[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

Correction to: [89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

Missing Electronic Supplementary Materials.

Imaging disease activity of rheumatoid arthritis by macrophage targeting using second generation translocator protein positron emission tomography tracers.

BACKGROUND: Positron emission tomography (PET) imaging of macrophages using the translocator protein (TSPO) tracer (R)-[11C]PK11195 has shown the promise to image rheumatoid arthritis (RA). To further improve TSPO PET for RA imaging, second generation TSPO tracers [11C]DPA-713 and [18F]DPA-714 have recently been evaluated pre-clinically showing better imaging characteristics. OBJECTIVE: A clinical proof of concept study to evaluate [11C]DPA-713 and [18F]DPA-714 to visualize arthritis in RA patients. METHODS: RA patients (n = 13) with at least two active hand joints were included. PET/CT scans of the hands were obtained after injection of [18F]DPA-714, [11C]DPA-713 and/or (R)-[11C]PK11195 (max. 2 tracers pp). Standardized uptake values (SUVs) and target-to-background (T/B) ratios were determined. Imaging data of the 3 different tracers were compared by pooled post-hoc testing, and by a head to head comparison. RESULTS: Clinically active arthritis was present in 110 hand joints (2-17 pp). Arthritic joints were visualized with both [11C]DPA-713 and [18F]DPA-714. Visual tracer uptake corresponded with clinical signs of arthritis in 80% of the joints. Mean absolute uptake in PET-positive joints was significantly higher for [11C]DPA-713 than for [18F]DPA-714, the latter being not significantly different from (R)-[11C]PK11195 uptake. Background uptake was lower for both DPA tracers compared with that of (R)-[11C]PK11195. Higher absolute uptake and lower background resulted in two-fold higher T/B ratios for [11C]DPA-713. CONCLUSIONS: [11C]DPA-713 and [18F]DPA-714 visualize arthritic joints in active RA patients and most optimal arthritis imaging results were obtained for [11C]DPA-713. Second generation TSPO macrophage PET provides new opportunities for both early diagnosis and therapy monitoring of RA.

Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small-cell lung cancer.

PD-L1 immunohistochemistry correlates only moderately with patient survival and response to PD-(L)1 treatment. Heterogeneity of tumor PD-L1 expression might limit the predictive value of small biopsies. Here we show that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with non-small-cell lung cancer. Whole body PD-(L)1 PET-CT reveals significant tumor tracer uptake heterogeneity both between patients, as well as within patients between different tumor lesions.

An automatic delineation method for bone marrow absorbed dose estimation in (89)Zr PET/CT studies.

BACKGROUND: The study aims to develop and validate an automatic delineation method for estimating red bone marrow (RM) activity concentration and absorbed dose in (89)Zr positron emission tomography/computed tomography (PET/CT) studies. Five patients with advanced colorectal cancer received 37.1 ± 0.9 MBq [(89)Zr] cetuximab within 2 h after administration of a therapeutic dose of 500 mg m(-2) unlabelled cetuximab. Per patient, five PET/CT scans were acquired on a Gemini TF-64 PET/CT scanner at 1, 24, 48, 96 and 144 h post injection. Low dose CT data were used to manually generate volumes of interest (VOI) in the lumbar vertebrae (LV). In addition, LV VOI were generated automatically using an active contour method in a low dose CT. RM activity was then determined by mapping the low dose CT-derived RM VOI onto the corresponding PET scans. Finally, these activities were used to derive residence times and, subsequently, the self and total RM absorbed doses using OLINDA/EXM 1.1. RESULTS: High correlations (r (2) > 0.85) between manual and automated VOI methods were obtained for both RM activity concentrations and total absorbed doses. On average, the automatic method provided values that were lower than 5 % compared to the manual method. CONCLUSIONS: An automated and efficient VOI method, based on an active contour approach, was developed, enabling accurate estimates of RM activity concentrations and total absorbed doses.

89Zr-immuno-PET for imaging of long circulating drugs and disease targets: why, how and when to be applied?

Positron emission tomography (PET) with 89Zr-labeled monoclonal antibodies (mAbs) or other targeted vehicles (e.g., peptides, nanoparticles and cells), collectively called "89Zr-immuno-PET", can be used for better understanding of disease targets and the in vivo behavior of targeted drugs. This will become increasingly important in the development of next generation mAbs, which are characterized by high potency and/or multiple binding domains. This review provides practical information for researchers who want to implement 89Zr-immuno-PET for answering their own biological and pathological questions or for steering their own drug development program. An overview is given of the reagents, labeling protocols, quality tests and critical steps to come to high quality 89Zr-conjugates, while possibilities for further improvement are discussed. Since PET has the advantage of allowing quantitative imaging, information is provided about standardization of 89Zr quantification. Issues are summarized for consideration when starting preclinical or clinical 89Zr-immuno-PET studies, to enable at the end unequivocal interpretation of results. Finally, many appealing examples are provided of what can be learned from 89Zr-immuno-PET studies, while future directions are outlined. Most of the current examples are still on the characterization of mAbs in oncology, but the review will show that 89Zr-immuno-PET harbors potential for many kinds of targeted drugs and diseases, as well as for elucidating biological processes.

Validation of simplified dosimetry approaches in 89Zr-PET/CT: the use of manual versus semi-automatic delineation methods to estimate organ absorbed doses.

PURPOSE: Increasing interest in immuno-positron emission tomography (PET) studies requires development of dosimetry methods which will provide accurate estimations of organ absorbed doses. The purpose of this study is to develop and validate simplified dosimetry approaches for (89)Zirconium-PET (Zr-PET)/computed tomography (CT) studies. METHODS: Five patients with advanced colorectal cancer received 37.1 ± 0.9 MBq (89)Zr-cetuximab within 2 h after administration of a therapeutic dose of 500 mg m(-2) cetuximab. PET/CT scans were obtained 1, 24, 48, 94, and 144 h post injection. Volumes of interest (VOIs) were manually delineated in lungs, liver, spleen, and kidneys for all scans, providing a reference VOI set. Simplified manual VOIs were drawn independently on CT scans using larger voxel sizes. The transformation of VOIs based on rigid and/or nonrigid registrations of the first CT scan (CT1) onto all successive CT scans was also investigated. The transformation matrix obtained from each registration was applied to the manual VOIs of CT1 to obtain VOIs for the successive scans. Dice similarity coefficient (DSC) and Hausdorff distance were used to assess the performance of the registrations. Organ total activity, organ absorbed dose, and effective dose were calculated for all methods. RESULTS: Semi-automatic delineation based on nonrigid registration showed excellent agreement for lungs and liver (DSC: 0.90 ± 0.04; 0.81 ± 0.06) and good agreement for spleen and kidneys (DSC: 0.71 ± 0.07; 0.66 ± 0.08). Hausdorff distance ranged from 13 to 16 mm depending on the organ. Simplified manual delineation methods, in liver and lungs, performed similarly to semi-automatic delineation methods. For kidneys and spleen, however, poorer accuracy in total activity and absorbed dose was observed, as the voxel size increased. Organ absorbed dose and total activity based on nonrigid registration were within 10%. The effective dose was within ±3% for all VOI delineation methods. CONCLUSIONS: A fast, semi-automatic, and accurate delineation method based on nonrigid registration was developed for determination of organ absorbed and effective dose in (89)Zr-PET/CT studies which may also be applied to other long-lived radionuclide PET/CT studies.

Construction of an artificial saliva reservoir in an existing maxillary denture.

A technique is presented for the construction of an artificial saliva reservoir in an existing denture. Compared with the construction of a new reservoir denture, adapting an existing denture can reduce the cost by approximately two thirds.