Brain metabolites in cholinergic and glutamatergic pathways are altered by pancreatic cancer cachexia.

BACKGROUND: Cachexia is a major cause of morbidity in pancreatic ductal adenocarcinoma (PDAC) patients. Our purpose was to understand the impact of PDAC-induced cachexia on brain metabolism in PDAC xenograft studies, to gain new insights into the causes of cachexia-induced morbidity. Changes in mouse and human plasma metabolites were characterized to identify underlying causes of brain metabolic changes. METHODS: We quantified metabolites, detected with high-resolution 1 H magnetic resonance spectroscopy, in the brain and plasma of normal mice (n = 10) and mice bearing cachexia (n = 10) or non-cachexia (n = 9) inducing PDAC xenografts as well as in human plasma obtained from normal individuals (n = 24) and from individuals with benign pancreatic disease (n = 20) and PDAC (n = 20). Statistical significance was defined as a P value ≤0.05. RESULTS: The brain metabolic signature of cachexia-inducing PDAC was characterized by a significant depletion of choline of -27% and -21% as well as increases of glutamine of 13% and 9% and formate of 21% and 14%, relative to normal controls and non-cachectic tumour-bearing mice, respectively. Good to moderate correlations with percent weight change were found for choline (r = 0.70), glutamine (r = -0.58), and formate (r = -0.43). Significant choline depletion of -38% and -30%, relative to normal controls and non-cachectic tumour-bearing mice, respectively, detected in the plasma of cachectic mice likely contributed to decreased brain choline in cachectic mice. Similarly, relative to normal controls and patients with benign disease, choline levels in human plasma samples of PDAC patients were significantly lower by -12% and -20% respectively. A comparison of plasma metabolites from PDAC patients with and without weight loss identified significant changes in glutamine metabolism. CONCLUSIONS: Disturbances in metabolites of the choline/cholinergic and glutamine/glutamate/glutamatergic neurotransmitter pathways may contribute to morbidity. Metabolic normalization may provide strategies to reduce morbidity. The human plasma metabolite changes observed may lead to the development of companion diagnostic markers to detect PDAC and PDAC-induced cachexia.

Utility of CT Radiomics Features in Differentiation of Pancreatic Ductal Adenocarcinoma From Normal Pancreatic Tissue.

OBJECTIVE. The objective of our study was to determine the utility of radiomics features in differentiating CT cases of pancreatic ductal adenocarcinoma (PDAC) from normal pancreas. MATERIALS AND METHODS. In this retrospective case-control study, 190 patients with PDAC (97 men, 93 women; mean age ± SD, 66 ± 9 years) from 2012 to 2017 and 190 healthy potential renal donors (96 men, 94 women; mean age ± SD, 52 ± 8 years) without known pancreatic disease from 2005 to 2009 were identified from radiology and pathology databases. The 3D volume of the pancreas was manually segmented from the preoperative CT scans by four trained researchers and verified by three abdominal radiologists. Four hundred seventy-eight radiomics features were extracted to express the phenotype of the pancreas. Forty features were selected for analysis because of redundancy of computed features. The dataset was divided into 255 training cases (125 normal control cases and 130 PDAC cases) and 125 validation cases (65 normal control cases and 60 PDAC cases). A random forest classifier was used for binary classification of PDAC versus normal pancreas of control cases. Accuracy, sensitivity, and specificity were calculated. RESULTS. Mean tumor size was 4.1 ± 1.7 (SD) cm. The overall accuracy of the random forest binary classification was 99.2% (124/125), and AUC was 99.9%. All PDAC cases (60/60) were correctly classified. One case from a renal donor was misclassified as PDAC (1/65). The sensitivity was 100%, and specificity was 98.5%. CONCLUSION. Radiomics features extracted from whole pancreas can be used to differentiate between CT cases from patients with PDAC and healthy control subjects with normal pancreas.

Precision Radiology Residency Training: Special Distinction Tracks for Noninterpretative Professional Development.

RATIONALE AND OBJECTIVES: The role of a radiologist has expanded beyond the tripartite mission of patient care, education, and research to include cross-specialty consultation for patient management, innovative solutions to improve health-care quality and safety, device design, and policy advocacy. As such, radiology residency programs should incorporate formalized training to prepare residents for these various professional roles. MATERIALS AND METHODS: Since the 2015-2016 academic year, five training tracks focused on noninterpretative skills have been integrated into our residency training program: Clinician Educator, Quality Improvement, Entrepreneurship/Innovation, Health Policy Advocacy, and High-Value Care. Each track is longitudinal, with a set of requirements throughout the residents' training necessary to achieve certification at graduation. RESULTS: To date nine residents have participated in the programs, including two who received distinction in two separate tracks. Residents in each of the tracks have implemented successful initiatives related to the focus area. As such, these tracks enrich training by ensuring that residents make meaningful contributions to the department and institution during their training and disseminate successful initiatives through presentation at national meetings and publications. CONCLUSION: The duration of a radiology residency and resources available in an academic center provide opportunities for residency program directors to advance residents' skills in important noninterpretative components of radiology practice. Regardless of whether residents pursue academic medicine or private practice, these skills are necessary for graduates to become valuable members of a radiology practice and serve as national leaders in the field of radiology.

Brief Report: Interleukin-17A-Dependent Asymmetric Stem Cell Divisions Are Increased in Human Psoriasis: A Mechanism Underlying Benign Hyperproliferation.

The balance between asymmetric and symmetric stem cell (SC) divisions is key to tissue homeostasis, and dysregulation of this balance has been shown in cancers. We hypothesized that the balance between asymmetric cell divisions (ACDs) and symmetric cell divisions (SCDs) would be dysregulated in the benign hyperproliferation of psoriasis. We found that, while SCDs were increased in squamous cell carcinoma (SCC) (human and murine), ACDs were increased in the benign hyperproliferation of psoriasis (human and murine). Furthermore, while sonic hedgehog (linked to human cancer) and pifithrinα (p53 inhibitor) promoted SCDs, interleukin (IL)-1α and amphiregulin (associated with benign epidermal hyperproliferation) promoted ACDs. While there was dysregulation of the ACD:SCD ratio, no change in SC frequency was detected in epidermis from psoriasis patients, or in human keratinocytes treated with IL-1α or amphiregulin. We investigated the mechanism whereby immune alterations of psoriasis result in ACDs. IL17 inhibitors are effective new therapies for psoriasis. We found that IL17A increased ACDs in human keratinocytes. Additionally, studies in the imiquimod-induced psoriasis-like mouse model revealed that ACDs in psoriasis are IL17A-dependent. In summary, our studies suggest an association between benign hyperproliferation and increased ACDs. This work begins to elucidate the mechanisms by which immune alteration can induce keratinocyte hyperproliferation. Altogether, this work affirms that a finely tuned balance of ACDs and SCDs is important and that manipulating this balance may constitute an effective treatment strategy for hyperproliferative diseases. Stem Cells 2017;35:2001-2007.