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Pancreatic ductal adenocarcinoma cancer (PDAC) is a highly lethal malignancy requiring efficient detection when the primary tumor is still resectable. We previously developed the MxPancreasScore comprising 9 analytes and serum carbohydrate antigen 19-9 (CA19-9), achieving an accuracy of 90.6%. The necessity for 5 different analytical platforms and multiple analytical runs, however, hindered clinical applicability. We therefore aimed to develop a simpler single-analytical run, single-platform diagnostic signature.We evaluated 941 patients (PDAC, 356; chronic pancreatitis [CP], 304; nonpancreatic disease, 281) in 3 multicenter independent tests, and identification (ID) and validation cohort 1 (VD1) and 2 (VD2) were evaluated. Targeted quantitative plasma metabolite analysis was performed on a liquid chromatography-tandem mass spectrometry platform. A machine learning-aided algorithm identified an improved (i-Metabolic) and minimalistic metabolic (m-Metabolic) signatures, and compared them for performance.The i-Metabolic Signature, (12 analytes plus CA19-9) distinguished PDAC from CP with area under the curve (95% confidence interval) of 97.2% (97.1%-97.3%), 93.5% (93.4%-93.7%), and 92.2% (92.1%-92.3%) in the ID, VD1, and VD2 cohorts, respectively. In the VD2 cohort, the m-Metabolic signature (4 analytes plus CA19-9) discriminated PDAC from CP with a sensitivity of 77.3% and specificity of 89.6%, with an overall accuracy of 82.4%. For the subset of 45 patients with PDAC with resectable stages IA-IIB tumors, the sensitivity, specificity, and accuracy were 73.2%, 89.6%, and 82.7%, respectively; for those with detectable CA19-92 U/mL, 81.6%, 88.7%, and 84.5%, respectively; and for those with CA19-937 U/mL, 39.7%, 94.1%, and 76.3%, respectively.The single-platform, single-run, m-Metabolic signature of just 4 metabolites used in combination with serum CA19-9 levels is an innovative accurate diagnostic tool for PDAC at the time of clinical presentation, warranting further large-scale evaluation.

Based on the known properties of ambroxol and dexamethasone to inhibit inflammation and increase endogenous surfactant levels, the potential advantage of donor pretreatment with either drug was investigated in an acute rat double-lung transplant model. Donor animals were randomly assigned to one of three treatment groups: an ambroxol group (AMB; 0.4 mg/kg), a dexamethasone group (DX; 2 mg/kg); or an untreated control group (CN). Drugs were given intraperitoneally 6 h prior to harvest. Following standard preservation and 16 h of cold ischemia, the donor double lung block was implanted into syngeneic recipients using custom-designed stents for the vascular anastomosis. During reperfusion, serial measurements of graft pulmonary vascular resistance and alveolar-arterial oxygen difference were obtained. Separate graft ventilation allowed determination of graft dynamic lung compliance. Final assessment included weight gain and histology. For phospholipid analysis, lung lavages were performed in the three study groups at the end of reperfusion and compared to levels before graft harvest. Donor pretreatment did not significantly affect preharvest phospholipid levels. Survival following graft ischemia and reperfusion was shortest after AMB (92 ± 5 min) and longest after DX (110 ± 5 min; DX vs AMB P < 0.03) and CN (116 ± 4 min; CN vs AMB P < 0.02). DX pretreatment provided better compliance (P < 0.02) and lower vascular resistance (P < 0.0001) than AMB treatment. Airway resistance was lower in the AMB and DX groups than in controls (P < 0.04 and P < 0.02, respectively). The alveolar-arterial oxygen difference was markedly similar in all groups. Graft weight gain amounted to 114 % ± 10 % in AMB, 88 % ± 12 % in DX, and 98 % ± 13 % in CN (P = NS). Thus, in this rat lung transplantation model, donor pretreatment with dexamethasone did not improve graft function compared to untreated controls and donor pretreatment with ambroxol was found to be potentially detrimental to graft function during reperfusion.

The pulmonary vasodilatory effects of prostacyclin (PGI2) were compared with inhaled nitric oxide (NO) for donor treatment in an acute double lung transplantation model in the rat. The PGI2 group (n=10) received 35 μg/kg PGI2 both intravenously and into the flush solution. The NO group (n=10) was ventilated before and during perfusion with nitric oxide for an expiratory NO concentration of 20 ppm. Both groups were compared with untreated controls (n=10). Following cold ischemia of 16 hr the donor lungs were implanted in syngeneic recipients via specially designed stents to the left pulmonary artery and vein. Separate graft ventilation permitted determination of compliance and resistance. During 120 min of reperfusion serial measurements of graft pulmonary vascular resistance (PVR) and alveolar arterial oxygen difference (AAD02) were obtained. Final graft assessment included weight gain and histological analysis. Data are listed as mean±SE. The type of donor pretreatment had a definite and negative impact on survival (NO: 106±6, controls: 116±4, PGI2: 120±0 min; P