BackgroundThe 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.ResultsFifty-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)).ConclusionsIn 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.

Phantom program analysis to assess the variability in PET image quantification between different PET-CT centres

Human primary immunodeficiencies (PIDs) comprise a broad group of inherited disorders characterised by developmental or functional defects of myeloid or lymphoid haemapoietic-derived cells, as well as non-haemapoietic cells involved in protective immunity. More than 150 different forms of PIDs affecting distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, natural killer cells, and T and B lymphocytes have been described [1]. Clinically, PIDs can be associated with any combination of infectious disease, autoimmunity, auto-inflammatory, allergy and malignancy. The best known PIDs show Mendelian inheritance and first become symptomatic during childhood. However, the field of PIDs is rapidly expanding and PIDs showing non-Mendelian inheritance and/or affecting primarily adult patients is being increasingly recognized. Conventional PIDs are typically seen as rare monogenic conditions associated with detectable immunologic abnormalities, resulting in a broad susceptibility to multiple and recurrent infections caused by weakly pathogenic and more virulent microorganisms. By opposition to these conventional PIDs, nonconventional primary immunodeficiencies as Mendelian conditions manifesting in otherwise healthy patients as a narrow susceptibility to infections, recurrent or otherwise, caused by weakly pathogenic or more virulent microbes are now reported [2]. By now, up to 120 diseasecausing genes have been identified. This molecular characterisation of PIDs has helped to increase our understanding of their physiopathology. The study of these diseases has provided essential insights into the functioning of the immune system with the ultimate goal of facilitating diagnosis and treatment.