68Ga-FAPI PET/CT Interobserver Agreement on Tumor Assessment: An International Multicenter Prospective Study.

68Ga-fibroblast activation protein inhibitors (FAPIs) are promising radiotracers for cancer imaging, with emerging data in the recent years. Nonetheless, the interobserver agreement on 68Ga-FAPI PET/CT study interpretations in cancer patients remains poorly understood. Methods: 68Ga-FAPI PET/CT was performed on 50 patients with various tumor entities (sarcoma [n = 10], colorectal cancer [n = 10], pancreatic adenocarcinoma [n = 10], genitourinary cancer [n = 10], and other types of cancer [n = 10]). Fifteen masked observers reviewed and interpreted the images using a standardized approach for local, local nodal, and metastatic involvement. Observers were grouped by experience as having a low (<30 prior 68Ga-FAPI PET/CT studies; n = 5), intermediate (30-300 studies; n = 5), or high level of experience (>300 studies; n = 5). Two independent readers with a high level of experience and unmasked to clinical information, histopathology, tumor markers, and follow-up imaging (CT/MRI or PET/CT) served as the standard of reference (SOR). Observer groups were compared by overall agreement (percentage of patients matching SOR) and Fleiss κ with mean and corresponding 95% CI. We defined acceptable agreement as a κ value of at least 0.6 (substantial or higher) and acceptable accuracy as at least 80%. Results: Highly experienced observers agreed substantially on all categories (primary tumor: κ = 0.71; 95% CI, 0.71-0.71; local nodal involvement: κ = 0.62; 95% CI, 0.61-0.62; distant metastasis: κ = 0.75; 95% CI, 0.75-0.75), whereas observers with intermediate experience showed substantial agreement on primary tumor (κ = 0.73; 95% CI, 0.73-0.73) and distant metastasis (κ = 0.65; 95% CI, 0.65-0.65) but moderate agreement on local nodal stages (κ = 0.55; 95% CI, 0.55-0.55). Observers with low experience had moderate agreement on all categories (primary tumor: κ = 0.57; 95% CI, 0.57-0.58; local nodal involvement: κ = 0.51; 95% CI, 0.51-0.52; distant metastasis: κ = 0.54; 95% CI, 0.53-0.54). Compared with SOR, the accuracy for readers with high, intermediate, and low experience was 85%, 83%, and 78%, respectively. In summary, only highly experienced readers showed substantial agreement and a diagnostic accuracy of at least 80% in all categories. Conclusion: The interpretation of 68Ga-FAPI PET/CT for cancer imaging had substantial reproducibility and accuracy among highly experienced observers only, especially for local nodal and metastatic assessments. Therefore, for accurate interpretation of different tumor entities and pitfalls, we recommend training or experience with at least 300 representative scans for future clinical readers.

Frequency and malignancy rate of incidental focal salivary gland lesions identified by 18F-fluorodeoxyglucose-positron emission tomography.

PURPOSE: We aimed to evaluate the frequency and malignancy rate of incidental salivary gland lesions (ISGLs) in patients undergoing 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT). METHODS: Using a predefined algorithm, all descriptions of FDG-PET/CT scans performed in the North Denmark Region at the Department of Nuclear Medicine, Aalborg University Hospital from 1.12 2009 to 31.12 2019 were electronically searched for focal uptake in one or more salivary glands. RESULTS: In total, 28,362 FDG-PET/CT scans were performed in the study period. ISGLs were found in 197 (0.7%). A total of 193 (98%) had parotid gland ISGL, and four (2%) had submandibular ISGL. No sublingual lesions were found. Ultimately, 117 patients (60%) were referred to the Department of Otorhinolaryngology-Head and Neck Surgery for evaluation. Fine needle aspiration biopsy was performed in 97 patients, and the most frequent cytopathology was Warthin's tumour (n = 62). Two patients had verified malignancy: one with histopathologically proven acinic cell carcinoma and one with cytopathologically proven metastasis from an oral squamous cell carcinoma. CONCLUSIONS: Incidental salivary gland findings on FDG-PET/CT are rare, and the risk of malignancy is low. Patients with ISGL may be evaluated secondary to the primary disease, but special attention should be given to patients with prior or known head-and-neck malignancies and patients with symptoms from the salivary glands, including swelling.

Prevalence and significance of incidental findings on 68 Ga-DOTA-conjugated somatostatin receptor-targeting peptide PET/CT: a systematic review of the literature.

AIM: We aimed to evaluate the prevalence of incidental 68 Ga-DOTA-conjugated somatostatin receptor-targeting peptide PET/CT (SSTR PET/CT) findings, their clinical significance in the need for follow-up, and their risk of malignancy. MATERIALS AND METHODS: Studies reporting incidental SSTR PET/CT findings were systematically searched in PubMed, Cochrane, Embase and Web of Science literature published prior to 1st of May 2020. Studies were filtered by two independent readers for eligibility based on title and abstract, and subsequently on full text. The main exclusion criteria were: 1) pathological findings that matched scan indication, 2) known organ specific disease and/or incidental findings confirmed on other scan modality prior to SSTR PET/CT, 3) lack of diagnosis and/or follow up, and 4) results published in proceedings or conference abstracts. RESULTS: Twenty-one studies, comprising a total of 2906 subjects, were eligible for the analysis. Studies included were retrospective cohort studies on incidental SSTR PET/CT findings in a specific organ (n = 2888, 7/21) or case reports (n = 18, 14/21). A total of 133 subjects had incidental SSTR PET/CT findings. Incidental findings were predominantly seen in the thyroid gland (n = 65), spine (n = 30), brain (n = 26) and breast (n = 6). Seventeen of 133 (13%) incidental findings were malignant on final diagnosis. Incidental breast findings were associated with the highest risk of malignancy (67%). In the thyroid, incidental SSTR uptake was caused by malignancy in 8%, all presenting as focal uptake. The lowest risk was seen in the spine with a malignancy rate of 3% in patients with incidental SSTR uptake and benign cases were interpreted as vertebral hemangiomas on CT. Incidental SSTR PET/CT findings in other locations were of malignant etiology in two out of six cases (33%) and should be evaluated individually. CONCLUSION: The most incidental SSTR PET/CT findings were found in the thyroid gland, spine, and brain. The risk of malignancy was greatest in incidental SSTR PET/CT findings in the breast, cranially, and thyroid gland. The results of the present study can prove useful in the interpretation of atypical findings on SSTR PET/CT and in the counseling of clinicians.

Lesion detection in 18F-sodium fluoride bone imaging: a comparison of attenuation-corrected versus nonattenuation-corrected PET reconstructions from modern PET-CT systems.

OBJECTIVES: An earlier study demonstrated comparable lesion detection between attenuation-corrected (AC) and nonattenuation-corrected (NAC) 18F-sodium fluoride (NaF) PET images, which is relevant for computed tomography (CT) radiation dose-saving. However, this finding may not be applicable to newer systems. The aim was to compare lesion detection between AC and NAC NaF PET images on modern PET-CT systems. METHODS: One expert and one nonexpert observer retrospectively surveyed NaF PET data in 25 breast cancer patients. At both lesion and patient level, each observer classified bone abnormalities as malignant, equivocal or benign, from NAC and AC PET images in the absence of CT. Expert interpretation of NaF PET-CT with the review of all diagnostic imaging/pathology reports for at least the subsequent 12 months provided reference standard metastases status at the patient level. Two-tailed Wilcoxon signed-rank tests measured statistically significant differences in total lesion detection between AC and NAC PET. Quadratic-weighted kappa score measured agreement in patient metastases status between observers. RESULTS: On a lesion-basis, AC PET images showed significantly more lesions than NAC for both the expert (122 versus 96; P = 0.002) and nonexpert (146 versus 132; P = 0.036) observers, with a large number of patients demonstrating disparity between AC and NAC images. For metastases status at the patient level without CT, NAC PET showed slightly better diagnostic accuracy than AC due to fewer false-positive results, as fewer lesions were identified. CONCLUSION: AC PET data provided superior lesion detection to NAC in NaF bone examinations and are thus required for clinical interpretation.

Combination of Forced Diuresis with Additional Late Imaging in 68Ga-PSMA-11 PET/CT: Effects on Lesion Visibility and Radiotracer Uptake.

Renal excretion of some prostate-specific membrane antigen (PSMA) ligands and consequently increased bladder activity can obscure locally relapsing prostate cancer lesions in PSMA PET/CT. Furthermore, additional late imaging in PSMA PET/CT provides a useful method to clarify uncertain findings. The aim of this retrospective study was to investigate a modified imaging protocol combining late additional imaging with hydration and forced diuresis in individuals undergoing additional late scanning for uncertain lesions or low prostate-specific antigen. Methods: We compared an older protocol with a newer one. In the old protocol, patients undergoing 68Ga-PSMA-11 PET/CT were examined at 90 min after injection, with 1 L of oral hydration beginning at 30 min after injection and 20 mg of furosemide given intravenously at 1 h after injection, followed by additional late imaging at 2.5 h after injection without further preparation. In the new protocol, a second group received the same procedure as before, with an additional 0.5 L of oral hydration and 10 mg of furosemide intravenously 30 min before the late imaging. We examined 132 patients (76 with the old protocol and 56 with the new one) with respect to urinary bladder activity (SUVmean), prostate cancer lesion uptake (SUVmax), and lesion contrast (ratio of tumor SUVmax to bladder SUVmean for local relapses and ratio of tumor SUVmax to gluteal-muscle SUVmean for nonlocal prostate cancer lesions). Results: Bladder activity was significantly greater for the old protocol in the late scans than for the new protocol (ratio of bladder activity at 2.5 h to bladder activity at 1.5 h, 2.33 ± 1.17 vs. 1.37 ± 0.50, P < 0.0001). Increased tumor SUVmax and contrast were seen at 2.5 h compared with 1.5 h (P < 0.0001 for old protocol; P = 0.02 for new protocol). Increased bladder activity for the old protocol resulted in decreased lesion-to-bladder contrast, which was not the case for the new protocol. Tumor-to-background ratios increased at late imaging for both protocols, but the increase was significantly lower for the new protocol. For the old protocol, comparing the 1.5-h to the 2.5-h acquisitions, 4 lesions in 4 patients (4/76 = 5.2% of the cohort) were visible at the postdiuresis 1.5-h acquisition but not at 2.5 h, having been obscured as a result of the higher bladder activity. In the new protocol, 2 of 56 (3.6%) patients had lesions visible only at late imaging, and 2 patients had lesions that could be better discriminated at late imaging. Conclusion: Although the combination of diuretics and hydration can be a useful method to increase the visualization and detectability of locally recurrent prostate cancer in standard 68Ga-PSMA-11 PET/CT, their effects do not sufficiently continue into additional late imaging. Additional diuresis and hydration are recommended to improve the visibility, detection, and diagnostic certainty of local recurrences.

Prospective comparative study of 18F-sodium fluoride PET/CT and planar bone scintigraphy for treatment response assessment of bone metastases in patients with prostate cancer.

AIM: To compare 18F-sodium fluoride positron emission tomography/computed tomography (NaF PET/CT) and 99mTc-labelled diphosphonate bone scan (BS) for the monitoring of bone metastases in patients with prostate cancer undergoing anti-cancer treatment. MATERIAL AND METHODS: Data from 64 patients with prostate cancer were included. The patients received androgen-deprivation therapy (ADT), next-generation hormonal therapy (NGH) or chemotherapy. The patients had a baseline scan and 1-3 subsequent scans during six months of treatment. Images were evaluated by experienced nuclear medicine physicians and classified for progressive disease (PD) or non-PD according to the Prostate Cancer Working Group 2 (PCWG-2) criteria. The patients were also classified as having PD/non-PD according to the clinical and prostate-specific antigen (PSA) responses. RESULTS: There was no difference between NaF PET/CT and BS in the detection of PD and non-PD during treatment (McNemar's test, p = .18). The agreement between BS and NaF PET/CT for PD/non-PD was moderate (Cohen's kappa 0.53, 95% confidence interval 0.26-0.79). Crude agreement between BS and NaF PET/CT for the assessment of PD/non-PD was 86% (89% for ADT, n = 28; 88% for NGH, n = 16, and 80% for chemotherapy, n = 20). In most discordant cases, BS found PD when NaF PET/CT did not, or BS detected PD on an earlier scan than NaF PET/CT. Biochemical progression (27%) occurred more frequently than progression on functional imaging (BS, 22% and NaF PET/CT, 14%). Clinical progression was rare (11%), and almost exclusively seen in patients receiving chemotherapy. CONCLUSION: There was no difference between NaF PET/CT and BS in the detection of PD and non-PD; however, BS seemingly detects PD by the PCWG-2 criteria earlier than NaF-PET, which might be explained by the fact that NaF-PET is more sensitive at the baseline scan.

Comparison of two methods based on photoplethysmography for the diagnosis of peripheral arterial disease.

AIM: To examine the interchangeability of two methods for distal pressure measurement based on photoplethysmography using a truncated or full display of the arterial inflow curve, respectively. METHODS: Toe and ankle pressures were obtained from 69 patients suspected of peripheral arterial disease (PAD). Observer reproducibility of the curve readings was examined by blinded reassessment of the pressure curves in a randomly selected subgroup (60 limbs). RESULTS: There were no significant differences in mean pressures between the two methods (p for all > .455). The limits of agreement for the differences were -15.0-15.4 mmHg for right toe pressures, -16.3-16.2 mmHg for left toe pressures, -14.2-15.7 mmHg for right ankle pressures, and -18.3-17.7 mmHg for left ankle pressures. Correlation analysis revealed intraclass correlation coefficients ≥0.960 for all measuring sites. Cohen's Kappa showed excellent agreement in diagnostic classification, with κ = 0.930 for the diagnosis of PAD and perfect agreement in the diagnosis of critical limb ischemia (κ = 1.000). The analysis of intra-observer variation for curve reading showed limits of agreement of -3.9-4.0 for toe pressures and -7.6-7.7 for ankle pressures for the method involving truncated display and -3.1-3.2 for toe pressures and -6.3-8.6 for ankle pressures for the method involving full display of the signal. CONCLUSION: The present study shows minimal differences in diagnostic classification, as well as in ankle and toe pressures, between the full display and the truncated display of the photoplethysmographic pulse signal. Furthermore, the inter-observer variation was low for both of the photoplethysmographic methods investigated.

Prospective multicenter study of bone scintigraphy in consecutive patients with newly diagnosed prostate cancer.

BACKGROUND: International guidelines uniformly suggest no routine staging of bone metastasis in patients with bone scintigraphy (BS) in low-risk prostate cancer (PCa). These recommendations are based on retrospective investigations only. In addition, BS has most often been reported as a definitive investigation with no room for equivocal cases. OBJECTIVE: The objective of this study was to determine the diagnostic value of BS in a large cohort of consecutive patients with newly diagnosed PCa. DESIGN, SETTING, AND PARTICIPANTS: Over a period of 1.5 years in 2008 to 2009, consecutive patients with newly diagnosed PCa were enrolled in a noninterventional, multicenter, observational study. All patients had a whole-body, planar BS. Clinical history and clinical, pathological, and biochemical data were obtained from electronic patient files and questionnaires. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Bone scintigraphy was classified into 4 categories as nonmalignant, equivocal, likely malignant, or multiple metastasis. The primary end point was final imaging, which was a composite end point of BS and additional CT and MRI investigations. RESULTS AND LIMITATIONS: A total of 635 eligible patients were recruited. Their median prostate-specific antigen (PSA) was 15 ng/mL, median Gleason was 7, and 80% of patients had local disease (T1 or T2). The proportion of nonmalignant BS was 61%, equivocal scans 26%, and likely or definitive metastasis 13%. A total of 154 patients had additional CT or MRI investigations. The final imaging diagnosis showed a prevalence of bone metastases in 87 (13.7%) of 635 patients. No bone metastases were observed in (1) patients with PSA of less than 10 ng/mL, independently of the clinical Tstage and Gleason score (n = 212) and (2) PSA of less than 20 ng/mL if Tstage is less than T3 and Gleason score is less than 8 (n = 97). Approximately 50% of the patients enrolled in this study met these criteria. CONCLUSION: This is the first prospective trial to demonstrate that BS can be avoided in patients with low-risk PCa.

Chronic intestinal ischemia and splanchnic blood-flow: reference values and correlation with body-composition.

AIM: To determine the splanchnic blood flow and oxygen uptake in healthy-subjects and patients and to relate the findings to body-composition. METHODS: The total splanchnic blood flow (SBF) and oxygen uptake (SO2U) were measured in 20 healthy volunteers (10 women) and 29 patients with suspected chronic intestinal ischemia (15 women), age 40-85 years, prior to and after a standard meal. The method is based on the Fick principle using the continuous infusion of an indicator (99mTechnetium-labelled mebrofenin) and catheterization of an artery and the hepatic vein. An angiography of the intestinal arteries was performed during the same investigation. A whole-body dual-energy x-ray absorptiometry scan was performed in healthy volunteers to determine body composition. RESULTS: Angiography revealed no atherosclerotic lesions in the intestinal arteries. The mean baseline SBF was 1087 mL/min (731-1390), and this value increased significantly to 1787 mL/min after the meal in healthy volunteers (P < 0.001). The baseline SBF in patients was 1080 mL/min, which increased to 1718 mL/min postprandially (P < 0.001). The baseline SBF was independent of age, sex, lean body mass and percentage of body fat. The mean meal-induced increase in SBF was equal to 282 mL/min + 5.4 mL/min × bodyweight, (P = 0.025). The SO2U in healthy volunteers and patients was 50.7 mL/min and 48.0 mL/min, respectively, and these values increased to 77.5 mL/min and 75 mL/min postprandially, respectively. Both baseline and postprandial SO2U were directly related to lean body mass. Age and sex exerted no impact on SO2U. CONCLUSION: A direct correlation between body weight and the postprandial increase in SBF was observed. The effect of body weight should be considered in the diagnosis of chronic intestinal ischemia.

Validation of 99mTechnetium-labeled mebrofenin hepatic extraction method to quantify meal-induced splanchnic blood flow responses using a porcine model.

The aim of this study was to evaluate the measurement of the total splanchnic blood flow (SBF) using a clinical diagnostic method based on Fick's principle and hepatic extraction of 99mTc-mebrofenin (99mTc-MBF) compared with a paraaminohippuric acid (pAH) dilution method in a porcine model. Another aim was to investigate whether enterohepatic cycling of 99mTc-MBF affected the SBF measurement. Five indwelling catheters were placed in each pig (n = 15) in the portal, mesenteric, and hepatic veins, as well as in the aorta and the vena cava. The SBF was measured using both methods. The portal blood flow; the intestinal and hepatic oxygen uptake; the net fluxes of oxygen, lactate, and glucose; and the extraction fraction (EF) of 99mTc-MBF were measured before and for 70 min after feeding. The mean baseline SBF was 2,961 ml/min vs. 2,762 ml/min measured by pAH and 99mTc-MBF, respectively, and increased significantly to 3,977 ml/min and 3,981 ml/min postprandially. The hepatic EF of 99mTc-MBF decreased from 40% at the start of the investigation to 16% 70 min after feeding. The arterial-portal difference in 99mTc-MBF concentration was 0.21% (P = 0.48), indicating no intestinal extraction or metabolism. The clinical method for measuring the SBF based on hepatic 99mTc-MBF extraction is robust compared with the indicator dilution method, despite the decrease seen in hepatic extraction of 99mTc-MBF. Because there was no difference in the content of 99mTc-MBF between the arterial and portal vein plasma, the SBF can be calculated from an arterial and a hepatic vein sample.