Kevin P. Horn

FDG and FLT-PET for Early measurement of response to 37.5 mg daily sunitinib therapy in metastatic renal cell carcinoma

BackgroundMetastatic renal cell carcinoma has a poor prognosis and an intrinsic resistance to standard treatment. Sunitinib is an oral receptor tyrosine kinase inhibitor that has been used as a first-line targeted therapy in metastatic renal cell carcinoma. While computed tomography (CT) is currently the gold standard for response assessment in oncological trials, numerous studies have shown that positron emission tomography (PET) imaging can provide information predictive of tumor response to treatment earlier than the typical interval for standard of care follow-up CT imaging. In this exploratory study we sought to characterize early tumor response in patients with metastatic renal cell carcinoma treated with continuous daily 37.5xa0mg sunitinib therapy.MethodsTwenty patients underwent dynamic acquisition positron emission tomography (PET) imaging using 18u2009F-fluorodeoxyglucose (FDG) and 18u2009F-fluorothymidine (FLT) at baseline and early in treatment (after 1, 2, 3 or 4xa0weeks) with 37.5xa0mg continuous daily dosing of sunitinib. Semi-quantitative analyses were performed to characterize the tumor metabolic (FDG) and proliferative (FLT) responses to treatment.ResultsProliferative responses were observed in 9/19 patients and occurred in 2 patients at one week (the earliest interval evaluated) after the initiation of therapy. A metabolic response was observed in 5/19 patients, however this was not observed until after two weeks of therapy were completed. Metabolic progression was observed in 2/19 patients and proliferative progression was observed in 1/19 patients. Baseline FDG-PET tumor maximum standardized uptake values correlated inversely with overall survival (pu2009=u20090.0036). Conversely, baseline 18u2009F-fluorothymidine PET imaging did not have prognostic value (pu2009=u20090.56) but showed a greater early response rate at 1–2 weeks after initiating therapy.ConclusionsWhile preliminary in nature, these results show an immediate and sustained proliferative response followed by a delayed metabolic response beginning after two weeks in metastatic renal cell carcinoma treated with a continuous daily dose of 37.5xa0mg sunitinib. The results provide evidence of tumor response to lower-dose sunitinib while also supporting the inclusion of PET imaging as a tool for early assessment in oncological clinical trials.Trial registrationID: NCT00694096

Short-Term Practice Effects and Brain Hypometabolism: Preliminary Data from an FDG PET Study

Practice effects are improvements in cognitive test scores due to repeated exposure to the same tests. Typically viewed as error, short-term practice effects have been shown to provide valuable clinical information about diagnosis, prognosis, and treatment outcomes in older patients with mild cognitive impairments. This study examined short-term practice effects across one week and brain hypometabolism on fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) in 25 older adults (15 intact, 10 Mild Cognitive Impairment). Averaged cerebral brain metabolism on FDG PET was correlated with multiple cognitive scores at baseline in those with Mild Cognitive Impairment, and short-term practice effects accounted for additional variance in these same subjects. The relationship between brain metabolism and cognition (either at baseline or practice effects) was minimal in the intact individuals. Although needing replication in larger samples, short-term practice effects on tests of executive functioning and memory may provide valuable information about biomarkers of Alzheimers disease.

Is Cancer Protective for Subsequent Alzheimer’s Disease Risk? Evidence From the Utah Population Database

ObjectivenSeveral studies have suggested that cancer is associated with a reduced risk of the development of Alzheimers disease (AD). This study seeks to improve our understanding of the association between cancer and the development of AD by showing how mortality selection alters this relationship.nnnMethodnA retrospective cohort study was carried out examining 92,425 individuals (47,873 women and 44,552 men) from the Utah Population Database with and without a history of any primary cancer identified by the Utah Cancer Registry. All individuals were aged 65-79 years and free of dementia in 1992 and followed for upwards of 18 years (1992-2009) for AD ascertainment, which was identified using diagnostic information from Medicare claims data.nnnResultsnWe replicate previous results suggesting that cancer is associated with reduced risk of subsequent AD under specific statistical model specifications. However, these results should not be interpreted as evidence of an etiological association. We conclude that higher rates of overall mortality among individuals with cancer relative to those without cancer induce the widely reported putative protective association with cancer.nnnConclusionnCareful consideration of model specification and the profound effects of mortality selection in the older adult population is essential when investigating the relationship between aging-related diseases such as cancer and AD. We show that cancer does not provide protection from AD as previously described in the literature. Social scientists seeking to understand social disparities in disease outcomes among older adults may therefore want to strongly consider the role of mortality selection which, if uncorrected, may generate biased associations.

Amyloid positivity using [18F]Flutemetamol-PET and cognitive deficits in nondemented community-dwelling older adults

Little research exists examining the relationship between beta-amyloid neuritic plaque density via [18F]flutemetamol binding and cognition; consequently, the purpose of the current study was to compare cognitive performances among individuals having either increased amyloid deposition (Flute+) or minimal amyloid deposition (Flute−). Twenty-seven nondemented community-dwelling adults over the age of 65 underwent [18F]flutemetamol amyloid-positron emission tomography imaging, along with cognitive testing using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and select behavioral measures. Analysis of variance was used to identify the differences among the cognitive and behavioral measures between Flute+/Flute− groups. Flute+ participants performed significantly worse than Flute− participants on RBANS indexes of immediate memory, language, delayed memory, and total scale score, but no significant group differences in the endorsed level of depression or subjective report of cognitive difficulties were observed. Although these results are preliminary, [18F]flutemetamol accurately tracks cognition in a nondemented elderly sample, which may allow for better prediction of cognitive decline in late life.

Correlation of Glioma Proliferation and Hypoxia by Luciferase, Magnetic Resonance, and Positron Emission Tomography Imaging

Gliomas are the most common type of primary, malignant brain tumor and significantly impact patients, who have a median survival of ~1xa0year depending on mutational background. Novel imaging modalities such as luciferase bioluminescence, micro-magnetic resonance imaging (micro-MRI), micro-computerized tomography (micro-CT), and micro-positron emission tomography (micro-PET) have expanded the portfolio of tools available to study this disease. Hypoxia, a key oncogenic driver of glioma and mechanism of resistance, can be studied in vivo by the concomitant use of noninvasive MRI and PET imaging. We present a protocol involving stereotactic injection of syngenic F98 luciferase-expressing glioma cells generated by our laboratory into Fischer 344 rat brains and imaging using luciferase. In addition, 18-F-fludeoxyglucose, 18F-fluoromisonidazole, and 18F-fluorothymidine PET imaging are compared with quantified luciferase flux. These tools can potentially be used for assessing tumor growth characteristics, hypoxia, mutational effects, and treatment effects.

Relationship between 18F-Flutemetamol uptake and RBANS performance in non-demented community-dwelling older adults

Abstract Objective: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been used extensively for clinical care and in research for patients with mild cognitive impairment and Alzheimer’s disease (AD); however, relatively few studies have evaluated the relationship between RBANS performance and AD imaging biomarkers. The purpose of the current study was to evaluate the association between a relatively new amyloid positron emission tomography imaging biomarker and performance on the RBANS. Methods: Twenty-seven nondemented community-dwelling adults over the age of 65 underwent 18F-Flutemetamol amyloid– positron emission tomography imaging, along with cognitive testing using the RBANS and select behavioral measures. Partial correlation coefficients were used to identify relationships between the imaging and behavioral markers. Results: After controlling for age and education, amyloid deposition and RBANS Indexes of Immediate Memory, Delayed Memory, and Total Scale score were significantly correlated (p’s < .001, r’s = −.73 to −.77, d’s = 2.13–2.39), with greater amyloid burden being associated with lower RBANS scores. The Delayed Memory Index was particularly highly associated with 18F-Flutemetamol binding (r2 = .59, p < .001, d = 2.39). Neither 18F-Flutemetamol binding nor RBANS performance was significantly correlated with levels of depression, subjective cognitive difficulties, or premorbid intellect. Conclusions: Because of the limited use of amyloid imaging in clinical settings due to high cost and lack of reimbursement, these findings suggest that in particular RBANS Delayed Memory Index may be a cost-efficient tool to identify early signs of AD pathology, and its use may enlighten clinical decision-making regarding potential progression to dementia due to AD.

HOW AMYLOID PET CHANGES COGNITIVE CARE: A BROADER VIEW

Background:Hypertension and Type 2 diabetes are cardiovascular disease risk factors (CVD-RFs) associated with pathological aging, including Alzheimer’s disease (AD) and vascular dementia. Mid-life hypertension and diabetes predict late-life white matter alterations including white matter hyperintensities (WMH) associated with dementia. Further, evidence suggests that theseCVD-RFsmay exert their impact as early as the third or fourth decade of life in affected individuals. Hypertension and diabetes are two of the most prevalent CVDRFs in minority populations, and rates of treatment-related control in these populations lag behind those of non-Hispanic Whites. Work is needed to detect white matter vulnerability associated with CVDRFs before overt damage occurs. Given that myelin degradation is thought to contribute to white matter damage, we focused this study on multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) as it relates to CVD-RFs in an ethnically diverse sample of older adults. Methods: Forty-six non-demented/ non-depressed participants (mean age1⁄466.4 years; 56% female; equal % Black/Hispanic/non-Hispanic White) underwent 3TMRI. mcDESPOT quantified ‘restricted’ water trapped within the lipid bilayers of myelin sheath, providing a measure of myelin water fraction (MWF). Regardless of medication status, systolic blood pressure (SBP) was determined via two readings separated by 5-minute intervals; blood glucose was measured by fasting levels of hemoglobin A1c. Separate age-adjusted linear regressions investigated the associations betweenSBPandA1conwhole-brainMWF.Analyseswere fully corrected for multiple comparisons and utilized threshold-free cluster enhancement. Results:Higher SBP was associated with lower MWF within deepwhitematter and parietal regions (p<.05), whereas greater A1c was associated with lower MWF in deep white matter and more temporal regions (p<.05; see Figure 1a). Similar associations were noted in a subset of fifteen Hispanics at increased risk for uncontrolled CVD-RFs (see Figure 1b). Conclusions:Higher levels of SBP and A1c are associated with decreased myelin integrity in a sample of older, ethnically diverse adults. These results suggest that mcDESPOT may be a useful tool to detect the adverse effects of CVD-RFs onwhitematter integrity in and around areas ofWMH in older non-demented/nondepressed adults.