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BackgroundThe liver plays a key role in amino acid metabolism. In former studies, a ratio between branched-chain and aromatic amino acids (Fischer’s ratio) revealed associations with hepatic encephalopathy. Furthermore, low concentrations of branched-chain amino acids were linked to sarcopenia in literature. Encephalopathy and sarcopenia are known to dramatically worsen the prognosis. Aim of this study was to investigate a complex panel of plasma amino acids in the context of mortality in patients with end-stage liver disease.Methods166 patients evaluated for orthotopic liver transplantation were included. 19 amino acids were measured from citrated plasma samples using mass spectrometry. We performed survival analysis for plasma amino acid constellations and examined the relationship to established mortality predictors.Results33/166 (19.9%) patients died during follow-up. Lower values of valine (p<0.001), Fischer’s ratio (p<0.001) and valine to phenylalanine ratio (p<0.001) and higher values of phenylalanine (p<0.05) and tyrosine (p<0.05) were significantly associated with mortality. When divided in three groups, the tertiles discriminated cumulative survival for valine (p = 0.016), phenylalanine (p = 0.024) and in particular for valine to phenylalanine ratio (p = 0.003) and Fischer’s ratio (p = 0.005). Parameters were also significantly correlated with MELD and MELD-Na score.ConclusionsAmino acids in plasma are valuable biomarkers to determine increased risk of mortality in patients with end-stage liver disease. In particular, valine concentrations and constellations composed of branched-chain and aromatic amino acids were strongly associated with prognosis. Due to their pathophysiological importance, the identified amino acids could be used to examine individual dietary recommendations to serve as potential therapeutic targets.

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Background: Minimally invasive pancreatic surgery (MIPS) has developed over the last 3 decades and is nowadays experiencing an increased interest from the surgical community. With increasing awareness of both the public and the surgical community on patient safety, optimization of training has gained importance. For implementation of MIPS we propose 3 training phases. The first phase focuses on developing basic skills and procedure specific skills with the help of simulation, biotissue drills, video libraries, live case observations, and training courses. The second phase consists of index procedures, fellowships, and proctoring programs to ensure patient safety during the first procedures. During the third phase the surgeons aim is to safely implement the procedure into standard practice while minimizing learning curve related excess morbidity and mortality. Case selection, skills assessment, feedback, and mentoring are important methods to optimize this phase. The residual learning curve can reach up to 100 cases depending on the surgeons’ previous experience, selection of cases, and definition of the parameters used to assess the learning curve. Adequate training and high procedural volume are key to implementing MIPS safely.

IMPORTANCEThe progression of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas to malignant disease is still poorly understood. Observational and surgical series have failed to provide comprehensive information.OBJECTIVE To identify dynamic variables associated with the development of malignant neoplasms by combining pathological features with data from preoperative repeated observations. DESIGN, SETTING, AND PARTICIPANTSThe Crossover Observational Multicentric Study included a retrospective cohort of patients with branch-duct IPMNs (BD IPMNs) enrolled in a surveillance program from January 1, 2000, to December 31, 2019. Patients were enrolled from 5 referral centers: the Pancreas Institute, Verona,

IMPORTANCEThe use of neoadjuvant therapy (NAT) in resectable pancreatic ductal adenocarcinoma (PDAC) remains controversial. A favorable pathologic response (complete or marked tumor regression) to NAT is associated with better outcomes in patients with resected PDAC. The role of NAT for early systemic control compared with immediate surgical resection for PDAC is under investigation. In the era of precision medicine, biomarkers for patient selection and prediction of therapy response are crucial.OBJECTIVE To evaluate the use of assessment for protein expression on fine-needle aspiration (FNA) biopsy specimens in predicting pathologic response to NAT in treatment-naive patients. DESIGN, SETTING, AND PARTICIPANTSThis was a single-institution prognostic study from a high-volume center for pancreatic cancer. All specimens were obtained between January 1, 2009, and December 31, 2018, with a median (SE) follow-up of 20.2 (1.4) months. Analysis of the data was performed from October 1, 2019, to April 30, 2021. Targeted RNA sequencing of frozen FNA biopsy specimens from a discovery cohort of 23 patients was performed to identify genes with aberrant expression that was associated with patients' pathologic response to NAT. Immunohistochemical staining was performed on an additional 80 FNA biopsy specimens to assess expression of matrix metalloproteinase 7 (MMP-7) and its association with pathologic response. Receiver operating characteristic curves for prediction of favorable pathologic response were determined. RESULTSIn the discovery cohort (12 [52.1%] male; 3 [13.0%] Black and 20 [86.9%] White), RNA sequencing showed that lower MMP-7 expression was associated with favorable pathologic response (College of American Pathologists system scores of 0 [complete response] and 1 [marked response]). In the validation cohort (40 [50.0%] female; 9 [11.3%] Black and 71 [88.7%] White), patients with negative MMP-7 expression were significantly more likely to have a favorable pathologic response (odds ratio, 21.25; 95% CI, 6.19-72.95; P = .001). Receiver operating characteristic curves for prediction of favorable pathologic response from multivariable Cox proportional hazards regression modeling showed that MMP-7 expression increased the area under the curve from 0.726 to 0.906 (P < .001) even after stratifying by resectability status. The positive predictive value and negative predictive value of MMP-7 protein expression on FNA biopsy specimens in predicting unfavorable pathologic response (scores of 2 [partial response] or 3 [poor or no response]) were 88.2% and 73.9%, respectively.CONCLUSIONS AND RELEVANCE Assessment of MMP-7 expression on FNA biopsy specimens at the time of diagnosis may help identify patients who would benefit the most from NAT.

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