Final Results of a Prospective Evaluation of the Predictive Value of Interim Positron Emission Tomography in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP-14 (SAKK 38/07)

PURPOSE Our main objective was to prospectively determine the prognostic value of [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) after two cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone given every 14 days (R-CHOP-14) under standardized treatment and PET evaluation criteria. PATIENTS AND METHODS Patients with any stage of diffuse large B-cell lymphoma were treated with six cycles of R-CHOP-14 followed by two cycles of rituximab. PET/CT examinations were performed at baseline, after two cycles (and after four cycles if the patient was PET-positive after two cycles), and at the end of treatment. PET/CT examinations were evaluated locally and by central review. The primary end point was event-free survival at 2 years (2-year EFS). RESULTS Median age of the 138 evaluable patients was 58.5 years with a WHO performance status of 0, 1, or 2 in 56%, 36%, or 8% of the patients, respectively. By local assessment, 83 PET/CT scans (60%) were reported as positive and 55 (40%) as negative after two cycles of R-CHOP-14. Two-year EFS was significantly shorter for PET-positive compared with PET-negative patients (48% v 74%; P = .004). Overall survival at 2 years was not significantly different, with 88% for PET-positive versus 91% for PET-negative patients (P = .46). By using central review and the Deauville criteria, 2-year EFS was 41% versus 76% (P < .001) for patients who had interim PET/CT scans after two cycles of R-CHOP-14 and 24% versus 72% (P < .001) for patients who had PET/CT scans at the end of treatment. CONCLUSION Our results confirmed that an interim PET/CT scan has limited prognostic value in patients with diffuse large B-cell lymphoma homogeneously treated with six cycles of R-CHOP-14 in a large prospective trial. At this point, interim PET/CT scanning is not ready for clinical use to guide treatment decisions in individual patients.

New Clinical Indications for (18)F/(11)C-choline, New Tracers for Positron Emission Tomography and a Promising Hybrid Device for Prostate Cancer Staging: A Systematic Review of the Literature

CONTEXT Radiolabelled choline positron emission tomography has changed the management of prostate cancer patients. However, new emerging radiopharmaceutical agents, like radiolabelled prostate specific membrane antigen, and new promising hybrid imaging will begin new challenges in the diagnostic field. OBJECTIVE The continuous evolution in nuclear medicine has led to the improvement in the detection of recurrent prostate cancer (PCa), particularly distant metastases. New horizons have been opened for radiolabelled choline positron emission tomography (PET)/computed tomography (CT) as a guide for salvage therapy or for the assessment of systemic therapies. In addition, new tracers and imaging tools have been recently tested, providing important information for the management of PCa patients. Herein we discuss: (1) the available evidence in literature on radiolabelled choline PET and their recent indications, (2) the role of alternative radiopharmaceutical agents, and (3) the advantages of a recent hybrid imaging device (PET/magnetic resonance imaging) in PCa. EVIDENCE ACQUISITION Data from recently published (2010-2015), original articles concerning the role of choline PET/CT, new emerging radiotracers, and a new imaging device are analysed. This review is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. EVIDENCE SYNTHESIS In the restaging phase, the detection rate of choline PET varies between 4% and 97%, mainly depending on the site of recurrence and prostate-specific antigen levels. Both 68gallium (68Ga)-prostate specific membrane antigen and 18F-fluciclovine are shown to be more accurate in the detection of recurrent disease as compared with radiolabelled choline PET/CT. Particularly, Ga68-PSMA has a detection rate of 50% and 68%, respectively for prostate-specific antigen levels < 0.5ng/ml and 0.5-2ng/ml. Moreover, 68Ga- PSMA PET/magnetic resonance imaging demonstrated a particularly higher accuracy in detecting PCa than PET/CT. New tracers, such as radiolabelled bombesin or urokinase-type plasminogen activator receptor, are promising, but few data in clinical practice are available today. CONCLUSIONS Some limitations emerge from the published papers, both for radiolabelled choline PET/CT and also for new radiopharmaceutical agents. Efforts are still needed to enhance the impact of published data in the world of oncology, in particular when new radiopharmaceuticals are introduced into the clinical arena. PATIENT SUMMARY In the present review, the authors summarise the last evidences in clinical practice for the assessment of prostate cancer, by using nuclear medicine modalities, like positron emission tomography/computed tomography and positron emission tomography/magnetic resonance imaging.

Influence of end-expiratory level and tidal volume on gravitational ventilation distribution during tidal breathing in healthy adults

Our understanding of regional filling of the lung and regional ventilation distribution is based on studies using stepwise inhalation of radiolabelled tracer gases, magnetic resonance imaging and positron emission tomography. We aimed to investigate whether these differences in ventilation distribution at different end-expiratory levels (EELs) and tidal volumes (V (T)s) held also true during tidal breathing. Electrical impedance tomography (EIT) measurements were performed in ten healthy adults in the right lateral position. Five different EELs with four different V (T)s at each EEL were tested in random order, resulting in 19 combinations. There were no measurements for the combination of the highest EEL/highest V (T). EEL and V (T) were controlled by visual feedback based on airflow. The fraction of ventilation directed to different slices of the lung (VENT(RL1)-VENT(RL8)) and the rate of the regional filling of each slice versus the total lung were analysed. With increasing EEL but normal tidal volume, ventilation was preferentially distributed to the dependent lung and the filling of the right and left lung was more homogeneous. With increasing V (T) and maintained normal EEL (FRC), ventilation was preferentially distributed to the dependent lung and regional filling became more inhomogeneous (p < 0.05). We could demonstrate that regional and temporal ventilation distribution during tidal breathing was highly influenced by EEL and V (T).

PET-CT-guided interventions in the management of FDG-positive lesions in patients suffering from solid malignancies: initial experiences

Positron emission tomography-computed tomography (PET-CT) has gained widespread acceptance as a staging investigation in the diagnostic workup of malignant tumours and may be used to visualize metabolic changes before the evolution of morphological changes. To make histology of PET findings without distinctive structural changes available for treatment decisions, we developed a protocol for multimodal image-guided interventions using an integrated PET-CT machine. We report our first experience in 12 patients admitted for staging and restaging of breast cancer, non-small cell lung cancer, cervical cancer, soft tissue sarcoma, and osteosarcoma. Patients were repositioned according to the findings in PET-CT and intervention was planned based on a subsequent single-bed PET-CT acquisition of the region concerned. The needle was introduced under CT guidance in a step-by-step technique and correct needle position in the centre of the FDG avid lesion was assured by repetition of a single-bed PET-CT acquisition before sampling. The metabolically active part of lesions was accurately targeted in all patients and representative samples were obtained in 92%. No major adverse effects occurred. We conclude that PET-CT guidance for interventions is feasible and may be promising to optimize the diagnostic yield of CT-guided interventions and to make metabolically active lesions without morphological correlate accessible to percutaneous interventions.

Transconvolution and the virtual positron emission tomograph--a new method for cross calibration in quantitative PET∕CT imaging

PURPOSE Positron emission tomography (PET)∕computed tomography (CT) measurements on small lesions are impaired by the partial volume effect, which is intrinsically tied to the point spread function of the actual imaging system, including the reconstruction algorithms. The variability resulting from different point spread functions hinders the assessment of quantitative measurements in clinical routine and especially degrades comparability within multicenter trials. To improve quantitative comparability there is a need for methods to match different PET∕CT systems through elimination of this systemic variability. Consequently, a new method was developed and tested that transforms the image of an object as produced by one tomograph to another image of the same object as it would have been seen by a different tomograph. The proposed new method, termed Transconvolution, compensates for differing imaging properties of different tomographs and particularly aims at quantitative comparability of PET∕CT in the context of multicenter trials. METHODS To solve the problem of image normalization, the theory of Transconvolution was mathematically established together with new methods to handle point spread functions of different PET∕CT systems. Knowing the point spread functions of two different imaging systems allows determining a Transconvolution function to convert one image into the other. This function is calculated by convolving one point spread function with the inverse of the other point spread function which, when adhering to certain boundary conditions such as the use of linear acquisition and image reconstruction methods, is a numerically accessible operation. For reliable measurement of such point spread functions characterizing different PET∕CT systems, a dedicated solid-state phantom incorporating (68)Ge∕(68)Ga filled spheres was developed. To iteratively determine and represent such point spread functions, exponential density functions in combination with a Gaussian distribution were introduced. Furthermore, simulation of a virtual PET system provided a standard imaging system with clearly defined properties to which the real PET systems were to be matched. A Hann window served as the modulation transfer function for the virtual PET. The Hann's apodization properties suppressed high spatial frequencies above a certain critical frequency, thereby fulfilling the above-mentioned boundary conditions. The determined point spread functions were subsequently used by the novel Transconvolution algorithm to match different PET∕CT systems onto the virtual PET system. Finally, the theoretically elaborated Transconvolution method was validated transforming phantom images acquired on two different PET systems to nearly identical data sets, as they would be imaged by the virtual PET system. RESULTS The proposed Transconvolution method matched different PET∕CT-systems for an improved and reproducible determination of a normalized activity concentration. The highest difference in measured activity concentration between the two different PET systems of 18.2% was found in spheres of 2 ml volume. Transconvolution reduced this difference down to 1.6%. In addition to reestablishing comparability the new method with its parameterization of point spread functions allowed a full characterization of imaging properties of the examined tomographs. CONCLUSIONS By matching different tomographs to a virtual standardized imaging system, Transconvolution opens a new comprehensive method for cross calibration in quantitative PET imaging. The use of a virtual PET system restores comparability between data sets from different PET systems by exerting a common, reproducible, and defined partial volume effect.

Cancer of the oral cavity and oropharynx

Tumours in the oral cavity and oropharynx differ in presentation and prognosis and the detection of spread of tumour from one subsite to another is essential for the T-staging. This article reviews the anatomy and describes the pattern of spread of different cancers arising in the oral cavity and oropharynx; the imaging findings on computerized tomography and magnetic resonance imaging are also described. Brief mention is made on the role of newer imaging modalities such as [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography, perfusion studies and diffusion-weighted magnetic resonance imaging.

[The role of PET imaging in patients with lymphoma]

Positron-Emission-Tomography (PET) has emerged as a diagnostic gold standard for most tumor entities during the last 20 years, especially for patients suffering from malignant lymphoma. The development and distribution of machines allowing for hybrid imaging, i.e. the simultaneous acquisition of PET and CT datasets, and the possibility to assess even small pathologic findings with fused PET/CT image visualization, once more significantly improved the diagnostic accuracy of PET. Based on an excellent sensitivity the metabolic imaging with PET or PET/CT allows for a reliable overall assessment of patients with malignant lymphoma before therapy, for the early identification of non-responders during therapy, and for the diagnosis of relapse after therapy.

Dual-modality PET/CT instrumentation-today and tomorrow

Positron emission tomography (PET) has proven to be a clinically valuable imaging modality, particularly for oncology staging and therapy follow-up. The introduction of combined PET/CT imaging has helped address challenging imaging situations when anatomical information on PET-only was inadequate for accurate lesion localization. After a decade of PET/CT these combined systems have matured technically. Today, whole-body oncology staging is available with PET/CT in 15 min, or less. This review details recent developments in combined PET/CT instrumentation and points to implications for major applications in clinical oncology.

Deposition, imaging, and clearance: what remains to be done?

Deposition and clearance studies are used during product development and in fundamental research. These studies mostly involve radionuclide imaging, but pharmacokinetic methods are also used to assess the amount of drug absorbed through the lungs, which is closely related to lung deposition. Radionuclide imaging may be two-dimensional (gamma scintigraphy or planar imaging), or three-dimensional (single photon emission computed tomography and positron emission tomography). In October 2009, a group of scientists met at the "Thousand Years of Pharmaceutical Aerosols" conference in Reykjavik, Iceland, to discuss future research in key areas of pulmonary drug delivery. This article reports the session on "Deposition, imaging and clearance." The objective was partly to review our current understanding, but more importantly to assess "what remains to be done?" A need to standardize methodology and provide a regulatory framework by which data from radionuclide imaging methods could be compared between centers and used in the drug approval process was recognized. There is also a requirement for novel radiolabeling methods that are more representative of production processes for dry powder inhalers and pressurized metered dose inhalers. A need was identified for studies to aid our understanding of the relationship between clinical effects and regional deposition patterns of inhaled drugs. A robust methodology to assess clearance from small conducting airways should be developed, as a potential biomarker for therapies in cystic fibrosis and other diseases. The mechanisms by which inhaled nanoparticles are removed from the lungs, and the factors on which their removal depends, require further investigation. Last, and by no means least, we need a better understanding of patient-related factors, including how to reduce the variability in pulmonary drug delivery, in order to improve the precision of deposition and clearance measurements.

Arterial spin-labeling MRI perfusion in tuberous sclerosis: correlation with PET

Neuroimaging using magnetic resonance imaging (MRI) is required for the investigation of surgically intractable epilepsy. In addition to the standard MRI techniques, perfusion sequences can be added to improve visualization of the underlying pathological changes. Also, as arterial spin-labeling (ASL) MRI perfusion does not require contrast administration, it may even be advantageous in these patients. We report here on three patients with epilepsy and tuberous sclerosis who underwent brain MRI with ASL and positron emission tomography (PET), both of which were found to correlate with each other and with electrophysiological data.

Interictal arterial spin-labeling MRI perfusion in intractable epilepsy

INTRODUCTION: Magnetic resonance imaging (MRI) is required for the investigation of surgically intractable epilepsy. In addition to the standard MRI techniques, perfusion sequences can be added to improve visualization of underlying pathological changes. Arterial spin-labeling (ASL) MRI perfusion does not require contrast administration and, for this reason, may have advantages in these patients. METHODS: We report here on 16 patients with epilepsy who underwent MRI of the brain with ASL and positron emission tomography (PET). RESULTS: Despite a slightly reduced resolution with ASL, we found a correlation between ASL, PET and electrophysiological data, with hypoperfusion on ASL that corresponded with hypoperfusion on interictal PET. CONCLUSION: Given the correlation between ASL and PET and electrophysiology, perfusion with ASL could become part of the standard work-up in patients with epilepsy.

Functional Imaging of Pheochromocytoma with Ga-DOTATOC and C-HED in a Genetically Defined Rat Model of Multiple Endocrine Neoplasia

Rats affected by the MENX multitumor syndrome develop pheochromocytoma (100%). Pheochromocytomas are uncommon tumors and animal models are scarce, hence the interest in MENX rats to identify and preclinically evaluate novel targeted therapies. A prerequisite for such studies is a sensitive and noninvasive detection of MENXassociated pheochromocytoma. We performed positron emission tomography (PET) to determine whether rat pheochromocytomas are detected by tracers used in clinical practice, such as 68Ga-DOTATOC (somatostatin analogue) or (11)C-Hydroxyephedrine (HED), a norepinephrine analogue. We analyzed four affected and three unaffected rats. The PET scan findings were correlated to histopathology and immunophenotype of the tumors, their proliferative index, and the expression of genes coding for somatostatin receptors or the norepinephrine transporter. We observed that mean 68Ga-DOTATOC standard uptake value (SUV) in adrenals of affected animals was 23.3 ± 3.9, significantly higher than in control rats (15.4 ± 7.9; P = .03). The increase in mean tumor-to-liver ratio of (11)C-HED in the MENX-affected animals (1.6 ± 0.5) compared to controls (0.7 ± 0.1) was even more significant (P = .0016). In a unique animal model, functional imaging depicting two pathways important in pheochromocytoma biology discriminated affected animals from controls, thus providing the basis for future preclinical work with MENX rats.

In vivo evaluation in cynomolgus monkey brain and metabolism of [¹⁸F]fluorodeprenyl: a new MAO-B pet radioligand

In this study, we evaluated the in vivo characteristics of a new monoamine oxidase type B (MAO-B) radioligand, [¹⁸F]fluorodeprenyl, by positron emission tomography (PET) in two cynomolgus monkeys. The brain uptake of [¹⁸F]fluorodeprenyl was more than 7% (600% SUV) of the total injected radioactivity and similar to that of [¹¹C]deprenyl, an established MAO-B radioligand. The highest uptake was observed in the striatum, one of the MAO-B-rich regions, with a peak at approximately 2-3 min after injection, followed by lower uptake in the thalamus and the cortex and lowest uptake in the cerebellum. Brain uptake of [¹⁸F]fluorodeprenyl was largely inhibited by preadministration of the MAO-B inhibitor, L-deprenyl, whereas clorgyline, a MAO Type A blocker, had no significant inhibitory effect, thus demonstrating selectivity for MAO-B. [¹⁸F]Fluorodeprenyl showed relatively slow metabolism with the presence of two radiometabolite peaks with similar retention time as the labeled metabolites of [¹¹C]deprenyl. These results suggest that [¹⁸F]fluorodeprenyl is a potential PET radioligand for visualization of MAO-B activity.

18F-fluorodeoxyglucose uptake of bone and soft tissue sarcomas in pediatric patients

A high (18)F-fluorodeoxyglucose (FDG) uptake by positron emission tomography/computed tomography (PET/CT) imaging in sarcomas of adults has been reported. The current study aimed at defining the degree of (18)F-FDG uptake of pediatric sarcomas. This retrospective study included 29 patients (23 males, 6 females; mean age 14 ± 5 years) with soft tissue (n = 9) or bone (n = 20) sarcomas. Twenty-two patients (76%) underwent (18)F-FDG PET/CT and 7 (24%) had dedicated (18)F-FDG PET studies. Tumor (18)F-FDG uptake was quantified by standard uptake value (SUV)(max) and tumor-to-liver ratios (SUV ratios; tumor SUV(max)/liver SUV(mean)). Tumor SUV(max) and SUV ratios were correlated with tumor Ki-67 expression. SUV(max) ranged from 1.4 to 24 g/mL (median 2.5 g/mL) in soft tissue sarcomas and 1.6 to 20.4 g/mL (median 6.9 g/mL) in bone sarcomas (P = .03), and from 1.6 to 9.2 g/mL (median 3.9 g/mL) and 3.5 to 20.4 g/mL (median 12 g/mL) in Ewing sarcoma and osteosarcoma, respectively (P = .009). Tumor SUV ratios ranged from 0.8 to 8.7 (median 1.9) in soft tissue sarcomas and 1.4 to 8.9 (median 3.8) in bone sarcomas (P = .08). Ewing sarcoma had a significantly lower tumor SUV ratio than osteosarcoma (P = .01). Ki-67 expression correlated significantly with the (18)F-FDG uptake in bone but not in soft tissue sarcomas. All sarcomas were visualized by (18)F-FDG PET/CT imaging. A higher (18)F-FDG uptake was observed in osteosarcoma than in Ewing and soft tissue sarcomas. The results of this study suggest that the degree of tumor (18)F-FDG uptake is sufficient to allow for monitoring of therapeutic responses in pediatric sarcomas.

Comparison of C-11 methionine and C-11 choline for PET imaging of brain metastases: a prospective pilot study

The aim of the study was the comparison of C-11 methionine (MET) and C-11 choline (CHO) in the positron emission tomography (PET) imaging of brain metastases in correlation to the histopathology findings in stereotactic biopsy.