Granzyme B PET Imaging for Assessment of Disease Activity in Inflammatory Bowel Disease.

Developing a noninvasive imaging method to detect immune system activation with a high temporal resolution is key to improving inflammatory bowel disease (IBD) management. In this study, granzyme B (GZMB), typically released from cytotoxic T and natural killer cells, was targeted using PET with 68Ga-NOTA-GZP (where GZP is ß-Ala-Gly-Gly-Ile-Glu-Phe-Asp-CHO) to detect early intestinal inflammation in murine models of colitis. Methods: Bioinformatic analysis was used to assess the potential of GZMB as a biomarker for detecting IBD and predicting response to treatment. Human active and quiescent Crohn disease and ulcerative colitis tissues were stained for GZMB. We used IL-10-/- mice treated with dextran sulfate sodium (DSS) as an IBD model, wild-type C57BL/6J mice as a control, and anti-tumor necrosis factor as therapy. We used a murine GZMB-binding peptide conjugated to a NOTA chelator (NOTA-GZP) labeled with 68Ga as the PET tracer. PET imaging was conducted at 1, 3, and 4 wk after colitis induction to evaluate temporal changes. Results: Bioinformatic analysis showed that GZMB gene expression is significantly upregulated in human ulcerative colitis and Crohn disease compared with the noninflamed bowel by 2.98-fold and 1.92-fold, respectively; its expression is lower by 2.16-fold in treatment responders than in nonresponders. Immunofluorescence staining of human tissues demonstrated a significantly higher GZMB in patients with active than with quiescent IBD (P = 0.032).68Ga-NOTA-GZP PET imaging showed significantly increased bowel uptake in IL-10-/- mice with DSS-induced colitis compared with vehicle-treated IL-10-/- mice (SUVmean, 0.75 vs. 0.24; P < 0.001) and both vehicle- and DSS-treated wild-type mice (SUVmean, 0.26 and 0.37; P < 0.001). In the IL-10-/- DSS-induced colitis model, the bowel PET probe uptake decreased in response to treatment with tumor necrosis factor-α (SUVmean, 0.32; P < 0.001). There was a 4-fold increase in colonic uptake of 68Ga-NOTA-GZP in the colitis model compared with the control 1 wk after colitis induction. The uptake gradually decreased to approximately 2-fold by 4 wk after IBD induction; however, the inflamed bowel uptake remained significantly higher than control at all time points (week 4 SUVmean, 0.23 vs. 0.08; P = 0.001). Conclusion: GZMB is a promising biomarker to detect active IBD and predict response to treatment. This study provides compelling evidence to translate GZMB PET for imaging IBD activity in clinical settings.

Mechanism of Action and Translational Potential of (S)-Meclizine in Preemptive Prophylaxis Against Stroke.

BACKGROUND: Mild chemical inhibition of mitochondrial respiration can confer resilience against a subsequent stroke or myocardial infarction, also known as preconditioning. However, the lack of chemicals that can safely inhibit mitochondrial respiration has impeded the clinical translation of the preconditioning concept. We previously showed that meclizine, an over-the-counter antivertigo drug, can toggle metabolism from mitochondrial respiration toward glycolysis and protect against ischemia-reperfusion injury in the brain, heart, and kidney. Here, we examine the mechanism of action of meclizine and report the efficacy and improved safety of the (S) enantiomer. METHODS: We determined the anoxic depolarization latency, tissue and neurological outcomes, and glucose uptake using micro-positron emission tomography after transient middle cerebral artery occlusion in mice pretreated (-17 and -3 hours) with either vehicle or meclizine. To exclude a direct effect on tissue excitability, we also examined spreading depression susceptibility. Furthermore, we accomplished the chiral synthesis of (R)- and (S)-meclizine and compared their effects on oxygen consumption and histamine H1 receptor binding along with their brain concentrations. RESULTS: Micro-positron emission tomography showed meclizine increases glucose uptake in the ischemic penumbra, providing the first in vivo evidence that the neuroprotective effect of meclizine indeed stems from its ability to toggle metabolism toward glycolysis. Consistent with reduced reliance on oxidative phosphorylation to sustain the metabolism, meclizine delayed anoxic depolarization onset after middle cerebral artery occlusion. Moreover, the (S) enantiomer showed reduced H1 receptor binding, a dose-limiting side effect for the racemate, but retained its effect on mitochondrial respiration. (S)-meclizine was at least as efficacious as the racemate in delaying anoxic depolarization onset and decreasing infarct volumes after middle cerebral artery occlusion. CONCLUSIONS: Our data identify (S)-meclizine as a promising new drug candidate with high translational potential as a chemical preconditioning agent for preemptive prophylaxis in patients with high imminent stroke or myocardial infarction risk.

Percutaneous Intratumoral Immunoadjuvant Gel Increases the Abscopal Effect of Cryoablation for Checkpoint Inhibitor Resistant Cancer.

Percutaneous cryoablation is a common clinical therapy for metastatic and primary cancer. There are rare clinical reports of cryoablation inducing regression of distant metastases, known as the "abscopal" effect. Intratumoral immunoadjuvants may be able to augment the abscopal rate of cryoablation, but existing intratumoral therapies suffer from the need for frequent injections and inability to confirm target delivery, leading to poor clinical trial outcomes. To address these shortcomings, an injectable thermoresponsive gel-based controlled release formulation is developed for the FDA-approved Toll-like-receptor 7 (TLR7) agonist imiquimod ("Imigel") that forms a tumor-resident depot upon injection and contains a contrast agent for visualization under computed tomography (CT). The poly-lactic-co-glycolic acid-polyethylene glycol-poly-lactic-co-glycolic acid (PLGA-PEG-PLGA)-based amphiphilic copolymer gel's underlying micellar nature enables high drug concentration and a logarithmic release profile that is additive with the neo-antigen release from cryoablation, requiring only a single injection. Rheological testing demonstrated the thermoresponsive increase in viscosity at body temperature and radio-opacity via microCT. Its ability to significantly augment the abscopal rate of cryoablation is demonstrated in otherwise immunotherapy resistant metastatic tumors in two aggressive colorectal and breast cancer dual tumor models with an all or nothing response, responders generally demonstrating complete regression of bilateral tumors in 90-day survival studies.

Advantages of a Photodiode Detector Endoscopy System in Fluorescence-Guided Percutaneous Liver Biopsies.

Image-guided liver biopsies can improve their success rate when combined with the optical detection of Indocyanine Green (ICG) fluorescence accumulated in tumors. Previous works used a camera coupled to a thin borescope to capture and quantify images from fluorescence emission during procedures; however, light-scattering prevented the formation of sharp images, and the time response for weakly fluorescent tumors was very low. Instead, replacing the camera with a photodiode detector shows an improved temporal resolution in a more compact and lighter device. This work presents the new design in a comparative study between both detection technologies, including an assessment of the temporal response and sensitivity to the presence of background fluorescence.

DNA Damage by Radiopharmaceuticals and Mechanisms of Cellular Repair.

DNA is an organic molecule that is highly vulnerable to chemical alterations and breaks caused by both internal and external factors. Cells possess complex and advanced mechanisms, including DNA repair, damage tolerance, cell cycle checkpoints, and cell death pathways, which together minimize the potentially harmful effects of DNA damage. However, in cancer cells, the normal DNA damage tolerance and response processes are disrupted or deregulated. This results in increased mutagenesis and genomic instability within the cancer cells, a known driver of cancer progression and therapeutic resistance. On the other hand, the inherent instability of the genome in rapidly dividing cancer cells can be exploited as a tool to kill by imposing DNA damage with radiopharmaceuticals. As the field of targeted radiopharmaceutical therapy (RPT) is rapidly growing in oncology, it is crucial to have a deep understanding of the impact of systemic radiation delivery by radiopharmaceuticals on the DNA of tumors and healthy tissues. The distribution and activation of DNA damage and repair pathways caused by RPT can be different based on the characteristics of the radioisotope and molecular target. Here we provide a comprehensive discussion of the biological effects of RPTs, with the main focus on the role of varying radioisotopes in inducing direct and indirect DNA damage and activating DNA repair pathways.

Abdominal Positron Emission Tomography/Magnetic Resonance Imaging.

Hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) is highly suited for abdominal pathologies. A precise co-registration of anatomic and metabolic data is possible thanks to the simultaneous acquisition, leading to accurate imaging. The literature shows that PET/MRI is at least as good as PET/CT and even superior for some indications, such as primary hepatic tumors, distant metastasis evaluation, and inflammatory bowel disease. PET/MRI allows whole-body staging in a single session, improving health care efficiency and patient comfort.

COVID-19 in congenital heart disease (COaCHeD) study.

BACKGROUND: COVID-19 has caused significant worldwide morbidity and mortality. Congenital heart disease (CHD) is likely to increase vulnerability and understanding the predictors of adverse outcomes is key to optimising care. OBJECTIVE: Ascertain the impact of COVID-19 on people with CHD and define risk factors for adverse outcomes. METHODS: Multicentre UK study undertaken 1 March 2020-30 June 2021 during the COVID-19 pandemic. Data were collected on CHD diagnoses, clinical presentation and outcomes. Multivariable logistic regression with multiple imputation was performed to explore predictors of death and hospitalisation. RESULTS: There were 405 reported cases (127 paediatric/278 adult). In children (age <16 years), there were 5 (3.9%) deaths. Adjusted ORs (AORs) for hospitalisation in children were significantly lower with each ascending year of age (OR 0.85, 95% CI 0.75 to 0.96 (p<0.01)). In adults, there were 24 (8.6%) deaths (19 with comorbidities) and 74 (26.6%) hospital admissions. AORs for death in adults were significantly increased with each year of age (OR 1.05, 95% CI 1.01 to 1.10 (p<0.01)) and with pulmonary arterial hypertension (PAH; OR 5.99, 95% CI 1.34 to 26.91 (p=0.02)). AORs for hospitalisation in adults were significantly higher with each additional year of age (OR 1.03, 95% CI 1.00 to 1.05 (p=0.04)), additional comorbidities (OR 3.23, 95% CI 1.31 to 7.97 (p=0.01)) and genetic disease (OR 2.87, 95% CI 1.04 to 7.94 (p=0.04)). CONCLUSIONS: Children were at low risk of death and hospitalisation secondary to COVID-19 even with severe CHD, but hospital admission rates were higher in younger children, independent of comorbidity. In adults, higher likelihood of death was associated with increasing age and PAH, and of hospitalisation with age, comorbidities and genetic disease. An individualised approach, based on age and comorbidities, should be taken to COVID-19 management in patients with CHD.

Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are often diagnosed in advanced stages. Despite the advances in treatment approaches, including somatostatin analogs and peptide receptor radionuclide therapy (PRRT), these patients have no curative treatment option. Moreover, immunotherapy often yields modest results in NETs. We investigated whether combining PRRT using [177Lu]DOTATATE and immune checkpoint inhibition therapy improves treatment response in NETs. Methods: A gastroenteropancreatic NET model was generated by subcutaneous implantation of human QGP-1 cells in immune-reconstituted NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ mice engrafted with human peripheral blood mononuclear cells (n = 96). Mice were randomly assigned to receive pembrolizumab (anti-PD1), [177Lu]DOTATATE (PRRT), simultaneous anti-PD1 and PRRT (S-PRRT), anti-PD1 on day 0 followed by PRRT on day 3 (delayed PRRT [D-PRRT]), PRRT on day 0 followed by anti-PD1 (early PRRT [E-PRRT]), or vehicle as control (n = 12/group). Human granzyme-B-specific [68Ga]NOTA-hGZP PET/MRI was performed before and 6 d after treatment initiation, as an indicator of T-cell activation. Response to treatment was based on tumor growth over 21 d and on histologic analyses of extracted tissues on flow cytometry for T cells, hematoxylin and eosin staining, and immunohistochemical staining. Results: [68Ga]NOTA-hGZP PET/MRI showed significantly increased uptake in tumors treated with E-PRRT, S-PRRT, and anti-PD1 on day 6 compared with baseline (SUVmax: 3.36 ± 0.42 vs. 0.73 ± 0.23; 2.36 ± 0.45 vs. 0.76 ± 0.30; 2.20 ± 0.20 vs. 0.72 ± 0.28, respectively; P < 0.001), whereas no significant change was seen in PET parameters in the D-PRRT, PRRT, or vehicle groups (P > 0.05). Ex vivo analyses confirmed the PET results showing the highest granzyme-B levels and T cells (specifically CD8-positive effector T cells) in the E-PRRT group, followed by the S-PRRT and anti-PD1 groups. Tumor growth follow-up showed the most significant tumor size reduction in the E-PRRT group (baseline to day 21, 205.00 ± 30.70 mm3 vs. 78.00 ± 11.75 mm3; P = 0.0074). Tumors showed less growth reduction in the PRRT, D-PRRT, and S-PRRT groups than in the E-PRRT group (P < 0.0001). The vehicle- and anti-PD-1-treated tumors showed continued growth. Conclusion: Combination of PRRT and anti-PD1 shows the most robust inflammatory response to NETs and a better overall outcome than immune checkpoint inhibition or PRRT alone. The most effective regimen is PRRT preceding anti-PD1 administration by several days.

Harnessing imaging tools to guide immunotherapy trials: summary from the National Cancer Institute Cancer Imaging Steering Committee workshop.

As the immuno-oncology field continues the rapid growth witnessed over the past decade, optimising patient outcomes requires an evolution in the current response-assessment guidelines for phase 2 and 3 immunotherapy clinical trials and clinical care. Additionally, investigational tools-including image analysis of standard-of-care scans (such as CT, magnetic resonance, and PET) with analytics, such as radiomics, functional magnetic resonance agents, and novel molecular-imaging PET agents-offer promising advancements for assessment of immunotherapy. To document current challenges and opportunities and identify next steps in immunotherapy diagnostic imaging, the National Cancer Institute Clinical Imaging Steering Committee convened a meeting with diverse representation among imaging experts and oncologists to generate a comprehensive review of the state of the field.

Oncolytic HSV1 targets different growth phases of breast cancer leptomeningeal metastases.

Leptomeningeal metastasis is a fatal complication of breast cancer which results when cancer cells seed in the meninges. Currently there is no cure, limiting survival to less than four months. Treatment options are palliative. We studied a replication conditional Herpes simplex virus 1 (HSV1) in this regard and present the therapeutic efficacy of oncolytic HSV1 on different stages of breast cancer leptomeningeal metastases growth, namely the lag, intermediate, and exponential phases. These phases characterized in a murine model represent the early, intermediate, and late stages of leptomeningeal disease in patients. In this model, virus was introduced into the ventricular system by stereotactic surgery, the same path cancer cells were introduced to create leptomeningeal metastases. Tumor growth was measured with Gd-MRI and virus replication was assessed by FHBG-PET and Fluc bioluminescence. Imaging results were correlated with H&E and HSV-TK immunohistochemical staining. A remarkable growth inhibition was observed when the lag phase was targeted which was associated with multiple virus replication cycles. The onset of debilitating symptoms was delayed, and survival was lengthened by nearly 2 weeks. A growth inhibition similar to the lag phase was observed when the intermediate phase was targeted, associated with robust virus replication. The regression of existing tumor led to a reversal of neurological symptoms, extending survival by nearly one week. A modest response was observed when the lag phase was targeted lengthening survival by 3 days. Oncolytic HSV1 presents a novel treatment option for breast cancer leptomeningeal metastases with potential for targeting different disease stages where virus replication and tumor response can be monitored with molecular imaging techniques that are in the clinic.

Targeted Molecular Imaging as a Biomarker in Urologic Oncology.

Urologic malignancies constitute a large portion of annually diagnosed cancers. Timely diagnosis, accurate staging, and assessment of tumor heterogeneity are essential to devising the best treatment strategy for individual patients. The high sensitivity of molecular imaging allows for early and sensitive detection of lesions that were not readily detectable using conventional imaging techniques. Moreover, molecular imaging enables the interrogation of molecular processes used in targeted cancer therapies and predicts cancer response to treatment. Here we review the current advancements in molecular imaging of urologic cancers, including prostatic, vesical, renal testicular, and ureteral cancers.

Integrating Theranostics Into Patient Care Pathways: AJR Expert Panel Narrative Review.

Theranostics describes the coupling of a diagnostic biomarker and a therapeutic agent (i.e., a theranostic pair) that have a common target in tumor cells or their microenvironment. The term is increasingly associated with in vivo nuclear medicine oncologic applications that couple diagnostic imaging by means of gamma radiation with concomitant localized high-energy particulate radiation to a tissue expressing the common target. Several theranostic pairs have been translated into clinical practice in the United States and are poised to become a mainstay of cancer treatment. The purposes of this article are to review experience with theranostics for solid-organ malignancies and to address the practical integration into care pathways of ß-emitting therapies that include somatostatin analogue radioligands for neuroendocrine tumors, PSMA-directed therapy for prostate cancer, and 131I-MIBG therapy for tumors of neural crest origin. Toxicities related to theranostics administration and indications for cessation of therapy in patients who experience adverse events are also discussed. A multidisciplinary team-based approach for identifying patients most likely to respond to these agents, determining the optimal time for therapy delivery, and managing patient care throughout the therapeutic course is critical to the success of a radiotheranostic program.

Carbon-11-Labeled Methionine PET/CT in Patients With FDG-Occult Multiple Myeloma: A Prospective Pilot Study.

In a pilot study (ClinicalTrials.gov NCT02646085), seven patients with treated multiple myeloma and negative FDG PET/CT underwent amino acid imaging with 11C-methionine PET/CT. In five participants, 11C-methionine PET/CT showed focal uptake corresponding with lytic lesions; two to 18 lesions were found (SUVmax, 2.8-6.4). Findings indicated a potential role for 11C-methionine PET/CT in detecting residual disease after negative FDG PET/CT, thereby guiding further treatment.