Tax cuts are the GOP’s all-purpose remedy. Even for the coronavirus.

oscon: Beginner's Guide to Computer Vision - 2D/3D image fundamentals, OpenCV, OpenNI Library + more http://t.co/ph2dKrC9W4 #oscon #tutorial

The internet is a scary enough place as it is, and now with the added misinformation and panic surrounding the coronavirus pandemic, it's even scarier. Thanks to the United Nations and dozens of artists, however, the internet just got a little more beautiful. 

In late March, the UN put a call out to artists to help combat the spread of COVID-19. They sought creatives to create content around six areas of WHO and UN priority actions: personal hygiene, social distancing, knowing the symptoms, spreading kindness, myth-busting, and doing more/donating. Tens of thousands of artists answered the call in two weeks, and now the COVID-19 Response Creative Content Hub is available for browsing.  Read more...

Research Event

Event participants

Fadi El-Jardali, Professor of Health Policy and Systems, American University of Beirut
Moderator: Nadim Houry, Executive Director, Arab Reform Initiative

7 May 2020 , Volume 96, Number 3

Research Event

Event participants

Fadi El-Jardali, Professor of Health Policy and Systems, American University of Beirut
Moderator: Nadim Houry, Executive Director, Arab Reform Initiative

Webinar Research Event

Event participants

Conference Members Event

Webinar Research Event

Event participants

7 May 2020 , Volume 96, Number 3

7 May 2020 , Volume 96, Number 3

(University of Southampton) Scientists have published highly detailed images of lab-grown neurons using Extreme Ultraviolet radiation that could aid the analysis of neurodegenerative diseases.

Research Event

Event participants

Fadi El-Jardali, Professor of Health Policy and Systems, American University of Beirut
Moderator: Nadim Houry, Executive Director, Arab Reform Initiative

7 May 2020 , Volume 96, Number 3

Objective: To investigate the lesion detection rate of ¹⁸F-DCFPyL-PET/CT, a prostate-specific membrane antigen (PSMA) targeted PET agent, in biochemical relapse prostate cancer patients after primary local therapy. Methods: This is a prospective institutional review board-approved study of 90 patients with documented biochemical recurrence (median PSA 2.5 ng/mL, range 0.21-35.5 ng/mL) with negative conventional imaging after primary local therapies, including radical prostatectomy (n = 38), radiation (n = 27) or combination (n = 25). Patients on androgen deprivation therapy were excluded. Patients underwent whole-body ¹⁸F-DCFPyL-PET/CT (299.9±15.5 MBq) at 2 h p.i. PSMA-PET lesion detection rate was correlated with PSA, PSA kinetics and original primary tumor grade. Results: Seventy patients (77.8%) showed a positive PSMA-PET scan, identifying a total of 287 lesions: 37 prostate bed foci, 208 lymph nodes, and 42 bone/organ distant sites; 11 patients had a negative scan and 9 patients showed indeterminate lesions, which were considered negative in this study. The detection rates were 47.6% (n = 10/21), 50% (n = 5/10), 88.9% (n = 8/9), and 94% (n = 47/50) for PSA >0.2 to <0.5, 0.5 to <1.0, 1 to <2.0, and ≥2.0 ng/mL, respectively. In post-surgical patients, PSA, PSAdt and PSAvel correlated with PET results but the same was not true for post-radiation patients. These parameters also correlated with the extent of disease on PET (intrapelvic vs. extrapelvic). There was no significant difference between the rate of positive scans in patients with higher grade vs lower grade primary tumors (Gleason score ≥4+3 vs <3+4). Tumor recurrence was histology confirmed in 40% (28/70) of patients. On a per-patient basis, positive predictive value was 93.3% (95% CI, 77.6-99.2%) by histopathologic validation, and 96.2% (95% CI, 86.3-99.7%) by the combination of histology and imaging/clinical follow-up. Conclusion: ¹⁸F-DCFPyL-PET/CT imaging offers high detection rates in biochemically recurrent prostate cancer patients; and is positive in about 50% of patients with PSA <0.5 ng/mL, which could substantially impact clinical management. In post-surgical patients, ¹⁸F-DCFPyL-PET/CT correlates with PSA, PSAdt and PSAvel suggesting it may have prognostic value. ¹⁸F-DCFPyL-PET/CT is highly promising for localizing sites of recurrent prostate cancer.

Rationale: Lymphatic tracers can help visualize the lymphatic drainage patterns and sentinel nodes of individual prostate cancer patients. To determine the role of nuclear medicine, in particular the positional guidance of a SPECT/CT-based 3D imaging roadmap, in this process we studied to which extend fluorescence-guidance underestimated the number of target lesions. Methods: SPECT/CT imaging was performed after intraprostatic tracer administration of either ICG-^99mTc-nanocolloid (hybrid tracer group) or ^99mTc-nanocolloid to create a roadmap that depicted all sentinel nodes (SNs). Patients who received ^99mTc-nanocolloid were injected with "free" ICG immediately prior to surgery ("free" ICG group). Before unblinding, fluorescence-guidance was used for intraoperative SN identification. This was followed by extended pelvic lymph node dissection (ePLND). Following unblinding of the SPECT/CT images, the number of missed SN’s were recorded and their resection was pursued when the anatomy allowed. Results: Preoperative SPECT/CT revealed no differences in the SN identification rate between ICG-^99mTc-nanocolloid and ^99mTc-nanocolloid. However, fluorescence-guidance only allowed intraoperative removal of all SNs in 40% of patients in the hybrid tracer group and in 20% of patients in the "free" ICG group. Overall, 75.9% of the intraoperatively resected SNs in the hybrid tracer group and 51.8% of the SNs in the "free" ICG group were removed solely under fluorescence-guidance. During ePLND 22 additional SNs were resected (7 in the hybrid tracer group and 15 in the "free" ICG group). After unblinding 18 remaining SNs were identified (6 in the hybrid group and 12 in the "free" ICG group). In the "free" ICG group, ex vivo evaluation of the excised specimens revealed that 14 SNs removed under ePLND or after unblinding contained radioactivity but no fluorescence. Conclusion: The preoperative imaging roadmap provided by SPECT/CT enhanced the detection of prostate SNs in more ectopic locations in 17 of the 25 patients and the hybrid tracer ICG-^99mTc-nanocolloid was shown to outperform "free" ICG. Overall, fluorescence-guided pelvic nodal surgery underestimated the number of SNs in 60-80% of patients.

¹⁸F-PI-2620 is a positron emission tomography (PET) tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer’s disease (AD) and other neurodegenerative disorders. Preclinically, ¹⁸F-PI-2620 binds to both, 3R and 4R tau isoforms. The purpose of this first-in-human study was to evaluate the ability of ¹⁸F-PI-2620 to detect tau pathology in AD patients using PET imaging, as well as to assess its safety and tolerability of this new tau PET tracer. Methods: Participants with clinical diagnosis of probable AD and healthy controls (HC) underwent dynamic ¹⁸F-PI-2620 PET imaging for 180 min. ¹⁸F-PI-2620 binding was assessed visually and quantitatively using Distribution Volume Ratios (DVR) estimated from non-invasive tracer kinetics and standardized uptake value ratios (SUVR) measured at different time points post-injection (p.i.) with the cerebellar cortex as the reference region. Time-activity curves and SUVR were assessed in AD and HC, as well as DVR and SUVR correlations and effect size (Cohen’s d) over time. Results: ¹⁸F-PI-2620 showed peak brain uptake around 5 min p.i. and fast wash-out in non-target regions. In AD subjects, focal asymmetric uptake was evident in temporal and parietal lobes, precuneus, and posterior cingulate cortex. DVR and SUVR in these regions were significantly higher in AD compared to HC. Very low background signal was observed in HC. ¹⁸F-PI-2620 administration was safe and well tolerated. SUVR time activity curves in most regions and subjects achieved a secular equilibrium after 40 min p.i.. A strong correlation (R² > 0.93) was found between non-invasive DVR and SUVR for all imaging windows starting >30 min p.i.. Similar effect sizes between AD and HC groups were obtained across the different imaging windows. ¹⁸F-PI-2620 uptake in neocortical regions was significantly correlated with the degree of cognitive impairment. Conclusion: Initial clinical data obtained in AD and HC demonstrate the high image quality with excellent signal-to-noise of ¹⁸F-PI-2620 PET for imaging tau deposition in AD subjects. Non-invasive quantification using DVR and SUVR for 30 min imaging windows between 30-90 min p.i., e.g. 45-75 min, provides robust and significant discrimination between AD and HC subjects. ¹⁸F-PI-2620 uptake in expected regions is highly correlated to neurocognitive performance.

Numerous recent works highlight the limited utility of established tumor cell lines in recapitulating the heterogeneity of tumors in patients. More realistic preclinical cancer models are thought to be provided by transplantable, patient-derived tumor xenografts (PDX). Inter- and intra-tumor heterogeneity of PDX, however, present several challenges in developing optimal quantitative pipelines to assess response to therapy. The objective of this work was to develop and optimize image metrics of FDG-PET to assess response to combination docetaxel/carboplatin therapy in a co-clinical trial involving triple negative breast cancer (TNBC) PDX. We characterize the reproducibility of SUV metrics to assess response to therapy and optimize a preclinical PERCIST (µPERCIST) paradigm to complement clinical standards. Considerations in this effort included variability in tumor growth rate and tumor size; solid tumor vs. tumor heterogeneity and necrotic phenotype; and optimal selection of tumor slice versus whole tumor. A test-retest protocol was implemented to optimize the reproducibility of FDG-PET SUV thresholds, SUVpeak metrics, and µPERCIST parameters. In assessing response to therapy, FDG-PET imaging was performed at baseline and +4 days following therapy. The reproducibility, accuracy, variability, and performance of imaging metrics to assess response to therapy were determined. We defined an index—"Quantitative Response Assessment Score (QRAS)"—to integrate parameters of prediction and precision, and thus aid in selecting optimal image metrics of response to therapy. Our data suggests that a threshold value of 25% (SUV25) of SUVmax was highly reproducible (<9% variability). Concordance and reproducibility of µPERCIST were maximized at α=0.7 and β=2.8 and exhibited high correlation to SUV25 measures of tumor uptake. QRAS scores favor SUV25 followed by SUVP14 as optimal metrics of response to therapy. Additional studies are warranted to fully characterize the utility of SUV25 and µPERCIST SUVP14 as image metrics of response to therapy across a wide range of therapeutic regiments and PDX models.

Purpose: Although the incidence of de novo neuroendocrine prostate cancer (NEPC) is rare, recent data suggests that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine (NE) hallmarks and androgen receptor (AR)-suppression in prostate cancer (PC). Previous clinical reports indicate that PCs with a phenotype similar to NE tumors can be more amenable to imaging by ¹⁸F-Fluorodeoxyglucose (FDG) rather than PSMA-targeting radioligands. In this study, we evaluated the association between NE gene signature and FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported FDG-avidity of PSMA-suppressed tumors. Methods: Data mining approaches, cell lines and patient-derived xenograft (PDX) models were used to study the levels of 14 members of the SLC2A family (encoding GLUT proteins), 4 members of the hexokinase family (genes: HK1 to 3 and GCK) and PSMA (FOLH1 gene) following AR-inhibition and in correlation with NE hallmarks. Also, we characterize a NE-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no NE histopathology. We measured glucose uptake in a NE-induced in vitro model and a zebrafish model by non-radioactive imaging of glucose uptake using fluorescent glucose bioprobe, GB2-Cy3. Results: This work demonstrates that a NE gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of GCK (encoding glucokinase protein) and decreased expression of SLC2A12 correlated with earlier biochemical recurrence. In tumors treated with AR-inhibitors, high expression of GCK and low expression of SLC2A12 correlated with NE histopathology and PSMA gene suppression. GLUT12-suppression and amplification of glucokinase was observed in NE-induced PC cell lines and PDX models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. Conclusion: NE gene signature in NEPC and NELPC associates with a distinct transcriptional profile of GLUTs and HKs. PSMA-suppression correlates with GLUT12-suppression and glucokinase-amplification. Alteration of FDG uptake-associated genes correlated positively with higher glucose uptake in AR and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient pre-clinical method for monitoring non-radioactive glucose uptake.

Objectives: The detection of cancer micrometastasis for early diagnosis and treatment poses a great challenge for conventional imaging techniques. The aim of study is to evaluate the performance of photoacoustic imaging (PAI) in detecting hepatic micrometastases from melanoma in a very early stage and perform tumor resection by intraoperative photoacoustic image-guidance. Methods: In vivo studies were performed by following protocols approved by the Ethical Committee for Animal Research at Xiamen University. First, a B16 melanoma hepatic metastasis mouse model (n = 10) was established to study the development of micrometastases in vivo. Next, the hepatic metastasis mice models were imaged by scalable PAI instrument, ultrasound, 9.4 T high-resolution magnetic resonance imaging (MRI), positron emission tomography/computed tomography (PET/CT), and bioluminescence imaging. Photoacoustic images acquired with optical wavelengths spanning from 680 to 850 nm were spectrally unmixed by using a linear least-squares method to differentiate various components. Differences in the signal-to-background ratios among different modalities were determined with the two-tailed paired t test. The diagnosis results were assessed with histologic examinations. Excised liver samples from patients diagnosed with hepatic cancer were also examined to identify tumor boundary. In vivo metastatic melanoma removal in surgery was precisely guided by the portable PAI system. Results: PAI achieved as small as ~400 µm hepatic melanoma detection at a depth up to 7 mm in vivo, which could early detect small melanoma compared with ultrasound and MRI in mouse models. The signal ratio of tumor-to-liver acquired with PAI in micrometastases at 8 days (4.2 ± 0.2, n = 6) and 14 days (9.2 ± 0.4, n = 5) were significantly higher than those obtained with PET/CT (1.8 ± 0.1, n = 5 and 4.5 ± 0.2, n = 5, P <0.001 for both). Functional PAI provided dynamic oxygen saturation changes during tumor growth. The limit of detection was measured to be approximately 219 cells per microliter in vitro. We successfully performed intraoperative photoacoustic image-guided surgery in vivo using the rapid portable PAI system. Conclusion: Our findings offer a rapid and effective tool to noninvasively detect micrometastases and guide intraoperative resection as a complementary clinical imaging application.

P-glycoprotein (ABCB1) plays an important role at the blood-brain barrier (BBB) in promoting the clearance of neurotoxic beta-amyloid (Aß) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease (AD) patients. Treatment with drugs which induce cerebral ABCB1 activity may be a promising approach to delay the build-up of Aß deposits in the brain by enhancing the clearance of Aß peptides from the brain. The aim of this study was to investigate whether PET with the weak ABCB1 substrate radiotracer ¹¹C-metoclopramide can measure ABCB1 induction at the BBB in a beta-amyloidosis mouse model (APP/PS1-21 mice) and in wild-type mice. Methods: Groups of wild-type and APP/PS1-21 mice aged 50 or 170 days underwent ¹¹C-metoclopramide baseline PET scans or scans after intraperitoneal treatment with the rodent pregnane X receptor (PXR) activator 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN, 25 mg/kg) or its vehicle over 7 days. At the end of the PET scans, brains were harvested for immunohistochemical analysis of ABCB1 and Aß levels. In separate groups of mice, radiolabeled metabolites of ¹¹C-metoclopramide were determined in plasma and brain at 15 min after radiotracer injection. As an outcome parameter of cerebral ABCB1 activity, the elimination slope of radioactivity washout from the brain (kE,brain) was calculated. Results: PCN treatment resulted in an increased clearance of radioactivity from the brain as reflected by significant increases in kE,brain (from +26% to +54% relative to baseline). Immunohistochemical analysis confirmed ABCB1 induction in the brains of PCN-treated APP/PS1-21 mice with a concomitant decrease in Aß levels. There was a significant positive correlation between kE,brain values and ABCB1 levels in the brain. In wild-type mice, a significant age-related decrease in kE,brain values was found. Metabolite analysis showed that the majority of radioactivity in the brain was composed of unmetabolized ¹¹C-metoclopramide in all animal groups. Conclusion: ¹¹C-metoclopramide can measure ABCB1 induction in the mouse brain without the need to consider an arterial input function and may find potential application in AD patients to non-invasively evaluate strategies to enhance the clearance properties of the BBB.

Background: Accurate definition of the extent and severity of left-ventricular assist device (LVAD) infection may facilitate therapeutic decision making and targeted surgical intervention. Here, we explore the value of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for guidance of patient management. Methods: Fifty-seven LVAD-carrying patients received 85 whole-body ¹⁸F-FDG PET/CT scans for the work-up of device infection. Clinical follow-up was obtained over a period of up to two years. Results: PET/CT showed various patterns of infectious involvement of the 4 LVAD components: driveline entry point (77% of cases), subcutaneous driveline path (87%), pump pocket (49%) and outflow tract (58%). Driveline smears revealed staphylococcus or pseudomonas strains as the underlying pathogen in a majority of cases (48 and 34%, respectively). At receiver-operating characteristics analysis, an ¹⁸F-FDG standardized uptake value (SUV) >2.5 was most accurate to identify smear-positive driveline infection. Infection of 3 or all 4 LVAD components showed a trend towards lower survival vs infection of 2 or less components (P = 0.089), while involvement of thoracic lymph nodes was significantly associated with adverse outcome (P = 0.001 for nodal SUV above vs below median). Finally, patients that underwent early surgical revision within 3 months after PET/CT (n = 21) required significantly less inpatient hospital care during follow-up when compared to those receiving delayed surgical revision (n = 11; p<0.05). Conclusion: Whole-body ¹⁸F-FDG PET/CT identifies the extent of LVAD infection and predicts adverse outcome. Initial experience suggests that early image-guided surgical intervention may facilitate a less complicated subsequent course.

Background: Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy as they can constitute as much as 90% of tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinoline-based FAP-inhibitor PET tracer, ⁶⁸Ga-FAPI-04, has been previously shown to yield high tumor-to-background ratios (TBR) in patients with various cancers. Recent developments towards an improved compound for therapeutic application have identified FAPI-46 as a promising agent due to a longer tumor retention time in comparison with FAPI-04. Here we present a PET biodistribution and radiation dosimetry study of ⁶⁸Ga-FAPI-46 in cancer patients. Methods: Six patients with different cancers underwent serial ⁶⁸Ga-FAPI-46 PET/CT scans at three time points following radiotracer injection: 10 minutes, 1 hour, and 3 hours. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and body remainder. OLINDA/EXM v.1.1 software was used to fit and integrate the kinetic organ activity data to yield total body and organ time-integrated activity coefficients/residence times and finally organ absorbed doses. Standardized uptake values (SUV) and TBR were generated from the contoured tumor and source organ volumes. Spherical volumes in muscle and blood pool were also obtained for TBR (Tumor SUV_max / Organ SUVmean). Results: At all timepoints, the highest organ SUV_max was observed in the liver. Tumor and organ mean SUVs decreased whereas TBRs in all organs but the uterus increased with time. The highest TBRs at 3 hours were observed with the bone marrow (31.1), muscle (22.8), heart (19.1), and spleen (19.0). Organs with the highest effective doses were the bladder wall (2.41E-03 mSv/MBq), followed by ovaries (1.15E-03 mSv/MBq) and red marrow (8.49E-04mSv/MBq). The average effective total body dose was 7.80E-03 mSv/MBq. Thus for administration of 200 MBq ⁶⁸Ga-FAPI-46 the effective total body dose is 1.56 mSv ± 0.26 mSv, in addition to approximately 3.7 mSv from one low-dose CT scan done for attenuation correction. Conclusion: ⁶⁸Ga-FAPI-46 PET/CT has a favorable dosimetry profile with an estimated whole body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of ⁶⁸Ga-FAPI-46 (1.56± 0.26 mSv from the PET tracer and 3.7 mSv from one low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.

⁶⁸Ga-DOTATOC-PET/MRI (⁶⁸Gallium-DOTATOC-positron emission tomography/magnetic resonance imaging) combines the advantages of PET in the acquisition of metabolic-functional information with the high soft tissue contrast of MRI. Standardized uptake values (SUV) in tumors were suggested as a measure of somatostatin receptor expression. A challenge with receptor ligands is, that the distribution volume is confined to tissues with tracer-uptake, potentially limiting SUV quantification. In this study, different functional, three-dimensional (3D) SUV, apparent diffusion coefficient (ADC) parameters and arterial tumor enhancement were tested for the characterization of gastroendopancreatic neuroendocrine tumors (GEP-NET). Methods: For this single-center, cross-sectional study, 22 patients with 24 histologically confirmed GEP-NET lesions (15 men/7 women; median, 61 years, range, 43-81 years), who received hybrid ⁶⁸Ga-DOTA-PET/MRI examinations at 3T between January 2017 and July 2019 met eligibility criteria. SUVs, tumor-to-background ratios (TBR), the total functional tumor volume (TFTV), ADCmean and ADCmin were measured based on volumes of interest (VOI) and examined with receiver operating characteristic analysis to determine cut-off values for differentiation between low and intermediate grade GEP-NET. Spearman’s rank correlation coefficients were used to assess correlations between functional imaging parameters. Results: The ratio of PET-derived SUVmean and diffusion-weighted imaging (DWI)-derived ADCmin was introduced as a combined variable to predict tumor grade, outperforming single predictors. Based on a threshold ratio of 0.03 to be exceeded, tumors could be classified as grade 2 with a sensitivity of 86% and specificity of 100%. SUV and functional ADC values as well as arterial contrast enhancement parameters showed non-significant and mostly negligible correlations. Conclusion: As receptor density and tumor cellularity appear to be independent, potentially complementary phenomena, the combined PET/MRI ratio SUVmean/ADCmin may be used as a novel biomarker, allowing to differentiate between grade 1 and 2 GEP-NET.

Rationale: Despite its widespread use in oncology, the PET radiotracer ¹⁸F-FDG is ineffective for improving early detection of pancreatic ductal adenocarcinoma (PDAC). An alternative strategy for early detection of pancreatic cancer involves visualisation of high-grade pancreatic intraepithelial neoplasias (PanIN-3), generally regarded as the non-invasive precursors of PDAC. The DNA damage response is known to be hyper-activated in late-stage PanINs. Therefore, we investigated whether the SPECT imaging agent, ¹¹¹In-anti-H2AX-TAT, allows visualisation of the DNA damage repair marker H2AX in PanIN-3s in an engineered mouse model of PDAC, to facilitate early detection of PDAC. Methods: Genetically engineered KPC mice (KRasLSL.G12D/+; p53LSL.R172H/+; PdxCre) were imaged with ¹⁸F-FDG and ¹¹¹In-anti-H2AX-TAT. PanIN/PDAC presence visualised by histology was compared with autoradiography and immunofluorescence. Separately, the survival of KPC mice imaged with ¹¹¹In-anti-H2AX-TAT was evaluated. Results: In KPC mouse pancreata, H2AX expression was increased in high-grade PanINs, but not in PDAC, corroborating earlier results obtained from human pancreas sections. Uptake of ¹¹¹In-anti-H2AX-TAT, but not ¹¹¹In-IgG-TAT or ¹⁸F-FDG, within the pancreas was positively correlated with the age of KPC mice, which was correlated with the number of high-grade PanINs. ¹¹¹In-anti-H2AX-TAT localises preferentially in high-grade PanIN lesions, but not in established PDAC. Younger, non-tumour-bearing KPC mice that show uptake of ¹¹¹In-anti-H2AX-TAT in the pancreas survive significantly shorter than mice with physiological ¹¹¹In-anti-H2AX-TAT uptake. Conclusion: ¹¹¹In-anti-H2AX-TAT imaging allows non-invasive detection of DNA damage repair signalling upregulation in pre-invasive PanIN lesions and is a promising new tool to aid in the early detection and staging of pancreatic cancer.

Rationale: The treatment of choice for insulinomas and focal lesions in congenital hyperinsulinism (CHI) is surgery. However, intra-operative detection can be challenging. This could be overcome with intra-operative fluorescence imaging, which provides real-time lesion detection with a high spatial resolution. Here, a novel method for targeted near-infrared (NIR) fluorescence imaging of glucagon-like peptide 1 receptor (GLP-1R) positive lesions, using the GLP-1 agonist exendin-4, labeled with IRDye800CW, was examined in vitro and in vivo. Methods: A competitive binding assay was performed using Chinese hamster lung (CHL) cells transfected with the GLP-1R. Tracer biodistribution was determined in BALB/c nude mice bearing subcutaneous CHL-GLP-1R xenografts. In vivo NIR fluorescence imaging of CHL-GLP-1R xenografts was performed. Localization of the tracer in the pancreatic islets of BALB/c nude mice was examined using fluorescence microscopy. Laparoscopic imaging was performed to detect the fluorescent signal of the tracer in the pancreas of mini pigs. Results: Exendin-4-IRDye800CW binds the GLP-1R with an IC50 value of 3.96 nM. The tracer accumulates in CHL-GLP-1R xenografts. Subcutaneous CHL-GLP-1R xenografts were visualized using in vivo NIR fluorescence imaging. The tracer accumulates specifically in the pancreatic islets of mice and a clear fluorescent signal was detected in the pancreas of mini pigs. Conclusion: These date provide the first in vivo evidence of the feasibility of targeted fluorescence imaging of GLP-1R positive lesions. Intra-operative lesion delineation using exendin-4-IRDye800CW could benefit open as well as laparoscopic surgical procedures for removal of insulinomas and focal lesions in CHI.

[S-Methyl-¹¹C](±)-7-methoxy-3-(4-(4-(methylthio)phenyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol (¹¹C-NR2B-SMe) and its enantiomers were synthesized as candidates for imaging the NR2B subunit within the N-methyl-D-aspartate receptor with positron emission tomography (PET). Methods: Brains were scanned with PET for 90 min after intravenous injection of one of the candidate radioligands into rats. To detect any NR2B specific binding of radioligand in brain, various pre-blocking or displacing agents were evaluated for their impact on the PET brain imaging data. Radiometabolites from brain and other tissues were measured ex vivo and in vitro. Results: Each radioligand gave high early whole brain uptake of radioactivity, followed by a brief fast decline and then a slow final decline. ¹¹C-(S)-NR2B-SMe was studied extensively. Ex vivo measurements showed that radioactivity in rat brain at 30 min after radioligand injection was virtually unchanged radioligand. Only less lipophilic radiometabolites appeared in plasma. High-affinity NR2B ligands, Ro-25-6981, ifenprodil, and CO10124, showed increasing preblock of whole brain radioactivity retention with increasing dose (0.01 to 1.25 mg/kg, i.v.). Five 1 antagonists (FTC146, BD1407, F3, F4, and NE100) and four 1 agonists ((+)-pentazocine, (±)-PPCC, PRE-084, (+)-SKF10047) were ineffective preblocking agents, except FTC146 and F4 at high dose. Two potent 1 receptor agonists, TC1 and SA4503, showed dose-dependent preblocking effects in the presence or absence of pharmacological 1 receptor blockade with FTC146. Conclusion: ¹¹C-(S)-NR2B-SMe has adequate NR2B-specific PET signal in rat brain to warrant further evaluation in higher species. TC1 and SA4503 likely have off-target binding to NR2B in vivo.

Methods that provide rapid access to radiolabeled antibodies are vital in the development of diagnostic and radiotherapeutic agents for positron emission tomography (PET) or radioimmunotherapy. The human hepatocyte growth factor receptor (c-MET) signaling pathway is dysregulated in a number of malignancies including gastric cancer, and is an important biomarker in drug discovery. Here, we used a photoradiochemical approach to produce ⁸⁹Zr-radiolabeled onartuzumab (a monovalent, anti-human c-MET antibody), starting directly from the fully formulated drug (MetMAb). Methods: Simultaneous ⁸⁹Zr-radiolabeling and protein conjugation was performed in one-pot reactions containing ⁸⁹Zr-oxalate, the photoactive chelate DFO-aryl azide (DFO-ArN3) and MetMAb to give ⁸⁹ZrDFO-azepin-onartuzumab. As a control, ⁸⁹ZrDFO-Bn-NCS-onartuzumab was prepared via a conventional two-step process using pre-purified onartuzumab and DFO-Bn-NCS. Radiotracers were purified by using size-exclusion methods and evaluated by radiochromatography. Radiochemical stability was studied in human serum and immunoreactivity was determined by cellular binding assays using MKN-45 gastric carcinoma cells. PET imaging at multiple time points (0–72 h) was performed in female athymic nude mice bearing subcutaneous MKN-45 xenografts. Biodistribution experiments were performed after the final image. Tumor specificity of ⁸⁹ZrDFO-azepin-onartuzumab was assessed by competitive inhibition (blocking) studies. Results: Initial photoradiosynthesis experiments produced ⁸⁹ZrDFO-azepin-onartuzumab in <15 min. with an isolated decay-corrected radiochemical yield (RCY) of 24.8%, a radiochemical purity (RCP) ~90% and a molar activity (Am) of ~1.5 MBq nmol^-1. Reaction optimization improved the radiochemical conversion (RCC) of ⁸⁹ZrDFO-azepin-onartuzumab to 56.9±4.1% (n = 3), with isolated RCYs of 41.2±10.6% (n = 3), and RCPs >90%. Conventional methods produced ⁸⁹ZrDFO-Bn-NCS-onartuzumab with isolated RCY >97%, RCP >97% and Am ~14.0 MBq nmol^-1. Both radiotracers were immunoreactive and stable in human serum. PET imaging and biodistribution studies showed high tumor uptake for both radiotracers. By 72 h, tumor and liver uptake reached 15.37±5.21 %ID g^-1, 6.56±4.03 %ID g^-1, respectively for ⁸⁹ZrDFO-azepin-onartuzumab (n = 4), and 21.38±11.57 %ID g^-1 and 18.84±6.03 %ID g^-1 for ⁸⁹ZrDFO-Bn-NCS-onartuzumab (n = 4). Blocking experiments gave a statistically significant reduction in tumor uptake (6.34±0.47 %ID g^-1) of ⁸⁹ZrDFO-azepin-onartuzumab (n = 4). Conclusion: Experiments demonstrate that photoradiosynthesis is a viable alternative approach for producing ⁸⁹Zr-radiolabeled antibodies direct in protein formulation buffer which reduces protein aggregation and liver uptake.

Immune checkpoint blockade represents a promising approach in oncology, showing anti-tumor activities in various cancers. However, although being generally far more well-tolerated than classical cytotoxic chemotherapy, this treatment, too, may be accompanied by considerable side effects and not all patients benefit equally. Therefore, careful patient selection and monitoring of the treatment response is mandatory. At present, checkpoint-specific molecular imaging is increasingly investigated as a tool for patient selection and response evaluation. Here, an overview of the current developments in immune checkpoint imaging is provided.

Purpose: To assess the performance of full dose (FD) positron emission tomography (PET) image synthesis in both image and projection space from low-dose (LD) PET images/sinograms without sacrificing diagnostic quality using deep learning techniques. Methods: Clinical brain PET/CT studies of 140 patients were retrospectively employed for LD to FD PET conversion. 5% of the events were randomly selected from the FD list-mode PET data to simulate a realistic LD acquisition. A modified 3D U-Net model was implemented to predict FD sinograms in the projection-space (PSS) and FD images in image-space (PIS) from their corresponding LD sinograms/images, respectively. The quality of the predicted PET images was assessed by two nuclear medicine specialists using a five-point grading scheme. Quantitative analysis using established metrics including the peak signal-to-noise ratio (PSNR), structural similarity index metric (SSIM), region-wise standardized uptake value (SUV) bias, as well as first-, second- and high-order texture radiomic features in 83 brain regions for the test and evaluation dataset was also performed. Results: All PSS images were scored 4 or higher (good to excellent) by the nuclear medicine specialists. PSNR and SSIM values of 0.96 ± 0.03, 0.97 ± 0.02 and 31.70 ± 0.75, 37.30 ± 0.71 were obtained for PIS and PSS, respectively. The average SUV bias calculated over all brain regions was 0.24 ± 0.96% and 1.05 ± 1.44% for PSS and PIS, respectively. The Bland-Altman plots reported the lowest SUV bias (0.02) and variance (95% CI: -0.92, +0.84) for PSS compared with the reference FD images. The relative error of the homogeneity radiomic feature belonging to the Grey Level Co-occurrence Matrix category was -1.07 ± 1.77 and 0.28 ± 1.4 for PIS and PSS, respectively Conclusion: The qualitative assessment and quantitative analysis demonstrated that the FD PET prediction in projection space led to superior performance, resulting in higher image quality and lower SUV bias and variance compared to FD PET prediction in the image domain.

Respiratory motion during the CT and PET parts of a PET/CT scan leads to imperfect alignment of anatomical features seen by the two modalities. In this work, we concentrate on the effects of motion during CT. We propose a novel approach for improving the alignment. Methods: Respiratory waveform data were gathered during the CT and PET parts of 28 PET/CT scans of cancer patients with 40 lesions up to 3 cm size in the lung or upper abdomen. PET list-mode data were reconstructed by three reconstruction methods: PET/static, PET/EX or end of expiration (OncoFreeze), and a novel PET/matched method that used both waveforms. The three methods were compared. The distance between tumor positions in PET and CT were characterized in visual interpretation by physicians as well as quantitatively. Tumor standardized uptake values (SUV_max and SUVpeak) were determined relative to SUV based on the static method. Image noise was evaluated in the liver and compared to PET/static. Results: In visual interpretation, the rate of good alignment was 13/21, 13/23 and 18/21 for PET/static, PET/EX and PET/matched methods, respectively, and the mean PET-CT distances were 3.5, 5.1 and 2.8 mm. In visual comparison with PET/EX, the rate of good alignment was increased in 1/10 and 7/10 cases for PET/static and PET/matched. SUV_max was on average 21% higher than PET/static when either PET/EX or PET/matched was used. SUVpeak was 12% higher. Image noise in the liver was 15% higher than static for the PET/EX method, and 40% higher for PET/matched; that is, noise was much lower than in gated PET. Conclusion: Acquiring respiratory waveforms both in PET (as in the current state of the art) and in CT (an unusual key step in this approach) has the potential to improve the alignment of PET and CT images. A proposed method for using this information was tested. Improved alignment was demonstrated.

Studies demonstrate that the investigational ⁶⁴Cu-DOTATATE radiopharmaceutical may provide diagnostic and logistical benefits over available imaging agents for patients with somatostatin receptor (SSTR)-positive neuroendocrine tumors (NETs). Accordingly, we aimed to prospectively determine the lowest dose of ⁶⁴Cu-DOTATATE that facilitates diagnostic quality scans and evaluated the diagnostic performance and safety in a phase III study of patients with SSTR-expressing NETs. Methods: A dose-ranging study was conducted in 12 patients divided into 3 dose groups (111 MBq [3.0 mCi], 148 MBq [4.0 mCi], and 185 MBq [5.0 mCi] ± 10%) to determine the lowest dose of ⁶⁴Cu-DOTATATE that produced diagnostic quality PET/CT images. Using the ⁶⁴Cu-DOTATATE dose identified in the dose-ranging study, 3 independent nuclear medicine physicians who were blinded to all clinical information read PET/CT scans from 21 healthy volunteers and 42 NET-positive patients to determine those with "Disease" and "No Disease," as well as "Localized" versus "Metastatic" status. Blinded-reader evaluations were compared to a patient-specific standard of truth (SOT), which was established by an independent oncologist who used all previously available pathology, clinical, and conventional imaging data. Diagnostic performance calculated for ⁶⁴Cu-DOTATATE included sensitivity, specificity, negative predictive value, positive predictive value, and accuracy. Inter- and intra-reader reliability, as well as ability to differentiate between localized and metastatic disease, was also determined. Adverse events (AEs) were recorded from ⁶⁴Cu-DOTATATE injection through 48 hours post-injection. Results: The dose-ranging study identified 148 MBq (4.0 mCi) as the optimal dose to obtain diagnostic quality PET/CT images. Following database lock, diagnostic performance from an initial majority read of the 3 independent readers showed a significant 90.9% sensitivity (P = 0.0042) and 96.6% specificity (P < 0.0001) for detecting NETs, which translated to a 100.0% sensitivity and 96.8% specificity after correcting for an initial SOT misread. Excellent inter- and intra-reader reliability, as well as ability to distinguish between localized and metastatic disease, was also noted. No AEs were related to ⁶⁴Cu-DOTATATE, and no serious AEs were observed. Conclusion: ⁶⁴Cu-DOTATATE PET/CT is a safe imaging technique that provides high-quality and accurate images at a dose of 148 MBq (4.0 mCi) for the detection of somatostatin-expressing NETs.

Galectins are carbohydrate-binding proteins overexpressed in bladder cancer (BCa) cells. Dendritic galactose moieties have a high affinity for galectin-expressing tumor cells. We radiolabeled a dendritic galactose carbohydrate with fluorine-18 – ¹⁸F-labeled galactodendritic unit 4 – and examined its potential in imaging urothelial malignancies. Methods: The ¹⁸F-labeled 1st generation galactodendritic unit 4 was obtained from its tosylate precursor. We conducted in vivo studies in galectin-expressing UMUC3 orthotopic BCa model to determine the ability of ¹⁸F-labeled galactodendritic unit 4 to image BCa. Results: Intravesical administration of ¹⁸F-labeled galactodendritic unit 4 allowed specific accumulation of the carbohydrate radiotracer in galectin-1 overexpressing UMUC3 orthotopic tumors when imaged with PET. The ¹⁸F-labeled galactodendritic unit 4 was not found to accumulate in non-tumor murine bladders. Conclusion: The ¹⁸F-labeled galactodendritic unit 4 and similar analogs may be clinically relevant and exploitable for PET imaging of galectin-1 overexpressing bladder tumors.

Targeting tumor-expressed receptors using selective molecules for diagnostic, therapeutic or both diagnostic and therapeutic (theragnostic) purposes is a promising approach in oncological applications. Such approaches have increased significantly over the past decade. Peptides such as gastrin-releasing peptide receptors (GRPR) targeting radiopharmaceuticals are small molecules with fast blood clearance and urinary excretion. They demonstrate good tissue diffusion, low immunogenicity, and highly selective binding to their target cell-surface receptors. They are also easily produced. GRPR, part of the bombesin (BBN) family, are overexpressed in many tumors, including breast and prostate cancer, and therefore represent an attractive target for future development.

Objective: To assess the feasibility and accuracy of Cerenkov Luminescence Imaging (CLI) for assessment of surgical margins intraoperatively during radical prostatectomy (RPE). Methods: A single centre feasibility study included 10 patients with high-risk primary prostate cancer (PC). ⁶⁸Ga-PSMA PET/CT scans were performed followed by RPE and intraoperative CLI of the excised prostate. In addition to imaging the intact prostate, in the first two patients the prostate gland was incised and imaged with CLI to visualise the primary tumour. We compared the tumour margin status on CLI to postoperative histopathology. Measured CLI intensities were determined as tumour to background ratio (TBR). Results: Tumour cells were successfully detected on the incised prostate CLI images as confirmed by histopathology. 3 of 10 men had histopathological positive surgical margins (PSMs), and 2 of 3 PSMs were accurately detected on CLI. Overall, 25 (72%) out of 35 regions of interest (ROIs) proved to visualize a tumour signal according to standard histopathology. The median tumour radiance in these areas was 11301 photons/s/cm²/sr (range 3328 - 25428 photons/s/cm²/sr) and median TBR was 4.2 (range 2.1 – 11.6). False positive signals were seen mainly at the prostate base with PC cells overlaid by benign tissue. PSMA-immunohistochemistry (PSMA-IHC) revealed strong PSMA staining of benign gland tissue, which impacts measured activities. Conclusion: This feasibility showed that ⁶⁸Ga-PSMA CLI is a new intraoperative imaging technique capable of imaging the entire specimen’s surface to detect PC tissue at the resection margin. Further optimisation of the CLI protocol, or the use of lower-energetic imaging tracers such as ¹⁸F-PSMA, are required to reduce false positives. A larger study will be performed to assess diagnostic performance.

The overexpression of integrin αvβ6 in pancreatic cancer makes it a promising target for noninvasive positron emission tomography (PET) imaging. However, currently, most integrin αvβ6-targeting radiotracers are based on linear peptides, which are quickly degraded in the serum by proteinases. Herein, we aimed to develop and assess a ⁶⁸Ga-labeled integrin αvβ6-targeting cyclic peptide (⁶⁸Ga-cycratide) for PET imaging of pancreatic cancer. Methods: ⁶⁸Ga-cycratide was prepared, and its PET imaging profile was compared with that of the linear peptide (⁶⁸Ga-linear-pep) in an integrin αvβ6-positive BxPC-3 human pancreatic cancer mouse model. Five healthy volunteers (two women and three men) underwent whole-body PET/CT imaging after injection of ⁶⁸Ga-cycratide, and biodistribution and dosimetry calculations were determined. PET/CT imaging of two patients was performed to investigate the potential role of ⁶⁸Ga-cycratide in pancreatic cancer diagnosis and treatment monitoring. Results: ⁶⁸Ga-cycratide exhibited significantly higher tumor uptake than did ⁶⁸Ga-linear-pep in BxPC-3 tumor-bearing mice, owing—at least in part—to markedly improved in vivo stability. ⁶⁸Ga-cycratide could sensitively detect the pancreatic cancer lesions in an orthotopic mouse model and was well tolerated in all healthy volunteers. Preliminary PET/CT imaging in patients with pancreatic cancer demonstrated that ⁶⁸Ga-cycratide was comparable to ¹⁸F-fludeoxyglucose for diagnostic imaging and post-surgery tumor relapse monitoring. Conclusion: ⁶⁸Ga-cycratide is an integrin αvβ6-specific PET radiotracer with favorable pharmacokinetics and dosimetry profile. ⁶⁸Ga-cycratide is expected to provide an effective noninvasive PET strategy for pancreatic cancer lesion detection and therapy response monitoring.