Outcomes and risk score for distal pancreatectomy with celiac axis resection (DP-CAR) : an international multicenter analysis

Background: Distal pancreatectomy with celiac axis resection (DP-CAR) is a treatment option for selected patients with pancreatic cancer involving the celiac axis. A recent multicenter European study reported a 90-day mortality rate of 16%, highlighting the importance of patient selection. The authors constructed a risk score to predict 90-day mortality and assessed oncologic outcomes. Methods: This multicenter retrospective cohort study investigated patients undergoing DP-CAR at 20 European centers from 12 countries (model design 2000-2016) and three very-high-volume international centers in the United States and Japan (model validation 2004-2017). The area under receiver operator curve (AUC) and calibration plots were used for validation of the 90-day mortality risk model. Secondary outcomes included resection margin status, adjuvant therapy, and survival. Results: For 191 DP-CAR patients, the 90-day mortality rate was 5.5% (95 confidence interval [CI], 2.2-11%) at 5 high-volume (1 DP-CAR/year) and 18% (95 CI, 9-30%) at 18 low-volume DP-CAR centers (P=0.015). A risk score with age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, multivisceral resection, open versus minimally invasive surgery, and low- versus high-volume center performed well in both the design and validation cohorts (AUC, 0.79 vs 0.74; P=0.642). For 174 patients with pancreatic ductal adenocarcinoma, the R0 resection rate was 60%, neoadjuvant and adjuvant therapies were applied for respectively 69% and 67% of the patients, and the median overall survival period was 19months (95 CI, 15-25months). Conclusions: When performed for selected patients at high-volume centers, DP-CAR is associated with acceptable 90-day mortality and overall survival. The authors propose a 90-day mortality risk score to improve patient selection and outcomes, with DP-CAR volume as the dominant predictor

Cytosolic 5'-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites.

BACKGROUND: Cytosolic 5'-nucleotidase 1A (NT5C1A) dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Here, we investigate NT5C1A expression in pancreatic ductal adenocarcinoma (PDAC) and its impact on gemcitabine metabolism and therapeutic efficacy. METHODS: NT5C1A expression was determined by semiquantitative immunohistochemistry using tissue microarrays. Gemcitabine metabolites and response were assessed in several human and murine PDAC cell lines using crystal violet assays, Western blot, viability assays, and liquid chromatography tandem mass-spectrometry (LC-MS/MS). FINDINGS: NT5C1A was strongly expressed in tumor cells of a large subgroup of resected PDAC patients in two independent patient cohorts (44-56% score 2 and 8-26% score 3, n = 414). In contrast, NT5C1A was expressed at very low levels in the tumor stroma, and neither stromal nor tumoral expression was a prognostic marker for postoperative survival. In vitro, NT5C1A overexpression increased gemcitabine resistance by reducing apoptosis levels and significantly decreased intracellular amounts of cytotoxic dFdCTP in +NT5C1A tumor cells. Co-culture experiments with conditioned media from +NT5C1A PSCs improved gemcitabine efficacy in tumor cells. In vivo, therapeutic efficacy of gemcitabine was significantly decreased and serum levels of the inactive gemcitabine metabolite dFdU significantly increased in mice bearing NT5C1A overexpressing tumors. INTERPRETATION: NT5C1A is robustly expressed in tumor cells of resected PDAC patients. Moreover, NT5C1A mediates gemcitabine resistance by decreasing the amount of intracellular dFdCTP, leading to reduced tumor cell apoptosis and larger pancreatic tumors in mice. Further studies should clarify the role of NT5C1A as novel predictor for gemcitabine treatment response in patients with PDAC

Active flexible concentric ring electrode for non-invasive surface bioelectrical recordings

Bioelectrical surface recordings are usually performed by unipolar or bipolar disc electrodes even though they entail the serious disadvantage of having poor spatial resolution. Concentric ring electrodes give improved spatial resolution, although this type of electrode has so far only been implemented in rigid substrates and as they are not adapted to the curvature of the recording surface may provide discomfort to the patient. Moreover, the signals recorded by these electrodes are usually lower in amplitude than conventional disc electrodes. The aim of this work was thus to develop and test a new modular active sensor made up of concentric ring electrodes printed on a flexible substrate by thick-film technology together with a reusable battery-powered signal-conditioning circuit. Simultaneous ECG recording with both flexible and rigid concentric ring electrodes was carried out on ten healthy volunteers at rest and in motion. The results show that flexible concentric ring electrodes not only present lower skin electrode contact impedance and lower baseline wander than rigid electrodes but are also less sensitive to interference and motion artefacts. We believe these electrodes, which allow bioelectric signals to be acquired non-invasively with better spatial resolution than conventional disc electrodes, to be a step forward in the development of new monitoring systems based on Laplacian potential recordings.This research was supported in part by the Ministerio de Ciencia y Tecnologia de Espana (TEC2010-16945) and by the Universitat Politecnica de Valencia (PAID 2009/10-2298). The proof-reading of this paper was funded by the Universitat Politecnica de Valencia, Spain.Prats Boluda, G.; Ye Lin, Y.; García Breijo, E.; Ibáñez Civera, FJ.; Garcia Casado, FJ. (2012). Active flexible concentric ring electrode for non-invasive surface bioelectrical recordings. Measurement Science and Technology. 23(12):1-10. https://doi.org/10.1088/0957-0233/23/12/125703S1102312Malmivuo, J., & Plonsey, R. (1995). BioelectromagnetismPrinciples and Applications of Bioelectric and Biomagnetic Fields. doi:10.1093/acprof:oso/9780195058239.001.0001Gevins, A. (1989). Dynamic functional topography of cognitive tasks. Brain Topography, 2(1-2), 37-56. doi:10.1007/bf01128842Bradshaw, L. A., Wijesinghe, R. S., & Wikswo, Jr., J. P. (2001). Spatial Filter Approach for Comparison of the Forward and Inverse Problems of Electroencephalography and Magnetoencephalography. Annals of Biomedical Engineering, 29(3), 214-226. doi:10.1114/1.1352641Bradshaw, L. A., Richards, W. O., & Wikswo, J. P. (2001). Volume conductor effects on the spatial resolution of magnetic fields and electric potentials from gastrointestinal electrical activity. Medical & Biological Engineering & Computing, 39(1), 35-43. doi:10.1007/bf02345264Garcia-Casado, J., Martinez-de-Juan, J. L., & Ponce, J. L. (2005). Noninvasive Measurement and Analysis of Intestinal Myoelectrical Activity Using Surface Electrodes. IEEE Transactions on Biomedical Engineering, 52(6), 983-991. doi:10.1109/tbme.2005.846730SippensGroenewegen, A., Peeters, H. A. P., Jessurun, E. R., Linnenbank, A. C., Robles de Medina, E. O., Lesh, M. D., & van Hemel, N. M. (1998). Body Surface Mapping During Pacing at Multiple Sites in the Human Atrium. Circulation, 97(4), 369-380. doi:10.1161/01.cir.97.4.369Lian, J., Li, G., Cheng, J., Avitall, B., & He, B. (2002). Body surface Laplacian mapping of atrial depolarization in healthy human subjects. Medical & Biological Engineering & Computing, 40(6), 650-659. doi:10.1007/bf02345304Wu, D., Tsai, H. C., & He, B. (1999). On the Estimation of the Laplacian Electrocardiogram during Ventricular Activation. Annals of Biomedical Engineering, 27(6), 731-745. doi:10.1114/1.224Koka, K., & Besio, W. G. (2007). Improvement of spatial selectivity and decrease of mutual information of tri-polar concentric ring electrodes. Journal of Neuroscience Methods, 165(2), 216-222. doi:10.1016/j.jneumeth.2007.06.007Prats-Boluda, G., Garcia-Casado, J., Martinez-de-Juan, J. L., & Ye-Lin, Y. (2011). Active concentric ring electrode for non-invasive detection of intestinal myoelectric signals. Medical Engineering & Physics, 33(4), 446-455. doi:10.1016/j.medengphy.2010.11.009He, B., & Cohen, R. J. (1992). Body surface Laplacian mapping of cardiac electrical activity. The American Journal of Cardiology, 70(20), 1617-1620. doi:10.1016/0002-9149(92)90471-aBesio, W., Aakula, R., Koka, K., & Dai, W. (2006). Development of a Tri-polar Concentric Ring Electrode for Acquiring Accurate Laplacian Body Surface Potentials. Annals of Biomedical Engineering, 34(3), 426-435. doi:10.1007/s10439-005-9054-8Ye-Lin, Y., Garcia-Casado, J., Prats-Boluda, G., Ponce, J. L., & Martinez-de-Juan, J. L. (2009). Enhancement of the non-invasive electroenterogram to identify intestinal pacemaker activity. Physiological Measurement, 30(9), 885-902. doi:10.1088/0967-3334/30/9/002Hjorth, B. (1975). An on-line transformation of EEG scalp potentials into orthogonal source derivations. Electroencephalography and Clinical Neurophysiology, 39(5), 526-530. doi:10.1016/0013-4694(75)90056-5Perrin, F., Pernier, J., Bertnard, O., Giard, M. ., & Echallier, J. . (1987). Mapping of scalp potentials by surface spline interpolation. Electroencephalography and Clinical Neurophysiology, 66(1), 75-81. doi:10.1016/0013-4694(87)90141-6Nunez, P. L., & Westdorp, A. F. (1994). The surface laplacian, high resolution EEG and controversies. Brain Topography, 6(3), 221-226. doi:10.1007/bf01187712Srinivasan, R., Nunez, P. L., Tucker, D. M., Silberstein, R. B., & Cadusch, P. J. (1996). Spatial sampling and filtering of EEG with spline Laplacians to estimate cortical potentials. Brain Topography, 8(4), 355-366. doi:10.1007/bf01186911Farina, D., & Cescon, C. (2001). Concentric-ring electrode systems for noninvasive detection of single motor unit activity. IEEE Transactions on Biomedical Engineering, 48(11), 1326-1334. doi:10.1109/10.959328G. Besio, C. C. Lu, P. P. Tarjan, W. (2001). A Feasibility Study for Body Surface Cardiac Propagation Maps of Humans from Laplacian Moments of Activation. Electromagnetics, 21(7-8), 621-632. doi:10.1080/027263401752246243Li, G., Wang, Y., Lin, L., Jiang, W., Wang, L. L., Lu, S. C.-Y., & Besio, W. G. (2005). Active Laplacian electrode for the data-acquisition system of EHG. Journal of Physics: Conference Series, 13, 330-335. doi:10.1088/1742-6596/13/1/077Engel, J., Chen, J., & Liu, C. (2003). Development of polyimide flexible tactile sensor skin. Journal of Micromechanics and Microengineering, 13(3), 359-366. doi:10.1088/0960-1317/13/3/302Papakostas, T. V., Lima, J., & Lowe, M. (s. f.). A large area force sensor for smart skin applications. Proceedings of IEEE Sensors. doi:10.1109/icsens.2002.1037366Stieglitz, T. (2001). Flexible biomedical microdevices with double-sided electrode arrangements for neural applications. Sensors and Actuators A: Physical, 90(3), 203-211. doi:10.1016/s0924-4247(01)00520-9Hamilton, P. S., & Tompkins, W. J. (1986). Quantitative Investigation of QRS Detection Rules Using the MIT/BIH Arrhythmia Database. IEEE Transactions on Biomedical Engineering, BME-33(12), 1157-1165. doi:10.1109/tbme.1986.325695Besio, W., & Chen, T. (2007). Tripolar Laplacian electrocardiogram and moment of activation isochronal mapping. Physiological Measurement, 28(5), 515-529. doi:10.1088/0967-3334/28/5/006Besio, G., Koka, K., Aakula, R., & Weizhong Dai. (2006). Tri-polar concentric ring electrode development for Laplacian electroencephalography. IEEE Transactions on Biomedical Engineering, 53(5), 926-933. doi:10.1109/tbme.2005.863887Setti, L., Fraleoni-Morgera, A., Ballarin, B., Filippini, A., Frascaro, D., & Piana, C. (2005). An amperometric glucose biosensor prototype fabricated by thermal inkjet printing. Biosensors and Bioelectronics, 20(10), 2019-2026. doi:10.1016/j.bios.2004.09.022Reddy, A. S. G., Narakathu, B. B., Atashbar, M. Z., Rebros, M., Rebrosova, E., & Joyce, M. K. (2011). Gravure Printed Electrochemical Biosensor. Procedia Engineering, 25, 956-959. doi:10.1016/j.proeng.2011.12.235Gruetzmann, A., Hansen, S., & Müller, J. (2007). Novel dry electrodes for ECG monitoring. Physiological Measurement, 28(11), 1375-1390. doi:10.1088/0967-3334/28/11/005LI, G., LIAN, J., SALLA, P., CHENG, J., RAMACHANDRA, I., SHAH, P., … HE, B. (2003). Body Surface Laplacian Electrocardiogram of Ventricular Depolarization in Normal Human Subjects. Journal of Cardiovascular Electrophysiology, 14(1), 16-27. doi:10.1046/j.1540-8167.2003.02199.

Length of Variable Numbers of Tandem Repeats in the Carboxyl Ester Lipase (CEL) Gene May Confer Susceptibility to Alcoholic Liver Cirrhosis but Not Alcoholic Chronic Pancreatitis

Background Carboxyl-ester lipase (CEL) contributes to fatty acid ethyl ester metabolism, which is implicated in alcoholic pancreatitis. The CEL gene harbours a variable number of tandem repeats (VNTR) region in exon 11. Variation in this VNTR has been linked to monogenic pancreatic disease, while conflicting results were reported for chronic pancreatitis (CP). Here, we aimed to investigate a potential association of CEL VNTR lengths with alcoholic CP. Methods Overall, 395 alcoholic CP patients, 218 patients with alcoholic liver cirrhosis (ALC) serving as controls with a comparable amount of alcohol consumed, and 327 healthy controls from Germany and the United Kingdom (UK) were analysed by determination of fragment lengths by capillary electrophoresis. Allele frequencies and genotypes of different VNTR categories were compared between the groups. Results Twelve repeats were overrepresented in UK ACP patients (P = 0.04) compared to controls, whereas twelve repeats were enriched in German ALC compared to alcoholic CP patients (P = 0.03). Frequencies of CEL VNTR lengths of 14 and 15 repeats differed between German ALC patients and healthy controls (P = 0.03 and 0.008, respectively). However, in the genotype and pooled analysis of VNTR lengths no statistical significant association was depicted. Additionally, the 16–16 genotype as well as 16 repeats were more frequent in UK ALC than in alcoholic CP patients (P = 0.034 and 0.02, respectively). In all other calculations, including pooled German and UK data, allele frequencies and genotype distributions did not differ significantly between patients and controls or between alcoholic CP and ALC. Conclusions We did not obtain evidence that CEL VNTR lengths are associated with alcoholic CP. However, our results suggest that CEL VNTR lengths might associate with ALC, a finding that needs to be clarified in larger cohorts

Postoperative outcomes in oesophagectomy with trainee involvement

BACKGROUND: The complexity of oesophageal surgery and the significant risk of morbidity necessitates that oesophagectomy is predominantly performed by a consultant surgeon, or a senior trainee under their supervision. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on postoperative outcomes in an international multicentre setting. METHODS: Data from the multicentre Oesophago-Gastric Anastomosis Study Group (OGAA) cohort study were analysed, which comprised prospectively collected data from patients undergoing oesophagectomy for oesophageal cancer between April 2018 and December 2018. Procedures were grouped by the level of trainee involvement, and univariable and multivariable analyses were performed to compare patient outcomes across groups. RESULTS: Of 2232 oesophagectomies from 137 centres in 41 countries, trainees were involved in 29.1 per cent of them (n = 650), performing only the abdominal phase in 230, only the chest and/or neck phases in 130, and all phases in 315 procedures. For procedures with a chest anastomosis, those with trainee involvement had similar 90-day mortality, complication and reoperation rates to consultant-performed oesophagectomies (P = 0.451, P = 0.318, and P = 0.382, respectively), while anastomotic leak rates were significantly lower in the trainee groups (P = 0.030). Procedures with a neck anastomosis had equivalent complication, anastomotic leak, and reoperation rates (P = 0.150, P = 0.430, and P = 0.632, respectively) in trainee-involved versus consultant-performed oesophagectomies, with significantly lower 90-day mortality in the trainee groups (P = 0.005). CONCLUSION: Trainee involvement was not found to be associated with significantly inferior postoperative outcomes for selected patients undergoing oesophagectomy. The results support continued supervised trainee involvement in oesophageal cancer surgery

Sentinel lymph node biopsy in colon cancer: A prospective multicenter trial

INTRODUCTION:: The clinical impact of sentinel lymph node biopsy (SLNB) in colon cancer is still controversial. The purpose of this prospective multicenter trial was to evaluate its clinical value to predict the nodal status and identify factors that influence these results. METHODS:: Colon cancer patients without prior colorectal surgery or irradiation were eligible. The sentinel lymph node (SLN) was identified intraoperatively by subserosal blue dye injection around the tumor. The SLN underwent step sections and immunohistochemistry (IHC), if classified free of metastases after routine hematoxylin and eosin examination. RESULTS:: At least one SLN (median, n = 2) was identified in 268 of 315 enrolled patients (detection rate, 85%). Center experience, lymphovascular invasion, body mass index (BMI), and learning curve were positively associated with the detection rate. The false-negative rate to identify pN+ patients by SLNB was 46% (38 of 82). BMI showed a significant association to the false-negative rate (P < 0.0001), the number of tumor-involved lymph nodes was inversely associated. If only slim patients (BMI </=24) were investigated in experienced centers (>22 patients enrolled), the sensitivity increased to 88% (14 of 16). Moreover, 21% (30 of 141) of the patients, classified as pN0 by routine histopathology, revealed micrometastases or isolated tumor cells (MM/ITC) in the SLN. CONCLUSIONS:: The contribution of SLNB to conventional nodal staging of colon cancer patients is still unspecified. Technical problems have to be resolved before a definite conclusion can be drawn in this regard. However, SLNB identifies about one fourth of stage II patients to reveal MM/ITC in lymph nodes. Further studies must clarify the clinical impact of these findings in terms of prognosis and the indication of adjuvant therapy