Metastatic and sentinel lymph node mapping using intravenously delivered Panitumumab-IRDye800CW.

Rationale: Sentinel lymph node biopsy (SLNB) is a well-established minimally invasive staging procedure that maps the spread of tumour metastases from their primary site to the regional lymphatics. Currently, the procedure requires the local peri-tumoural injection of radiolabelled and/or optical agents, and is therefore operator dependent, disruptive to surgical workflow and restricted largely to a small subset of malignancies that can be readily accessed externally for local tracer injection. The present study set out to determine whether intravenous (IV) infusion of a tumor-targeted tracer could identify sentinel and metastatic lymph nodes (LNs) in order to overcome these limitations. Methods: We examined 27 patients with oral squamous cell carcinoma (OSCC), 18 of whom were clinically node negative (cN0). Patients were infused intravenously with 50mg of Panitumumab-IRDye800CW prior to surgical resection of their primary tumour with neck dissection and/or SLNB. Lymphadenectomy specimens underwent fluorescence molecular imaging to evaluate tracer distribution to LNs. Results: A total of 960 LNs were analysed, of which 34 (3.5%) contained metastatic disease. Panitumumab-IRDye800CW preferentially localized to metastatic and sentinel LNs as evidenced by a higher fluorescent signal relative to other lymph nodes. The median MFI of metastatic LNs was significantly higher than the median MFI of benign LNs (0.06 versus 0.02, p < 0.05). Furthermore, selecting the highest five fluorescence intensity LNs from individual specimens resulted in 100% sensitivity, 85.8% specificity and 100% negative predictive value (NPV) for the detection of occult metastases and 100% accuracy for clinically staging the neck. In the cN+ cohort, assessment of the highest 5 fluorescence LNs per patient had 87.5% sensitivity, 93.2% specificity and 99.1% NPV for the detection of metastatic nodes. Conclusion: When intravenously infused, a tumour-targeted tracer localized to sentinel and metastatic lymph nodes. Further validation of an IV tumor-targeted tracer delivery approach for SLNB could dramatically change the practice of SLNB, allowing its application to other malignancies where the primary tumour is not accessible for local tracer injection.

High-Specific-Activity-131I-MIBG versus 177Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma.

Targeted radionuclide therapies (TRT) using 131I-metaiodobenzylguanidine (131I-MIBG) and peptide receptor radionuclide therapy (177Lu or 90Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-131I-MIBG therapy was approved by the FDA and both 177Lu-DOTATATE and 131I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.

Clinical Evaluation of 68Ga-PSMA-II and 68Ga-RM2 PET Images Reconstructed With an Improved Scatter Correction Algorithm.

OBJECTIVE: Gallium-68-labeled radiopharmaceuticals pose a challenge for scatter estimation because their targeted nature can produce high contrast in these regions of the kidneys and bladder. Even small errors in the scatter estimate can result in washout artifacts. Administration of diuretics can reduce these artifacts, but they may result in adverse events. Here, we investigated the ability of algorithmic modifications to mitigate washout artifacts and eliminate the need for diuretics or other interventions. MATERIALS AND METHODS: The model-based scatter algorithm was modified to account for PET/MRI scanner geometry and challenges of non-FDG tracers. Fifty-three clinical 68Ga-RM2 and 68Ga-PSMA-11 whole-body images were reconstructed using the baseline scatter algorithm. For comparison, reconstruction was also processed with modified sampling in the single-scatter estimation and with an offset in the scatter tail-scaling process. None of the patients received furosemide to attempt to decrease the accumulation of radiopharmaceuticals in the bladder. The images were scored independently by three blinded reviewers using the 5-point Likert scale. RESULTS: The scatter algorithm improvements significantly decreased or completely eliminated the washout artifacts. When comparing the baseline and most improved algorithm, the image quality increased and image artifacts were reduced for both 68Ga-RM2 and for 68Ga-PSMA-11 in the kidneys and bladder regions. CONCLUSION: Image reconstruction with the improved scatter correction algorithm mitigated washout artifacts and recovered diagnostic image quality in 68Ga PET, indicating that the use of diuretics may be avoided.

Intragastric Meal Distribution During Gastric Emptying Scintigraphy for Assessment of Fundic Accommodation: Correlation with Symptoms of Gastroparesis.

Impaired fundic accommodation (FA) limits fundic relaxation and the ability to act as a reservoir for food. Assessing intragastric meal distribution (IMD) during gastric emptying scintigraphy (GES) allows for a simple measure of FA. The 3 goals of this study were to evaluate trained readers' (nuclear medicine and radiology physicians) visual assessments of FA from solid-meal GES; develop software to quantify GES IMD; and correlate symptoms of gastroparesis with IMD and gastric emptying. Methods: After training to achieve a consensus interpretation of GES FA, 4 readers interpreted FA in 148 GES studies from normal volunteers and patients. Mixture distribution and κ-agreement analyses were used to assess reader consistency and agreement of scoring of FA. Semiautomated software was used to quantify IMD (ratio of gastric counts in the proximal stomach to those in the total stomach) at 0, 1, 2, 3, and 4 h after ingestion of a meal. Receiver-operating-characteristic analysis was performed to optimize the diagnosis of abnormal IMD at 0 min (IMD0) with impaired FA. IMD0, GES, water load testing, and symptoms were then compared in 177 patients with symptoms of gastroparesis. Results: Reader pairwise weighted κ-values for the visual assessment of FA averaged 0.43 (moderate agreement) for normal FA versus impaired FA. Readers achieved 84.0% consensus and 85.8% reproducibility in assessing impaired FA. IMD0 based on the division of the stomach into proximal and distal halves averaged 0.809 (SD, 0.083) for normal FA and 0.447 (SD, 0.132) (P < 0.01) for impaired FA. On the basis of receiver-operating-characteristic analysis, the optimal cutoff for IMD0 discrimination of normal FA from impaired FA was 0.568 (sensitivity, 86.7%; specificity, 91.7%). Of 177 patients with symptoms of gastroparesis, 129 (72.9%) had delayed gastric emptying; 25 (14.1%) had abnormal IMD0 Low IMD0 (impaired FA) was associated with increased early satiety (P = 0.02). Conclusion: FA can be assessed visually during routine GES with moderate agreement and high reader consistency. Visual and quantitative assessments of FA during GES can yield additional information on gastric motility to help explain patients' symptoms.

Carcinoid Syndrome Complicating a Pancreatic Neuroendocrine Tumor: A Case Report.

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms. These tumors can produce a wide variety of hormones that can lead to syndromes of hormone excess, such as carcinoid syndrome. We present the case of a 47-year-old man who presented with right upper quadrant abdominal pain and emesis. He was found to have metastatic pancreatic NET and was treated with systemic chemotherapy. He subsequently developed dyspnea on exertion and was found to have severe right-sided heart disease secondary to elevated levels of serum serotonin. He was successfully treated with surgical tricuspid and pulmonic valve replacement. True carcinoid syndrome with pancreatic NETs is rare, but, as a treatable complication of the disease, is an important entity for which oncologists should be familiar.

68Ga-PSMA-11 PET/CT in Newly Diagnosed Carcinoma of the Prostate: Correlation of Intraprostatic PSMA Uptake with Several Clinical Parameters.

68Ga-prostate-specific membrane antigen (PSMA) PET/CT is a promising diagnostic tool for patients with prostate cancer. Our study evaluates SUVs in benign prostate tissue and malignant, intraprostatic tumor lesions and correlates results with several clinical parameters. Methods: One hundred four men with newly diagnosed prostate carcinoma and no previous therapy were included in this study. SUVmax was measured and correlated with biopsy findings and MRI. Afterward, data were compared with current prostate-specific antigen (PSA) values, Gleason score (GS), and d'Amico risk classification. Results: In this investigation a mean SUVmax of 1.88 ± 0.44 in healthy prostate tissue compared with 10.77 ± 8.45 in malignant prostate lesions (P < 0.001) was observed. Patients with higher PSA, higher GS, and higher d'Amico risk score had statistically significant higher PSMA uptake on PET/CT (P < 0.001 each). Conclusion: PSMA PET/CT is well suited for detecting the intraprostatic malignant lesion in patients with newly diagnosed prostate cancer. Our findings indicate a significant correlation of PSMA uptake with PSA, GS, and risk classification according to the d'Amico scale.

Clinical evaluation of TOF versus non-TOF on PET artifacts in simultaneous PET/MR: a dual centre experience.

PURPOSE: Our objective was to determine clinically the value of time-of-flight (TOF) information in reducing PET artifacts and improving PET image quality and accuracy in simultaneous TOF PET/MR scanning. METHODS: A total 65 patients who underwent a comparative scan in a simultaneous TOF PET/MR scanner were included. TOF and non-TOF PET images were reconstructed, clinically examined, compared and scored. PET imaging artifacts were categorized as large or small implant-related artifacts, as dental implant-related artifacts, and as implant-unrelated artifacts. Differences in image quality, especially those related to (implant) artifacts, were assessed using a scale ranging from 0 (no artifact) to 4 (severe artifact). RESULTS: A total of 87 image artifacts were found and evaluated. Four patients had large and eight patients small implant-related artifacts, 27 patients had dental implants/fillings, and 48 patients had implant-unrelated artifacts. The average score was 1.14 ± 0.82 for non-TOF PET images and 0.53 ± 0.66 for TOF images (p < 0.01) indicating that artifacts were less noticeable when TOF information was included. CONCLUSION: Our study indicates that PET image artifacts are significantly mitigated with integration of TOF information in simultaneous PET/MR. The impact is predominantly seen in patients with significant artifacts due to metal implants.

Bone-Targeted Imaging and Radionuclide Therapy in Prostate Cancer.

Although selective metabolic and receptor-based molecular agents will surely be included in the future of prostate cancer diagnosis and therapy, currently available inorganic compounds-such as 18F-NaF for the diagnosis of bony disease and 223RaCl2 for the therapy of bone metastases-were recently shown to be superior to standard 99mTc-phosphonates for diagnosis and 153Sm-ethylenediaminetetramethylene phosphonate or 89SrCl2 for therapy. The advantages of 18F-NaF include improved lesion detection and, when used in combination with CT, improved diagnostic confidence and specificity. In addition to being the first approved α-emitter, 223RaCl2 is the first radiopharmaceutical to show an increase in overall survival, a decrease in skeletal events, palliation of bone pain, and a low profile of adverse reactions (which are mild and manageable). The management of metastatic bone disease with 223RaCl2 is uniquely satisfying, as patients can be monitored directly during their monthly treatment visits.

Bombesin-Targeted PET of Prostate Cancer.

Imaging plays an important role in prostate cancer (PC), including accurate evaluation of the extent of disease, assessment of sites of recurrent disease, and monitoring of response to treatment. Molecular imaging techniques are among the novel developments related to the imaging of PC, and various SPECT and PET radiopharmaceuticals are now available in clinical trials or commercially. Here we describe the preclinical and clinical use of gastrin-releasing peptide receptors as targets for the imaging of PC, with a focus on the development of PET tracers for the imaging of gastrin-releasing peptide receptor-positive tumors.

Pilot Preclinical and Clinical Evaluation of (4S)-4-(3-[18F]Fluoropropyl)-L-Glutamate (18F-FSPG) for PET/CT Imaging of Intracranial Malignancies.

PURPOSE: (S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is a novel radiopharmaceutical for Positron Emission Tomography (PET) imaging. It is a glutamate analogue that can be used to measure xC- transporter activity. This study was performed to assess the feasibility of 18F-FSPG for imaging orthotopic brain tumors in small animals and the translation of this approach in human subjects with intracranial malignancies. EXPERIMENTAL DESIGN: For the small animal study, GS9L glioblastoma cells were implanted into brains of Fischer rats and studied with 18F-FSPG, the 18F-labeled glucose derivative 18F-FDG and with the 18F-labeled amino acid derivative 18F-FET. For the human study, five subjects with either primary or metastatic brain cancer were recruited (mean age 50.4 years). After injection of 300 MBq of 18F-FSPG, 3 whole-body PET/Computed Tomography (CT) scans were obtained and safety parameters were measured. The three subjects with brain metastases also had an 18F-FDG PET/CT scan. Quantitative and qualitative comparison of the scans was performed to assess kinetics, biodistribution, and relative efficacy of the tracers. RESULTS: In the small animals, the orthotopic brain tumors were visualized well with 18F-FSPG. The high tumor uptake of 18F-FSPG in the GS9L model and the absence of background signal led to good tumor visualization with high contrast (tumor/brain ratio: 32.7). 18F-FDG and 18F-FET showed T/B ratios of 1.7 and 2.8, respectively. In the human pilot study, 18F-FSPG was well tolerated and there was similar distribution in all patients. All malignant lesions were positive with 18F-FSPG except for one low-grade primary brain tumor. In the 18F-FSPG-PET-positive tumors a similar T/B ratio was observed as in the animal model. CONCLUSIONS: 18F-FSPG is a novel PET radiopharmaceutical that demonstrates good uptake in both small animal and human studies of intracranial malignancies. Future studies on larger numbers of subjects and a wider array of brain tumors are planned. TRIAL REGISTRATION: ClinicalTrials.gov NCT01186601.

Fusion dual-tracer SPECT-based hepatic dosimetry predicts outcome after radioembolization for a wide range of tumour cell types.

PURPOSE: Fusion dual-tracer SPECT imaging enables physiological rather than morphological voxel-based partitioning and dosimetry for (90)Y hepatic radioembolization (RE). We evaluated its prognostic value in a large heterogeneous cohort of patients with extensive hepatic malignancy. METHODS: A total of 122 patients with primary or secondary liver malignancy (18 different cell types) underwent SPECT imaging after intraarterial injection of (99m)Tc macroaggregated albumin (TcMAA) as a simulation of subsequent (90)Y microsphere distribution, followed by administration of an excess of intravenous (99m)Tc-labelled sulphur colloid (TcSC) as a biomarker for functional liver, and a second SPECT scan. TcMAA distribution was used to estimate (90)Y radiation absorbed dose in tumour (D T) and in functional liver. Laboratory and clinical follow-up were recorded for 12 weeks after RE, and radiographic responses according to (m)RECIST were evaluated at 3 and 6 months. Dose-response relationships were determined for efficacy and toxicity. RESULTS: Patients were treated with a median of 1.73 GBq activity of resin microspheres (98 patients) or glass microspheres (24 patients), in a whole-liver approach (97 patients) or a lobar approach (25 patients). The objective response rate was 41% at 3 months and 48% at 6 months. Response was correlated with D T (P < 0.01). Median overall survival was 10.1 months (95% confidence interval 7.4 - 12.8 months). Responders lived for 36.0 months compared to 8.7 months for nonresponders (P < 0.01). Stratified for tumour cell type, D T was independently associated with survival (P < 0.01). Absorbed dose in functional liver was correlated with toxicity grade change (P < 0.05) and RE-induced liver disease (P < 0.05). CONCLUSION: Fusion dual-tracer SPECT imaging offers a physiology-based functional imaging tool to predict efficacy and toxicity of RE. This technique can be refined to define dosing thresholds for specific tumour types and treatments, but appears generally predictive even in a heterogeneous cohort.

Circulating tumor microemboli diagnostics for patients with non-small-cell lung cancer.

INTRODUCTION: Circulating tumor microemboli (CTM) are potentially important cancer biomarkers, but using them for cancer detection in early-stage disease has been assay limited. We examined CTM test performance using a sensitive detection platform to identify stage I non-small-cell lung cancer (NSCLC) patients undergoing imaging evaluation. METHODS: First, we prospectively enrolled patients during 18F-FDG PET-CT imaging evaluation for lung cancer that underwent routine phlebotomy where CTM and circulating tumor cells (CTCs) were identified in blood using nuclear (DAPI), cytokeratin (CK), and CD45 immune-fluorescent antibodies followed by morphologic identification. Second, CTM and CTC data were integrated with patient (age, gender, smoking, and cancer history) and imaging (tumor diameter, location in lung, and maximum standard uptake value [SUVmax]) data to develop and test multiple logistic regression models using a case-control design in a training and test cohort followed by cross-validation in the entire group. RESULTS: We examined 104 patients with NSCLC, and the subgroup of 80 with stage I disease, and compared them to 25 patients with benign disease. Clinical and imaging data alone were moderately discriminating for all comers (Area under the Curve [AUC] = 0.77) and by stage I disease only (AUC = 0.77). However, the presence of CTM combined with clinical and imaging data was significantly discriminating for diagnostic accuracy in all NSCLC patients (AUC = 0.88, p value = 0.001) and for stage I patients alone (AUC = 0.87, p value = 0.002). CONCLUSION: CTM may add utility for lung cancer diagnosis during imaging evaluation using a sensitive detection platform.

The clinical use of PET/CT in the evaluation of melanoma.

Positron emission tomography combined with computed tomography (PET/CT) has emerged in the last decade as a dominant imaging modality used for staging, monitoring response and surveillance of various cancers, including melanoma. Using 2-deoxy-2-((18)F)fluoro-D-glucose ((18)F-FDG) as the radiopharmaceutical, PET/CT has demonstrated its efficacy and its utility in the management of patients with advanced melanoma. Nonetheless, challenges remain in the early stage evaluation of melanoma and in the development of novel radiotracers to better characterize lesions found on PET/CT. This chapter focuses on the advantages and limitations of this imaging modality in melanoma. We also detail and describe the approach to perform (18)F-FDG PET/CT, the methods to accurately quantify lesions, as well as the pearls/pitfalls of image interpretation. Finally, an overview of preclinical and investigational clinical radiopharmaceuticals is presented.

Prognostic utility of 90Y radioembolization dosimetry based on fusion 99mTc-macroaggregated albumin-99mTc-sulfur colloid SPECT.

UNLABELLED: Planning hepatic (90)Y radioembolization activity requires balancing toxicity with efficacy. We developed a dual-tracer SPECT fusion imaging protocol that merges data on radioactivity distribution with physiologic liver mapping. METHODS: Twenty-five patients with colorectal carcinoma and bilobar liver metastases received whole-liver radioembolization with resin microspheres prescribed as per convention (mean administered activity, 1.69 GBq). As part of standard treatment planning, all patients underwent SPECT imaging after intraarterial injection of 37 MBq of (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) to simulate subsequent (90)Y distribution. Immediately afterward, patients received 185 MBq of labeled sulfur colloid ((99m)Tc-SC) intravenously as a biomarker for normal hepatic reticuloendothelial function and SPECT was repeated. The SPECT images were coregistered and fused. A region-based method was used to predict the (90)Y radiation absorbed dose to functional liver tissue (DFL) by calculation of (99m)Tc-MAA activity in regions with (99m)Tc-SC uptake. Similarly, the absorbed dose to tumor (DT) was predicted by calculation of (99m)Tc-MAA activity in voxels without (99m)Tc-SC uptake. Laboratory data and radiographic response were measured for 3 mo, and the survival of patients was recorded. SPECT-based DT and DFL were correlated with parameters of toxicity and efficacy. RESULTS: Toxicity, as measured by increase in serum liver enzymes, correlated significantly with SPECT-based calculation of DFL at all time points (P < 0.05) (mean DFL, 27.9 Gy). Broad biochemical toxicity (>50% increase in all liver enzymes) occurred at a DFL of 24.5 Gy and above. In addition, in uni- and multivariate analysis, SPECT-based calculation of DT (mean DT, 44.2 Gy) correlated with radiographic response (P < 0.001), decrease in serum carcinoembryonic antigen (P < 0.05), and overall survival (P < 0.01). The cutoff value of DT for prediction of 1-y survival was 55 Gy (area under the receiver-operating-characteristic curve = 0.86; P < 0.01). Patients who received a DT of more than 55 Gy had a median survival of 32.8 mo, compared with 7.2 mo in patients who received less (P < 0.05). CONCLUSION: Dual-tracer (99m)Tc-MAA-(99m)Tc-SC fusion SPECT offers a physiology-based imaging tool with significant prognostic power that may lead to improved personalized activity planning.

An observational study of circulating tumor cells and (18)F-FDG PET uptake in patients with treatment-naive non-small cell lung cancer.

INTRODUCTION: We investigated the relationship of circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC) with tumor glucose metabolism as defined by (18)F-fluorodeoxyglucose (FDG) uptake since both have been associated with patient prognosis. MATERIALS & METHODS: We performed a retrospective screen of patients at four medical centers who underwent FDG PET-CT imaging and phlebotomy prior to a therapeutic intervention for NSCLC. We used an Epithelial Cell Adhesion Molecule (EpCAM) independent fluid biopsy based on cell morphology for CTC detection and enumeration (defined here as High Definition CTCs or "HD-CTCs"). We then correlated HD-CTCs with quantitative FDG uptake image data calibrated across centers in a cross-sectional analysis. RESULTS: We assessed seventy-one NSCLC patients whose median tumor size was 2.8 cm (interquartile range, IQR, 2.0-3.6) and median maximum standardized uptake value (SUVmax) was 7.2 (IQR 3.7-15.5). More than 2 HD-CTCs were detected in 63% of patients, whether across all stages (45 of 71) or in stage I disease (27 of 43). HD-CTCs were weakly correlated with partial volume corrected tumor SUVmax (r = 0.27, p-value = 0.03) and not correlated with tumor diameter (r = 0.07; p-value = 0.60). For a given partial volume corrected SUVmax or tumor diameter there was a wide range of detected HD-CTCs in circulation for both early and late stage disease. CONCLUSIONS: CTCs are detected frequently in early-stage NSCLC using a non-EpCAM mediated approach with a wide range noted for a given level of FDG uptake or tumor size. Integrating potentially complementary biomarkers like these with traditional patient data may eventually enhance our understanding of clinical, in vivo tumor biology in the early stages of this deadly disease.

Root cause analysis of gastroduodenal ulceration after yttrium-90 radioembolization.

INTRODUCTION: A root cause analysis was performed on the occurrence of gastroduodenal ulceration after hepatic radioembolization (RE). We aimed to identify the risk factors in the treated population and to determine the specific mechanism of nontarget RE in individual cases. METHODS: The records of 247 consecutive patients treated with yttrium-90 RE for primary (n = 90) or metastatic (n = 157) liver cancer using either resin (n = 181) or glass (n = 66) microspheres were reviewed. All patients who developed a biopsy-proven microsphere-induced gastroduodenal ulcer were identified. Univariate and multivariate analyses were performed on baseline parameters and procedural data to determine possible risk factors in the total population. Individual cases were analyzed to ascertain the specific cause, including identification of the culprit vessel(s) leading to extrahepatic deposition of the microspheres. RESULTS: Eight patients (3.2 %) developed a gastroduodenal ulcer. Stasis during injection was the strongest independent risk factor (p = 0.004), followed by distal origin of the gastroduodenal artery (p = 0.004), young age (p = 0.040), and proximal injection of the microspheres (p = 0.043). Prolonged administrations, pain during administration, whole liver treatment, and use of resin microspheres also showed interrelated trends in multivariate analysis. Retrospective review of intraprocedural and postprocedural imaging showed a probable or possible culprit vessel, each a tiny complex collateral vessel, in seven patients. CONCLUSION: Proximal administrations and those resulting in stasis of flow presented increased risk for gastroduodenal ulceration. Patients who had undergone bevacizumab therapy were at high risk for developing stasis.