Validation of automated body composition analysis using diagnostic computed tomography imaging in patients with pancreatic cancer.

BACKGROUND: Sarcopenia is associated with complications and inferior oncologic outcomes in solid tumors. Axial computed tomography (CT) scans can be used to evaluate sarcopenia, however manual quantification is laborious. We sought to validate an automated method of quantifying muscle cross-sectional area (CSA) in patients with pancreatic adenocarcinoma (PDAC). METHODS: Mid-L3 CT images from patients with PDAC were analyzed: CSAs of skeletal muscle (SM) were measured using manual segmentation and the software AutoMATiCA, and then compared with linear regression. RESULTS: Five-hundred-twenty-five unique scans were analyzed. There was robust correlation between manual and automated segmentation for L3 CSA (R2 0.94, P < 0.001). Bland-Altman analysis demonstrated a consistent overestimation of muscle CSA by AutoMATiCA with a mean difference of 5.7%. A correction factor of 1.06 was validated using a unique test dataset of 36 patients with non-PDAC peripancreatic malignancies. CONCLUSIONS: Automated muscle CSA measurement with AutoMATiCA is highly efficient and yields results highly correlated with manual measurement. These findings support the potential use of high-throughput sarcopenia analysis with abdominal CT scans for both clinical and research purposes.

Neoadjuvant Therapy Is Associated with Improved Chemotherapy Delivery and Overall Survival Compared to Upfront Resection in Pancreatic Cancer without Increasing Perioperative Complications.

The role of neoadjuvant chemoradiotherapy and/or chemotherapy (neoCHT) in patients with pancreatic ductal adenocarcinoma (PDAC) is poorly defined. We hypothesized that patients who underwent neoadjuvant therapy (NAT) would have improved systemic therapy delivery, as well as comparable perioperative complications, compared to patients undergoing upfront resection. This is an IRB-approved retrospective study of potentially resectable PDAC patients treated within an academic quaternary referral center between 2011 and 2018. Data were abstracted from the electronic medical record using an institutional cancer registry and the National Surgical Quality Improvement Program. Three hundred and fourteen patients were eligible for analysis and eighty-one patients received NAT. The median overall survival (OS) was significantly improved in patients who received NAT (28.6 vs. 20.1 months, p = 0.014). Patients receiving neoCHT had an overall increased mean duration of systemic therapy (p < 0.001), and the median OS improved with each month of chemotherapy delivered (HR = 0.81 per month CHT, 95% CI (0.76-0.86), p < 0.001). NAT was not associated with increases in early severe post-operative complications (p = 0.47), late leaks (p = 0.23), or 30-90 day readmissions (p = 0.084). Our results show improved OS in patients who received NAT, driven largely by improved chemotherapy delivery, without an apparent increase in early or late perioperative complications compared to patients undergoing upfront resection.

Cannabinoid Signaling Recruits Astrocytes to Modulate Presynaptic Function in the Suprachiasmatic Nucleus.

Circadian rhythms are 24-h cycles in physiology regulated by the suprachiasmatic nucleus (SCN) in the brain, where daily cues act on SCN neurons to alter clock timing. Cannabinoid signaling modulates SCN neuronal activity, although the mechanism remains unclear. We propose that neuronal activity generates endocannabinoid release, activating astrocyte Ca2+ signaling, which releases adenosine and activates adenosine-1 receptors (A1Rs) on the presynaptic axon terminals, decreasing GABA release. We demonstrated, in mice, that activation of cannabinoid-1 receptors (CB1R) with the agonist WIN 55,212-2 (WIN) reduced the miniature GABA receptor-mediated postsynaptic current (mGPSC) frequency by a mechanism that requires astrocytes and A1R. WIN activated an intracellular Ca2+ signaling pathway in astrocytes. Activating this intracellular Ca2+ pathway with designer receptors exclusively activated by designer drugs (DREADDs) also decreased the mGPSC frequency and required A1R activation. The frequency of spontaneous Ca2+ events, including those induced by depolarization of a postsynaptic SCN neuron, was reduced by blocking CB1R activation with AM251, demonstrating neuronal endocannabinoid signaling modulates astrocytic Ca2+ signaling in the SCN. Finally, daytime application of WIN or adenosine phase advanced the molecular circadian clock, indicating that this cannabinoid signaling pathway is vital for the timing of circadian rhythms.