Neoadjuvant immunotherapy of locoregionally advanced solid tumors.

Definitive management of locoregionally advanced solid tumors presents a major challenge and often consists of a combination of surgical, radiotherapeutic and systemic therapy approaches. Upfront surgical treatment with or without adjuvant radiotherapy carries the risks of significant morbidities and potential complications that could be lasting. In addition, these patients continue to have a high risk of local or distant disease relapse despite the use of standard adjuvant therapy. Preoperative neoadjuvant systemic therapy has the potential to significantly improve clinical outcomes, particularly in this era of expanding immunotherapeutic agents that have transformed the care of patients with metastatic/unresectable malignancies. Tremendous progress has been made with neoadjuvant immunotherapy in the treatment of several locoregionally advanced resectable solid tumors leading to ongoing phase 3 trials and change in clinical practice. The promise of neoadjuvant immunotherapy has been supported by the high pathologic tumor response rates in early trials as well as the durability of these responses making cure a more achievable potential outcome compared with other forms of systemic therapy. Furthermore, neoadjuvant studies allow the assessment of radiologic and pathological responses and the access to biospecimens before and during systemic therapy. Pathological responses may guide future treatment decisions, and biospecimens allow the conduct of mechanistic and biomarker studies that may guide future drug development. On behalf of the National Cancer Institute Early Drug Development Neoadjuvant Immunotherapy Working Group, this article summarizes the current state of neoadjuvant immunotherapy of solid tumors focusing primarily on locoregionally advanced melanoma, gynecologic malignancies, gastrointestinal malignancies, non-small cell lung cancer and head and neck cancer including recent advances and our expert recommendations related to future neoadjuvant trial designs and associated clinical and translational research questions.

Coronary CT Angiography with Photon-counting CT: First-In-Human Results.

Background Spatial resolution, soft-tissue contrast, and dose-efficient capabilities of photon-counting CT (PCCT) potentially allow a better quality and diagnostic confidence of coronary CT angiography (CCTA) in comparison to conventional CT. Purpose To compare the quality of CCTA scans obtained with a clinical prototype PCCT system and an energy-integrating detector (EID) dual-layer CT (DLCT) system. Materials and Methods In this prospective board-approved study with informed consent, participants with coronary artery disease underwent retrospective electrocardiographically gated CCTA with both systems after injection of 65-75 mL of 400 mg/mL iodinated contrast agent at 5 mL/sec. A prior phantom task-based quality assessment of the detectability index of coronary lesions was performed. Ultra-high-resolution parameters were used for PCCT (1024 matrix, 0.25-mm section thickness) and EID DLCT (512 matrix, 0.67-mm section thickness). Three cardiac radiologists independently performed a blinded analysis using a five-point quality score (1 = insufficient, 5 = excellent) for overall image quality, diagnostic confidence, and diagnostic quality of calcifications, stents, and noncalcified plaques. A logistic regression model, adjusted for radiologists, was used to evaluate the proportion of improvement in scores with the best method. Results Fourteen consecutive participants (12 men; mean age, 61 years ± 17) were enrolled. Scores of overall quality and diagnostic confidence were higher with PCCT images with a median of 5 (interquartile range [IQR], 2) and 5 (IQR, 1) versus 4 (IQR, 1) and 4 (IQR, 3) with EID DLCT images, using a mean tube current of 255 mAs ± 0 versus 349 mAs ± 111 for EID DLCT images (P < .01). Proportions of improvement with PCCT images for quality of calcification, stent, and noncalcified plaque were 100%, 92% (95% CI: 71, 98), and 45% (95% CI: 28, 63), respectively. In the phantom study, detectability indexes were 2.3-fold higher for lumen and 2.9-fold higher for noncalcified plaques with PCCT images. Conclusion Coronary CT angiography with a photon-counting CT system demonstrated in humans an improved image quality and diagnostic confidence compared with an energy-integrating dual-layer CT. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Sandfort and Bluemke in this issue.

In Vivo Molecular K-Edge Imaging of Atherosclerotic Plaque Using Photon-counting CT.

Background Macrophage burden is a major factor in the risk of atherosclerotic plaque rupture, and its evaluation remains challenging with molecular noninvasive imaging approaches. Photon-counting CT (PCCT) with k-edge imaging aims to allow for the specific detection of macrophages using gold nanoparticles. Purpose To perform k-edge imaging in combination with gold nanoparticles to detect and quantify the macrophage burden within the atherosclerotic aortas of rabbits. Materials and Methods Atherosclerotic and control New Zealand white rabbits were imaged before and at several time points up to 2 days after intravenous injection of gold nanoparticles (3.5 mL/kg, 65 mg gold per milliliter). Aortic CT angiography was performed at the end of the follow-up using an intravenous injection of an iodinated contrast material. Gold k-edge and conventional CT images were reconstructed for qualitative and quantitative assessment of the macrophage burden. PCCT imaging results were compared with findings at histologic examination, quantitative histomorphometry, transmission electron microscopy, and quantitative inductively coupled plasma optical emission spectrometry. Pearson correlations between the macrophage area measured in immunostained sections and the concentration of gold and attenuation measured in the corresponding PCCT sections were calculated. Results Seven rabbits with atherosclerosis and four control rabbits without atherosclerosis were analyzed. In atherosclerotic rabbits, calcifications were observed along the aortic wall before injection. At 2 days after injection of gold nanoparticles, only gold k-edge images allowed for the distinction of plaque enhancement within calcifications and for lumen enhancement during angiography. A good correlation was observed between the gold concentration measured within the wall and the macrophage area in 35 plaques (five per rabbit) (r = 0.82; 95% CI: 0.67, 0.91; P < .001), which was higher than that observed on conventional CT images (r = 0.41; 95% CI: 0.09, 0.65; P = .01). Transmission electron microscopy and inductively coupled plasma optical emission spectrometry analyses confirmed the gold k-edge imaging findings. Conclusion Photon-counting CT with gold nanoparticles allowed for the noninvasive evaluation of both molecular and anatomic information in vivo in rabbits with atherosclerotic plaques. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Leiner in this issue.

Network for Biomarker Immunoprofiling for Cancer Immunotherapy: Cancer Immune Monitoring and Analysis Centers and Cancer Immunologic Data Commons (CIMAC-CIDC).

PURPOSE: Immunoprofiling to identify biomarkers and integration with clinical trial outcomes are critical to improving immunotherapy approaches for patients with cancer. However, the translational potential of individual studies is often limited by small sample size of trials and the complexity of immuno-oncology biomarkers. Variability in assay performance further limits comparison and interpretation of data across studies and laboratories. EXPERIMENTAL DESIGN: To enable a systematic approach to biomarker identification and correlation with clinical outcome across trials, the Cancer Immune Monitoring and Analysis Centers and Cancer Immunologic Data Commons (CIMAC-CIDC) Network was established through support of the Cancer MoonshotSM Initiative of the National Cancer Institute (NCI) and the Partnership for Accelerating Cancer Therapies (PACT) with industry partners via the Foundation for the NIH. RESULTS: The CIMAC-CIDC Network is composed of four academic centers with multidisciplinary expertise in cancer immunotherapy that perform validated and harmonized assays for immunoprofiling and conduct correlative analyses. A data coordinating center (CIDC) provides the computational expertise and informatics platforms for the storage, integration, and analysis of biomarker and clinical data. CONCLUSIONS: This overview highlights strategies for assay harmonization to enable cross-trial and cross-site data analysis and describes key elements for establishing a network to enhance immuno-oncology biomarker development. These include an operational infrastructure, validation and harmonization of core immunoprofiling assays, platforms for data ingestion and integration, and access to specimens from clinical trials. Published in the same volume are reports of harmonization for core analyses: whole-exome sequencing, RNA sequencing, cytometry by time of flight, and IHC/immunofluorescence.

Virtual versus true non-contrast dual-energy CT imaging for the diagnosis of aortic intramural hematoma.

PURPOSE: To assess whether virtual non-contrast (VNC) images derived from contrast dual-layer dual-energy computed tomography (DL-DECT) images could replace true non-contrast (TNC) images for aortic intramural hematoma (IMH) diagnosis in acute aortic syndrome (AAS) imaging protocols by performing quantitative as well as qualitative phantom and clinical studies. MATERIALS AND METHODS: Patients with confirmed IMH were included retrospectively in two centers. For in vitro imaging, a custom-made phantom of IMH was placed in a semi-anthropomorphic thorax phantom (QRM GmbH) and imaged on a DL-DECT at 120 kVp under various conditions of patient size, radiation exposure, and reconstruction modes. For in vivo imaging, 21 patients (70 ± 13 years) who underwent AAS imaging protocols at 120 kVp were included. In both studies, contrast-to-noise ratio (CNR) between hematoma and lumen was compared using a paired t test. Diagnostic confidence (1 = non-diagnostic, 4 = exemplary) for VNC and TNC images was rated by two radiologists and compared. Effective radiation doses for each acquisition were calculated. RESULTS: In both the phantom and clinical studies, we observed that the CNRs were similar between the VNC and TNC images. Moreover, both methods allowed differentiating the hyper-attenuation within the hematoma from the blood. Finally, we obtained equivalent high diagnostic confidence with both VNC and TNC images (VNC = 3.2 ± 0.7, TNC = 3.1 ± 0.7; p = 0.3). Finally, by suppressing TNC acquisition and using VNC, the mean effective dose reduction would be 40%. CONCLUSION: DL-DECT offers similar performances with VNC and TNC images for IMH diagnosis without compromise in diagnostic image quality. KEY POINTS: • Dual-layer dual-energy CT enables virtual non-contrast imaging from a contrast-enhanced acquisition. • Virtual non-contrast imaging with dual-layer dual-energy CT reduces the number of acquisitions and radiation exposure in acute aortic syndrome imaging protocol. • Dual-layer dual-energy CT has the potential to become a suitable imaging tool for acute aortic syndrome.

Spectral Photon-Counting Computed Tomography (SPCCT): in-vivo single-acquisition multi-phase liver imaging with a dual contrast agent protocol.

Diagnostic imaging of hepatocellular carcinoma (HCC) requires a liver CT or MRI multiphase acquisition protocol. Patients would benefit from a high-resolution imaging method capable of performing multi-phase imaging in a single acquisition without an increase in radiation dose. Spectral Photon-Counting Computed Tomography (SPCCT) has recently emerged as a novel and promising imaging modality in the field of diagnostic radiology. SPCCT is able to distinguish between two contrast agents referred to as multicolor imaging because, when measuring in three or more energy regimes, it can detect and quantify elements with a K-edge in the diagnostic energy range. Based on this capability, we tested the feasibility of a dual-contrast multi-phase liver imaging protocol via the use of iodinated and gadolinated contrast agents on four healthy New Zealand White (NZW) rabbits. To perform a dual-contrast protocol, we injected the agents at different times so that the first contrast agent visualized the portal phase and the second the arterial phase, both of which are mandatory for liver lesion characterization. We demonstrated a sensitive discrimination and quantification of gadolinium within the arteries and iodine within the liver parenchyma. In the hepatic artery, the concentration of gadolinium was much higher than iodine (8.5 ± 3.9 mg/mL versus 0.7 ± 0.1 mg/mL) contrary to the concentrations found in the liver parenchyma (0.5 ± 0.3 mg/mL versus 4.2 ± 0.3 mg/mL). In conclusion, our results confirm that SPCCT allows in-vivo dual contrast qualitative and quantitative multi-phase liver imaging in a single acquisition.

Multicolour imaging with spectral photon-counting CT: a phantom study.

BACKGROUND: To evaluate the feasibility of multicolour quantitative imaging with spectral photon-counting computed tomography (SPCCT) of different mixed contrast agents. METHODS: Phantoms containing eleven tubes with mixtures of varying proportions of two contrast agents (i.e. two selected from gadolinium, iodine or gold nanoparticles) were prepared so that the attenuation of each tube was about 280 HU. Scans were acquired at 120 kVp and 100 mAs using a five-bin preclinical SPCCT prototype, generating conventional, water, iodine, gadolinium and gold images. The correlation between prepared and measured concentrations was assessed using linear regression. The cross-contamination was measured for each material as the root mean square error (RMSE) of its concentration in the other material images, where no signal was expected. The contrast-to-noise ratio (CNR) relative to a phosphate buffered saline tube was calculated for each contrast agent. RESULTS: The solutions had similar attenuations (279 ± 10 HU, mean ± standard deviation) and could not be differentiated on conventional images. However, a distinction was observed in the material images within the same samples, and the measured and prepared concentrations were strongly correlated (R2 ≥ 0.97, 0.81 ≤ slope ≤ 0.95, -0.68 ≤ offset ≤ 0.89 mg/mL). Cross-contamination in the iodine images for the mixture of gold and gadolinium contrast agents (RMSE = 0.34 mg/mL) was observed. CNR for 1 mg/mL of contrast agent was better for the mixture of iodine and gadolinium (CNRiodine = 3.20, CNRgadolinium = 2.80) than gold and gadolinium (CNRgadolinium = 1.67, CNRgold = 1.37). CONCLUSIONS: SPCCT enables multicolour quantitative imaging. As a result, it should be possible to perform imaging of multiple uptake phases of a given tissue/organ within a single scan by injecting different contrast agents sequentially.

Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability.

BACKGROUND: Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear. METHODS: In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neuron specific NMDA receptor 1 knockout mice. RESULTS: The mice displayed increased baseline gamma power, as well as sociocognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increased neuronal excitability. CONCLUSIONS: Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological, and behavioral changes related to SZ.

Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits.

NMDA-receptor (NMDAR) hypofunction is strongly implicated in the pathophysiology of schizophrenia. Several convergent lines of evidence suggest that net excitation propagated by impaired NMDAR signaling on GABAergic interneurons may be of particular interest in mediating several aspects of schizophrenia. However, it is unclear which behavioral domains are governed by a net increase of excitation and whether modulating downstream GABAergic signaling can reverse neural and thus behavioral deficits. The current study determines the selective contributions of NMDAR dysfunction on PV-containing interneurons to electrophysiological, cognitive, and negative-symptom-related behavioral phenotypes of schizophrenia using mice with a PVcre-NR1flox-driven ablation of NR1 on PV-containing interneurons. In addition, we assessed the efficacy of one agent that directly modulates GABAergic signaling (baclofen) and one agent that indirectly modifies NMDAR-mediated signaling through antagonism of mGluR5 receptors (2-methyl-6-(phenylethynyl) pyridine (MPEP)). The data indicate that loss of NMDAR function on PV interneurons impairs self-care and sociability while increasing N1 latency and baseline gamma power, and reducing induction and maintenance of long-term potentiation. Baclofen normalized baseline gamma power without corresponding effects on behavior. MPEP further increased N1 latency and reduced social behavior in PVcre/NR1+/+ mice. These two indices were negatively correlated before and following MPEP such that as N1 latency increases, sociability decreases. This finding suggests a predictive role for N1 latency with respect to social function. Although previous data suggest that MPEP may be beneficial for core features of autism spectrum disorders, current data suggest that such effects require intact function of NMDAR on PV interneurons.

Electroencephalographic and early communicative abnormalities in Brattleboro rats.

Reductions in the levels of the neuropeptide vasopressin (VP) and its receptors have been associated with schizophrenia. VP is also critical for appropriate social behaviors in humans as well as rodents. One of the prominent symptoms of schizophrenia is asociality and these symptoms may develop prodromally. A reduction in event-related potential (ERP) peak amplitudes is an endophenotype of schizophrenia. In this study, we use the Brattleboro (BRAT) rat to assess the role of VP deficiency in vocal communication during early development and on auditory ERPs during adulthood. BRAT rats had similar vocal communication to wild-type littermate controls during postnatal days 2 and 5 but the time between vocalizations was increased and the power of the vocalizations was reduced beginning at postnatal day 9. During adulthood, BRAT rats had deficits in auditory ERPs including reduced N40 amplitude and reduced low and high gamma intertrial coherence. These results suggest that the role of VP on vocal communication is an age-dependent process. Additionally, the deficits in ERPs indicate an impairment of auditory information processing related to the reduction in VP. Therefore, manipulation of the VP system could provide a novel mechanism for treatment for negative symptoms of schizophrenia.

Knockout of NMDA receptors in parvalbumin interneurons recreates autism-like phenotypes.

Autism is a disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors with few effective treatments. New evidence suggests that autism has reliable electrophysiological endophenotypes and that these measures may be caused by n-methyl-d-aspartic acid receptor (NMDAR) disruption on parvalbumin (PV)-containing interneurons. These findings could be used to create new translational biomarkers. Recent developments have allowed for cell-type selective knockout of NMDARs in order to examine the perturbations caused by disrupting specific circuits. This study examines several electrophysiological and behavioral measures disrupted in autism using a PV-selective reduction in NMDA R1 subunit. Mouse electroencephalograph (EEG) was recorded in response to auditory stimuli. Event-related potential (ERP) component amplitude and latency analysis, social testing, and premating ultrasonic vocalizations (USVs) recordings were performed. Correlations were examined between the ERP latency and behavioral measures. The N1 ERP latency was delayed, sociability was reduced, and mating USVs were impaired in PV-selective NMDA Receptor 1 Knockout (NR1 KO) as compared with wild-type mice. There was a significant correlation between N1 latency and sociability but not between N1 latency and premating USV power or T-maze performance. The increases in N1 latency, impaired sociability, and reduced vocalizations in PV-selective NR1 KO mice mimic similar changes found in autism. Electrophysiological changes correlate to reduced sociability, indicating that the local circuit mechanisms controlling N1 latency may be utilized in social function. Therefore, we propose that behavioral and electrophysiological alterations in PV-selective NR1 KO mice may serve as a useful model for therapeutic development in autism. Autism Res 2013, 6: 69-77. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression.

RATIONALE: A number of studies have associated reduced Akt1 expression with vulnerability for schizophrenia. Although mice with deletion of a single copy of the Akt1 gene (Akt1(+/-)) show reduced Akt1 expression relative to wild-type (WT) animals, the extent to which these mice show schizophrenia-like phenotypic changes and/or increased susceptibility to epigenetic or non-genetic factors related to schizophrenia is unknown. OBJECTIVES: Mutant mice were assessed on electroencephalographic/event-related potential (EEG/ERP) and behavioral (acoustic startle and pre-pulse inhibition) measures relevant to schizophrenia. Mice were also assessed following exposure to the NMDA receptor antagonist ketamine, a potent psychotomimetic drug, in order to assess the role of reduced Akt1 expression as a vulnerability factor for schizophrenia. Methods Akt1(+/-), Akt1(-/-), and WT mice received a series of paired-click, white noise stimuli, following ketamine (50 mg/kg) and saline injections. EEG was analyzed for ERPs and event-related power. Akt1(+/-) and WT mice were also assessed on PPI following ketamine (50 mg/kg) or saline injection. RESULTS: Akt1(+/-) and Akt1(-/-) mice displayed reduced amplitude of the P20 component of the ERP to the first click of a paired-click stimulus, as well as reduced S1-S2 difference for P20 and N40 components, following ketamine. Mutant mice also showed increased reduction in gamma synchrony and theta suppression following ketamine. Akt1(+/-) mice displayed reduced pre-pulse inhibition. CONCLUSIONS: Reduced genetic expression of Akt1 facilitated ketamine-induced changes of EEG and behavior in mice, suggesting that reduced Akt1 expression can serve as a vulnerability factor for schizophrenia.

Subchronic ketamine treatment leads to permanent changes in EEG, cognition and the astrocytic glutamate transporter EAAT2 in mice.

Ketamine is an NMDA receptor antagonist with psychotomimetic, dissociative, amnestic and euphoric effects. When chronically abused, ketamine users display deficits in cognition and information processing, even following long-term abstinence from the drug. While animal studies have shown evidence of behavioral changes and cognitive deficits that mimic those seen in humans within the period immediately following subchronic ketamine, a few animal studies have assessed long-term changes following cessation of ketamine exposure. To this end, the present study assessed event related potentials (ERPs) and EEG oscillations in mice exposed to subchronic ketamine following a 6month period of abstinence from the drug. Ketamine-treated mice showed no change in P20, but did show marked reductions in amplitude of the later N40 and P80 components, consistent with previous studies of acute ketamine exposure. Additionally, ketamine-treated animals showed a significant reduction in stimulus evoked theta oscillations. To assess the functional significance of these changes, mice were also assessed on a series of behavioral and cognitive tests, including progressive ratio (motivation), extinction (behavioral flexibility) and win-shift radial maze (spatial memory). Subchronic ketamine produced marked disruptions in reversal learning and spatial memory. Analysis of brains from ketamine-treated mice failed to show evidence of neuronal degeneration as determined by NueN immunohistochemistry, but did show increased astrocyte proliferation and decreased expression of the glial specific glutamate transporter, GLT-1. These results strongly suggest: 1) that subchronic ketamine induces significant changes in brain function that long exceed exposure to the drug; 2) that ketamine exposure in mice induces lasting cognitive impairments closely resembling those observed in human ketamine abusers; 3) that ERP and EEG measures are highly sensitive to alterations in brain function associated with reduced cognitive function; and 4) that the brain changes induced by chronic ketamine treatment are suggestive of long-term adaptive or plastic, rather than degenerative, changes.

Nicotine normalizes event related potentials in COMT-Val-tg mice and increases gamma and theta spectral density.

Regulation of dopamine neurotransmission is essential for cognitive processes. In humans and rodents, the relationship between dopamine signaling and cognitive performance is described as a dose-dependent, inverted-U curve whereby excess or insufficiency of dopamine in prefrontal cortex has detrimental effects. Previous studies have indicated that prefrontal dopamine levels are associated with genetic variation in catechol-O-methyltransferase (COMT), a regulatory enzyme that controls dopamine availability. Furthermore, smokers who carry the high-activity COMT-Val allele are more prone to cognitive deficits and have an increased risk of smoking relapse. The present study employed transgenic mice expressing the human COMT-Val variant to determine the effects of the high-activity COMT allele on electrophysiological markers, including the P20, N40, and P80 components of the auditory event-related potential, as well as baseline and auditory event-related power and phase-synchrony in theta and gamma ranges. We also examined the effects of nicotine on these measures to investigate the potential effects of smoking on COMT-mediated electrophysiological activity. COMT-Val-tg mice displayed increased N40 latency and decreased P80 amplitude as well as reduced baseline theta and gamma power. Nicotine increased P20 and P80 amplitudes, decreased N40 amplitude, increased P20 and N40 latencies, and reduced P80 latency. Nicotine also increased the event-related power and phase synchrony, yielding an increase in signal-to-noise ratio across theta and gamma ranges. COMT activity specifically alters long-latency components of the event-related response. Nicotine restored normal event-related activity among COMT-Val-tg mice, suggesting one mechanism through which nicotine may normalize cognitive function among people with the high-activity allele.