Kemp, Bradley J.

Abstract While dose escalation of radiotherapy (DERT) has failed to improve overall survival (OS) or progression-free survival (PFS) for glioblastoma in previous studies, a recent phase II clinical trial utilizing 18F-DOPA-PET-directed DERT demonstrated improved PFS in MGMT-unmethylated patients and OS in MGMT-methylated patients compared to historical controls. This planned secondary analysis sought to determine 1) how 18F-DOPA-PET changes RT volumes beyond standard MRI-planning, 2) which patients benefit most and least from this protocol, 3) which are mostly likely to experience clinically significant radionecrosis after DERT, and 4) patterns of failure after DERT. For 69 evaluable patients, median MRI-defined, PET-defined, and combined low-dose gross tumor volumes (GTV51) were 54 cc (range 9-248), 23 cc (0.4-179), and 62 cc (10-260), respectively. Median MRI-defined, PET-defined, and combined high-dose GTVs (GTV76) were 32 cc (range 4-136), 6 cc (0.1-138), and 34 cc (4-162), respectively. 18F-DOPA-PET resulted in a median volumetric expansion of 13% (0-243%) and 5% (0-217%) from MRI-defined low-dose and high-dose GTV’s, respectively. Central failures ( >95% of recurrence tumor volume) occurred within the 76 Gy, 60 Gy, and 51 Gy isodose lines in 32 (46%), 60 (87%), and 64 (93%) patients, respectively. Recursive partitioning analysis stratified patients by OS and PFS. Patients with 18F-DOPA-PET-defined GTV76 > 7.8cc, MRI-defined GTV76 > 42.7cc, and MGMT promotor-unmethylated tumors had the shortest OS, while patients with smaller PET and MRI-defined tumors had the longest OS (median 10.4 vs. 64.6 months, p< 0.001). Similarly, PFS was worst in patients with 18F-DOPA-PET-defined GTV76 > 2.17 cc who had biopsy only (median PFS 3.2 months, p< 0.001). Patients with 18F-DOPA-PET-defined GTV51 > 50 cc had the highest risk of grade 3+ radionecrosis (p< 0.001). In conclusion, larger 18F-DOPA-PET and MRI-defined tumor volumes were associated with worse outcomes, and 18F-DOPA-PET-directed DERT appears to reduce risk of central recurrence in high-dose volumes.

Prostate‐specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68Ga‐PSMA‐11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68Ga‐PSMA‐11 PET was prospectively performed in patients with treatment‐naïve HCC on a digital PET scanner using cyclotron‐produced 68Ga. Uptake was graded qualitatively and semi‐quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor‐associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10‐5) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = −0.753; P = 1.58 × 10‐6). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68Ga‐PSMA‐11 standardized uptake value: SUVmax (median [range] 9.2 [4.9‐28.4]), SUVmean 4.7 (2.4‐12.7), and tumor‐to‐liver background ratio 2 (1.1‐11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68Ga‐PSMA‐11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

Background: The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O 2 consumption [MVO 2 ]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O 2 extraction. Lastly, we assessed whether coupling of MVO 2 to EW (mechanical efficiency) was impaired in HFpEF. Methods and Results: In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11 C-acetate positron emission tomography assessing MVO 2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO 2 , and MBF. With dobutamine, LV EW, MVO 2 , and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O 2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. Conclusions: In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O 2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O 2 supply relative to demand, and is associated with reserve dysfunction.

Positron emission tomography (PET) radiopharmaceuticals can noninvasively measure free fatty acid (FFA) uptake into adipose tissue. We studied 29 volunteers to test whether abdominal and femoral subcutaneous adipose tissue FFA uptake measured using [1- 11 C]palmitate PET agrees with FFA storage rates measured using an intravenous bolus of [1- 14 C]palmitate and adipose biopsies. The dynamic left ventricular cavity PET images combined with blood sample radioactivity corrected for the 11 CO 2 content were used to create the blood time activity curve (TAC), and the constant ( K i ) was determined using Patlak analysis of the TACs generated for regions of interest in abdominal subcutaneous fat. These data were used to calculate palmitate uptake rates in abdominal subcutaneous adipose tissue (µmol·kg −1 ·min −1 ). Immediately after the dynamic imaging, a static image of the thigh was taken to measure the standardized uptake value (SUV) in thigh adipose tissue, which was scaled to each participant’s abdominal adipose tissue SUV to calculate thigh adipose palmitate uptake rates. Abdominal adipose palmitate uptake using PET [1- 11 C]palmitate was correlated with, but significantly ( P < 0.001) greater than, FFA storage measured using [1- 14 C]palmitate and adipose biopsy. Thigh adipose palmitate measured using PET calculation was positively correlated ( R 2 = 0.44, P < 0.0001) with and not different from the biopsy approach. The relative differences between PET measured abdominal subcutaneous adipose tissue palmitate uptake and biopsy-measured palmitate storage were positively correlated ( P = 0.03) with abdominal subcutaneous fat. We conclude that abdominal adipose tissue FFA uptake measured using PET does not equate to adipose FFA storage measured using biopsy techniques.

PET radiopharmaceuticals can noninvasively measure free fatty acid (FFA) tissue uptake. Investigators often use PET scan-derived data to calculate FFA flux. We tested whether the [1-11C]palmitate PET measures of palmitate flux provide results equivalent to a continuous infusion of [U-13C]palmitate. Nine volunteers participated in study 1 to evaluate whether a rapidly (10–20 s) given bolus of [1-11C]palmitate affects calculated flux results. Thirty volunteers participated in study 2, which was identical to study 1 except that the [1-11C]palmitate bolus was given over 1 min. Volunteers in both studies also received a continuous intravenous infusion of [U-13C]palmitate. Plasma palmitate concentrations and enrichment were measured by liquid chromatography-mass spectrometry. The PET/CT images were analyzed on a workstation running PMOD. Palmitate flux was estimated using PET time-activity curve (TAC) data from regions of interest in the left ventricle (LV) and aorta both with and without hybrid TACs that employed the11CO2-corrected data for the first 5 min and the11CO2-corrected blood radioactivity for the remainder of the PET scan. Palmitate flux in study 1 measured with PET [1-11C]palmitate and [U-13C]palmitate were not correlated, and the PET [1-11C]palmitate flux was significantly less than the [U-13C]palmitate measured flux. In study 2, the palmitate flux using PET [1-11C]palmitate hybrid LV models provided closer mean estimates of [U-13C]palmitate measured flux. The best PET calculation approaches predicted 64% of the interindividual variance in [U-13C]palmitate measured flux. Palmitate kinetics measured using [1-11C]palmitate/PET do not provide the same palmitate kinetic results as the continuous infusion [U-13C]palmitate approach.

AbstractIntroductionTau‐positron emission tomography (PET) imaging with AV1451 is sensitive to Alzheimer disease (AD)–related tau deposition in the brain. We (1) examined regional variation of average tau‐PET standardized uptake value ratios (SUVRs) in a young normal population (30–49 years) and corrected for the regional variability and (2) tested if the standardized values (z‐scores) scaled appropriately to capture regional Alzheimer‐specific (i.e., amyloid sensitive) tau‐PET changes in individuals aged 50+ years.MethodsWe identified 490 individuals (70 between 30–49 years as a reference group and 420 cognitively normal between 50–95 years of age) with tau‐PET and amyloid PET scans from the Mayo Clinic Study of Aging.ResultsThere was intrinsic regional variability in average tau‐PET SUVR with uptakes higher in some regions than others, even in the younger individuals who would have minimal or no neurofibrillary tangles. We corrected for this using region of interest–specific z‐scores based on the reference group. Amyloid and tau‐PET uptake were associated throughout the brain after adjusting for age, with the highest correlations in the medial temporal regions.DiscussionRegions with high‐average SUVR are not necessarily those with the greatest tau pathology. Standardization is therefore recommended. Standardization of the data “realigns” the data such that the regional tau z‐scores are informative of the disease process, that is, regions with high z‐scores now coincide with regions correlated with amyloid deposition. Medial temporal structures, specifically entorhinal cortex–tau, may be useful as an AD‐specific tau‐PET signature due to its sensitivity to amyloid.

Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). 63 Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD. Dynamic PET imaging of the brain was performed for 30 minutes following intravenous administration of 63 Zn-zinc citrate (∼330 MBq). Subsequently, body PET images were acquired. Urine and venous blood were analyzed to give information on urinary excretion and pharmacokinetics. Regional cerebral 63 Zn clearances were compared with 11 C-Pittsburgh Compound B ( 11 C-PiB) and 18 F-fluorodeoxyglucose ( 18 F-FDG) imaging data. 63 Zn-zinc citrate was well tolerated in human participants with no adverse events monitored. Tissues of highest uptake were liver, pancreas, and kidney, with moderate uptake being seen in intestines, prostate (in males), thyroid, spleen, stomach, pituitary, and salivary glands. Moderate brain uptake was observed, and regional dependencies were observed in 63 Zn clearance kinetics in relationship with regions of high amyloid-β plaque burden ( 11 C-PiB) and 18 F-FDG hypometabolism. In conclusion, zinc transport was successfully imaged in human participants using the PET probe 63 Zn-zinc citrate. Primary sites of uptake in the digestive system accent the role of zinc in gastrointestinal function. Preliminary information on zinc kinetics in patients with AD evidenced regional differences in clearance rates in correspondence with regional amyloid-β pathology, warranting further imaging studies of zinc homeostasis in patients with AD.