Peter Oturai

Clinical PET of Neuroendocrine Tumors Using 64Cu-DOTATATE: First-in-Humans Study

UNLABELLED The use of positron emitter-labeled compounds for somatostatin receptor imaging (SRI) has become attractive because of the prospect of improved spatial resolution, accelerated imaging procedures, and the ability to quantify tissue radioactivity concentrations. This paper provides results from first-in-humans use of (64)Cu-DOTATATE, an avidly binding somatostatin receptor ligand linked to a radioisotope with intermediate half-life and favorable positron energy (half-life, 12.7 h; maximum positron energy, 0.653 MeV). METHODS In a prospective setup, 14 patients with a history of neuroendocrine tumors underwent both PET/CT with (64)Cu-DOTATATE and SPECT/CT with our current routine imaging agent (111)In-diethylenetriaminepentaacetic acid-octreotide. After intravenous injection of 193-232 MBq of (64)Cu-DOTATATE, whole-body PET scans were acquired at 1 h (n = 14), 3 h (n = 12), and 24 h (n = 5) after administration. Tissue radioactivity concentrations for normal organs and lesions were quantified, and standardized uptake values were calculated for the early (1 h) and delayed (3 h) scans. Using the data for 5 patients, we assessed the radiation dose with OLINDA/EXM software. Furthermore, the clinical performance of (64)Cu-DOTATATE with respect to lesion detection was compared with conventional SRI. RESULTS SRI with (64)Cu-DOTATATE produced images of excellent quality and high spatial resolution. Images were characterized by high and stable tumor-to-background ratios over an imaging time window of at least 3 h. Compared with conventional scintigraphy, (64)Cu-DOTATATE PET identified additional lesions in 6 of 14 patients (43%). In 5 patients, lesions were localized in organs and organ systems not previously known as metastatic sites, including the early-stage detection of a secondary neuroendocrine tumor in a patient with a known mutation in the multiple endocrine neoplasia type I gene. All major additional findings seen only on PET could be confirmed on the basis of a clinical follow-up interval of 18 mo. Calculated radiation dose estimates yielded an effective dose of 6.3 mSv for an injected activity of 200 MBq of (64)Cu-DOTATATE, with the liver being the organ with the highest absorbed radiation dose (0.16 mGy/MBq). CONCLUSION This first-in-humans study supports the clinical use of (64)Cu-DOTATATE for SRI with excellent imaging quality, reduced radiation burden, and increased lesion detection rate when compared with (111)In-diethylenetriaminepentaacetic acid-octreotide.

Vasoactive intestinal polypeptide evokes only a minimal headache in healthy volunteers.

The role of the parasympathetic nervous system in the pathogenesis of migraine is disputed. The headache-eliciting effect of the parasympathetic neurotransmitter, vasoactive intestinal polypeptide (VIP), and its effect on cerebral arteries and brain haemodynamics has not been systematically studied in man. We hypothesized that infusion of VIP might induce headache in healthy subjects and cause changes in cerebral haemodynamics. VIP (8 pmol/kg per min) or placebo (0.9± saline) was infused for 25 min into 12 healthy young volunteers in a crossover, double-blind design. Headache was scored on a verbal rating scale from 0 to 10, regional cerebral blood flow (rCBF) was measured with single-photon emission computed tomography and 133Xe inhalation and mean flow velocity in the middle cerebral artery (VmeanMCA) was measured with transcranial Doppler ultrasonography. The headache was very mild with a maximum score of 2 and described as a pressing or throbbing sensation. Five participants developed headache during VIP and one during placebo. During the infusion, a significant drop in VmeanMCA was seen for VIP compared with placebo (P < 0.001), but the effect quickly waned and no difference was found when comparing the time between 30 and 120 min. In addition, no significant difference in the diameter of the MCA could be found during the infusion. No significant differences in rCBF (P = 0.10) were found between VIP and placebo. A marked dilation of the superficial temporal artery was seen (P = 0.04) after VIP in the first 30 min but no difference was found when comparing the time between 30 and 120 min. We found no difference in mean arterial blood pressure between VIP and placebo days but the heart rate increased significantly on a VIP day compared with a placebo day (AUC0–30min, P < 0.001). Plasma VIP was significantly higher on a VIP day compared with placebo (AUC0–80min, P < 0.001). These results show that VIP causes a decrease in VmeanMCA without affecting rCBF. In spite of a marked vasodilator effect in the extracranial vessels and increased plasma VIP, healthy subjects developed only a very mild headache.

The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers

PACAP38 is an endogenous peptide located in trigeminal perivascular nerve fibers in the brain. It reduces neuronal loss and infarct size in animal stroke models and has been proposed a candidate substance for human clinical studies of stroke. The effect on systemic hemodynamics and regional cerebral blood flow (rCBF) is not well understood. We here present the first study of the effect of PACAP38 on cerebral hemodynamics in humans. PACAP (10 pmol kg(-1) min(-1)) or placebo (0.9% saline) was infused for 20 min into 12 healthy young volunteers in a cross over, double blind study. rCBF was measured with SPECT and (133)Xe inhalation and mean blood flow velocity in the middle cerebral artery was measured with transcranial Doppler ultrasonography. End tidal partial pressure of CO(2) (P(et)CO(2)) and vital parameters were recorded throughout the 2 hour study period. PACAP38 decreased rCBF in all regions of interest (ROIs) by approximately 3-10%, though not uniformly significant. P(et)CO(2) decreased significantly during PACAP38 infusion compared to placebo (P=0.032), peak decrease was 8.9+/-3.8%. After correction for P(et)CO(2), rCBF remained unchanged in most ROIs. Heart rate increased 61.9+/-22.4% (P<0.0001 vs. placebo). These findings suggest that PACAP38 has no major direct effect on rCBF in healthy volunteers. The marked increase in heart rate and the reduction in rCBF caused by decreased P(et)CO(2) are important dose-limiting factors to consider in future clinical studies.

Prostaglandin E2 (PGE2) Induces Headache in Healthy Subjects

The role of prostanoids in nociception is well established. The headache-eliciting effects of prostaglandin E2 (PGE2) and its possible mechanisms have previously not been systematically studied in man. We hypothesized that infusion of PGE2 might induce headache and vasodilation of cranial vessels. PGE2 (0.40 μg kg−1 min−1) or saline was infused for 25 min into 11 healthy subjects in a cross-over, double-blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (VMCA) by transcranial Doppler and diameter of the superficial temporal artery (STA) by high-resolution ultrasonography. All 11 subjects reported headache on the PGE2 day and no subjects reported headache on the placebo day (P = 0.001). During the immediate phase (0–30 min) (P = 0.005) and the postinfusion phase (30–90 min) (P = 0.005), the area under the curve for headache score was significantly larger on the PGE2 day compared with the placebo day. PGE2 caused dilatation of the STA (23.5%; 95% CI 14.0, 37.8) and the MCA (8.3%; 95% CI 4.0, 12.6). We suggest that PGE2 induces headache by activation and sensitization of cranial perivascular sensory afferents.

Prostacyclin (epoprostenol) induces headache in healthy subjects.

Abstract The role of prostanoids in nociception is well established. The headache eliciting effects of prostacyclin (prostaglandin I2, (PGI2)) and its possible mechanisms had previously not been systematically studied in man. We hypothesized that infusion of PGI2 might induce headache and vasodilatation of cranial vessels. A stable analog of PGI2 epoprostenol (10 ng/kg/min) was infused for 25 min into 12 healthy subjects in a cross‐over, double‐blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (Vmean MCA) by the transcranial doppler and diameter of the superficial temporal artery (STA) by a high‐resolution ultrasonography unit. During the immediate phase (0–30 min) and the post‐infusion phase (30–90 min), 11 subjects reported headache on the PGI2 day and no subjects reported headache on the placebo day (p = 0.002). During epoprostenol (0–30 min) and in the post‐infusion phase (30–90 min), the area under the curve (AUC) for headache score was significantly larger than during and after placebo (p = 0.005). PGI2 caused headache associated with the dilatation of STA (AUC, p < 0.001), but no significant dilatation of the MCA (AUC, p = 0.508). These data indicate that PGI2 induced headache might be due to activation and sensitization of sensory afferents around extracranial arteries.

64Cu-DOTATATE PET for Neuroendocrine Tumors: a Prospective Head-to-Head Comparison with 111In-DTPA-octreotide in 112 Patients

Neuroendocrine tumors (NETs) can be visualized using radiolabeled somatostatin analogs. We have previously shown the clinical potential of 64Cu-DOTATATE in a small first-in-human feasibility study. The aim of the present study was, in a larger prospective design, to compare on a head-to-head basis the performance of 64Cu-DOTATATE and 111In-diethylenetriaminepentaacetic acid (DTPA)-octreotide (111In-DTPA-OC) as a basis for implementing 64Cu-DOTATATE as a routine. Methods: We prospectively enrolled 112 patients with pathologically confirmed NETs of gastroenteropancreatic or pulmonary origin. All patients underwent both PET/CT with 64Cu-DOTATATE and SPECT/CT with 111In-DTPA-OC within 60 d. PET scans were acquired 1 h after injection of 202 MBq (range, 183–232 MBq) of 64Cu-DOTATATE after a diagnostic contrast-enhanced CT scan. Patients were followed for 42–60 mo for evaluation of discrepant imaging findings. The McNemar test was used to compare the diagnostic performance. Results: Eighty-seven patients were congruently PET- and SPECT-positive. No SPECT-positive cases were PET-negative, whereas 10 false-negative SPECT cases were identified using PET. The diagnostic sensitivity and accuracy of 64Cu-DOTATATE (97% for both) were significantly better than those of 111In-DTPA-OC (87% and 88%, respectively, P = 0.017). In 84 patients (75%), 64Cu-DOTATATE identified more lesions than 111In-DTPA-OC and always at least as many. In total, twice as many lesions were detected with 64Cu-DOTATATE than with 111In-DTPA-OC. Moreover, in 40 of 112 cases (36%) lesions were detected by 64Cu-DOTATATE in organs not identified as disease-involved by 111In-DTPA-OC. Conclusion: With these results, we demonstrate that 64Cu-DOTATATE is far superior to 111In-DTPA-OC in diagnostic performance in NET patients. Therefore, we do not hesitate to recommend implementation of 64Cu-DOTATATE as a replacement for 111In-DTPA-OC.

Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder: A Randomized Clinical Trial

Importance Compared with the general population, patients with schizophrenia have a 2- to 3-fold higher mortality rate primarily caused by cardiovascular disease. Previous interventions designed to counteract antipsychotic-induced weight gain and cardiometabolic disturbances reported limited effects. Objectives To determine the effects of the glucagon-like peptide-1 receptor agonist liraglutide added to clozapine or olanzapine treatment of schizophrenia spectrum disorders. Design, Setting, and Participants This randomized clinical double-blind trial enrolled participants at 2 clinical sites in Denmark. Of 214 eligible participants with a schizophrenia spectrum disorder, 103 were randomized to liraglutide or placebo. Participants received stable treatment with clozapine or olanzapine, were overweight or obese, and had prediabetes. Data were collected from May 1, 2013, through February 25, 2016. Interventions Treatment for 16 weeks with once-daily subcutaneous injection of liraglutide or placebo. Trial drug therapy was titrated during the first 2 weeks of the study. Main Outcomes and Measures The primary end point was change in glucose tolerance estimated by a 75-g oral glucose tolerance test result. Secondary end points included change in body weight and cardiometabolic parameters. Results Of the 103 patients undergoing randomization (60 men [58.3%] and 43 women [41.7%]), 97 were included in the efficacy analysis, with a mean (SD) age of 42.5 (10.5) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 33.8 (5.9). The liraglutide and placebo groups had comparable characteristics (mean [SD] age, 42.1 [10.7] vs 43.0 [10.5] years; 30 men in each group; mean [SD] body mass index, 33.7 [5.1] vs 33.9 [6.6]). A total of 96 randomized participants (93.2%) completed the trial. Glucose tolerance improved in the liraglutide group compared with the placebo group (P < .001). Altogether, 30 liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%) (P < .001; number needed to treat, 2). Body weight decreased with liraglutide compared with placebo (−5.3 kg; 95% CI, −7.0 to −3.7 kg). Reductions in waist circumference (−4.1 cm; 95% CI, −6.0 to −2.3 cm), systolic blood pressure (−4.9 mm Hg; 95% CI, −9.5 to −0.3 mm Hg), visceral fat (−250.19 g; 95% CI, −459.9 to −40.5 g), and low-density lipoprotein levels (−15.4 mg/dL; 95% CI, −23.2 to −7.7 mg/dL) occurred with liraglutide compared with placebo. Adverse events with liraglutide affected mainly the gastrointestinal tract. Conclusions and Relevance Liraglutide significantly improved glucose tolerance, body weight, and cardiometabolic disturbances in patients with schizophrenia spectrum disorders treated with clozapine or olanzapine. Trial Registration clinicaltrials.gov Identifier: NCT01845259

64Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with 68Ga-DOTATOC in 60 Patients

The somatostatin receptor subtype 2 is expressed on macrophages, an abundant cell type in the atherosclerotic plaque. Visualization of somatostatin receptor subtype 2, for oncologic purposes, is frequently made using the DOTA-derived somatostatin analogs DOTATOC or DOTATATE for PET. We aimed to compare the uptake of the PET tracers 68Ga-DOTATOC and 64Cu-DOTATATE in large arteries, in the assessment of atherosclerosis by noninvasive imaging technique, combining PET and CT. Further, the correlation of uptake and cardiovascular risk factors was investigated. Methods: Sixty consecutive patients with neuroendocrine tumors underwent both 68Ga-DOTATOC and 64Cu-DOTATATE PET/CT scans, in random order. For each scan, the maximum and mean standardized uptake values (SUVs) were calculated in 5 arterial segments. In addition, the blood-pool–corrected target-to-background ratio was calculated. Uptake of the tracers was correlated with cardiovascular risk factors collected from medical records. Results: We found detectable uptake of both tracers in all arterial segments studied. Uptake of 64Cu-DOTATATE was significantly higher than 68Ga-DOTATOC in the vascular regions both when calculated as maximum and mean uptake. There was a significant association between Framingham risk score and the overall maximum uptake of 64Cu-DOTATATE using SUV (r = 0.4; P = 0.004) as well as target-to-background ratio (r = 0.3; P = 0.04), whereas no association was found with 68Ga-DOTATOC. The association of risk factors and maximum SUV of 64Cu-DOTATATE was found driven by body mass index, smoking, diabetes, and coronary calcium score (P < 0.001, P = 0.01, P = 0.005, and P = 0.03, respectively). Conclusion: In a series of oncologic patients, vascular uptake of 68Ga-DOTATOC and 64Cu-DOTATATE was found, with highest uptake of the latter. Uptake of 64Cu-DOTATATE, but not of 68Ga-DOTATOC, was correlated with cardiovascular risk factors, suggesting a potential role for 64Cu-DOTATATE in the assessment of atherosclerosis.

Radioactive Seed Localization or Wire-guided Localization of Nonpalpable Invasive and In Situ Breast Cancer: A Randomized, Multicenter, Open-label Trial

Objective: To compare the rate of positive resection margins between radioactive seed localization (RSL) and wire-guided localization (WGL) after breast conserving surgery (BCS). Background: WGL is the current standard for localization of nonpalpable breast lesions in BCS, but there are several difficulties related to the method. Methods: From January 1, 2014 to February 4, 2016, patients with nonpalpable invasive breast cancer or DCIS visible on ultrasound were enrolled in this randomized, multicenter, open-label clinical trial, and randomly assigned to RSL or WGL. The primary outcome was margin status after BCS. Secondary outcomes were duration of the surgical procedure, weight of surgical specimen, and patients’ pain perception. Analyses were performed by intention-to-treat (ITT) and per protocol. Results: Out of 444 eligible patients, 413 lesions representing 409 patients were randomized; 207 to RSL and 206 to WGL. Twenty-three did not meet inclusion criteria, chose to withdraw, or had a change in surgical management and were excluded. The remaining 390 lesions constituted the ITT population. Here, resection margins were positive in 23 cases (11.8%) in the RSL group compared with 26 cases (13.3%) in the WGL group (P = 0.65). The per-protocol analysis revealed no difference in margin status (P = 0.62). There were no significant differences in the duration of the surgical procedure (P = 0.12), weight of the surgical specimen (P = 0.54) or the patients’ pain perception (P = 0.28). Conclusion: RSL offers a major logistic advantage, as localization can be done several days before surgery without any increase in positive resection margins compared with WGL.

Automated Bone Scan Index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide.

BackgroundHaving performed analytical validation studies, we are now assessing the clinical utility of the upgraded automated Bone Scan Index (BSI) in metastatic castration-resistant prostate cancer (mCRPC). In the present study, we retrospectively evaluated the discriminatory strength of the automated BSI in predicting overall survival (OS) in mCRPC patients being treated with enzalutamide.MethodsRetrospectively, we included patients who received enzalutamide as a clinically approved therapy for mCRPC and had undergone bone scan prior to starting therapy. Automated BSI, prostate-specific antigen (PSA), hemoglobin (HgB), and alkaline phosphatase (ALP) were obtained at baseline. Change in automated BSI and PSA were obtained from patients who have had bone scan at week 12 of treatment follow-up. Automated BSI was obtained using the analytically validated EXINI BoneBSI version 2. Kendall’s tau (τ) was used to assess the correlation of BSI with other blood-based biomarkers. Concordance index (C-index) was used to evaluate the discriminating strength of automated BSI in predicting OS.ResultsEighty mCRPC patients with baseline bone scans were included in the study. There was a weak correlation of automated BSI with PSA (τ = 0.30), with HgB (τ = −0.17), and with ALP (τ = 0.56). At baseline, the automated BSI was observed to be predictive of OS (C-index 0.72, standard error (SE) 0.03). Adding automated BSI to the blood-based model significantly improved the C-index from 0.67 to 0.72, p = 0.017. Treatment follow-up bone scans were available from 62 patients. Both change in BSI and percent change in PSA were predictive of OS. However, the combined predictive model of percent PSA change and change in automated BSI (C-index 0.77) was significantly higher than that of percent PSA change alone (C-index 0.73), p = 0.041.ConclusionsThe upgraded and analytically validated automated BSI was found to be a strong predictor of OS in mCRPC patients. Additionally, the change in automated BSI demonstrated an additive clinical value to the change in PSA in mCRPC patients being treated with enzalutamide.