Utility of PET to Appropriately Select Patients for PSMA-Targeted Theranostics.

ABSTRACT: The majority of aggressive prostate cancers overexpress the transmembrane protein prostate-specific membrane antigen (PSMA). PSMA is, therefore, an attractive target for drug development. Over the last decade, numerous PSMA-targeted radiopharmaceuticals for imaging and therapy have been developed and investigated in theranostic combination. PSMA-targeted radiopharmaceuticals for imaging have been primarily developed for PET. PSMA PET provides whole-body evaluation of the degree of PSMA expression on tumors and potentially provides a method to better select patients for PSMA-targeted therapy. Numerous PSMA-targeted therapeutic agents using ß- or α-particle emitters are under study in clinical trials. In particular, the ß-particle-emitting radioisotope 177Lu bound to PSMA-targeted small molecules have ongoing and completed late-stage clinical trials in metastatic castration-resistant prostate cancer. To define the most appropriate patient group for PSMA-targeted therapeutics, multiple studies have investigated PSMA and FDG PET/CT to establish PET parameters as predictive and prognostic biomarkers. This article discusses recent clinical trials that examine the optimal use of PET for the selection of patients for PSMA-targeted therapeutics and provides an integrative overview of choice of PET tracer(s), targeting molecule, therapeutic radioisotope, nonradioactive therapy, and cancer type (prostate or nonprostate).

A Retrospective Investigation: Outcome Comparisons Between Septic Patients With and Without Secondary Diagnosis of Hypothyroidism From a Rural Midwest Hospital.

Background Sepsis morbidity and mortality rates have remained high despite recent developments in clinical guidelines aimed to curtail this disease process. Understanding how sepsis interacts with comorbidities and pre-existing disease states is necessary for improving sepsis treatment. Accounting for specific pre-existing conditions in the treatment of sepsis patients may not only improve patient outcomes but also reduce healthcare costs by preventing possible complications. We sought to evaluate whether the presence of hypothyroidism affects outcomes in septic patients. Methods In this retrospective observational study, we analyzed the patient dataset from a not-for-profit rural hospital from January 2019 through June 2020. We chose the initial patient sample based on International Classification of Disease (ICD10) codes for sepsis. We then used the ICD10 code for hypothyroidism within that sample to identify the septic patients with hypothyroidism. We did two-sample proportion summary hypothesis tests to identify differences in mortality and 30-day readmission rates. Results In our dataset, we had 1,122 patients with sepsis, of whom 225 had hypothyroidism. There was no difference in sepsis outcomes between patients who had hypothyroidism compared to patients who did not have hypothyroidism. Additionally, we did not find sufficient evidence to conclude that the patient's sex affects sepsis outcomes in hypothyroid patients.  Conclusion  Within this Midwest population, the sepsis outcomes were not impacted by having hypothyroidism as a secondary diagnosis. Additionally, there was no sufficient evidence to suggest an impact on sepsis outcomes based on sex, either male or female, when considering concomitant hypothyroidism.

Systems Genetics in Human Endothelial Cells Identifies Non-coding Variants Modifying Enhancers, Expression, and Complex Disease Traits.

The identification of causal variants and mechanisms underlying complex disease traits in humans is important for the progress of human disease genetics; this requires finding strategies to detect functional regulatory variants in disease-relevant cell types. To achieve this, we collected genetic and transcriptomic data from the aortic endothelial cells of up to 157 donors and four epigenomic phenotypes in up to 44 human donors representing individuals of both sexes and three major ancestries. We found thousands of expression quantitative trait loci (eQTLs) at all ranges of effect sizes not detected by the Gene-Tissue Expression Project (GTEx) in human tissues, showing that novel biological relationships unique to endothelial cells (ECs) are enriched in this dataset. Epigenetic profiling enabled discovery of over 3,000 regulatory elements whose activity is modulated by genetic variants that most frequently mutated ETS, AP-1, and NF-kB binding motifs, implicating these motifs as governors of EC regulation. Using CRISPR interference (CRISPRi), allele-specific reporter assays, and chromatin conformation capture, we validated candidate enhancer variants located up to 750 kb from their target genes, VEGFC, FGD6, and KIF26B. Regulatory SNPs identified were enriched in coronary artery disease (CAD) loci, and this result has specific implications for PECAM-1, FES, and AXL. We also found significant roles for EC regulatory variants in modifying the traits pulse pressure, blood protein levels, and monocyte count. Lastly, we present two unlinked SNPs in the promoter of MFAP2 that exhibit pleiotropic effects on human disease traits. Together, this supports the possibility that genetic predisposition for complex disease is manifested through the endothelium.

Regional Changes in Brain 18F-FDG Uptake After Prophylactic Cranial Irradiation and Chemotherapy in Small Cell Lung Cancer May Reflect Functional Changes.

Chemotherapy followed by prophylactic cranial irradiation (PCI) is associated with increased survival in patients with small cell lung cancer but is associated with fatigue and cognitive impairment. This retrospective study evaluated regional differences in 18F-FDG uptake by the brain before and after PCI. The null hypothesis was that direct toxic effects on the brain from PCI and chemotherapy are symmetric; thus, asymmetric deviations may reflect functional changes due to therapy. Methods: Electronic medical records from 2013 to 2016 were reviewed for patients with small cell lung cancer, MRI of brain negative for metastasis, and 18F-FDG PET/CT scans before and after PCI. As the standard of care, patients received first-line chemotherapy or chemoradiation to the thorax followed by PCI. The 18F-FDG PET/CT scans nearest the PCI were selected. Sixteen patients met these initial criteria. Commercially available PET software was used to register and subtract the PET scans before and after PCI to obtain difference maps. Occipital and cerebellar regions were excluded from the final statistical analysis given the known high variability and misregistration. The χ2 test was used to analyze the data. Results: Two patients had 18F-FDG uptake differences only in the occipital and cerebellar regions. The software registration failed on 1 patient's scans. Therefore, 13 patients were included in the final analysis. Nine of 13 patients demonstrated significant unilateral changes in only 1 region of the brain, and 3 of 13 showed significant changes unilaterally in 2 regions. The χ2 test revealed a significant unilateral regional difference on a patient level (χ2 = 6.24, P = 0.025). The most commonly affected brain region was the frontal lobe. Conclusion: Significantly more patients had unilateral than bilateral regional differences (both increases and decreases) in 18F-FDG uptake in the brain before and after PCI. This finding suggests that differences in unilateral distribution are related to functional changes, since direct toxicity alone from PCI and chemotherapy would be symmetric. The frontal region was the most commonly affected, suggesting a potential contributing etiology for cognitive impairment and decreased executive function after therapy.

18F-FDG PET/CT for the Evaluation of Primary Eosinophilic Granuloma of the Hypothalamus.

A 21-y-old man who presented with polyuria and polydipsia was discovered to have diabetes insipidus due to eosinophilic granuloma of the hypothalamus. 18F-FDG PET/CT, which was performed as a metastatic work-up, revealed an intensely 18F-FDG-avid hypothalamic mass and no other sites of disease.