Increased lesion detectability in patients with locally advanced breast cancer-A pilot study using dynamic whole-body [18F]FDG PET/CT.

BACKGROUND: Accurate diagnosis of axillary lymph node (ALN) metastases is essential for prognosis and treatment planning in breast cancer. Evaluation of ALN is done by ultrasound, which is limited by inter-operator variability, and by sentinel lymph node biopsy and/or ALN dissection, none of which are without risks and/or long-term complications. It is known that conventional 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) has limited sensitivity for ALN metastases. However, a recently developed dynamic whole-body (D-WB) [18F]FDG PET/CT scanning protocol, allowing for imaging of tissue [18F]FDG metabolic rate (MRFDG), has been shown to have the potential to increase lesion detectability. The study purpose was to examine detectability of malignant lesions in D-WB [18F]FDG PET/CT compared to conventional [18F]FDG PET/CT. RESULTS: This study prospectively included ten women with locally advanced breast cancer who were referred for an [18F]FDG PET/CT as part of their diagnostic work-up. They all underwent D-WB [18F]FDG PET/CT, consisting of a 6 min single bed dynamic scan over the chest region started at the time of tracer injection, a 64 min dynamic WB PET scan consisting of 16 continuous bed motion passes, and finally a contrast-enhanced CT scan, with generation of MRFDG parametric images. Lesion visibility was assessed by tumor-to-background and contrast-to-noise ratios using volumes of interest isocontouring tumors with a set limit of 50% of SUVmax and background volumes placed in the vicinity of tumors. Lesion visibility was best in the MRFDG images, with target-to-background values 2.28 (95% CI: 2.04-2.54) times higher than target-to-background values in SUV images, and contrast-to-noise values 1.23 (95% CI: 1.12-1.35) times higher than contrast-to-noise values in SUV images. Furthermore, five imaging experts visually assessed the images and three additional suspicious lesions were found in the MRFDG images compared to SUV images; one suspicious ALN, one suspicious parasternal lymph node, and one suspicious lesion located in the pelvic bone. CONCLUSIONS: D-WB [18F]FDG PET/CT with MRFDG images show potential for improved lesion detectability compared to conventional SUV images in locally advanced breast cancer. Further validation in larger cohorts is needed. CLINICAL TRIAL REGISTRATION: The trial is registered in clinicaltrials.gov, NCT05110443, https://www. CLINICALTRIALS: gov/study/NCT05110443?term=NCT05110443&rank=1 .

Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64 Cu PET/CT study in healthy humans.

BACKGROUND AND AIMS: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption. APPROACH AND RESULTS: Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 ( 64 Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the 64 Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic 64 Cu uptake reflect the effect of drugs on intestinal absorption. 64 Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic 64 Cu activity 1 hour after 64 Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p <0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p <0.02, indicating strong inhibition of intestinal 64 Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p <0.04. CONCLUSIONS: In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.

Effects of tetrathiomolybdate on copper metabolism in healthy volunteers and in patients with Wilson disease.

BACKGROUND & AIMS: In Wilson disease (WD), copper accumulates in the liver and brain causing disease. Bis-choline tetrathiomolybdate (TTM) is a potent copper chelator that may be associated with a lower risk of inducing paradoxical neurological worsening than conventional therapy for neurologic WD. To better understand the mode of action of TTM, we investigated its effects on copper absorption and biliary excretion. METHODS: In a double-blind randomized setting, hepatic 64Cu activity was examined after orally administered 64Cu by PET/CT in 16 healthy volunteers before and after seven days of TTM treatment (15 mg/d) or placebo. Oral 64Cu was administered one hour after the final TTM dose. Changes in hepatic 64Cu activity reflected changes in intestinal 64Cu uptake. Additionally, in four patients with WD, the distribution of 64Cu in venous blood, liver, gallbladder, kidney, and brain was followed after i.v. 64Cu dosing for up to 68 hours before and after seven days of TTM (15 mg/day), using PET/MRI. Increased gallbladder 64Cu activity was taken as evidence of increased biliary 64Cu excretion. RESULTS: In healthy volunteers, TTM reduced intestinal 64Cu uptake by 82% 15 hours after the oral 64Cu dose. In patients with WD, gallbladder 64Cu activity was negligible before and after TTM, while TTM effectively retained 64Cu in the blood, significantly reduced hepatic 64Cu activity at all time-points and significantly reduced cerebral 64Cu activity two hours after the intravenous 64Cu dose. CONCLUSIONS: While we did not show an increase in biliary excretion of 64Cu following TTM administration, we demonstrated that TTM effectively inhibited most intestinal 64Cu uptake and retained 64Cu in the blood stream, limiting the exposure of organs like the liver and brain to 64Cu. IMPACT AND IMPLICATIONS: Bis-choline tetrathiomolybdate (TTM) is an investigational copper chelator being developed for the treatment of Wilson disease. In animal models of Wilson disease, TTM has been shown to facilitate biliary copper excretion. In the present human study, TTM surprisingly did not facilitate biliary copper excretion but instead reduced intestinal copper uptake to a clinically significant degree. Our study builds on our understanding of human copper metabolism and the mechanism of action of TTM.

Distribution of non-ceruloplasmin-bound copper after i.v. 64Cu injection studied with PET/CT in patients with Wilson disease.

Background & Aims: In Wilson disease (WD), copper accumulation and increased non-ceruloplasmin-bound copper in plasma lead to liver and brain pathology. To better understand the fate of non-ceruloplasmin-bound copper, we used PET/CT to examine the whole-body distribution of intravenously injected 64-copper (64Cu). Methods: Eight patients with WD, five heterozygotes, and nine healthy controls were examined by dynamic PET/CT for 90 min and static PET/CT up to 20 h after injection. We measured 64Cu activity in blood and tissue and quantified the kinetics by compartmental analysis. Results: Initially, a large fraction of injected 64Cu was distributed to extrahepatic tissues, especially skeletal muscle. Thus, across groups, extrahepatic tissues accounted for 45-58% of the injected dose (%ID) after 10 min, and 45-55% after 1 h. Kinetic analysis showed rapid exchange of 64Cu between blood and muscle as well as adipose tissue, with 64Cu retention in a secondary compartment, possibly mitochondria. This way, muscle and adipose tissue may protect the brain from spikes in non-ceruloplasmin-bound copper. Tiny amounts of cerebral 64Cu were detected (0.2%ID after 90 min and 0.3%ID after 6 h), suggesting tight control of cerebral copper in accordance with a cerebral clearance that is 2-3-fold lower than in muscle. Compared to controls, patients with WD accumulated more hepatic copper 6-20 h after injection, and also renal copper at 6 h. Conclusion: Non-ceruloplasmin-bound copper is initially distributed into a number of tissues before being redistributed slowly to the eliminating organ, the liver. Cerebral uptake of copper is extremely slow and likely highly regulated. Our findings provide new insights into the mechanisms of copper control. Impact and implications: Maintaining non-ceruloplasmin-bound copper within the normal range is an important treatment goal in WD as this "free" copper is considered toxic to the liver and brain. We found that intravenously injected non-ceruloplasmin-bound copper quickly distributed to a number of tissues, especially skeletal muscle, subcutaneous fat, and the liver, while uptake into the brain was slow. This study offers new insights into the mechanisms of copper control, which may encourage further research into potential new treatment targets. Clinical trial number: 2016-001975-59.

Electrochemical Cellulase-Linked ELASA for Rapid Liquid Biopsy Testing of Serum HER-2/neu.

Non-invasive liquid biopsy assays for blood-circulating biomarkers of cancer allow both its early diagnosis and treatment monitoring. Here, we assessed serum levels of protein HER-2/neu, overexpressed in a number of aggressive cancers, by the cellulase-linked sandwich bioassay on magnetic beads. Instead of traditional antibodies we used inexpensive reporter and capture aptamer sequences, transforming the enzyme-linked immuno-sorbent assay (ELISA) into an enzyme-linked aptamer-sorbent assay (ELASA). The reporter aptamer was conjugated to cellulase, whose digestion of nitrocellulose film electrodes resulted in the electrochemical signal change. ELASA, optimized relative aptamer lengths (dimer vs monomer and trimer), and assay steps allowed 0.1 fM detection of HER-2/neu in the 10% human serum in 1.3 h. Urokinase plasminogen activator and thrombin as well as human serum albumin did not interfere, and liquid biopsy analysis of serum HER-2/neu was similarly robust but 4 times faster and 300 times cheaper than both electrochemical and optical ELISA. Simplicity and low cost of cellulase-linked ELASA makes it a perspective diagnostic tool for fast and accurate liquid biopsy detection of HER-2/neu and of other proteins for which aptamers are available.

Inclusion of Metabolic Tumor Volume in Prognostic Models of Bone and Soft Tissue Sarcoma Increases the Prognostic Value.

Sarcomas are rare and have a high mortality rate. Further prognostic classification, with readily available parameters, is warranted, and several studies have examined circulating biomarkers and PET parameters separately. This single-site, retrospective study aimed to examine the prognostic values of several scoring systems in combination with PET parameters. We included 148 patients with sarcoma, who were treated and scanned at Aarhus University Hospital from 1 January 2016 to 31 December 2019. The Akaike information criterion and Harrell's concordance index were used to evaluate whether the PET parameters added prognostic information to existing prognostic models using circulating biomarkers. Of the PET parameters, metabolic tumor volume (MTV) performed best, and when combined with the existing prognostic models, the prognostic value improved in all models. Backward stepwise selection was used to create a new model, SBSpib, which included albumin, lymphocytes, and one PET parameter, MTV. It has scores ranging from zero to three and increasing hazard ratios; HR = 4.83 (1.02-22.75) for group one, HR = 7.40 (1.6-33.42) for group two, and HR = 17.32 (3.45-86.93) for group three. Consequently, implementing PET parameters in prognostic models improved the prognostic value. SBSpib is a new prognostic model that includes both circulating biomarkers and PET parameters; however, validation in another sarcoma cohort is warranted.

Extracardiac findings with increased perfusion during clinical O-15-H2O PET/CT myocardial perfusion imaging: A case series.

BACKGROUND: Coincidental extracardiac findings with increased perfusion were reported during myocardial perfusion imaging (MPI) with various retention radiotracers. Clinical parametric O-15-H2O PET MPI yielding quantitative measures of myocardial blood flow (MBF) was recently implemented at our facility. We aim to explore whether similar extracardiac findings are observed using O-15-H2O. METHODS AND RESULTS: All patients (2963) were scanned with O-15-H2O PET MPI according to international guidelines and extracardiac findings were collected. In contrast to parametric O-15-H2O MBF images, extracardiac perfusion was assessed using summed images. Biopsy histopathology and other imaging modalities served as reference standards. Various malignant lesions with increased perfusion were detected, including lymphomas, large-celled neuroendocrine tumour, breast, and lung cancer plus metastases from colonic and renal cell carcinomas. Furthermore, inflammatory and hyperplastic benign conditions with increased perfusion were observed: rib fractures, gynecomastia, atelectasis, sarcoidosis, pneumonia, chronic lung inflammation and fibrosis, benign lung nodule, chronic diffuse lung infiltrates, pleural plaques and COVID-19 infiltrates. CONCLUSIONS: Malignant and benign extracardiac coincidental findings with increased perfusion are readily visible and frequently seen on O-15-H2O PET MPI. We recommend evaluating the summed O-15-H2O PET images in addition to the low-dose CT attenuation images.

The pathophysiology of Wilson's disease visualized: A human 64 Cu PET study.

BACKGROUND AND AIMS: Wilson's disease (WD) is a genetic disease with systemic accumulation of copper that leads to symptoms from the liver and brain. However, the underlying defects in copper transport kinetics are only partly understood. We sought to quantify hepatic copper turnover in patients with WD compared with heterozygote and control subjects using PET with copper-64 (64 Cu) as a tracer. Furthermore, we assessed the diagnostic potential of the method. APPROACH AND RESULTS: Nine patients with WD, 5 healthy heterozygote subjects, and 8 healthy controls were injected with an i.v. bolus of 64 Cu followed by a 90-min dynamic PET scan of the liver and static whole-body PET/CT scans after 1.5, 6, and 20 h. Blood 64 Cu concentrations were measured in parallel. Hepatic copper retention and redistribution were evaluated by standardized uptake values (SUVs). At 90 min, hepatic SUVs were similar in the three groups. In contrast, at 20 h postinjection, the SUV in WD patients (mean ± SEM, 31 ± 4) was higher than in heterozygotes (24 ± 3) and controls (21 ± 4; p < 0.001). An SUV-ratio of hepatic 64 Cu concentration at 20 and 1.5 h completely discriminated between WD patients and control groups (p < 0.0001; ANOVA). By Patlak analysis of the initial 90 min of the PET scan, the steady-state hepatic clearance of 64 Cu was estimated to be slightly lower in patients with WD than in controls (p = 0.04). CONCLUSIONS: 64 Cu PET imaging enables visualization and quantification of the hepatic copper retention characteristic for WD patients. This method represents a valuable tool for future studies of WD pathophysiology, and may assist the development of therapies, and accurate diagnosis.

Absent 18F-FDG Uptake in the Brain-Unsuspected Brain Death.

Brain death is the complete, irreversible cessation of brain function, including the capacity for brainstem, respiratory, and vegetative activities. It is a clinical diagnosis that can be supplemented with brain perfusion imaging. Absent cerebral blood flow can be visualized with CT angiography or perfusion scintigraphy. F-FDG PET/CT, visualizing glucose uptake, is another approach that has been shown to indicate brain death in small case series. We here present a case with unsuspected absent F-FDG uptake and thus no metabolic activity, in the brain. The patient was declared brain dead later the same day.

Immobilization Decreases FOXO3a Phosphorylation and Increases Autophagy-Related Gene and Protein Expression in Human Skeletal Muscle.

Immobilization of the lower limbs promotes a catabolic state that reduces muscle mass, whereas physical training promotes an anabolic state that increases muscle mass. Understanding the molecular mechanisms underlying this is of clinical interest, as loss of muscle mass is a major complication to critical illness in humans. To determine the molecular regulation of protein synthesis and degradation during muscle loss and hypertrophy, we examined skeletal muscle biopsies from healthy human subjects after 2 weeks unilateral immobilization of a lower limb and during 6 weeks of physical rehabilitation. We have previously shown that cross-sectional area of the knee muscle-extensors decreased by ∼10% during immobilization and was completely restored during rehabilitation. Here we provide novel data to suggest that autophagy is an important underlying mechanism involved in regulation of muscle mass. Protein expression of MuRF1 and ATROGIN-1 did not change during the study, indicating that the recruitment of substrates to the proteasomes was unaltered. Phosphorylation of mTORat Ser2448 did not change during the study, and neither did phosphorylation of the mTORC1 substrates 4EBP1 Thr37/46 and p70S6K Thr389, suggesting that this pathway does not suppress protein synthesis during muscle wasting. Protein levels of p62 and ULK1 increased during immobilization and returned to baseline levels during rehabilitation. Same pattern was observed for FOXO3a phosphorylation at Ser318/321, suggesting transcriptional activation during immobilization and inactivation during rehabilitation. To investigate this further, we analyzed mRNA expression of seven autophagy-related genes controlled by FOXO3a. Five of these (p62, LC3B, BECLIN-1, ATG12, and BNIP3) increased during immobilization and returned to baseline during rehabilitation. In conclusion, immobilization of a lower limb increases autophagy-related gene and protein expression in human skeletal muscle in a pattern that mirrors FOXO3a phosphorylation. These findings could imply that FOXO3a dependent transcriptional regulation of autophagy is involved in the regulation of muscle mass in humans. CLINICAL TRIAL REGISTRATION: The study was approved by the Ethics Committee of Copenhagen (j.no. H-1-2010-016).

Biodistribution of [11C]-Metformin and mRNA Expression of Placentae Metformin Transporters in the Pregnant Chinchilla.

Background: While metformin is the first-line pharmacological treatment of diabetes mellitus type 2, this drug is not considered safe to use in pregnant women because of its unknown consequences for the fetus. In this study, we aimed to investigate the biodistribution of metformin in the pregnant chinchilla, a species exhibiting placental characteristics comparable with the pregnant woman. Furthermore, we aimed to investigate the expression of metformin transporters in humans and chinchillas, respectively, in order to evaluate the pregnant chinchilla as a novel animal model for the use of metformin in pregnancy. Methods: Three chinchillas in the last part of gestation were injected with [11C]-metformin and scanned by PET/CT for 70 minutes to visualize the distribution. To investigate the difference in expression of placenta transporters between humans and chinchillas, PCR was performed on samples from five chinchilla placentae and seven human placentae. Results: Dynamic PET with [11C]-metformin showed that the metformin distribution in chinchillas was similar to that in nonpregnant humans, with signal from kidneys, liver, bladder, and submandibular glands. Conversely, no radioactive signal was observed from the fetuses, and no metformin was accumulated in the chinchilla fetus when measuring the SUV. PCR of placental mRNA showed that the human placentae expressed OCT3, whereas the chinchilla placentae expressed OCT1. Conclusion: Since metformin did not pass the placenta barrier in the pregnant chinchilla, as it is known to do in humans, we do not suggest the chinchilla as a future animal model of metformin in pregnancies.

Hepatic exposure of metformin in patients with non-alcoholic fatty liver disease.

AIMS: Metformin is first-line treatment of type 2 diabetes mellitus and reduces cardiovascular events in patients with insulin resistance and type 2 diabetes. Target tissue for metformin action is thought to be the liver, where metformin distribution depends on facilitated transport by polyspecific transmembrane organic cation transporters (OCTs). Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the western world with strong associations to insulin resistance and the metabolic syndrome, but whether NAFLD affects metformin biodistribution to the liver is not known. In this study, the primary aim was to investigate in vivo hepatic uptake of metformin dynamically in humans with variable degrees of liver affection. As a secondary aim, we wished to correlate hepatic metformin distribution with OCT gene transcription determined in diagnostic liver biopsies. METHODS: Eighteen patients with biopsy-proven NAFLD were investigated using 11C-metformin PET/CT technique. Gene transcripts of OCTs were determined by real-time polymerase chain reaction (PCR). RESULTS: We observed similar hepatic volume of distribution of metformin between patients with simple steatosis and non-alcoholic steatohepatitis (NASH) (Vd 2.38 ± 0.56 vs. 2.10 ± 0.39, P = 0.3). There was no association between hepatic exposure to metformin and the degree of inflammation or fibrosis, and no clear correlation between metformin distribution and OCT gene transcription. CONCLUSION: Metformin is distributed to the liver in patients with NAFLD and the distribution is not impaired by inflammation or fibrosis. The findings imply that metformin action in liver in patients with NAFLD may be preserved.

Growth hormone acts along the PPARγ-FSP27 axis to stimulate lipolysis in human adipocytes.

The lipolytic effects of growth hormone (GH) have been known for half a century and play an important physiological role for substrate metabolism during fasting. In addition, sustained GH-induced lipolysis is causally linked to insulin resistance. However, the underlying molecular mechanisms remain elusive. In the present study, we obtained experimental data in human subjects and used human adipose-derived stromal vascular cells (hADSCs) as a model system to elucidate GH-triggered molecular signaling that stimulates adipose tissue lipolysis and insulin resistance in human adipocytes. We discovered that GH downregulates the expression of fat-specific protein (FSP27), a negative regulator of lipolysis, by impairing the transcriptional ability of the master transcriptional regulator, peroxisome proliferator-activated receptor-γ (PPARγ) via MEK/ERK activation. Ultimately, GH treatment promotes phosphorylation of PPARγ at Ser273 and causes its translocation from nucleus to the cytosol. Surprisingly, FSP27 overexpression inhibited PPARγ Ser273 phosphorylation and promoted its nuclear retention. GH antagonist treatment had similar effects. Our study identifies a novel signaling mechanism by which GH transcriptionally induces lipolysis via the MEK/ERK pathway that acts along PPARγ-FSP27 in human adipose tissue.

Prolonged fasting-induced metabolic signatures in human skeletal muscle of lean and obese men.

Insulin resistance is a well-known physiological adaptation to prolonged fasting in healthy skeletal muscle. Obesity is associated with insulin resistance and metabolic inflexibility in skeletal muscle, and a pronounced increase in the risk of metabolic complications. Under the hypothesis that the metabolic traits of insulin resistance associated with prolonged fasting are different from insulin resistance associated with obesity, we examined nine obese and nine lean participants during 12 and 72h of fasting, respectively. Insulin resistance in obese participants was associated with impaired insulin signaling, and reduced levels of glucose-6-phosphate and TCA-cycle intermediates. 72h of fasting in lean participants reduced insulin-stimulated glucose uptake to levels similar to obese participants fasted for 12h. This was associated with increased lipid oxidation, but not accumulation of diacylglycerol or acylcarnitines and impairment of insulin signaling. Prolonged fasting was associated with pronounced increases in ß-hydroxybutyrate and ß- hydroxybutyrylcarnitine levels in skeletal muscle suggesting augmented ketone body metabolism. Fasting induced insulin resistance may be a consequence of substrate competition. The underlying mechanism behind insulin resistance in obesity is thus not comparable to the physiological adaptations in skeletal muscle induced by prolonged fasting in lean participants.

Insulin inhibits autophagy signaling independent of counterregulatory hormone levels but does not affect the effects of exercise.

Acute exercise increases autophagic signaling through Unc-51 like kinase-1 (ULK1) in human skeletal muscle during both anabolic and catabolic conditions. The aim of the present study was to investigate if changes in ULK1 Ser555 phosphorylation during exercise are reflected by changes in phosphorylation of a newly identified ULK1 substrate (ATG14 Ser29) and to elucidate the involvement of circulatory hormones in the regulation of autophagy in human skeletal muscle. We show that 1 h of cycling exercise increases ATG14 Ser29 phosphorylation during both hyperinsulinemic euglycemic and euinsulinemic euglycemic conditions. This could suggest that counterregulatory hormones stimulate autophagy in skeletal muscle, as circulating concentrations of these hormones are highly elevated during exercise. Furthermore, ATG14 Ser29 correlated positively with ULK1 phosphorylation, suggesting that ULK1 Ser555 (activating site) phosphorylation reflects ULK1 kinase activity. In a separate series of experiments, we show that insulin stimulates ULK1 phosphorylation at Ser757 (inhibitory site) in both hypoglycemic and euglycemic conditions, suggesting that counterregulatory hormones (such as epinephrine, norepinephrine, growth hormone, and glucagon) have limited effects on autophagy signaling in human skeletal muscle. In conclusion, 1 h of cycling exercise increases phosphorylation of ATG14 at Ser29 in a pattern that mirrors ULK1 phosphorylation at Ser555. Moreover, insulin effects on autophagy signaling in human skeletal muscle are independent of hypoglycemic and euglycemic conditions.NEW & NOTEWORTHY Autophagy signaling is regulated in a hierarchical order by exercise, insulin, and counterregulatory hormones. Exercise-induced autophagy signaling is stimulated by local factors in skeletal muscle rather than circulatory hormones. Unc-51 like kinase-1 (ULK1) phosphorylation at Ser555 reflects ULK1 kinase activity.

68Ga-PSMA Uptake in Middle Lobe Syndrome.

Prostate cancer cells have abundant expression of the cell surface protein prostate-specific membrane antigen (PSMA). In recent years, PET radioligands detecting this protein has therefore gained substantial interest in prostate cancer staging. It turned out that PSMA expression can be evident in both malignant and benign lesions, and we have previously reported that pulmonary opacities and bronchiectasis can be avid on Ga-PSMA PET/CT. Here, we present a case with Ga-PSMA accumulation in nonobstructive middle lobe syndrome, which further indicate that benign changes in the lungs may be falsely interpreted as malignant disease.

Metastases From Colorectal Cancer Avid on 68Ga-PSMA PET/CT.

Ga-PSMA PET/CT is currently used for detection of prostate cancer including metastases, even at low prostate-specific antigen values. A grown number of reports have shown increased uptake of PSMA in neovessels of nonprostatic malignancies including lung cancer, and recently a case report has demonstrated increased PSMA uptake in colorectal adenocarcinoma. In this case report, we demonstrate increased Ga-PMSA uptake on PET/CT in metastases from previously treated colon adenocarcinoma, and it illustrates the importance of histology of suspicious lesions on Ga-PSMA PET/CT.

Altered gene expression and repressed markers of autophagy in skeletal muscle of insulin resistant patients with type 2 diabetes.

This case-control study was designed to investigate the gene expression profile in skeletal muscle from severely insulin resistant patients with long-standing type 2 diabetes (T2D), and to determine associated signaling pathways. Gene expression profiles were examined by whole transcriptome, strand-specific RNA-sequencing and associated signaling was determined by western blot. We identified 117 differentially expressed gene transcripts. Ingenuity Pathway Analysis related these differences to abnormal muscle morphology and mitochondrial dysfunction. Despite a ~5-fold difference in plasma insulin, we did not observe any difference in phosphorylation of AKT or AS160, although other insulin-sensitive cascades, as mTOR/4EBP1, had retained their sensitivity. Autophagy-related gene (ATG14, RB1CC1/FIP200, GABARAPL1, SQSTM1/p62, and WIPI1) and protein (LC3BII, SQSTM1/p62 and ATG5) expression were decreased in skeletal muscle from the patients, and this was associated with a trend to increased phosphorylation of the insulin-sensitive regulatory transcription factor FOXO3a. These data show that gene expression is highly altered and related to mitochondrial dysfunction and abnormal morphology in skeletal muscle from severely insulin resistant patients with T2D, and that this is associated with decreased expression of autophagy-related genes and proteins. We speculate that prolonged treatment with high doses of insulin may suppress autophagy thereby generating a vicious cycle maintaining insulin resistance.

Subcutaneous Lobular Capillary Hemangioma on 68Ga-PSMA PET/CT.

We present a case of a subcutaneous process in the abdominal wall with high prostate-specific membrane antigen (PSMA) activity on Ga-PSMA PET/CT. Histology demonstrated a benign lobular capillary hemangioma with a high vascular density, with highly PSMA-positive endothelial cells. It is well known that PSMA is expressed in different tissue, including neovasculature in various malignant tumors, and the knowledge is rapidly evolving as new discoveries appear.

Pulmonary Opacities and Bronchiectasis Avid on 68Ga-PSMA PET.

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer, and the expression increases with tumor aggressiveness, metastatic disease, and recurrence. Despite its name, PSMA is also expressed in neovasculature of other tumors including lung cancer. Here, we demonstrate a case of increased PSMA expression on Ga-PSMA PET/CT in benign lung opacities and bronchiectasis in a prostate cancer patient. Thus, increased PSMA activity in the lungs may be due to both benign and malignant diseases and warrants further evaluation.