Dietary Caffeine and Brain Dopaminergic Function in Parkinson Disease.

OBJECTIVE: This study was undertaken to investigate the effects of dietary caffeine intake on striatal dopamine function and clinical symptoms in Parkinson disease in a cross-sectional and longitudinal setting. METHODS: One hundred sixty-three early Parkinson disease patients and 40 healthy controls were investigated with [123I]FP-CIT single photon emission computed tomography, and striatal dopamine transporter binding was evaluated in association with the level of daily coffee consumption and clinical measures. After a median interval of 6.1 years, 44 patients with various caffeine consumption levels underwent clinical and imaging reexamination including blood caffeine metabolite profiling. RESULTS: Unmedicated early Parkinson disease patients with high coffee consumption had 8.3 to 15.4% lower dopamine transporter binding in all studied striatal regions than low consumers, after accounting for age, sex, and motor symptom severity. Higher caffeine consumption was further associated with a progressive decline in striatal binding over time. No significant effects of caffeine on motor function were observed. Blood analyses demonstrated a positive correlation between caffeine metabolites after recent caffeine intake and dopamine transporter binding in the ipsilateral putamen. INTERPRETATION: Chronic caffeine intake prompts compensatory and cumulative dopamine transporter downregulation, consistent with caffeine's reported risk reduction in Parkinson disease. However, this decline does not manifest in symptom changes. Transiently increased dopamine transporter binding after recent caffeine intake has implications for dopaminergic imaging guidelines. ANN NEUROL 2024;96:262-275.

Serotonergic and dopaminergic control of impulsivity in gambling disorder.

Gambling disorder (GD) is major public health issue. The disorder is often characterized by elevated impulsivity with evidence from analogous substance use disorders underlining prominent roles of brain monoamines in addiction susceptibility and outcome. Critically, GD allows the study of addiction mechanisms without the confounder of the effects of chronic substances. Here, we assessed the roles of striatal dopamine transporter binding and extrastriatal serotonin transporter binding in GD as a function of impulsivity using [123 I]FP-CIT SPECT imaging in 20 older adults with GD (DSM-5 criteria; mean age 64 years) and 40 non-GD age- and sex-matched controls. We focused on GD in older individuals because there are prominent age-related changes in neurotransmitter function and because there are no reported neuroimaging studies of GD in older adults. Volume-of-interest-based and voxelwise analyses were performed. GD patients scored clearly higher on impulsivity and had higher tracer binding in the ventromedial prefrontal cortex than controls (p < 0.001), likely reflecting serotonin transporter activity. The binding in the medial prefrontal cortex positively correlated with impulsivity over the whole sample (r = 0.62, p < 0.001) as well as separately in GD patients (r = 0.46, p = 0.04) and controls (r = 0.52, p < 0.001). Striatal tracer binding, reflecting dopamine transporter activity was also positively correlated with impulsivity but showed no group differences. These findings highlight the role of prefrontal serotonergic function in GD and impulsivity. They identify cerebral coordinates of a potential target for neuromodulation for both GD and high impulsivity, a core phenotypic dimensional cognitive marker in addictions.

Association between bone mineral metabolism and vascular calcification in end-stage renal disease.

BACKGROUND: Development of vascular calcification is accelerated in patients with end-stage renal disease. In addition to traditional risk factors of cardiovascular disease (CVD) abnormal bone and mineral metabolism together with many other factors contribute to the excess cardiovascular burden in patients on dialysis. Aortic calcification score and coronary calcification score are predictive of CVD and mortality. The aim of this study was to evaluate the possible relationship between arterial calcification and bone metabolism. METHODS: Thirty two patients on dialysis were included. All patients underwent a bone biopsy to assess bone histomorphometry and a 18F-NaF PET scan. Fluoride activity was measured in the lumbar spine (L1 - L4) and at the anterior iliac crest. Arterial calcification scores were assessed by computerized tomography for quantification of coronary artery calcification score and lateral lumbar radiography for aortic calcification score. RESULTS: This study group showed high prevalence of arterial calcification and 59% had verified CVD. Both CAC and AAC were significantly higher in patients with verified CVD. Only 22% had low turnover bone disease. There was a weak association between fluoride activity, which reflects bone turnover, measured in the lumbar spine, and CAC and between PTH and CAC. There was also a weak association between erosion surfaces and AAC. No significant association was found between calcification score and any other parameter measured. CONCLUSIONS: The results in this study highlight the complexity, when evaluating the link between bone remodeling and vascular calcification in patients with multiple comorbidities and extensive atherosclerosis. Several studies suggest an impact of bone turnover on development of arterial calcification and there is some evidence of reduced progression of vascular calcification with improvement in bone status. The present study indicates an association between vascular calcification and bone turnover, even though many parameters of bone turnover failed to show significance. In the presence of multiple other factors contributing to the development of calcification, the impact of bone remodeling might be diminished. TRIAL REGISTRATION: The study is registered in ClinicalTrials.gov protocol registration and result system, ID is NCT02967042 . Date of registration is 17/11/2016.

Bioactive glass granules versus standard autologous and allogeneic bone grafts: a randomized trial of 49 adult bone tumor patients with a 10-year follow-up.

BACKGROUND AND PURPOSE: As a synthetic bone void filler, bioactive glasses (BGs) may enhance angiogenesis and osteogenesis. In this randomized trial, we compared the clinical efficacy of BG granules and standard bone grafts in patients undergoing surgery for benign bone tumors. PATIENTS AND METHODS: 49 recruited patients were randomized to receive BG granules or undergo conventional bone grafting to fill defects following tumor removal. As the standard of care, small-sized defects were filled with autologous graft, and large-sized defects were filled with allogeneic graft. The primary endpoint was treatment success at 1 year, defined by no reoperation, no tumor recurrence, and no device-related adverse events. Secondary endpoints included patient-reported outcomes (Rand-36 and pain scores) and quantitative assessment of blood flow and metabolic activity by means of 18F-fluoride PET/CT imaging. As an off-trial group, 15 children and adolescents (age < 18 years) underwent tumor removal and BG-filling, without randomization. RESULTS: At 1-year, 21 of 25 BG-treated patients (risk estimate 0.84, 95% confidence interval [CI] 0.70-0.98) and 20 of 24 patients in the standard of care group (0.83, CI 0.68-0.98) met the criteria for treatment success. The groups had similar Rand-36 scores. In patients with small defects, BG filling was associated with shorter operative time and less postoperative pain at 1 month. In patients with large defects, blood flow was similar, but BG-filled defects showed higher metabolic activity than allograft-filled defects at 1-year. The survey of the postoperative period ≥10 years revealed no BG-related adverse events. INTERPRETATION: BG granules had similar overall rates of treatment success compared with autografts and allografts, but large-scale trials are needed for the confirmation of clinical equivalence. The extended metabolic activity confirms the expected cellular responses of osseointegrated BG granules.

Prospective comparison of 18F-PSMA-1007 PET/CT, whole-body MRI and CT in primary nodal staging of unfavourable intermediate- and high-risk prostate cancer.

PURPOSE: To prospectively compare 18F-prostate-specific membrane antigen (PSMA)-1007 positron emission tomography (PET)/CT, whole-body magnetic resonance imaging (WBMRI) including diffusion-weighted imaging (DWI) and standard computed tomography (CT), in primary nodal staging of prostate cancer (PCa). METHODS: Men with newly diagnosed unfavourable intermediate- or high-risk PCa prospectively underwent 18F-PSMA-1007 PET/CT, WBMRI with DWI and contrast-enhanced CT within a median of 8 days. Six readers (two for each modality) independently reported pelvic lymph nodes as malignant, equivocal or benign while blinded to the other imaging modalities. Sensitivity, specificity and accuracy were reported according to optimistic (equivocal lesions interpreted as benign) and pessimistic (equivocal lesions interpreted as malignant) analyses. The reference standard diagnosis was based on multidisciplinary consensus meetings where available histopathology, clinical and follow-up data were used. RESULTS: Seventy-nine patients completed all the imaging modalities, except for one case of interrupted WBMRI. Thirty-one (39%) patients had pelvic lymph node metastases, which were detected in 27/31 (87%), 14/31 (45%) and 8/31 (26%) patients by 18F-PSMA-1007 PET/CT, WBMRI with DWI and CT, respectively (optimistic analysis). In 8/31 (26%) patients, only 18F-PSMA-1007 PET/CT detected malignant lymph nodes, while the other two imaging modalities were reported as negative. At the patient level, sensitivity and specificity values for 18F-PSMA-1007 PET/CT, WBMRI with DWI and CT in optimistic analysis were 0.87 (95%CI 0.71-0.95) and 0.98 (95%CI 0.89-1.00), 0.37 (95%CI 0.22-0.55) and 0.98 (95%CI 0.89-1.00) and 0.26 (95%CI 0.14-0.43) and 1.00 (95%CI 0.93-1.00), respectively. CONCLUSION: 18F-PSMA-1007 PET/CT showed significantly greater sensitivity in nodal staging of primary PCa than did WBMRI with DWI or CT, while maintaining high specificity. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT03537391.

Bone Histomorphometry and 18F-Sodium Fluoride Positron Emission Tomography Imaging: Comparison Between only Bone Turnover-based and Unified TMV-based Classification of Renal Osteodystrophy.

Bone biopsy is the gold standard for characterization of renal osteodystrophy (ROD). However, the classification of the subtypes of ROD based on histomorphometric parameters is not unambiguous and the range of normal values for turnover differ in different publications. 18F-Sodium Fluoride positron emission tomography (18F-NaF PET) is a dynamic imaging technique that measures turnover. 18F-NaF PET has previously been shown to correlate with histomorphometric parameters. In this cross-sectional study, 26 patients on dialysis underwent a 18F-NaF PET and a bone biopsy. Bone turnover-based classification was assessed using Malluche's historical reference values for normal bone turnover. In unified turnover-mineralization-volume (TMV)-based classification, the whole histopathological picture was evaluated and the range for normal turnover was set accordingly. Fluoride activity was measured in the lumbar spine (L1-L4) and at the anterior iliac crest. On the basis of turnover-based classification of ROD, 12% had high turnover and 61% had low turnover bone disease. On the basis of unified TMV-based classification of ROD, 42% had high turnover/hyperparathyroid bone disease and 23% had low turnover/adynamic bone disease. When using unified TMV-based classification of ROD, 18F-NaF PET had an AUC of 0.86 to discriminate hyperparathyroid bone disease from other types of ROD and an AUC of 0.87, for discriminating adynamic bone disease. There was a disproportion between turnover-based classification and unified TMV-based classification. More research is needed to establish normal range of bone turnover in patients with CKD and to establish the role of PET imaging in ROD.

18F-FDG positron emission tomography/computed tomography of cardiac implantable electronic device infections.

BACKGROUND: The diagnosis of cardiac implantable electronic device (CIED) infection is challenging because of its variable presentations. We studied the value of 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in the detection of CIED infection. METHODS AND RESULTS: Thirty patients with suspected CIED infection underwent 18F-FDG-PET/CT. The control group was ten patients with asymptomatic CIED who underwent cancer-related 18F-FDG-PET/CT. 18F-FDG-PET/CT was evaluated visually, semiquantitatively as maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR). Final diagnosis of CIED infection was based on clinical and bacteriological data. 18F-FDG-PET/CT was visually positive in all 9 patients with recent (≤ 8 weeks) implantation of CIED, but only 4 had confirmed CIED infection. 18F-FDG-PET/CT was true positive in 9 out of 21 cases with remote implantation of CIED and false positive in 3 (14.3%) cases. 18F-FDG-PET/CT was also false positive in 3 (30%) cases of control group. The SUVmax of the pocket area was significantly higher in patients with CIED infection than in the control group (4.8 ± 2.4 vs 2.0 ± .8, P < .001). By using the cut-off value of TBR ≥ 1.8, sensitivity of 18F-FDG-PET/CT for the diagnosis of CIED infection in patients with remote implantation was 90% and specificity 73%, PPV 75%, and NPV 89%. CONCLUSIONS: 18F-FDG-PET/CT is a sensitive but nonspecific method in the diagnosis of CIED infection.

18F-FDG-PET/CT based total metabolic tumor volume change during neoadjuvant chemotherapy predicts outcome in advanced epithelial ovarian cancer.

OBJECTIVE: To evaluate the predictive potential of total metabolic tumor volume (MTV) reduction during neoadjuvant chemotherapy (NACT) with 18F-FDG-PET/CT in an advanced FIGO stage III/IV epithelial ovarian cancer (EOC) patient cohort. METHODS: Twenty-nine primarily inoperable EOC patients underwent 18F-FDG-PET/CT before and after NACT. The pre- and post-NACT total MTV, in addition to the percentage MTV reduction during NACT, were compared with primary therapy outcome and progression-free survival (PFS). ROC-analysis determined an optimal threshold for MTV reduction identifying patients with progressive or stable disease (PD/SD) at the end of primary therapy. A multivariate analysis with residual tumor (0/>0), FIGO stage (III/IV) and MTV reduction compared to PFS was performed. The association between MTV reduction and overall survival (OS) was evaluated. RESULTS: The median pre- and post-NACT total MTV were 352 cm3 (range 150 to 1322 cm3) and 51 cm3 (range 0 to 417 cm3), respectively. The median MTV reduction during NACT was 89% (range 24% to 100%). Post-NACT MTV and MTV reduction associated with primary therapy outcome (MTV post-NACT p = 0.007, MTV reduction p = 0.001) and PFS (MTV post-NACT p = 0.005, MTV reduction p = 0.005). MTV reduction <85% identified the PD/SD patients (sensitivity 70%, specificity 78%, AUC 0.79). In a multivariate analysis, MTV reduction (p = 0.002) and FIGO stage (p = 0.003) were statistically significant variables associated with PFS. MTV reduction during NACT corresponded to OS (p = 0.05). CONCLUSION: 18F-FDG-PET/CT is helpful in NACT response evaluation. Patients with total MTV reduction <85% during NACT might be candidates for second-line chemotherapy and clinical trials, instead of interval debulking surgery.

18F-FDG positron emission tomography/computed tomography in infective endocarditis.

BACKGROUND: The diagnosis of infective endocarditis (IE), especially the diagnosis of prosthetic valve endocarditis (PVE) is challenging since echocardiographic findings are often scarce in the early phase of the disease. We studied the use of 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in IE. METHODS: Sixteen patients with suspected PVE and 7 patients with NVE underwent visual evaluation of 18F-FDG-PET/CT. 18F-FDG uptake was measured also semiquantitatively as maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR). The modified Duke criteria were used as a reference. RESULTS: There was strong, focal 18F-FDG uptake in the area of the affected valve in all 6 cases of definite PVE, in 3 of 5 possible PVE cases, and in 2 of 5 rejected cases. In all patients with definite PVE, SUVmax of the affected valve was higher than 4 and TBR higher than 1.8. In contrast to PVE, only 1 of 7 patients with NVE had uptake of 18F-FDG by PET/CT in the valve area. Embolic infectious foci were detected in 58% of the patients with definite IE. CONCLUSIONS: 18F-FDG-PET/CT appears to be a sensitive method for the detection of paravalvular infection associated with PVE. Instead, the sensitivity of PET/CT is limited in NVE.

Visual versus automated analysis of [I-123]FP-CIT SPECT scans in parkinsonism.

The clinical evaluation of dopamine transporter (DAT) SPECT scans typically relies on visual analysis in combination with an automated semi-quantitative method. The interpretation of the results may be difficult in cases that show disagreement between the two methods on the borderline of abnormality. The frequency and clinical characteristics of such cases are unclear. Automated semi-quantitative analyses and independent visual analyses by two experienced nuclear medicine physicians and four inexperienced raters were performed for 120 patients with clinically uncertain parkinsonism scanned with brain [I-123]FP-CIT SPECT. Agreement was evaluated with kappa statistics. The clinical characteristics of patients who had discrepant findings between the two analysis methods were investigated. The expert raters outperformed nonexperts in terms of agreement between visual and automated analyses (κ = 0.66, 0.72 vs. 0.23-0.54) and between raters (κ = 0.81 vs. 0.44-0.63). Twelve patients showed discrepant findings between the visual and automated analyses. These patients were older compared to other patients (p = 0.023), had 17.6 % lower mean striatal tracer binding compared to normal scans (p = 0.003) and 62.7 % higher compared to abnormal scans (p < 0.001). After a minimum of 4.5 years of clinical follow-up, none of these patients developed neurodegenerative parkinsonism. Clinical DAT SPECT scans show discrepancies between visual and automated analyses in 10 % of cases. The patients with discrepant findings are older, show normal to slightly abnormal tracer binding, and importantly, do not develop neurodegenerative parkinsonism syndromes. Visual analyses by experienced raters are reliable, but the diagnostic accuracy in discrepant cases can be improved by an automated method.

18F-FDG-PET/CT can identify histopathological non-responders to platinum-based neoadjuvant chemotherapy in advanced epithelial ovarian cancer.

OBJECTIVE: The aim of this study was to examine the relationship between the reduction of maximum standardized uptake values (SUVmax) in 18F-FDG-PET/CT to histopathological changes obtained with neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer (EOC). We wanted to evaluate whether 18F-FDG-PET/CT is useful for identifying patients who will not respond to NACT and would therefore benefit from second-line chemotherapy instead of interval debulking surgery (IDS). METHODS: Twenty-six primarily inoperable EOC patients treated with NACT were enrolled in this study. 18F-FDG-PET/CT imaging was performed before diagnostic laparoscopy and after three to four NACT cycles. The relationship between the decrease in omental SUVmax from before to after NACT with omental histopathological response was examined in samples taken from the corresponding anatomical sites during IDS. Patients were divided into three groups according to chemotherapy-induced histopathological changes. Serum CA125 and HE4 halftimes during NACT as well as Ki-67 antigen expression in IDS samples were determined. RESULTS: The median omental SUVmax change during NACT was -64% (range-16% to -84%), and it was associated with histopathological response (p=0.004, OR 0.9, CI 0.84-0.97). A SUVmax decrease of less than 57% identified histopathological non-responders. Progression-free survival (PFS) differed between the poor, moderate and good histopathological response groups (0.9 year vs. 1.2 years vs. 1.4 years, respectively, p=0.05). The SUVmax change was not associated with PFS. CONCLUSION: 18F-FDG-PET/CT was able to identify patients who would not respond to NACT. To obtain a histopathological response in EOC, a substantial metabolic response in 18F-FDG-PET/CT is necessary.

Prospective evaluation of planar bone scintigraphy, SPECT, SPECT/CT, 18F-NaF PET/CT and whole body 1.5T MRI, including DWI, for the detection of bone metastases in high risk breast and prostate cancer patients: SKELETA clinical trial.

PURPOSE: Detection of bone metastases in breast and prostate cancer patients remains a major clinical challenge. The aim of the current trial was to compare the diagnostic accuracy of (99m)Tc-hydroxymethane diphosphonate ((99m)Tc-HDP) planar bone scintigraphy (BS), (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT and whole body 1.5 Tesla magnetic resonance imaging (MRI), including diffusion weighted imaging, (wbMRI+DWI) for the detection of bone metastases in high risk breast and prostate cancer patients. MATERIAL AND METHODS: Twenty-six breast and 27 prostate cancer patients at high risk of bone metastases underwent (99m)Tc-HDP BS, (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT and wbMRI+DWI. Five independent reviewers interpreted each individual modality without the knowledge of other imaging findings. The final metastatic status was based on the consensus reading, clinical and imaging follow-up (minimal and maximal follow-up time was 6, and 32 months, respectively). The bone findings were compared on patient-, region-, and lesion-level. RESULTS: (99m)Tc-HDP BS was false negative in four patients. In the region-based analysis, sensitivity values for (99m)Tc-HDP BS, (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT, and wbMRI+DWI were 62%, 74%, 85%, 93%, and 91%, respectively. The number of equivocal findings for (99m)Tc-HDP BS, (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT and wbMRI+DWI was 50, 44, 5, 6, and 4, respectively. CONCLUSION: wbMRI+DWI showed similar diagnostic accuracy to (18)F-NaF PET/CT and outperformed (99m)Tc-HDP SPECT/CT, and (99m)Tc-HDP BS.

Positron emission tomography detects greater blood flow and less blood flow heterogeneity in the exercising skeletal muscles of old compared with young men during fatiguing contractions.

The purpose of this study was to investigate blood flow and its heterogeneity within and among the knee muscles in five young (26 ± 6 years) and five old (77 ± 6 years) healthy men with similar levels of physical activity while they performed two types of submaximal fatiguing isometric contraction that required either force or position control. Positron emission tomography (PET) and [(15)O]-H2O were used to determine blood flow at 2 min (beginning) and 12 min (end) after the start of the tasks. Young and old men had similar maximal forces and endurance times for the fatiguing tasks. Although muscle volumes were lower in the older subjects, total muscle blood flow was similar in both groups (young men: 25.8 ± 12.6 ml min(-1); old men: 25.1 ± 15.4 ml min(-1); age main effect, P = 0.77) as blood flow per unit mass of muscle in the exercising knee extensors was greater in the older (12.5 ± 6.2 ml min(-1) (100 g)(-1)) than the younger (8.6 ± 3.6 ml min(-1) (100 g)(-1)) men (age main effect, P = 0.001). Further, blood flow heterogeneity in the exercising knee extensors was significantly lower in the older (56 ± 27%) than the younger (67 ± 34%) men. Together, these data show that although skeletal muscles are smaller in older subjects, based on the intact neural drive to the muscle and the greater, less heterogeneous blood flow per gram of muscle, old fit muscle achieves adequate exercise hyperaemia.

Differences in striatal dopamine transporter density between tremor dominant and non-tremor Parkinson's disease.

PURPOSE: Parkinson's disease (PD) can manifest with a tremor-dominant or a non-tremor (akinetic-rigid) phenotype. Although the tremor-dominant subtype may show a better prognosis, there is limited information on the phenotypic differences regarding the level of striatal dopamine transmission. The present study investigated striatal dopamine transporter (DAT) binding characteristics in a large sample of patients with and without tremor. METHODS: [(123)I]FP-CIT SPECT scans of 231 patients with a clinical diagnosis of PD and abnormal FP-CIT binding (157 with tremor, 74 without tremor) and 230 control patients with normal FP-CIT binding (148 with tremor, 82 without tremor) were analysed using an automated region-of-interest analysis of the scans (BRASS). Specific striatal binding ratios were compared between phenotypes and groups using age, sex, and symptom duration, predominant side of symptoms, dopaminergic medications and scanner as covariates. RESULTS: Patients with PD had 28.1 - 65.0 % lower binding in all striatal regions compared to controls (p < 0.001). The mean FP-CIT caudate nucleus uptake and the left caudate nucleus uptake were higher in PD patients with tremor than in PD patients without tremor (mean 9.0 % higher, left 10.5 % higher; p < 0.05), whereas there were no differences between tremor and non-tremor control patients. No significant effects of tremor on DAT binding were observed in the anterior or posterior putamen. CONCLUSION: The motor phenotype is associated with the extent of caudate dopamine terminal loss in PD, as dopamine function is relatively more preserved in tremor patients. Symptom type is related to caudate dopamine function only in association with Parkinsonian dopaminergic degeneration, not in intact dopamine systems in patients with non-PD tremor.

Prognostic value of tumour blood flow, [¹8F]EF5 and [¹8F]FDG PET/CT imaging in patients with head and neck cancer treated with radiochemotherapy.

PURPOSE: In order to improve the treatment of squamous cell carcinoma of the head and neck, precise information on the treated tumour's biology is required and the prognostic importance of different biological parameters needs to be determined. The aim of our study was to determine the predictive value of pretreatment PET/CT imaging using [(18)F]FDG, a new hypoxia tracer [(18)F]EF5 and the perfusion tracer [(15)O]H2O in patients with squamous cell cancer of the head and neck treated with radiochemotherapy. METHODS: The study group comprised 22 patients with confirmed squamous cell carcinoma of the head and neck who underwent a PET/CT scan using the above tracers before any treatment. Patients were later treated with a combination of radiochemotherapy and surgery. Parametric blood flow was calculated from dynamic [(15)O]H2O PET images using a one-tissue compartment model. [(18)F]FDG images were analysed by calculating standardized uptake values (SUV) and metabolically active tumour volumes (MATV). [(18)F]EF5 images were analysed by calculating tumour-to-muscle uptake ratios (T/M ratio). A T/M ratio of 1.5 was considered a significant threshold and used to determine tumour hypoxic subvolumes (HS) and hypoxic fraction area. The findings were finally correlated with the pretreatment clinical findings (overall stage and TNM stage) as well as the outcome following radiochemotherapy in terms of local control and overall patient survival. RESULTS: Tumour stage and T-classification did not show any significant differences in comparison to the patients' metabolic and functional characteristics measured on PET. Using the Cox proportional hazards model, a shorter overall survival was associated with MATV (p = 0.008, HR = 1.108), maximum [(18)F]EF5 T/M ratio (p = 0.0145, HR = 4.084) and tumour HS (p = 0.0047, HR = 1.112). None of the PET parameters showed a significant effect on patient survival in the log-rank test, although [(18)F]EF5 maximum T/M ratio was the closest (p = 0.109). By contrast, tumour blood flow was not correlated with any of the clinical endpoints. There were no statistically significant correlations among [(18)F]FDG SUVmax, [(18)F]EF5 T/M ratio and blood flow. CONCLUSION: Our study in a limited number of patients confirmed the importance of MATV in the prognosis of locally advanced squamous cell carcinoma of the head and neck. It is of interest that high uptake of the hypoxia tracer [(18)F]EF5 showed a stronger correlation with a poor clinical outcome than [(18)F]FDG uptake. This confirms the importance of hypoxia in treatment outcome and suggests that [(18)F]EF5 may act as a surrogate marker of radioresistance.

Correlation of 18F-FDG PET/CT assessments with disease activity and markers of inflammation in patients with early rheumatoid arthritis following the initiation of combination therapy with triple oral antirheumatic drugs.

PURPOSE: This study evaluated the potential of functional imaging to monitor disease activity and response to treatment with disease-modifying antirheumatic drugs (DMARD) in DMARD-naive patients with early rheumatoid arthritis (RA). METHODS: The study involved 17 patients with active RA in whom combination therapy was initiated with methotrexate, sulfasalazine, hydroxychloroquine, and low-dose oral prednisolone. Clinical disease activity was assessed at screening, at baseline and after 2, 4, 8 and 12 weeks of therapy. (18)F-FDG PET/CT of all joints was performed at baseline and after 2 and 4 weeks of therapy. RESULTS: (18)F-FDG maximum standardized uptake values showed a reduction of 22 ± 13 % in 76 % of patients from baseline to week 2 and a reduction of 29 ± 13 % in 81 % of patients from baseline to week 4. The percentage decrease in (18)F-FDG uptake from baseline to week 2 correlated with clinical outcome, as measured by the disease activity score (DAS-28) at week 12. In addition, changes in C-reactive protein levels and erythrocyte sedimentation rate were positively associated with changes shown by PET. CONCLUSION: (18)F-FDG PET/CT findings after 2 and 4 weeks of triple combination oral DMARD therapy correlated with treatment efficacy and clinical outcome in patients with early RA. (18)F-FDG PET/CT may help predict the therapeutic response to novel drug treatments.

A prospective comparison of integrated FDG-PET/contrast-enhanced CT and contrast-enhanced CT for pretreatment imaging of advanced epithelial ovarian cancer.

OBJECTIVE: The use of tumor debulking surgery in the management of epithelial ovarian cancer (EOC), which is often disseminated in the peritoneal cavity at the time of diagnosis, has a significant impact on prognosis. We compared (18)F-fluorodeoxyglucose (FDG) positron emission tomography/contrast-enhanced computed tomography (PET/CT) to contrast-enhanced CT for the detection of dissemination into the abdominal cavity preventing successful primary debulking surgery. METHODS: Forty-one women with EOC underwent preoperative whole-body low-dose FDG-PET/CT followed by diagnostic high dose contrast-enhanced CT scan, and the results were compared with systematically recorded surgical findings as a reference standard. Both site-based and patient-based analyses were conducted. RESULTS: FDG-PET/CT was superior to conventional CT for the detection of carcinomatosis in subdiaphragmatic peritoneal surfaces (p=0.020) and in the bowel mesentery (p=0.001). Patient-based analysis of upper abdominal areas requiring extensive surgical procedures showed no significant differences between the two imaging methods. The sensitivity of PET/CT and CT was poor in certain areas of the peritoneal cavity (64% vs. 27% in the small bowel mesentery and 65% vs. 55% in the right upper abdomen). Extra-abdominal disease spread was detected by PET/CT in 32 patients and by CT in 25 patients. CONCLUSIONS: PET/CT was not superior to CT for the detection of intra-abdominal disease spread. Patients with suspected EOC should be referred for upfront radical surgery regardless of the results of preoperative imaging studies. PET/CT is more effective for the detection of extra-abdominal disease than CT, but the clinical significance of this finding is unclear.

Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma: Association with Metabolic Tumor Burden Determined with FDG-PET/CT.

BACKGROUND: The detection of circulating tumor DNA (ctDNA) with next-generation sequencing (NGS) in venous blood is a promising tool for the genomic profiling of head and neck squamous cell carcinoma (HNSCC). The association between ctDNA findings and metabolic tumor burden detected with FDG-PET/CT imaging is of particular interest for developing prognostic and predictive algorithms in HNSCC. METHODS: Twenty-six prospectively enrolled HNSCC patients were eligible for further analysis. All patients underwent tumor tissue and venous liquid biopsy sampling and FDG-PET/CT before definitive oncologic treatment. An NGS-based commercial panel was used for a genomic analysis of the samples. RESULTS: Maximum variant allele frequency (VAF) in blood correlated positively with whole-body (WB) metabolic tumor volume (MTV) and total lesion glycolysis (TLG) (r = 0.510, p = 0.008 and r = 0.584, p = 0.002, respectively). A positive liquid biopsy was associated with high WB-TLG using VAF ≥ 1.00% or ≥5.00% as a cut-off value (p = 0.006 or p = 0.003, respectively). Additionally, ctDNA detection was associated with WB-TLG when only concordant variants detected in both ctDNA and tissue samples were considered. CONCLUSIONS: A high metabolic tumor burden based on FDG imaging is associated with a positive liquid biopsy and high maximum VAF. Our findings suggest a complementary role of metabolic and genomic signatures in the pre-treatment evaluation of HNSCC.

FDG PET/CT in staging of advanced epithelial ovarian cancer: frequency of supradiaphragmatic lymph node metastasis challenges the traditional pattern of disease spread.

OBJECTIVE: Epithelial ovarian cancer (EOC) spreads intra-abdominally and to the retroperitoneal lymph nodes. A greater number of distant metastases are revealed by (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) compared to conventional imaging methods. We aimed to investigate the presence and anatomic distribution of supradiaphragmatic lymph node metastasis (LNM) detected with pretreatment FDG PET/CT. METHODS: Thirty women with advanced stage (IIC-IV) EOC were scanned with whole body contrast-enhanced FDG PET/CT prior to surgery/neoadjuvant chemotherapy. We performed PET/CT analysis qualitatively and quantitatively. Additionally, contrast-enhanced CT was analyzed blinded to PET/CT scan. Intra-abdominal dissemination was verified by surgery and histopathology. Metabolically active lymph nodes were biopsied when possible. The clinical characteristics of patients with and without supradiaphragmatic LNM were compared. RESULTS: In 20/30 patients (67%) FDG PET/CT detected supradiaphragmatic LNM in one or more locations, whereas conventional CT found LNM in 10 patients (33%). Fourteen patients had parasternal, 14 cardiophrenic, 8 other mediastinal, 6 axillar, and 1 subclavian LNM. Microscopy of all four biopsied lymph nodes (three axillar and one subclavian) confirmed metastatic dissemination. The patients with supradiaphragmatic LNM had significantly more ascites (p<0.01), higher CA 125 levels, and more frequent subdiaphragmal carcinomatosis (p<0.03) compared to patients without supradiaphragmatic LNM in preoperative FDG PET/CT. CONCLUSIONS: A significant number of patients with advanced EOC showed supradiaphragmatic LNM in pre-treatment PET/CT. Our findings suggest that the route of EOC cells from the peritoneal cavity to the lymphatic system permeates the diaphragm mainly to the cardiophrenic and continues to parasternal lymph nodes.