STING activation counters glioblastoma by vascular alteration and immune surveillance.

Glioblastoma (GBM) is an aggressive brain tumor with a median survival of 15 months and has limited treatment options. Immunotherapy with checkpoint inhibitors has shown minimal efficacy in combating GBM, and large clinical trials have failed. New immunotherapy approaches and a deeper understanding of immune surveillance of GBM are needed to advance treatment options for this devastating disease. In this study, we used two preclinical models of GBM: orthotopically delivering either GBM stem cells or employing CRISPR-mediated tumorigenesis by adeno-associated virus, to establish immunologically proficient and non-inflamed tumors, respectively. After tumor development, the innate immune system was activated through long-term STING activation by a pharmacological agonist, which reduced tumor progression and prolonged survival. Recruitment and activation of cytotoxic T-cells were detected in the tumors, and T-cell specificity towards the cancer cells was observed. Interestingly, prolonged STING activation altered the tumor vasculature, inducing hypoxia and activation of VEGFR, as measured by a kinome array and VEGF expression. Combination treatment with anti-PD1 did not provide a synergistic effect, indicating that STING activation alone is sufficient to activate immune surveillance and hinder tumor development through vascular disruption. These results guide future studies to refine innate immune activation as a treatment approach for GBM, in combination with anti-VEGF to impede tumor progression and induce an immunological response against the tumor.

Fasting gallbladder volume is increased in patients with Parkinson's disease.

INTRODUCTION: Autonomic denervation in patients with Parkinson's disease (PD) and isolated REM-sleep behavior disorder (iRBD) could impede gallbladder function leading to increased fasting gallbladder volume (fGBV) and higher risk of gallstones. We aimed to determine fGBV in patients with PD, iRBD, and healthy controls (HCs). METHODS: We included 189 subjects; 100 patients with PD, 21 with iRBD, and 68 HCs. fGBV was determined from abdominal CT scans, and radiopaque gallstone frequency was evaluated. RESULTS: Median fGBV was 35.7 ml in patients with PD, 31.8 ml in iRBD, and 27.8 ml in HCs (Kruskal-Wallis test: P = 0.0055). Post-tests adjusted for multiple comparison revealed a significant group difference between patients with PD and HCs (P = 0.0038). In the PD group, 23% had enlarged fGBV (cut-off at mean + 2 x standard deviation (SD) in the HC group). No difference in fGBV was observed between iRBD and the other two groups. The total prevalence of gallstones was 6.4% with no differences between the three groups. CONCLUSION: Almost a quarter of patients with PD in our cohort exhibited increased fGBV. This study illuminates a potentially overlooked topic in PD research and calls for more studies on biliary dysfunction.

A Screening-Based Method for Identifying Patients with REM Sleep Behaviour Disorder in a Danish Community Setting.

Isolated REM sleep behaviour disorder (iRBD) is a predictive marker of prodromal Lewy body disease. iRBD prevalence in the general population is around 1%, but it remains under-diagnosed, even though symptoms are alleviated by medication. We developed a population screening strategy and identified 16 iRBD patients by conducting telephone interviews and polysomnography examinations. We compared our population-screened cohort with sleep-center referred patients and found higher MoCA scores and lower MDS-UPDRS-III scores in our patients. In conclusion, screening can be used to identify iRBD patients in a cost-effective manner with the benefit of identifying patients at a very early disease stage.

In vivo positron emission tomography imaging of decreased parasympathetic innervation in the gut of vagotomized patients.

BACKGROUND: Parasympathetic neuropathy is a key feature in many common disorders, including diabetes, neurological disorders, and cancers, but few objective methods exist for assessing damage to the parasympathetic nervous system, particularly in the gastrointestinal system. This study aimed to validate the use of 11 C-donepezil positron emission tomography (PET) to assess parasympathetic integrity in a group of vagotomized patients. METHODS: Sixteen healthy controls and 12 patients, vagotomized due to esophagectomy, underwent 11 C-donepezil PET, measurement of colonic transit time, quantification of plasma pancreatic polypeptide (PP), and assessment of subjective long-term symptoms. KEY RESULTS: Vagotomized patients had significantly decreased PET signal in the small intestine and colon compared with healthy controls (5.7 [4.4-7.9] vs 7.4 [4.5-11.3], P = .01 and 1.4 [1.1-2.1] vs 1.6 [1.4-2.4], P < .01, respectively). Vagotomized patients also displayed a significantly increased colonic transit time (2.9 ± 0.9 h vs 1.9 ± 0.8 h), P < .01 and increased volumes of the small intestine and colon (715 ccm [544-1177] vs 443 ccm [307-613], P < .01 and 971 ccm [713-1389] vs 711 ccm [486-1394], P = .01, respectively). Patients and controls did not differ in PP ratio levels after sham feeding, but PP ratio at 10 minutes. after sham feeding and PET signal intensity in the small intestine was positively correlated (P = .03). CONCLUSIONS AND INFERENCES: We found significantly decreased 11 C-donepezil signal in the intestine of vagotomized patients, supporting that 11 C-donepezil PET is a valid measure of intestinal parasympathetic denervation.

The relationship between tumor aggressiveness and cholinergic PET imaging in prostate cancer tissue. A proof-of-concept study.

It was recently shown that high-risk prostate carcinoma (PCa) exhibited parasympathetic neurogenesis. The PET tracer 11C-donepezil is a marker of parasympathetic innervation. Therefore, we studied if parasympathetic nerve density in PCa measured with 11C-donepezil PET correlated with PCa aggressiveness and if metastases could be visualized. Twenty-six patients were included into three groups with varying tumor aggressiveness. Dynamic and static PET scans were performed. Maximal standardized uptake values (SUVmax) were determined in lesions within the prostate, lymph nodes, and bones. SUVmax in primary PCa were compared between groups, and comparisons between SUVmax and Gleason score and Prostate-specific antigen (PSA) were performed. Kinetic modelling was performed and time-activity curves of healthy tissue and tumor tissue fitted and compared. Tumor kinetic parameters were normalized to those of healthy tissue producing ratios of K1 and k2. Median SUVmax in primary PCa was higher in high-grade compared to low-grade PCa (P = 0.052). No correlation was seen between Gleason score and SUVmax (P = 0.28). A trend-level correlation was seen between PSA and SUVmax (P = 0.078). Median SUVmax was 7.7 (4.7-22.5) for suspected lymph node metastases and 8.2 (5.4-14.8) for suspected bone metastases. A significant difference was seen between time-activity tissue curves for low- and high-grade PCa (P = 0.012). Highly significant differences were seen in K1- and k2-ratios between low- and high-grade PCa (P = 0.0006 and P < 0.0001). We showed that 11C-donepezil accumulates in primary PCa and metastases. Simple SUVmax values of the cancer hot spots were higher in high-risk tumors compared to low-risk tumors. Further studies should elucidate the importance of cholinergic neurogenesis for prostate cancer biology.

18F-Fluciclovine PET/CT in Suspected Residual or Recurrent High-Grade Glioma.

PURPOSE: To retrospectively investigate the uptake of F-fluciclovine on PET/CT in patients with suspected recurrent high-grade glioma (HGG). METHODS: Twenty-one patients were included. The standard of truth was histopathologic interpretation if available. When histopathology was not available or rebiopsy did not show signs of malignancy, clinical follow-up including MRI and clinical outcome was considered the standard of truth. RESULTS: All 21 patients met the reference standard of either histopathologic proof of HGG recurrence (n = 10) or disease progression clinically and with tumor growth corresponding to the primary tumor sites on follow-up MRI (n = 11). Median time from PET/CT to death was 5 months (range, 1-20 months). Median time from primary diagnosis to death was 14.5 months (range, 6 to >400). Average SUVmax of the lesions was 8.3 ± 5.3 (SD) and 0.34 ± 0.13 for normal brain tissue. Median lesion-to-background ratio was 21.6 (range, 3.1-84.4). In 4 patients, F-fluciclovine PET/CT detected small satellite tumors that had not been reported on MR. CONCLUSIONS: The uptake of F-fluciclovine in clinically and/or histopathologically confirmed recurrent HGG is high compared with the uptake reported for other amino acid PET tracers. Because of the high tumor uptake and thus high tracer contrast, small satellite tumors with a diameter below usual reported PET spatial resolution and not reported on MRI were detected in 4 patients. As no patients with confirmed treatment-related changes were included, we cannot as of yet ascertain the ability of F-fluciclovine PET to discriminate between recurrent HGG and treatment-related changes, for example, pseudoprogression and radionecrosis.

Acetylcholinesterase-associated inflammation in patients with giant cell arteritis. Evaluation by histology and 11C-donepezil PET/CT.

OBJECTIVES: To investigate the in-situ expression of acetylcholinesterase (AChE) in the inflamed vessel wall of patients with biopsy-positive giant cell arteritis (GCA) as compared to biopsy-negative non-GCA patients, and to evaluate the in-vivo expression of AChE in patients with large-vessel GCA (LVGCA) by 11C-donepezil (AChE inhibitor) positron emission tomography/computed tomography (PET/CT). METHODS: Twenty-four biopsy-positive GCA and 44 biopsy-negative non-GCA patients were included for AChE histology. Immunohistochemical methods were used to determine the AChE expression. The histological inflammation and the AChE expression were assessed by an experienced pathologist on a 3-point scale. Two patients with newly diagnosed 18F-fluorodeoxyglucose (18F-FDG) PET/CT verified LVGCA were included for 11C-donepezil PET/CT. PET images were assessed by an experienced nuclear medicine physician. RESULTS: AChE was expressed in all 24 positive temporal artery biopsies, 10/24 showed high AChE expression (grade 2) and 14/24 showed moderate AChE expression (grade 1). No AChE expression was observed outside the media smooth muscle cells (grade 0) in any of the biopsy-negative non-GCA patients. The AChE expression was in 86% agreement with the histological inflammation. The AChE expression was not associated with any clinical or biochemical findings. In both LV-GCA patients, PET/CT revealed extensive vascular FDG uptake but no 11C-donepezil uptake. CONCLUSIONS: AChE is highly expressed in the inflamed vessel wall of patients with GCA. Although, 11C-donepezil PET/CT showed no vascular uptake in the FDG PET/CT verified LV-GCA patients, histological findings raise the possibility that AChE can be used in the development of new diagnostic and disease monitoring tools for GCA.

18F-FACBC PET/MRI in Diagnostic Assessment and Neurosurgery of Gliomas.

PURPOSE: This pilot study aimed to evaluate the amino acid tracer F-FACBC with simultaneous PET/MRI in diagnostic assessment and neurosurgery of gliomas. MATERIALS AND METHODS: Eleven patients with suspected primary or recurrent low- or high-grade glioma received an F-FACBC PET/MRI examination before surgery. PET and MRI were used for diagnostic assessment, and for guiding tumor resection and histopathological tissue sampling. PET uptake, tumor-to-background ratios (TBRs), time-activity curves, as well as PET and MRI tumor volumes were evaluated. The sensitivities of lesion detection and to detect glioma tissue were calculated for PET, MRI, and combined PET/MRI with histopathology (biopsies for final diagnosis and additional image-localized biopsies) as reference. RESULTS: Overall sensitivity for lesion detection was 54.5% (95% confidence interval [CI], 23.4-83.3) for PET, 45.5% (95% CI, 16.7-76.6) for contrast-enhanced MRI (MRICE), and 100% (95% CI, 71.5-100.0) for combined PET/MRI, with a significant difference between MRICE and combined PET/MRI (P = 0.031). TBRs increased with tumor grade (P = 0.004) and were stable from 10 minutes post injection. PET tumor volumes enclosed most of the MRICE volumes (>98%) and were generally larger (1.5-2.8 times) than the MRICE volumes. Based on image-localized biopsies, combined PET/MRI demonstrated higher concurrence with malignant findings at histopathology (89.5%) than MRICE (26.3%). CONCLUSIONS: Low- versus high-grade glioma differentiation may be possible with F-FACBC using TBR. F-FACBC PET/MRI outperformed MRICE in lesion detection and in detection of glioma tissue. More research is required to evaluate F-FACBC properties, especially in grade II and III tumors, and for different subtypes of gliomas.

Non-invasive quantification of tumor blood flow in prostate cancer using 15O-H2O PET/CT.

Tumor blood flow (TBF) measurements in prostate cancer (PCa) provide an integrative index of tumor growth, which could be important for primary diagnosis and therapy response evaluation. 15O-water PET is the non-invasive gold standard but is technically demanding. The aim of this study was to compare the accuracy of three different non-invasive strategies with an invasively measured arterial input function (BSIF): Using image-derived input functions (IDIF) from either 1) a separate heart scan or 2) the pelvic scan or 3) a populations-based input function (PBIF). Nine patients with biopsy-verified PCa scheduled for prostatectomy were included. All patients were characterized with serum levels of PSA (s-PSA), multiparametric magnetic resonance imaging (mpMRI) and post-surgical histopathology Gleason Grade. Dynamic 15O-water was performed of the heart and the pelvic area 15 minutes apart. TBF estimated from both wash-in (K1) and wash-out (k2) constants was calculated using a one-compartmental model. Results: Mean (range) s-PSA was 12 (3-27) ng/mL, Gleason Grade Group was 2.9 (1-5), k2 was 0.44 (0.007-1.2), and K1 was 0.24 (0.07-0.55) mL/mL/min. k2 (BSIF) correlated with s-PSA (r=0.86, P<0.01) and Gleason Grade Group (rho=0.78, P=0.01). BSIF, heart-IDIF and PBIF provided near-identical k2 and K1 (r>0.95, P<0.001) with slopes near unity. The correlations of BSIF and pelvic-IDIF rate constants were good (r>0.95, P<0.001), but individual errors high. In conclusion, non-invasive protocols for 15O-water PET with IDIF or PBIF accurately measures perfusion in prostate cancer and might be useful for evaluation of tumor aggressiveness and treatment response.

Pancreatic Polypeptide in Parkinson's Disease: A Potential Marker of Parasympathetic Denervation.

BACKGROUND AND OBJECTIVES: Parkinson's disease (PD) patients experience several non-motor symptoms from the gastrointestinal tract that may partly be caused by parasympathetic deficiency. The pancreas is densely innervated by the vagus nerve, which mediates early meal-induced secretion of pancreatic polypeptide (PP). Early secretion after sham feeding has been validated as a marker of vagal integrity. Thus, the aim was to evaluate the ratio of increased PP plasma levels after sham feeding in PD and correlate findings with gastrointestinal transit time (GITT). METHODS: Twenty-five PD patients and 17 controls were included. PP, insulin, and blood glucose levels were measured before, during, and after sham feeding with white bread and chocolate spread. GITT was measured using radiopaque markers. Furthermore, faeces samples were analyzed for pancreatic elastase enzyme as a marker of exocrine pancreatic function. RESULTS: PD patients showed significantly lower PP ratio levels after sham feeding, which was most pronounced at 10 minutes. No significant association was seen between attenuated PP response and GITT in PD patients. No between-group differences were seen in glucose or insulin levels over time, but PD patients showed generally lower insulin levels compared to controls. No difference was found in faeces pancreatic elastase. CONCLUSIONS: Early-to-moderate stage PD patients demonstrated significantly decreased PP response after sham feeding suggestive of vagal denervation.

Multimodal 18F-Fluciclovine PET/MRI and Ultrasound-Guided Neurosurgery of an Anaplastic Oligodendroglioma.

BACKGROUND: Structural magnetic resonance imaging (MRI) and histopathologic tissue sampling are routinely performed as part of the diagnostic workup for patients with glioma. Because of the heterogeneous nature of gliomas, there is a risk of undergrading caused by histopathologic sampling errors. MRI has limitations in identifying tumor grade and type, detecting diffuse invasive growth, and separating recurrences from treatment induced changes. Positron emission tomography (PET) can provide quantitative information of cellular activity and metabolism, and may therefore complement MRI. In this report, we present the first patient with brain glioma examined with simultaneous PET/MRI using the amino acid tracer 18F-fluciclovine (18F-FACBC) for intraoperative image-guided surgery. CASE DESCRIPTION: A previously healthy 60-year old woman was admitted to the emergency care with speech difficulties and a mild left-sided hemiparesis. MRI revealed a tumor that was suggestive of glioma. Before surgery, the patient underwent a simultaneous PET/MRI examination. Fused PET/MRI, T1, FLAIR, and intraoperative three-dimensional ultrasound images were used to guide histopathologic tissue sampling and surgical resection. Navigated, image-guided histopathologic samples were compared with PET/MRI image data to assess the additional value of the PET acquisition. Histopathologic analysis showed anaplastic oligodendroglioma in the most malignant parts of the tumor, while several regions were World Health Organization (WHO) grade II. CONCLUSIONS: 18F-Fluciclovine uptake was found in parts of the tumor where regional WHO grade, cell proliferation, and cell densities were highest. This finding suggests that PET/MRI with this tracer could be used to improve accuracy in histopathologic tissue sampling and grading, and possibly for guiding treatments targeting the most malignant part of extensive and eloquent gliomas.

Functional image-guided dose escalation in gliomas using of state-of-the-art photon vs. proton therapy.

BACKGROUND: Recurrences of glioma are usually local, suggesting the need for higher tumor dose. We investigated the boundaries for dose escalation of an 18F-fluoro-ethyl-tyrosine positron emission tomography defined target by intensity-modulated photon therapy (IMRT), volumetric modulated arc therapy (VMAT) and intensity-modulated proton therapy (IMPT). MATERIALS AND METHODS: Standard dose (60 Gy) and dose-escalated plans were calculated for seven patients using IMRT, VMAT and IMPT. The achieved boost dose, the dose to the organs at risk (OAR), the dose homogeneity (defined as overdose volume, ODV) and the ratio of the 30 Gy isodose curve and the boost volume (R30) were compared. The risk of radionecrosis was estimated using the ratio of the dose volume histograms of the brain (range 30-60 Gy). RESULTS: The mean boost dose was 77.1 Gy for IMRT, 79.2 Gy for VMAT and 85.1 GyE for IMPT. Compared with the standard plan, the ODV was unchanged and the R30 increased (17%) for IMRT. For VMAT, the ODV decreased (7%) and the R30 was unchanged whereas IMPT substantially decreased ODV (61%), R30 (22%), OAR doses as well as the risk of radionecrosis. CONCLUSIONS: Dose escalation can be achieved with IMRT, VMAT and IMPT while respecting normal tissue constraints, yet with IMPT being most favorable.

Cholinergic PET imaging in infections and inflammation using 11C-donepezil and 18F-FEOBV.

INTRODUCTION: Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated. METHODS: We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer. RESULTS: In mice, the FDG uptake in abscesses peaked at 24 h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120-144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen. DISCUSSION: The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic mechanisms of immune modulation, but also clinical applications for diagnosing infections, inflammatory disorders, and cancer inflammation.

Appendectomy and risk of Parkinson's disease: A nationwide cohort study with more than 10 years of follow-up.

OBJECTIVES: The appendix may be a key site for the initiation of Parkinson's disease (PD) pathology. We examined the hypothesis that appendectomy is associated with lower PD risk. METHODS: We used Danish medical and administrative registries to construct a cohort of all patients in Denmark with an operation code of appendectomy during 1980-2010 (n = 265,758) and a matched general population comparison cohort (n = 1,328,790). Using Cox regression, we computed hazard ratios and corresponding 95% confidence intervals for PD, adjusting for potential confounders and stratifying on age at appendectomy (≤45 years / > 45 years), sex, and follow-up time. RESULTS: During follow-up ( > 10 years), PD incidence was 0.19 and 0.15 per 1,000 person-years at risk in the appendectomy cohort and in the general population comparison cohort, respectively, yielding a slightly increased risk of PD (adjusted hazard ratio = 1.14; 95% confidence interval 1.03-1.27). Findings were consistent after more than 20 years of follow-up and when stratified on age of appendectomy and sex. CONCLUSION: Appendectomy was associated with a small increase in PD risk 10 or more years after surgery. © 2016 International Parkinson and Movement Disorder Society.

A dual tracer (68)Ga-DOTANOC PET/CT and (18)F-FDG PET/CT pilot study for detection of cardiac sarcoidosis.

BACKGROUND: Cardiac sarcoidosis (CS) is a potentially fatal condition lacking a single test with acceptable diagnostic accuracy. (18)F-FDG PET/CT has emerged as a promising imaging modality, but is challenged by physiological myocardial glucose uptake. An alternative tracer, (68)Ga-DOTANOC, binds to somatostatin receptors on inflammatory cells in sarcoid granulomas. We therefore aimed to conduct a proof-of-concept study using (68)Ga-DOTANOC to diagnose CS. In addition, we compared diagnostic accuracy and inter-observer variability of (68)Ga-DOTANOC vs. (18)F-FDG PET/CT. METHODS: Nineteen patients (seven female) with suspected CS were prospectively recruited and dual tracer scanned within 7 days. PET images were reviewed by four expert readers for signs of CS and compared to the reference standard (Japanese ministry of Health and Welfare CS criteria). RESULTS: CS was diagnosed in 3/19 patients. By consensus, 11/19 (18)F-FDG scans and 0/19 (68)Ga-DOTANOC scans were rated as inconclusive. The sensitivity of (18)F-FDG PET for diagnosing CS was 33 %, specificity was 88 %, PPV was 33 %, NPV was 88 %, and diagnostic accuracy was 79 %. For (68)Ga-DOTANOC, accuracy was 100 %. Inter-observer agreement was poor for (18)F-FDG PET (Fleiss' combined kappa 0.27, NS) and significantly better for (68)Ga-DOTANOC (Fleiss' combined kappa 0.46, p = 0.001). CONCLUSIONS: Despite prolonged pre-scan fasting, a large proportion of (18)F-FDG PET/CT images were rated as inconclusive, resulting in low agreement among reviewers and correspondingly poor diagnostic accuracy. By contrast, (68)Ga-DOTANOC PET/CT had excellent diagnostic accuracy with the caveat that inter-observer variability was still significant. Nevertheless, (68)Ga-DOTANOC PET/CT looks very promising as an alternative CS PET tracer. TRIAL REGISTRATION: Current Controlled Trials NCT01729169 .

Molecular imaging of cholinergic processes in prostate cancer using ¹¹C-donepezil and ¹8F-FEOBV.

PURPOSE: High-grade prostate cancer (PC) displays parasympathetic neoneurogenesis. We investigated the binding of two PET tracers that visualize cholinergic nerves in PC tissue using autoradiography. METHODS: Prostatectomy tissue was subjected to autoradiography with (11)C-donepezil and (18)F-FEOBV and correlated with Gleason scores (GS). Regions of interest on the autoradiograms were defined and quantified. Tracer binding in cancer tissue regions was compared with that in normal tissue. RESULTS: We included 13 patients with biopsy-verified PC. In particular, (11)C-donepezil uptake was higher in "high-grade" PC (GS ≥4 + 3) than in "low-grade" PC and benign hyperplasia. (11)C-donepezil uptake ranged from a mean of 56 % higher (GS 3 + 3) to 409 % higher (GS 4 + 4), and (18)F-FEOBV uptake ranged from 67 % higher (GS 3 + 3) to 194 % higher (GS 4 + 5). The uptake of both tracers was higher in PC with a high GS than in PC with a low GS, but the difference was significant only for (11)C-donepezil (p = 0.003). CONCLUSION: Uptake of PET tracers binding to cholinergic nerves was markedly higher in PC with a high GS than in PC with a low GS. This finding implies that (11)C-donepezil PET/CT may be able to differentiate between low-grade and high-grade PC.

Accuracy of 18F-FDG PET-CT in triaging lung cancer patients with suspected brain metastases for MRI.

OBJECTIVE: Brain metastases are common in lung cancer. Whole-body 2-deoxy-2-[fluorine-18]fluoro-D-glucose ([F]FDG) PET/computed tomography (CT) is used for general staging, but MRI is the best modality for characterizing brain abnormalities. We aimed to determine whether PET/CT is suitable for selecting patients for MRI on the suspicion of brain metastases. MATERIALS AND METHODS: F-FDG PET/CT (from the vertex to mid-thigh) was performed in 1108 consecutive patients suspected of lung cancer. The final diagnoses were extracted from medical records as lung cancer, with or without brain metastases, other kinds of cancers, or no cancer. The sensitivity, specificity, and positive predictive value for detecting brain metastases were calculated. Interobserver variation was tested in a subset of 88 PET/CT scans. RESULTS: Of the 1108 referred patients, 596 had lung cancer. Sixty-six had brain metastases. One PET/CT was false positive. Thirty-one scans were true positive among the 43 patients who were diagnosed with brain metastases 1 month before to 3 months after PET/CT (metastasis prevalence, 7.3%). Twelve PET/CT scans were false negative. Sensitivity, specificity, and positive predictive values were 72, 100, and 97%, respectively. Interobserver agreement between two experienced observers was high (κ=0.83), whereas agreement between the experienced and the inexperienced observer was poor. CONCLUSION: The sensitivity of brain PET/CT for detecting brain metastases in lung cancer was above 70%, and the specificity was very high. Thus, PET/CT may be suitable for selecting patients for MRI in diagnostic centers that do not perform routine MRI in the pretherapeutic staging workup. The agreement among experienced readers was very high.

Vagotomy and subsequent risk of Parkinson's disease.

OBJECTIVE: Parkinson's disease (PD) may be caused by an enteric neurotropic pathogen entering the brain through the vagal nerve, a process that may take over 20 years. We investigated the risk of PD in patients who underwent vagotomy and hypothesized that truncal vagotomy is associated with a protective effect, whereas superselective vagotomy has a minor effect. METHODS: We constructed cohorts of all patients in Denmark who underwent vagotomy during 1977-1995 and a matched general population cohort by linking Danish registries. We used Cox regression to compute hazard ratios (HRs) for PD and corresponding 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS: Risk of PD was decreased in patients who underwent truncal (HR = 0.85; 95% CI = 0.56-1.27; follow-up of >20 years: HR = 0.58; 95% CI: 0.28-1.20) compared to superselective vagotomy. Risk of PD was also decreased after truncal vagotomy when compared to the general population cohort (overall adjusted HR = 0.85; 95% CI: 0.63-1.14; follow-up >20 years, adjusted HR = 0.53; 95% CI: 0.28-0.99). In patients who underwent superselective vagotomy, risk of PD was similar to the general population (HR = 1.09; 95% CI: 0.84-1.43; follow-up of >20 years: HR = 1.16; 95% CI: 0.80-1.70). Statistical precision of risk estimates was limited. Results were consistent after external adjustment for unmeasured confounding by smoking. INTERPRETATION: Full truncal vagotomy is associated with a decreased risk for subsequent PD, suggesting that the vagal nerve may be critically involved in the pathogenesis of PD.

Spatial distribution of malignant tissue in gliomas: correlations of 11C-L-methionine positron emission tomography and perfusion- and diffusion-weighted magnetic resonance imaging.

BACKGROUND: The prognosis of glioma patients is contingent on precise target selection for stereotactic biopsies and the extent of tumor resection. (11)C-L-methionine (MET) positron emission tomography (PET) demonstrates tumor heterogeneity and invasion with high diagnostic accuracy. PURPOSE: To compare the spatial tumor distribution delineated by MET PET with that by perfusion- and diffusion-weighted magnetic resonance imaging (MRI), in order to understand the diagnostic value of these MRI methods, when PET is not available. MATERIAL AND METHODS: Presurgical MET PET and MRI, including perfusion- and diffusion-weighted MRI, were acquired in 13 patients (7 high-grade gliomas, 6 low-grade gliomas). A quantitative volume of interest analysis was performed to compare the modalities objectively, supplemented by a qualitative evaluation that assessed the clinical applicability. RESULTS: The inaccuracy of conventional MRI was confirmed (area under the curve for predicting voxels with high MET uptake = 0.657), whereas cerebral blood volume (CBV) maps calculated from perfusion data improved accuracy (area under the curve = 0.760). We considered CBV maps diagnostically comparable to MET PET in 5/7 cases of high-grade gliomas, but insufficient in all cases of low-grade gliomas when evaluated subjectively. Cerebral blood flow and apparent diffusion coefficient maps did not contribute to further accuracy. CONCLUSION: Adding perfusion-weighted MRI to the presurgical protocol can increase the diagnostic accuracy of conventional MRI and is a simple and well-established method compared to MET PET. However, the definition of low-grade gliomas with subtle or no alterations on cerebral blood volume maps remains a diagnostic challenge for stand-alone MRI.