Carmen Cepeda Franco

Background: Pancreatic ductal adenocarcinoma (PDAC) patients often present with early metastases after surgery, probably due to the mobilization of intraoperative circulating tumor cells (CTCs) and clusters. This exploratory study aimed to assess the potential association between the expression of substance P (SP) and neurokinin-1 receptor (NK-1R) in PDAC cells with CTC and cluster spread during pancreatoduodenectomy. Secondly, the potential impact on metastasis development and overall survival (OS) was also assessed. Methods: Twenty-one PDAC patients undergoing pancreatoduodenectomy were evaluated to analyze SP/NK-1R intra-tumor expression. Intraoperative portal vein samples were collected to quantify CTCs and clusters. Metastatic disease-free survival (MDFS) and OS were assessed during the 3-year follow-up. Results: High cytoplasmic expression of NK-1R in PDAC cells was associated with CTCs and cluster mobilization during surgery, between the beginning of the intervention and the resection of the pancreatic tumor ( P = 0.005 and P = 0.025, respectively). Cytoplasmic NK-1R expression in PDAC cells was also associated with lower MDFS 1 year after pancreatoduodenectomy ( P = 0.042). Similarly, the higher the cytoplasmic SP expression, the lower the OS ( P = 0.019). Conclusions: This exploratory study showed that higher NK-1R expression in PDAC cells’ cytoplasm was associated with higher intraoperative CTCs and cluster mobilization. A potential association between higher cytoplasmic expression of NK-1R and SP with lower MDFS and OS, respectively, was observed.

Background and Aims: Although GEMA‐Na outperforms MELD 3.0 for liver allocation, concerns about the subjectivity of its ascites component persist. We compared the performance of a GEMA‐Na iteration that excludes ascites with other allocation scores. Approach and Results: A multinational cohort study was conducted, including adult candidates for elective liver transplantation in the UK (2010–2020), Australia (1998–2020), and Spain (2016–2021). The primary outcome was mortality or delisting for sickness within 90 days. The prognostic impact of ascites was evaluated using multivariable Cox's regression. Discrimination was assessed using Harrell's c‐statistics (Hc). The study included 15 391 patients (28.5% women). The prevalence of the primary outcome was 5.8% in the UK, 5.3% in Australia, and 4.7% in Spain. The presence and severity of ascites was associated with an incremental risk of the primary outcome: 3.3% without ascites, 5.8% with mild ascites, and 7.7% with moderate–severe ascites ( p < 0.001). Removal of ascites from the GEMA‐Na score resulted in a one‐point reduction in 18% of patients (52.4% of patients with moderate–severe ascites). GEMA‐Na without ascites showed only a marginal decrease in discrimination (Hc = 0.755 vs. Hc = 0.753; p = 0.007) but still significantly outperformed MELD 3.0 (Hc = 0.734; p < 0.001) and MELD‐Na (Hc = 0.737; p < 0.001). In women, GEMA‐Na with and without ascites demonstrated comparable discrimination (Hc = 0.784 vs. Hc = 0.783; p = 0.61), both outperforming MELD 3.0 (Hc = 0.750; p < 0.001), and MELD‐Na (Hc = 0.749; p < 0.001). Conclusions: Despite the prognostic impact of ascites among liver transplant candidates, GEMA‐Na without ascites outperformed other scores in predicting wait‐list outcomes and may be used wherever the inclusion of ascites is considered too subjective.

Pancreatic surgery is considered one of the most challenging interventions by many surgeons, mainly due to retroperitoneal location and proximity to key and delicate vascular structures. These factors make pancreatic resection a demanding procedure, with successful rates far from optimal and frequent postoperative complications. Surgical planning is essential to improve patient outcomes, and in this regard, many technological advances made in the last few years have proven to be extremely useful in medical fields. This review aims to outline the potential and limitations of 3D digital and 3D printed models in pancreatic surgical planning, as well as the impact and challenges of novel technologies such as augmented/virtual reality systems or artificial intelligence to improve medical training and surgical outcomes.

Introduction: A positive surgical margin (R1 resection) is a relevant risk factor for local recurrence in patients with pancreatic ductal adenocarcinoma of the pancreas (PDAC). An intraoperative liquid biopsy (ILB) based on tumor cell mobilization could help to detect R1 resection intraoperatively. Objective: To evaluate the potential role of the intraoperative circulating tumor cells (CTCs) and cluster mobilization on the R0/R1 detection. Methods: Sixty-three patients with resectable PDAC of the head of the pancreas were prospective enrolled under the CETUPANC trial. Open pancreaticoduodenectomy (PD) was done in all patients. Intraoperative CTCs and clusters were determined during PD. Results: The overall rate of R1 resection was 34.9% (22/63 patients). Multivariate analysis showed that factors associated with R1 resection (AUC=0.920) were the presence of undifferentiated G3 tumor (P=0.017), microscopic vascular invasion (P=0.016), and the intraoperative increase of both free CTCs and clusters in portal vein determination from the beginning to the end of the surgery (P=0.002 and P=0.005, respectively). A specific logistic regression model, including delta end to baseline CTCs and cluster mobilization to achieve a combined cut-off to detect R1 detection was calculated (AUC=0.799). The obtained R1-index based on ILB had 84% of sensitivity and 68% of specificity to detect R1 resection. Conclusions: The ILB based on the intraoperative mobilization of CTCs and clusters from the beginning to the end of the PD was a predictive factor to detect R1 resection in patients with PDAC.

Circulating Tumor Cells (CTCs) are considered a prognostic marker in pancreatic cancer. In this study we present a new approach for counting CTCs and CTC clusters in patients with pancreatic cancer using the Isoflux^TM System with the Hough transform algorithm (Hough-Isoflux^TM). The Hough-Isoflux^TM approach is based on the counting of an array of pixels with a nucleus and cytokeratin expression excluding the CD45 signal. Total CTCs including free and CTC clusters were evaluated in healthy donor samples mixed with pancreatic cancer cells (PCCs) and in samples from patients with pancreatic ductal adenocarcinoma (PDAC). The Isoflux^TM System with manual counting was used in a blinded manner by three technicians who used Manual-Isoflux^TM as a reference. The accuracy of the Hough-Isoflux^TM approach for detecting PCC based on counted events was 91.00% [84.50, 93.50] with a PCC recovery rate of 80.75 ± 16.41%. A high correlation between the Hough-Isoflux^TM and Manual-Isoflux^TM was observed for both free CTCs and for clusters in experimental PCC (R² = 0.993 and R² = 0.902 respectively). However, the correlation rate was better for free CTCs than for clusters in PDAC patient samples (R² = 0.974 and R² = 0.790 respectively). In conclusion, the Hough-Isoflux^TM approach showed high accuracy for the detection of circulating pancreatic cancer cells. A better correlation rate was observed between Hough-Isoflux^TM approach and with the Manual-Isoflux^TM for isolated CTCs than for clusters in PDAC patient samples.

Post-surgical chemotherapy in pancreatic cancer has notorious side effects due to the high dose required. Multiple devices have been designed to tackle this aspect and achieve a delayed drug release. This study aimed to explore the controlled and sustained local delivery of a reduced drug dose from an irinotecan-loaded electrospun nanofiber membrane (named TARTESSUS) that can be placed on the patients’ tissue after tumor resection surgery. The drug delivery system formulation was made of polycaprolactone (PCL). The mechanical properties and the release kinetics of the drug were adjusted by the electrospinning parameters and by the polymer ratio between 10 w.t.% and 14 w.t.% of PCL in formic acid:acetic acid:chloroform (47.5:47.5:5). The irinotecan release analysis was performed and three different release periods were obtained, depending on the concentration of the polymer in the dissolution. The TARTESSUS device was tested in 2D and 3D cell cultures and it demonstrated a decrease in cell viability in 2D culture between 72 h and day 7 from the start of treatment. In 3D culture, a decrease in viability was seen between 72 h, day 7 (p < 0.001), day 10 (p < 0.001), 14 (p < 0.001), and day 17 (p = 0.003) as well as a decrease in proliferation between 72 h and day 10 (p = 0.030) and a reduction in spheroid size during days 10 (p = 0.001), 14 (p < 0.001), and 17 (p < 0.001). In conclusion, TARTESSUS showed a successful encapsulation of a chemotherapeutic drug and a sustained and delayed release with an adjustable releasing period to optimize the therapeutic effect in pancreatic cancer treatment.

Background. Effective biomarkers are needed to enable personalized medicine for pancreatic cancer patients. This study analyzes the prognostic value, in early pancreatic cancer, of single circulating tumor cell (CTC) and CTC clusters from the central venous catheter (CVC) and portal blood (PV). Methods. In total, 7 mL of PV and CVC blood from 35 patients with early pancreatic cancer were analyzed. CTC were isolated using a positive immunomagnetic selection. The detection and identification of CTC were performed by immunocytochemistry (ICC) and were analyzed by Epi-fluorescence and confocal microscopy. Results. CTC and the clusters were detected both in PV and CVC. In both samples, the CTC number per cluster was higher in patients with grade three or poorly differentiated tumors (G3) than in patients with well (G1) or moderately (G2) differentiated. Patients with fewer than 185 CTC in PV exhibited a longer OS than patients with more than 185 CTC (24.5 vs. 10.0 months; p = 0.018). Similarly, patients with fewer than 15 clusters in PV showed a longer OS than patients with more than 15 clusters (19 vs. 10 months; p = 0.004). These significant correlations were not observed in CVC analyses. Conclusions. CTC presence in PV could be an important prognostic factor to predict poor prognosis in early pancreatic cancer. In addition, the number of clustered-CTC correlate to a tumor negative differentiation degree and, therefore, could be used as a diagnostic biomarker for pancreatic cancer.