Metformin and pancreatic neuroendocrine tumors:A systematic review and meta-analysis

BACKGROUND Most patients with advanced pancreatic neuroendocrine tumors(pNETs)die due to tumor progression.Therefore,identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant.In this perspective,metformin is emerging as a molecule of interest.Retrospective studies have described metformin,a widely used agent for the treatment of patients with type 2 diabetes mellitus(T2DM),to be effective in modulating different tumor-related events,including cancer incidence,recurrence and survival by inhibiting mTOR phosphorylation.This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET.AIM To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and posttreatment outcomes of pNET.METHODS A systematic review of the published literature was undertaken,focusing on the role of T2DM and metformin in insurgence and prognosis of pNET,measured through outcomes of tumor-free survival(TFS),overall survival and progression free survival.RESULTS A total of 13 studies(5674 patients)were included in this review.Analysis of 809 pNET cases from five retrospective studies(low study heterogeneity with I^(2)=0%)confirms the correlation between T2DM and insurgence of pNET(OR=2.13,95%CI=1.56-4.55;P<0.001).The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients(hazard ratio=1.84,95%CI=0.78-2.90;P<0.001).The study heterogeneity was intermediate,with I^(2)=51%.A few studies limited the possibility of performing pooled analysis in the setting of metformin;therefore,results were heterogeneous,with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET.CONCLUSION T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients.Unfortunately,a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.

Utility of preoperative systemic inflammatory biomarkers in predicting postoperative complications after pancreaticoduodenectomy: Literature review and single center experience

BACKGROUND The role of preoperative inflammatory biomarkers(PIBs)in predicting postoperative morbidity has been assessed in colorectal and otorhinolaryngeal surgery.However,data regarding the role that preoperative inflammatory biomarkers have on morbidity after pancreaticoduodenectomiy(PD)are less consistent.AIM To assess the utility of PIBs in predicting postoperative complications after pancreaticoduodenectomy.METHODS A database of 317 consecutive pancreaticoduodenectomies performed from April 2003 to November 2018 has been retrospectively analyzed.Data regarding preoperative neutrophil-to-lymphocyte ratio(NLR),derived NLR and C-reactive protein(CRP),and postoperative complications of 238 cases have been evaluated.Exclusion criteria were:age<18-years-old,previous neoadjuvant treatment,absence of data about PIBs,concomitant hematological disorders,and presence of active infections at the moment of the surgery.PIBs were compared using Mann-Whitney’s test and receiver operating characteristic(ROC)analysis was performed to define the cutoffs.The positive predictive value(PPV)was computed to evaluate the probability to develop complication.P-values<0.05 were considered statistically significant.RESULTS According to the literature findings,only four papers have been published reporting the relation between the inflammatory biomarkers and PD postoperative morbidity.A combination of preoperative and postoperative inflammatory biomarkers in predicting complications after PD and the utility of preoperative NLR in the development of postoperative pancreatic fistula(POPF)have been reported.The combination of PIBs and postoperative day-1 drains amylase has been reported to predict the incidence of POPF.According to our results,CRP values were significantly different between patients who had/did not have postoperative complications and abdominal collections(P<0.05).Notably,patients with preoperative CRP>8.81 mg/dL were at higher risk of both overall complications and abdominal collections(respectively P=0.0037,PPV=0.95,negative predictive value[NPV]=0.27 and P=0.016,PPV=0.59,NPV=0.68).Preoperative derived neutrophil-to-lymphocyte ratio(dNLR)(cut off>1.47)was also a predictor of abdominal collection(P=0.021,PPV=0.48,NPV=0.71).Combining CRP and dNLR,PPV increased to 0.67.NLR(cut off>1.65)was significantly associated with postoperative hemorrhage(P=0.016,PPV=0.17,NPV=0.98).CONCLUSION PIBs may predict complications after PD.During postoperative care,PIB levels could influence decisions regarding the timing of drains removal and the selection of patients who might benefit from second level diagnostic exams.

Validations of new cut-offs for surgical drains management and use of computerized tomography scan after pancreatoduodenectomy:The DALCUT trial

BACKGROUND Postoperative pancreatic fistula(POPF)is the most fearful complication after pancreatic surgery and can lead to severe postoperative complications such as surgical site infections,sepsis and bleeding.A previous study which identified cut-offs of drains amylase levels(DALs)determined on postoperative day(POD)1 and POD3,was able to significantly predict POPF,abdominal collections and biliary fistulas,when related to specific findings detected at the abdominal computerized tomography(CT)scan routinely performed on POD3.AIM To validate the cut-offs of DALs in POD1 and POD3,established during the previous study,to assess the risk of clinically relevant POPF and confirm the usefulness of abdominal CT scan on POD3 in patients at increased risk of abdominal collection.METHODS The DALCUT trial is an interventional prospective study.All patients who will undergo pancreatoduodenectomy(PD)for periampullary neoplasms will be considered eligible.All patients will receive clinical staging and,if eligible for surgery,will undergo routine preoperative evaluation.After the PD,daily DALs will be evaluated from POD1.Drains removal and possible requirement of abdominal CT scans in POD3 will be managed on the basis of the outcome of DALs in the first three postoperative days.RESULTS This prospective study could validate the role of DALs in the management of surgical drains and in assessing the risk or relevant complications after PD.Drains could be removed in POD3 in case of POD1 DALs<666 U/L and POD3 DALs<207 U/L.In case of POD3 DALs≥252,abdominal CT scan will be performed in POD3 to identify abdominal collections≥5 cm.In this latter category of patients,drains could be maintained beyond POD3.CONCLUSION The results of this trial will contribute to a better knowledge of POPF and management of surgical drains.