Feasibility and metabolic outcomes of a well-formulated ketogenic diet as an adjuvant therapeutic intervention for women with stage IV metastatic breast cancer: The Keto-CARE trial.

PURPOSE: Ketogenic diets may positively influence cancer through pleiotropic mechanisms, but only a few small and short-term studies have addressed feasibility and efficacy in cancer patients. The primary goals of this study were to evaluate the feasibility and the sustained metabolic effects of a personalized well-formulated ketogenic diet (WFKD) designed to achieve consistent blood beta-hydroxybutyrate (ßHB) >0.5 mM in women diagnosed with stage IV metastatic breast cancer (MBC) undergoing chemotherapy. METHODS: Women (n = 20) were enrolled in a six month, two-phase, single-arm WFKD intervention (NCT03535701). Phase I was a highly-supervised, ad libitum, personalized WFKD, where women were provided with ketogenic-appropriate food daily for three months. Phase II transitioned women to a self-administered WFKD with ongoing coaching for an additional three months. Fasting capillary ßHB and glucose were collected daily; weight, body composition, plasma insulin, and insulin resistance were collected at baseline, three and six months. RESULTS: Capillary ßHB indicated women achieved nutritional ketosis (Phase I mean: 0.8 mM (n = 15); Phase II mean: 0.7 mM (n = 9)). Body weight decreased 10% after three months, primarily from body fat. Fasting plasma glucose, plasma insulin, and insulin resistance also decreased significantly after three months (p < 0.01), an effect that persisted at six months. CONCLUSIONS: Women diagnosed with MBC undergoing chemotherapy can safely achieve and maintain nutritional ketosis, while improving body composition and insulin resistance, out to six months.

Higher Computed Tomography (CT) Scan Resolution Improves Accuracy of Patient-specific Mandibular Models When Compared to Cadaveric Gold Standard.

BACKGROUND: 3D-printed patient-specific anatomical models are becoming an increasingly popular tool for planning reconstructive surgeries to treat oral cancer. Currently there is a lack of information regarding model accuracy, and how the resolution of the computed tomography (CT) scan affects the accuracy of the final model. PURPOSE: The primary objective of this study was to determine the CT z-axis resolution necessary in creating a patient specific mandibular model with clinically acceptable accuracy for global bony reconstruction. This study also sought to evaluate the effect of the digital sculpting and 3D printing process on model accuracy. STUDY DESIGN: This was a cross-sectional study using cadaveric heads obtained from the Ohio State University Body Donation Program. INDEPENDENT VARIABLES: The first independent variable is CT scan slice thickness of either 0.675 , 1.25, 3.00, or 5.00 mm. The second independent variable is the three produced models for analysis (unsculpted, digitally sculpted, 3D printed). MAIN OUTCOME VARIABLE: The degree of accuracy of a model as defined by the root mean square (RMS) value, a measure of a model's discrepancy from its respective cadaveric anatomy. ANALYSES: All models were digitally compared to their cadaveric bony anatomy using a metrology surface scan of the dissected mandible. The RMS value of each comparison evaluates the level of discrepancy. One-way ANOVA tests (P < .05) were used to determine statistically significant differences between CT scan resolutions. Two-way ANOVA tests (P < .05) were used to determine statistically significant differences between groups. RESULTS: CT scans acquired for 8 formalin-fixed cadaver heads were processed and analyzed. The RMS for digitally sculpted models decreased as slice thickness decreased, confirming that higher resolution CT scans resulted in statistically more accurate model production when compared to the cadaveric gold standard. Furthermore, digitally sculpted models were significantly more accurate than unsculpted models (P < .05) at each slice thickness. CONCLUSIONS: Our study demonstrated that CT scans with slice thicknesses of 3.00 mm or smaller created statistically significantly more accurate models than models created from slice thicknesses of 5.00 mm. The digital sculpting process statistically significantly increased the accuracy of models and no loss of accuracy through the 3D printing process was observed.

Cytidine 5'-Diphosphocholine Corrects Alveolar Type II Cell Mitochondrial Dysfunction in Influenza-infected Mice.

Development of acute respiratory distress syndrome (ARDS) in influenza A virus (IAV)-infected mice is associated with inhibition of ATII (alveolar type II) epithelial cell de novo phosphatidylcholine synthesis, and administration of the phosphatidylcholine precursor cytidine 5'-diphosphocholine (CDP-choline) attenuates IAV-induced acute respiratory distress syndrome in mice. We hypothesized inhibition of phosphatidylcholine synthesis would also impact the function of ATII cell mitochondria. To test this hypothesis, adult C57BL/6 mice of both sexes were inoculated intranasally with 10,000 pfu/mouse influenza A/WSN/33 (H1N1). Control mice were mock-infected with virus diluent. Mice were treated with saline vehicle or CDP-choline (100 µg/mouse i.p.) once daily from 1 to 5 days postinoculation (dpi). ATII cells were isolated by a standard lung digestion protocol at 6 dpi for analysis of mitochondrial function. IAV infection increased uptake of the glucose analog fludeoxyglucose F 18 by the lungs and caused a switch from oxidative phosphorylation to aerobic glycolysis as a primary means of ATII cell ATP synthesis by 6 dpi. Infection also induced ATII cell mitochondrial depolarization and shrinkage, upregulation of PGC-1α, decreased cardiolipin content, and reduced expression of mitofusin 1, OPA1, DRP1, complexes I and IV of the electron transport chain, and enzymes involved in cardiolipin synthesis. Daily CDP-choline treatment prevented the declines in oxidative phosphorylation, mitochondrial membrane potential, and cardiolipin synthesis resulting from IAV infection but did not fully reverse the glycolytic shift. CDP-choline also did not prevent the alterations in mitochondrial protein expression resulting from infection. Taken together, our data show ATII cell mitochondrial dysfunction after IAV infection results from impaired de novo phospholipid synthesis, but the glycolytic shift does not.

Endovascular repair and open repair surgery of thoraco-abdominal aortic aneurysms cause drastically different types of spinal cord injury.

Both endovascular repair (EVR) and open repair (OR) surgery of thoraco-abdominal aortic aneurysms cause spinal cord (SC) injury that can lead to paraparesis or paraplegia. It has been assumed that mechanisms responsible for SC damage after EVR are similar to those after OR. This pilot study compared the pathophysiology of SC injury after EVR versus OR using a newly developed EVR dog model. An increasing number of stents similar to those used in patients were inserted in the aorta of three dogs to ensure thoracic or thoracic plus lumbar coverage. The aorta of OR dogs was cross-clamped for 45 min. Behavior assessment demonstrated unique patterns of proprioceptive ataxia and evolving paraparesis in EVR versus irreversible paraplegia in OR. MRI showed posterior signal in lumbar SC after EVR versus central cord edema after OR. Histopathology showed white matter edema in L3-L5 localized to the dorsal column medial lemniscus area associated with loss of myelin basic protein but not neurons after EVR, versus massive neuronal loss in the gray matter in L3-L5 after OR. Metabolome analysis demonstrates a distinctive chemical fingerprint of cellular processes in both interventions. Our results call for the development of new therapeutics tailored to these distinct pathophysiologic findings.

Enhancing Patient Experience With Internet Protocol Addressable Digital Light-Emitting Diode Lighting in Imaging Environments: A Phase I Study.

BACKGROUND: Conventional approaches to improve the quality of clinical patient imaging studies focus predominantly on updating or replacing imaging equipment; however, it is often not considered that patients can also highly influence the diagnostic quality of clinical imaging studies. Patient-specific artifacts can limit the diagnostic image quality, especially when patients are uncomfortable, anxious, or agitated. Imaging facility or environmental conditions can also influence the patient's comfort and willingness to participate in diagnostic imaging studies, especially when performed in visually unesthetic, anxiety-inducing, and technology-intensive imaging centers. When given the opportunity to change a single aspect of the environmental or imaging facility experience, patients feel much more in control of the otherwise unfamiliar and uncomfortable setting. Incorporating commercial, easily adaptable, ambient lighting products within clinical imaging environments allows patients to individually customize their environment for a more personalized and comfortable experience. OBJECTIVE: The aim of this pilot study was to use a customizable colored light-emitting diode (LED) lighting system within a clinical imaging environment and demonstrate the feasibility and initial findings of enabling healthy subjects to customize the ambient lighting and color. Improving the patient experience within clinical imaging environments with patient-preferred ambient lighting and color may improve overall patient comfort, compliance, and participation in the imaging study and indirectly contribute to improving diagnostic image quality. METHODS: We installed consumer-based internet protocol addressable LED lights using the ZigBee standard in different imaging rooms within a clinical imaging environment. We recruited healthy volunteers (n=35) to generate pilot data in order to develop a subsequent clinical trial. The visual perception assessment procedure utilized questionnaires with preprogrammed light/color settings and further assessed how subjects preferred ambient light and color within a clinical imaging setting. RESULTS: Technical implementation using programmable LED lights was performed without any hardware or electrical modifications to the existing clinical imaging environment. Subject testing revealed substantial variabilities in color perception; however, clear trends in subject color preference were noted. In terms of the color hue of the imaging environment, 43% (15/35) found blue and 31% (11/35) found yellow to be the most relaxing. Conversely, 69% (24/35) found red, 17% (6/35) found yellow, and 11% (4/35) found green to be the least relaxing. CONCLUSIONS: With the majority of subjects indicating that colored lighting within a clinical imaging environment would contribute to an improved patient experience, we predict that enabling patients to customize environmental factors like lighting and color to individual preferences will improve patient comfort and patient satisfaction. Improved patient comfort in clinical imaging environments may also help to minimize patient-specific imaging artifacts that can otherwise limit diagnostic image quality. TRIAL REGISTRATION: ClinicalTrials.gov NCT03456895; https://clinicaltrials.gov/ct2/show/NCT03456895.

Systemic Biodistribution and Intravitreal Pharmacokinetic Properties of Bevacizumab, Ranibizumab, and Aflibercept in a Nonhuman Primate Model.

Purpose: To determine the intravitreal pharmacokinetic properties and to study the systemic biodistribution characteristics of I-124-labeled bevacizumab, ranibizumab, and aflibercept with positron emission tomography-computed tomography (PET/CT) imaging in a nonhuman primate model. Methods: Three groups with four owl monkeys per group underwent intravitreal injection with 1.25 mg/0.05 mL I-124 bevacizumab, 0.5 mg/0.05 mL I-124 ranibizumab, or 2.0 mg/0.05 mL I-124 aflibercept in the right eye of each subject. All subjects were imaged using PET/CT on days 0, 1, 2, 4, 8, 14, 21, 28, and 35. Serum blood draws were performed at hours 1, 2, 4, 8, 12 and days 1, 2, 4, 8, 14, 21, 28, and 35. Radioactivity emission measurements were used to determine the intravitreal half-lives of each agent and to study the differences of radioactivity uptake in nonocular organs. Results: The intravitreal half-lives were 3.60 days for I-124 bevacizumab, 2.73 days for I-124 ranibizumab, and 2.44 days for I-124 aflibercept. Serum levels were highest and most prolonged for bevacizumab as compared to both ranibizumab and aflibercept. All agents were primarily excreted through the renal and mononuclear phagocyte systems. However, bevacizumab was also found in significantly higher levels in the liver, heart, and distal femur bones. Conclusions: Among the three anti-VEGF agents used in clinical practice, bevacizumab demonstrated the longest intravitreal retention time and aflibercept the shortest. Significantly higher and prolonged levels of bevacizumab were found in the serum as well as in the heart, liver, and distal bones. These differences may be considered by clinicians when formulating treatment algorithms for intravitreal therapies with these agents.

Advanced Functional Tumor Imaging and Precision Nuclear Medicine Enabled by Digital PET Technologies.

The purpose of this article is to provide a brief overview of the background, basic principles, technological evolution, clinical capabilities, and future directions for functional tumor imaging as PET evolves from the conventional photomultiplier tube-based platform into a fully digital detector acquisition platform. The recent introduction of solid-state digital photon counting PET detector is the latest evolution of clinical PET which enables faster time-of-flight timing resolution that leads to more precise localization of the annihilation events and further contributes to reduction in partial volume and thus makes high definition and ultrahigh definition PET imaging feasible with current standard acquisition procedures. The technological advances of digital PET can be further leveraged by optimizing many of the acquisition and reconstruction methodologies to achieve faster image acquisition to improve cancer patient throughput, lower patient dose in accordance with ALARA, and improved quantitative accuracy to enable biomarker capability. Digital PET technology will advance molecular imaging capabilities beyond oncology and enable Precision Nuclear Medicine.

ACL graft metabolic activity assessed by 18FDG PET-MRI.

BACKGROUND: To demonstrate the use of 18Fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) in combination (18FDG-PET) to assess the metabolic activity of ACL graft tissue and evaluate the utility of this technique for ligament imaging. METHODS: Twenty-one knees with intact ACL grafts in 19 patients at multiple time points following ACL reconstruction were recruited to participate. PET-MRI imaging was performed using a custom device to place knees in the same position for both studies. Images were co-registered for quantification of 18FDG-PET standardized uptake value (SUV) for the proximal, middle, and distal ACL was quantified. Signal in extra-articular muscle tissue in the index knee was also recorded as a control. Signal from each location was compared based on how far post-operative each knee was from ACL reconstruction (<6months, six to 12months, 12-24months, or >24months). RESULTS: Significant differences in 18FDG PET SUV between the four time points were observed in the proximal (p=0.02), middle (p=0.004), and distal (p=0.007) portions of the ACL graft. The greater than 24months group was noted to be different from other groups in each case. No difference in PET 18FDG SUV was noted in the extra-articular muscle in the index knee in each time group (p=0.61). CONCLUSIONS: Metabolic activity was noted to be significantly lower in grafts imaged greater than two years post-reconstruction relative to those grafts that had been in place for shorter periods of time.

Clinical feasibility of 90Y digital PET/CT for imaging microsphere biodistribution following radioembolization.

PURPOSE: The purpose of this study was to evaluate the clinical feasibility of next generation solid-state digital photon counting PET/CT (dPET/CT) technology and imaging findings in patients following 90Y microsphere radioembolization in comparison with standard of care (SOC) bremsstrahlung SPECT/CT (bSPECT/CT). METHODS: Five patients underwent SOC 90Y bremsstrahlung imaging immediately following routine radioembolization with 3.5 ± 1.7 GBq of 90Y-labeled glass microspheres. All patients also underwent dPET/CT imaging at 29 ± 11 h following radioembolization. Matched pairs comparison was used to compare image quality, image contrast and 90Y biodistribution between dPET/CT and bSPECT/CT images. Volumetric assessments of 90Y activity using different isocontour thresholds on dPET/CT and bSPECT/CT images were also compared. RESULTS: Digital PET/CT consistently provided better visual image quality and 90Y-to-background image contrast while depicting 90Y biodistribution than bSPECT/CT. Isocontour volumetric assessment using a 1% threshold precisely outlined 90Y activity and the treatment volume on dPET/CT images, whereas a more restrictive 20% threshold on bSPECT/CT images was needed to obtain comparable treatment volumes. The use of a less restrictive 10% threshold isocontour on bSPECT/CT images grossly overestimated the treatment volume when compared with the 1% threshold on dPET/CT images. CONCLUSIONS: Digital PET/CT is clinically feasible for the assessment of 90Y microsphere biodistribution following radioembolization, and provides better visual image quality and image contrast than routine bSPECT/CT with comparable acquisition times. With further optimization and clinical validation, dPET technology may allow faster and more accurate imaging-based assessment of 90Y microsphere biodistribution.

Minimum lesion detectability as a measure of PET system performance.

BACKGROUND: A phantom in combination with an imaging protocol was developed to measure the limit of small lesion detection on different PET systems. Seven small spheres with inner diameters ranging from 3.95 up to 15.43 mm were imaged in a Jaszczak ECT Phantom, in air, in a cold background, and with sphere to background contrast ratios of 15:1 down to 1.88:1. The imaging times varied from 1 to 16 min. The imaging protocol was performed on the Gemini TF and Vereos by Philips, the mCT and HRRT by Siemens, and the Discovery 710 by General Electric. For each scanning condition, the images were reconstructed with image voxel sizes of 1 to 4 mm cubic voxels. The reconstruction method used for each system was the one recommended by the manufacture to achieve best small image lesion detection results. A human observer study was performed to determine the smallest observable sphere for each scanning condition. RESULTS: All systems were able to image the smallest sphere of 3.95 mm inner diameter at the 15 to 1 signal to background ratio when imaged for 16 min. For a typical whole body per bed position scan time of 2 to 4 min, the smallest imaged sphere varied between 4.95 and 6.23 mm at the 15:1 contrast ratio and 12.43 and 15.43 mm at a contrast ratio of 1.88:1. In general, all systems were consistent with the Rose criteria when determining lesion detectability. CONCLUSIONS: Besides demonstrating that the current state of the art clinical PET/CT systems have the same lesion detection ability, the study demonstrates how sensitive scan time can be to detecting small lesions which have a relatively small contrast uptake in the range of just 2:1. This should help guide imaging protocols to use longer scan times over regions of the subject in which small lesions are suspect.

90Y Digital PET/CT Imaging Following Radioembolization.

Imaging of Y internal pair production with conventional photomultiplier detector PET technology has been previously reported for patients with malignant/metastatic liver lesions treated with Y radioembolization (RE). We present a 54-year-old man with unresectable liver metastases from rectal carcinoma (involving the right and left lobes) who was referred for Y RE and subsequently imaged using new solid-state digital photon counting technology (Vereos 64 Time-of-Flight PET/CT; Philips, Cleveland, OH). Despite imaging at 26 hours following RE, digital PET/CT provides improved image quality and Y-to-background contrast as well as accurate visualization of Y biodistribution when compared with Bremsstrahlung SPECT/CT.

Calibration approach for fluorescence lifetime determination for applications using time-gated detection and finite pulse width excitation.

Time-gated techniques are useful for the rapid sampling of excited-state (fluorescence) emission decays in the time domain. Gated detectors coupled with bright, economical, nanosecond-pulsed light sources like flashlamps and nitrogen lasers are an attractive combination for bioanalytical and biomedical applications. Here we present a calibration approach for lifetime determination that is noniterative and that does not assume a negligible instrument response function (i.e., a negligible excitation pulse width) as does most current rapid lifetime determination approaches. Analogous to a transducer-based sensor, signals from fluorophores of known lifetime (0.5-12 ns) serve as calibration references. A fast avalanche photodiode and a GHz-bandwidth digital oscilloscope is used to detect transient emission from reference samples excited using a nitrogen laser. We find that the normalized time-integrated emission signal is proportional to the lifetime, which can be determined with good reproducibility (typically <100 ps) even for data with poor signal-to-noise ratios ( approximately 20). Results are in good agreement with simulations. Additionally, a new time-gating scheme for fluorescence lifetime imaging applications is proposed. In conclusion, a calibration-based approach is a valuable analysis tool for the rapid determination of lifetime in applications using time-gated detection and finite pulse width excitation.

Characterization of dual-wavelength seminaphthofluorescein and seminapthorhodafluor dyes for pH sensing under high hydrostatic pressures.

Hydrostatic pressure is an important physical parameter in biology, with pressures in the few-hundred-atm range having significant effects on cellular morphology, metabolism, and viability. To ensure valid results when studying pressure effects using fluorescence spectroscopy and imaging methods, metabolic probes need to be characterized for high-pressure use. Of interest is the sensing of pH at high pressures due to the key role that pH plays in cellular function. Despite the availability of pH-sensitive dyes, only a few have been characterized for high-pressure use. Here we present the effects of pressure on the acid-base equilibria of four dual-wavelength seminaphthorhodafluor and seminaphthofluorescein dyes (pK(a)=6.6-7.8). Using phosphate buffers as high-pressure pH references, we investigate the pressure dependence of pK(a) for these dyes and determine the volume change associated with the acid-dissociation reaction. We find that if pressure-induced pK(a) changes are not accounted for during interpretation of emission spectra, systematic errors of up to 0.02 pH units per 100atm would result, comparable to previously measured pressure-induced pH changes in vivo. Results are validated by correctly sensing pH changes in Tris and acetate solutions. Methods presented here are applicable to other metabolic probes utilizing dual-wavelength ratiometric sensing modes.