Assay, Purity, and Impurity Profile of Phosphorothioate Oligonucleotide Therapeutics by Ion Pair-HPLC-MS.

The relatively large molecular size, diastereoisomeric nature, and complex impurity profiles of therapeutic phosphorothioate oligonucleotides create significant analytical challenges for the quality control laboratory. To overcome the lack of selectivity inherent to traditional chromatographic approaches, an ion pair liquid chromatography-mass spectrometry (LCMS) method combining ultraviolet and mass spectrometry quantification was developed and validated for >35 different oligonucleotide drug substances and products, including several commercialized drugs. The selection of chromatographic and spectrometric conditions, data acquisition and processing, critical aspects of sample and buffer preparation and instrument maintenance, and results from method validation experiments are discussed.

Potential for Increasing Uptake of Radiolabeled 68Ga-DOTATOC and 123I-MIBG in Patients with Midgut Neuroendocrine Tumors Using a Histone Deacetylase Inhibitor Vorinostat.

Background: Histone deacetylase (HDAC) inhibitors have been shown in preclinical studies to upregulate norepinephrine transporters in neuroblastoma and pheochromocytoma, and somatostatin receptors in pulmonary carcinoid, small cell lung cancer, and pancreatic neuroendocrine malignancies. This pilot imaging study in humans focuses on midgut neuroendocrine carcinoma metastatic to the liver, evaluating the effect of pretreatment with the HDAC inhibitor vorinostat on uptake of 123I-MIBG and 68Ga-DOTATOC. Materials and Methods: Multiple midgut neuroendocrine liver metastases in clinically stable subjects were imaged with 123I-MIBG and 68Ga-DOTATOC before and after a 4-d course of vorinostat. Scans were performed with strict attention to detail and timed about 1 month apart occurring just before monthly long-acting octreotide administrations. Uptake changes in tumor and normal liver parenchyma were assessed on positron emission computed tomography (PET/CT) with standardized uptake values and on single photon emission computed tomography (SPECT) with qualitative ratio images. Results: The experimental units were metastatic liver lesions within patients (n = 50). There was no significant difference in administered activity or uptake time between pairs of scans for either radiotracer. Statistically significant increase in maximum standardized uptake values (SUVmax) averaged over all lesions was noted on the 68Ga-DOTATOC PET scans (+11%, p < 0.01). SUVmax in normal liver showed no significant change (p = 0.12). There was no qualitative change in uptake of 123I-MIBG after vorinostat. Conclusions: In this pilot imaging study in patients with midgut neuroendocrine liver metastases, a short course of the HDAC inhibitor vorinostat induced a statistically significant increase in SUVmax on 68Ga-DOTATOC PET/computed tomography (CT) imaging in some hepatic neuroendocrine tumor metastases. There was no significant effect of vorinostat on tumor uptake of 123I-MIBG on SPECT/CT imaging. Given the pilot nature of this trial, the findings merit further investigation with a more rigorous protocol evaluating longer pretreatment and different dosages of vorinostat or other HDAC inhibitors, as well as effects on the therapeutic capability of 177Lu- or 90Y-somatostatin analogs.

Population structure drives cultural diversity in finite populations: A hypothesis for localized community patterns on Rapa Nui (Easter Island, Chile).

Understanding how and why cultural diversity changes in human populations remains a central topic of debate in cultural evolutionary studies. Due to the effects of drift, small and isolated populations face evolutionary challenges in the retention of richness and diversity of cultural information. Such variation, however, can have significant fitness consequences, particularly when environmental conditions change unpredictably, such that knowledge about past environments may be key to long-term persistence. Factors that can shape the outcomes of drift within a population include the semantics of the traits as well as spatially structured social networks. Here, we use cultural transmission simulations to explore how social network structure and interaction affect the rate of trait retention and extinction. Using Rapa Nui (Easter Island, Chile) as an example, we develop a model-based hypothesis for how the structural constraints of communities living in small, isolated populations had dramatic effects and likely led to preventing the loss of cultural information in both community patterning and technology.

Addition of 131I-MIBG to PRRT (90Y-DOTATOC) for Personalized Treatment of Selected Patients with Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic neuroendocrine tumors. Delivering a sufficient tumor radiation dose remains challenging because of critical-organ dose limitations. Adding 131I-metaiodobenzylguanidine (131I-MIBG) to PRRT may be advantageous in this regard. Methods: A phase 1 clinical trial was initiated for patients with nonoperable progressive neuroendocrine tumors using a combination of 90Y-DOTATOC plus 131I-MIBG. Treatment cohorts were defined by radiation dose limits to the kidneys and the bone marrow. Subject-specific dosimetry was used to determine the administered activity levels. Results: The first cohort treated subjects to a dose limit of 1,900 cGy to the kidneys and 150 cGy to the marrow. No dose-limiting toxicities were observed. Tumor dosimetry estimates demonstrated an expected dose increase of 34%-83% using combination therapy as opposed to 90Y-DOTATOC PRRT alone. Conclusion: These findings demonstrate the feasibility of using organ dose for a phase 1 escalation design and suggest the safety of using 90Y-DOTATOC and 131I-MIBG.

Overview of the First NRG Oncology-National Cancer Institute Workshop on Dosimetry of Systemic Radiopharmaceutical Therapy.

In 2018, the National Cancer Institute and NRG Oncology partnered for the first time to host a joint workshop on systemic radiopharmaceutical therapy (RPT) to specifically address dosimetry issues and strategies for future clinical trials. The workshop focused on current dosimetric approaches for clinical trials, strategies under development that would optimize dose reporting, and future desired or optimized approaches for novel emerging radionuclides and carriers in development. In this article, we review the main approaches that are applied clinically to calculate the absorbed dose. These include absorbed doses calculated over a variety of spatial scales, including whole body, organ, suborgan, and voxel, the last 3 of which are achievable within the MIRD schema (S value) and can be calculated with analytic methods or Monte Carlo methods, the latter in most circumstances. This article will also contrast currently available methods and tools with those used in the past, to propose a pathway whereby dosimetry helps the field by optimizing the biologic effect of the treatment and trial design in the drug approval process to reduce financial and logistical costs. We also briefly discuss the dosimetric equivalent of biomarkers to help bring a precision medicine approach to RPT implementation when merited by evidence collected during early-phase trial investigations. Advances in the methodology and related tools have made dosimetry the optimum biomarker for RPT.

Assay determination by mass spectrometry for oligonucleotide therapeutics.

Phosphorothioate oligonucleotide drugs typically contain product-related impurities that are difficult to resolve chromatographically from the parent oligonucleotide due to the size of these compounds and the large number of stereoisomers that comprise the parent. The presence of co-eluting impurities hinders the process of determining assay based on chromatographic separation alone. A mass spectrometry-based purity assessment of the main chromatography peak can be used to quantify co-eluting impurities and enable the accurate determination of assay, but a more direct measure of assay was desired due to the complexity of measuring all co-eluting impurities by mass spectrometry. Therefore, we developed an assay method that utilizes the specificity of mass spectrometry to measure the amount of active pharmaceutical ingredient in a sample, which eliminates the need for chromatographic separation of impurities from the product. This procedure uses a single quadrupole mass spectrometer and incorporates an internal standard that is co-sprayed with the analyte to compensate for the drift commonly associated with mass spectrometry-based quantitation. Using the mass spectrometry response ratio for sample to internal standard enables the method to achieve excellent linearity (R2 = 0.998), repeatability (relative standard deviation = 0.5%), intermediate precision (0.6%), and accuracy, with measured assay values consistently within 2.0% of expected. The results indicate the method possesses the accuracy and precision required for measuring assay in clinical and commercial stage pharmaceutical products. Since the method is based on the specificity of the mass spectrometer, and does not rely on chromatographic separation of impurities, the procedure should be applicable to a wide variety of oligonucleotide therapeutics regardless of sequence or chemical modifications.

Technical Note: Single time point dose estimate for exponential clearance.

OBJECTIVE: Although personalized dosimetry may be desirable for radionuclide therapy treatments, the multiple time samples required to determine the total integrated activity puts a burden on patients and clinic resources. The aim of this paper is to demonstrate that when some prior knowledge is known about the tracer kinetic parameters, the total integrated activity (and thus radiation dose) can be estimated from a single time sample. METHODS: Mathematical derivations have been performed to generate equations for the total integrated activity in terms of a single time sample of activity for monoexponential and biexponential clearance. Simulations were performed using both exponential models where the rate constants and associated parameters were randomly sampled from distributions with a known mean. The actual total integrated activity for each random sample was compared with the estimated total integrated activity using the mean value of the parameters. Retrospective analysis of 90 Y DOTATOC data from a clinical trial provided a comparison of actual kidney dose with the estimated kidney dose using the single time point approach. RESULTS: The optimal sampling time for the single point approach was found to be equal to the mean time of the rate constant. The simulation results for the monoexponential and biexpoential models were similar. Regressions comparing the actual and estimated total integrated activity had very high correlations (r2  > 0.95) along with acceptable standard errors of estimate, especially at the optimal sampling point. The retrospective analysis of the 90 Y DOTATOC data also yielded similar results with an r2  = 0.95 and a standard error of estimate of 61 cGy. CONCLUSIONS: In situations where there is prior knowledge about the population averages of kinetic parameters, these results suggest that the single time point approach can be used to estimate the total integrated activity and dose with sufficient accuracy to manage radionuclide therapy. This will make personalized dosimetry much easier to perform and more available to the community.

90Y-DOTATOC Dosimetry-Based Personalized Peptide Receptor Radionuclide Therapy.

Pretherapy PET with 86Y-DOTATOC is considered the ideal dosimetry protocol for 90Y-DOTATOC therapy; however, its cost, limited availability, and need for infusion of amino acids to mimic the therapy administration limit its use in the clinical setting. The goal of this study was to develop a dosimetric method for 90Y-DOTATOC using 90Y-DOTATOC PET/CT and bremsstrahlung SPECT/CT and to determine whether dosimetry-based administered activities differ significantly from standard administered activities. Methods: This was a prospective phase 2 trial of 90Y-DOTATOC therapy in patients with somatostatin receptor-positive tumors. 90Y-DOTATOC was given in 3 cycles 6-8 wk apart. In the first cycle of therapy, adults received 4.4 GBq and children received 1.85 GBq/m2; the subsequent administered activities were adjusted according to the dosimetry of the preceding cycle so as not to exceed a total kidney dose of 23 Gy and bone marrow dose of 2 Gy. The radiation dose to the kidneys was determined from serial imaging sessions consisting of time-of-flight 90Y-DOTATOC PET/CT at 5 h after therapy and 90Y-DOTATOC bremsstrahlung SPECT/CT at 6, 24, 48, and 72 h. The PET/CT data were used to measure the absolute concentration of 90Y-DOTATOC and to calibrate the bremsstrahlung SPECT kidney clearance data. The radiation dose to the kidneys was determined by multiplying the time-integrated activity (from the fitted biexponential curve of renal clearance of 90Y-DOTATOC) with the energy emitted per decay, divided by the mass of the kidneys. Results: The radiation dose to the kidneys per cycle of 90Y-DOTATOC therapy was highly variable among patients, ranging from 0.32 to 3.0 mGy/MBq. In 17 (85%) of the 20 adult patients who received the second and the third treatment cycles of 90Y-DOTATOC, the administered activity was modified by at least 20% from the starting administered activity. Conclusion: Renal dosimetry of 90Y-DOTATOC is feasible using 90Y-DOTATOC time-of-flight PET/CT and bremsstrahlung SPECT/CT and has a significant impact on the administered activity in treatment cycles.

Effect of fatigue on reading computed tomography examination of the multiply injured patient.

Our goal was to ascertain how fatigue affects performance in reading computed tomography (CT) examinations of patients with multiple injuries. CT images with multiple fractures from a previous study of satisfaction of search (SOS) were read by radiologists after a day of clinical work. Performance in this study with fatigued readers was compared to a previous study in which readers were not fatigued. Detection accuracy for obvious injuries was not affected by fatigue, but accuracy for subtle fractures was reduced ([Formula: see text]). An SOS effect on decision thresholds was evident mirroring recent studies. Without fatigue, readers spent more time interpreting and reporting findings as the number of the injuries increased. When fatigued, readers did not increase reading time as fracture number increased. Without fractures, reading time for not-fatigued and fatigued readers was the same ([Formula: see text]) but was significant ([Formula: see text]) with an added subtle fracture. The difference increased with a major injury ([Formula: see text]) and increased further with both a major injury and subtle fracture ([Formula: see text]). Fatigue and multiple abnormalities have independent effects on detection performance but do interact in determining search time.

The Impact of Fatigue on Satisfaction of Search in Chest Radiography.

RATIONALE AND OBJECTIVES: To assess the nature of the satisfaction of search (SOS) effect in chest radiography when observers are fatigued; determine if we could replicate recent findings that have documented the nature of the SOS effect to be due to a threshold shift rather than a change in diagnostic accuracy as in earlier film-based studies. MATERIALS AND METHODS: Nearing or at the end of a clinical workday, 20 radiologists read 64 chest images twice, once with and once without the addition of a simulated pulmonary nodule. Half of the images had different types of "test" abnormalities. Decision thresholds were analyzed using the center of the range of false-positive (FP) and true-positive (TP) fractions associated with each receiver operating characteristic (ROC) point for reporting test abnormalities. Detection accuracy was assessed with ROC technique and inspection time was recorded. RESULTS: The SOS effect was confirmed to be a reduction in willingness to respond (threshold shift). The center of the FP range was significantly reduced (FP = 0.10 without added nodules, FP = 0.05 with added nodules, F(1,18) = 19.85, P = 0.0003). The center of the TP range was significantly reduced (TP = 0.39 without added nodules, TP = 0.33 with added nodules, F(1,18) = 10.81, P = 0.004). CONCLUSIONS: This study suggests that fatigue does not change the nature of the SOS effect, but rather may be additive with the SOS effect. SOS reduces both TP and FP responses, whereas fatigue reduces TPs more than FPs.

Trauma in CT: The Role of Severe Injury on Satisfaction of Search Revised.

PURPOSE: The satisfaction-of-search (SOS) effect occurs when an abnormality on an image is missed because another is found. The aim of this experiment was to test whether severe distracting fractures control the magnitude of SOS on other fractures when both appear in a single CT image. METHODS: The institutional review board approved this study. The experimental (SOS) condition included 35 cervical spine CT cases, all of which contained severe cervical spine injuries. For each of these cases, a similar case was found that had no injuries. Image modification software was developed to add simulated fractures to each pair of cases, with and without a major injury. Sixteen different minor fractures were added to 16 of the 35 pairs of images. The 35 cases without native injuries constituted a control (non-SOS) condition mixed in a random order. Twenty radiologists read 35 mixed cases in each of two sessions. False-positive evaluations were collected only for cases without simulated fractures. RESULTS: An SOS effect on the detection of simulated fractures was not observed. There was a nonsignificant (P = .07) finding of poorer detection in the presence of cases with severe injuries. However, the magnitude of the effect was no greater than has been observed for less severe distracting injuries. CONCLUSIONS: The outcome agrees with the results of two previous experiments that failed to yield an SOS effect associated with detecting severe injuries, suggesting that the severity of a distracting injury does not determine whether a second injury is discovered.

The Influence of a Vocalized Checklist on Detection of Multiple Abnormalities in Chest Radiography.

RATIONALE AND OBJECTIVES: Although a checklist has been recommended for preventing satisfaction of search (SOS) errors, a previous research study did not demonstrate that benefit. However, observers in that study had to turn away from the image display to use the checklist. The current study tested a vocalized checklist to avoid this constraint. MATERIALS AND METHODS: A total of 64 chest computed radiographs, half containing various "test" abnormalities, were read twice by 20 radiologists, once with and once without the addition of a simulated pulmonary nodule. Readers used a vocalized checklist-directing search. Receiver operating characteristic (ROC) detection accuracy and decision thresholds were analyzed to study the effects of adding the nodule on detecting the test abnormalities. RESULTS: Adding nodules induced a substantial reluctance to report the other abnormalities (P < 0.001), as had been the case in the most recent study of the SOS effect in radiography. CONCLUSIONS: The vocalized checklist did not reduce nor eliminate the SOS effect on readiness to report further abnormalities. Although useful for organizing search and reporting, particularly among students, a vocalized checklist does not prevent SOS effects.

Satisfaction of Search in Chest Radiography 2015.

RATIONALE AND OBJECTIVES: Two decades have passed since the publication of laboratory studies of satisfaction of search (SOS) in chest radiography. Those studies were performed using film. The current investigation tests for SOS effects in computed radiography of the chest. METHODS: Sixty-four chest computed radiographs half demonstrating various "test" abnormalities were read twice by 20 radiologists, once with and once without the addition of a simulated pulmonary nodule. Receiver-operating characteristic detection accuracy and decision thresholds were analyzed to study the effects of adding the nodule on detecting the test abnormalities. Results of previous studies were reanalyzed using similar modern techniques. RESULTS: In the present study, adding nodules did not influence detection accuracy for the other abnormalities (P = .93), but did induce a reluctance to report them (P < .001). Adding nodules did not affect inspection time (P = .58) so the reluctance to report was not associated with reduced search. Reanalysis revealed a similar decision threshold shift that had not been recognized in the early studies of SOS in chest radiography (P < .01) in addition to reduced detection accuracy (P < .01). CONCLUSIONS: The nature of SOS in chest radiography has changed, but it is not clear why. ADVANCES IN KNOWLEDGE: SOS may be changing as a function of changes in radiology education and practice.

A theoretically-sufficient and computationally-practical technique for deterministic frequency seriation.

Frequency seriation played a key role in the formation of archaeology as a discipline due to its ability to generate chronologies. Interest in its utility for exploring issues of contemporary interest beyond chronology, however, has been limited. This limitation is partly due to a lack of quantitative algorithms that can be used to build deterministic seriation solutions. When the number of assemblages becomes greater than just a handful, the resources required for evaluation of possible permutations easily outstrips available computing capacity. On the other hand, probabilistic approaches to creating seriations offer a computationally manageable alternative but rely upon a compressed description of the data to order assemblages. This compression removes the ability to use all of the features of our data to fit to the seriation model, obscuring violations of the model, and thus lessens our ability to understand the degree to which the resulting order is chronological, spatial, or a mixture. Recently, frequency seriation has been reconceived as a general method for studying the structure of cultural transmission through time and across space. The use of an evolution-based framework renews the potential for seriation but also calls for a computationally feasible algorithm that is capable of producing solutions under varying configurations, without manual trial and error fitting. Here, we introduce the Iterative Deterministic Seriation Solution (IDSS) for constructing frequency seriations, an algorithm that dramatically constrains the search for potential valid orders of assemblages. Our initial implementation of IDSS does not solve all the problems of seriation, but begins to moves towards a resolution of a long-standing problem in archaeology while opening up new avenues of research into the study of cultural relatedness. We demonstrate the utility of IDSS using late prehistoric decorated ceramics from the Mississippi River Valley. The results compare favorably to previous analyses but add new details into the structure of cultural transmission of these late prehistoric populations.

Parallel synthesis and screening of peptide conjugates.

Peptide conjugates represent an emerging class of therapeutics. However, in contrast to that of small molecules and peptides, the discovery and optimization of peptide conjugates is low in throughput, resource intensive, time-consuming, and based on educated decisions rather than screening. A strategy for the parallel synthesis and screening of peptide conjugates is presented that (1) reduces variability in the conjugation steps; (2) provides a new method to rapidly and quantitatively measure conversion in crude conjugation mixtures; (3) introduces a purification step using an immobilized chemical scavenger that does not rely on protein-specific binding; and (4) is supported by robust analytical methods to characterize the large number of end products. Copper-free click chemistry is used as the chemoselective ligation method for conjugation and purification. The productivity in the generation and screening of peptide conjugates is significantly improved by applying this strategy as is demonstrated by the optimization of the anti-Angiopoietin-2 (Ang2) CovX-body, CVX-060, a peptide-antibody scaffold conjugate that has advanced in clinical trials for oncology indications.

Improved nuclear medicine uniformity assessment with noise texture analysis.

UNLABELLED: Because γ cameras are generally susceptible to environmental conditions and system vulnerabilities, they require routine evaluation of uniformity performance. The metrics for such evaluations are commonly pixel value-based. Although these metrics are typically successful at identifying regional nonuniformities, they often do not adequately reflect subtle periodic structures; therefore, additional visual inspections are required. The goal of this project was to develop, test, and validate a new uniformity analysis metric capable of accurately identifying structures and patterns present in nuclear medicine flood-field uniformity images. METHODS: A new uniformity assessment metric, termed the structured noise index (SNI), was based on the 2-dimensional noise power spectrum (NPS). The contribution of quantum noise was subtracted from the NPS of a flood-field uniformity image, resulting in an NPS representing image artifacts. A visual response filter function was then applied to both the original NPS and the artifact NPS. A single quantitative score was calculated on the basis of the magnitude of the artifact. To verify the validity of the SNI, an observer study was performed with 5 expert nuclear medicine physicists. The correlation between the SNI and the visual score was assessed with Spearman rank correlation analysis. The SNI was also compared with pixel value-based assessment metrics modeled on the National Electrical Manufacturers Association standard for integral uniformity in both the useful field of view (UFOV) and the central field of view (CFOV). RESULTS: The SNI outperformed the pixel value-based metrics in terms of its correlation with the visual score (ρ values for the SNI, integral UFOV, and integral CFOV were 0.86, 0.59, and 0.58, respectively). The SNI had 100% sensitivity for identifying both structured and nonstructured nonuniformities; for the integral UFOV and CFOV metrics, the sensitivities were only 62% and 54%, respectively. The overall positive predictive value of the SNI was 87%; for the integral UFOV and CFOV metrics, the positive predictive values were only 67% and 50%, respectively. CONCLUSION: The SNI accurately identified both structured and nonstructured flood-field nonuniformities and correlated closely with expert visual assessment. Compared with traditional pixel value-based analysis, the SNI showed superior performance in terms of its correlation with visual perception. The SNI method is effective for detecting and quantifying visually apparent nonuniformities and may reduce the need for more subjective visual analyses.

Feasibility and advantage of adding (131)I-MIBG to (90)Y-DOTATOC for treatment of patients with advanced stage neuroendocrine tumors.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is an effective form of treatment for patients with metastatic neuroendocrine tumors (NETs). However, delivering sufficient radiation dose to the tumor to result in a high percentage of long-term tumor remissions remains challenging because of the limits imposed on administered activity levels by radiation damage to normal tissues. The goal of this study was to evaluate the dosimetric advantages of adding (131)I meta-iodobenzylguanidine ((131)I-MIBG) to (90)Y DOTA Phe1-Tyr3-octreotide ((90)Y-DOTATOC) in patients with advanced stage midgut NETs. METHODS: Ten patients were imaged simultaneously with (131)I-MIBG and (111)In-pentetreotide (as a surrogate for (90)Y-DOTATOC) on days 1, 2, and 3 post-administration. Blood samples were obtained at the same time points. Using dosimetry measures from this data and our previously published methodology for calculating optimal combined administered activity levels for therapy, we determined the amount of (131)I-MIBG that could be added to (90)Y-DOTATOC without exceeding normal organ dose limits (marrow and kidneys) along with the expected increase in associated tumor dose, if any. RESULTS: We found that a median value of 34.6 GBq of (131)I-MIBG could be safely added to (90)Y-DOTATOC (delivered over multiple cycles) by reducing the maximum total deliverable (90)Y-DOTATOC by a median value of 24.5%. Taking this treatment approach, we found that there would be a median increase in deliverable tumor dose of 4,046 cGy in six of the ten subjects. Of note, there were a small number of metastases that were positive for only one or the other of these radiopharmaceuticals within the same subject. CONCLUSIONS: We conclude that approximately half of the patients with midgut NETs that are eligible for PRRT could reasonably be expected to benefit from the addition of (131)I-MIBG to (90)Y-DOTATOC.

Repeatability of gallium-68 DOTATOC positron emission tomographic imaging in neuroendocrine tumors.

OBJECTIVE: To evaluate the repeatability of gallium-68 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic (DOTA)-D-Phe1-Try3-octreotide (68Ga-DOTATOC) positron emission tomography (PET) in neuroendocrine tumors. METHODS: Five patients with neuroendocrine tumors were imaged with 68Ga-DOTATOC PET twice within 5 days. Maximum and mean standardized uptake values (SUVmax and SUVmean) and kinetic parameters (K-Patlak and K-influx) of target lesions were measured. The repeatability of these measurements was investigated. RESULTS: Forty-seven target lesions were identified on whole-body PET and 21 lesions on dynamic images. There was excellent repeatability with intraclass correlation coefficient of 0.99 for SUVmax, SUVmean, and K-Patlak, and 0.85 for K-influx. The median absolute percent differences and the interquartile ranges (IQR) between 2 scans for SUVmax and SUVmean were 7.4% (IQR, 14.1%) and 9.3% (IQR, 10.6%), respectively. The median absolute percent differences for K-Patlak and K-influx were 12.5% (IQR, 12.6%) and 29.9% (IQR, 22.4%), respectively. The SUVmax of target lesions did not differ by more than 25% between the 2 scans. CONCLUSIONS: 68Ga-DOTATOC PET imaging of neuroendocrine tumors is highly reproducible. A difference of more than 25% in SUVmax represents a change that is larger than the measurement error observed on repeated studies and should reflect a significant change in the biological character of the tumor.