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 & GE; 252, abdominal CT scan will be performed in POD3 to identify abdominal collections & GE; 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

CA19.9 Serum Level Predicts Lymph-Nodes Status in Resectable Pancreatic Ductal Adenocarcinoma: A Retrospective Single-Center Analysis

BackgroundThe choice between upfront surgery or neoadjuvant treatments (NAT) for resectable pancreatic ductal adenocarcinoma (R-PDAC) is controversial. R-PDAC with potential nodal involvement could benefit from NT. Ca (Carbohydrate antigen) 19.9 and serum albumin levels, alone or in combination, have proven their efficacy in assessing PDAC prognosis. The objective of this study was to evaluate the role of Ca 19.9 serum levels in predicting nodal status in R-PDAC.MethodsPreoperative Ca 19.9, as well as serum albumin levels, of 165 patients selected for upfront surgery have been retrospectively collected and correlated to pathological nodal status (N), resection margins status (R) and vascular resections (VR). We further performed ROC curve analysis to identify optimal Ca 19.9 cut-off for pN+, R+ and vascular resection prediction.ResultsIncreased Ca 19.9 levels in 114 PDAC patients were significantly associated with pN+ (p <0.001). This ability, confirmed in all the series by ROC curve analysis (Ca 19.9 >= 32 U/ml), was lost in the presence of hypoalbuminemia. Furthermore, Ca 19.9 at the cut off >418 U/ml was significantly associated with R+ (87% specificity, 36% sensitivity, p 0.014). Ca 19.9, at the cut-off >78 U/ml, indicated a significant trend to predict the need for VR (sensitivity 67%, specificity 53%; p = 0.059).ConclusionsIn R-PDAC with normal serum albumin levels, Ca 19.9 predicts pN+ and R+, thus suggesting a crucial role in deciding on NAT

Accuracy of magnetic resonance imaging to identify pseudocapsule invasion in renal tumors

Purpose: To evaluate accuracy of MRI in detecting renal tumor pseudocapsule (PC) invasion and to propose a classification based on imaging of PC status in patients with renal cell carcinoma. Methods: From January 2017 to June 2018, 58 consecutive patients with localized renal cell carcinoma were prospectively enrolled. MRI was performed preoperatively and PC was classified, according to its features, as follows: MRI-Cap 0 (absence of PC), MRI-Cap 1 (presence of a clearly identifiable PC), MRI-Cap 2 (focally interrupted PC), and MRI-Cap 3 (clearly interrupted and infiltrated PC). A 3D image reconstruction showing MRI-Cap score was provided to both surgeon and pathologist to obtain complete preoperative evaluation and to compare imaging and pathology reports. All patients underwent laparoscopic partial nephrectomy. In surgical specimens, PC was classified according to the renal tumor capsule invasion scoring system (i-Cap). Results: A concordance between MRI-Cap and i-Cap was found in 50/58 (86%) cases. ρ coefficient for each MRI-cap and iCap categories was: MRI-Cap 0: 0.89 (p < 0.0001), MRI-Cap1: 0.75 (p < 0.0001), MRI-Cap 2: 0.76 (p < 0.0001), and MRI-Cap3: 0.87 (p < 0.0001). Sensitivity, specificity, positive predictive value, negative predictive value, and AUC were: MRI-Cap 0: Se 97.87% Spec 83.3%, PPV 95.8%, NPV 90.9%, and AUC 90.9; MRI-Cap 1: Se 77% Spec 95.5%, PPV 83.3%, NPV 93.5%, and AUC 0.86; MRI-Cap 2- iCap 2: Se 88% Spec 90%, PPV 79%, NPV 95%, and AUC 0.89; MRI-Cap 3: Se 94% Spec 95%, PPV 88%, NPV 97%, and AUC 0.94. Conclusions: MRI-Cap classification is accurate in evaluating renal tumor PC features. PC features can provide an imaging-guided landmark to figure out where a minimal margin could be preferable during nephron-sparing surgery

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

BACKGROUNDThe 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.AIMTo assess the utility of PIBs in predicting postoperative complications after pancreaticoduodenectomy.METHODSA 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.RESULTSAccording 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).CONCLUSIONPIBs 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

Inhibition of the Autophagy Pathway Synergistically Potentiates the Cytotoxic Activity of Givinostat (ITF2357) on Human Glioblastoma Cancer Stem Cells

Increasing evidence highlighted the role of cancer stem cells (CSCs) in the development of tumor resistance to therapy, particularly in glioblastoma (GBM). Therefore, the development of new therapies, specifically directed against GBM CSCs, constitutes an important research avenue. Considering the extended range of cancer-related pathways modulated by histone acetylation/deacetylation processes, we studied the anti-proliferative and pro-apoptotic efficacy of givinostat (GVS), a pan-histone deacetylase inhibitor, on cell cultures enriched in CSCs, isolated from nine human GBMs. We report that GVS induced a significant reduction of viability and self-renewal ability in all GBM CSC cultures; conversely, GVS exposure did not cause a significant cytotoxic activity toward differentiated GBM cells and normal mesenchymal human stem cells. Analyzing the cellular and molecular mechanisms involved, we demonstrated that GVS affected CSC viability through the activation of programmed cell death pathways. In particular, a marked stimulation of macroautophagy was observed after GVS treatment. To understand the functional link between GVS treatment and autophagy activation, different genetic and pharmacological interfering strategies were used. We show that the up-regulation of the autophagy process, obtained by deprivation of growth factors, induced a reduction of CSC sensitivity to GVS, while the pharmacological inhibition of the autophagy pathway and the silencing of the key autophagy gene ATG7, increased the cell death rate induced by GVS. Altogether these findings suggest that autophagy represents a pro-survival mechanism activated by GBM CSCs to counteract the efficacy of the anti-proliferative activity of GVS. In conclusion, we demonstrate that GVS is a novel pharmacological tool able to target GBM CSC viability and its efficacy can be enhanced by autophagy inhibitory strategies

Mitochondrial myopathy and comorbid major depressive disorder. effectiveness of dTMS on gait and mood symptoms

Background: Mitochondrial myopathies (MMs) often present with leukoencephalopathy and psychiatric symptoms, which do not respond to or worsen with psychiatric drugs. Case report: A 67-year-old woman with a 10-year history of probable chronic progressive external ophthalmoplegia, an MM, had drug-resistant, anxious-depressive symptoms. Since she had never had seizures, we proposed 20 sessions of deep transcranial magnetic stimulation (dTMS) for her depression. Surprisingly, besides the expected improvement of depression, we observed marked improvement of movement disorder that lasted as long as the patient was undergoing dTMS. She also improved her performance on neuropsychological tests of executive function and cognitive speed. Depressive symptom improvement was persistent, while anxiety symptoms recurred after the end of the sessions. Conclusions: dTMSmay be an alternative antidepressant strategy in patients withMMs, provided that they are free from seizures. The mechanism of improvement of motor disturbance may relate to dorsolateral prefrontal cortex stimulation and improved executive function and needs further investigation

Coupling of the oxygen-linked interaction energy for inositol hexakisphosphate and bezafibrate binding to human HbA0.

The energetics of signal propagation between different functional domains (i.e. the binding sites for O2, inositol hexakisphospate (IHP), and bezafibrate (BZF)) of human HbA0 was analyzed at different heme ligation states and through the use of a stable, partially heme ligated intermediate. Present data allow three main conclusions to be drawn, and namely: (i) IHP and BZF enhance each others binding as the oxygenation proceeds, the coupling free energy going from close to zero in the deoxy state to -3.4 kJ/mol in the oxygenated form; (ii) the simultaneous presence of IHP and BZF stabilizes the hemoglobin T quaternary structure at very low O2 pressures, but as oxygenation proceeds it does not impair the transition toward the R structure, which indeed occurs also under these conditions; (iii) under room air pressure (i.e. pO2 = 150 torr), IHP and BZF together induce the formation of an asymmetric dioxygenated hemoglobin tetramer, whose features appear reminiscent of those suggested for transition state species (i.e. T- and R-like tertiary conformation(s) within a quaternary R-like structure)

Different Biliary Microbial Flora Influence Type of Complications after Pancreaticoduodenectomy: A Single Center Retrospective Analysis

Background: Bacterobilia is associated with postoperative morbidity after pancreaticoduodenectomy (PD), mostly due to infectious complications. The aim of this study was to investigate the prevalence of bacteria species isolated from intraoperative biliary cultures, and related complications after PD. Methods: An ANOVA test was used to assess the prevalence of isolated bacterial species and postoperative complications. The odds ratio was computed to evaluate the association between biliary cultures and each complication, Endoscopic Retrograde CholangioPancreatography (ERCP) and each complication, ERCP and biliary cultures, Delayed Gastric Emptying (DGE) and Postoperative Pancreatic Fistula (POPF). Results: Positive biliary cultures were found in 162/244 (66%) PDs. Different prevalences of polymicrobial biliary culture were detected in patients with postoperative complications. In SSIs, a significant prevalence of biliary culture positive for E. coli, Klebsiella pneumoni AE and Enterococcus f AE calis (p < 0.001) was detected. Prevalences of polymicrobial biliary cultures with Escherichia coli, Klebsiella pneumoni AE, Enterococcus f AE calis and Enterococcus f AE cium were significantly associated with POPF (p < 0.001). Biliary culture positive for Escherichia coli, Enterococcus f AE calis and Enterococcus f AE cium showed a higher prevalence of intra-abdominal collection and DGE (p < 0.001). Notably, Escherichia coli was significantly associated with DGE as a unique complication (OR = 2.94 (1.30-6.70); p < 0.01). Conclusions: Specific prevalences of polymicrobial bacterobilia are associated with major complications, while monomicrobial Escherichia coli bacterobilia is associated with DGE as a unique complication after PD

STRUCTURAL NEUROIMAGING IN PATIENTS WITH PANIC DISORDER: FINDINGS AND LIMITATIONS OF RECENT STUDIES

Background: Panic disorder, a relatively common anxiety disorder, is often associated to agoraphobia and may be disabling. Its neurobiological underpinnings are unknown, despite the proliferation of models and hypotheses concerning it; investigating its correlates could provide the means for better understanding its pathophysiology. Recent structural neuroimaging techniques may contribute to the identification of possible brain morphological alterations that could be possibly related to the clinical expression of panic disorder. Methods: Through careful major database searches, using terms keen to panic, agoraphobia, structural magnetic neuroimaging and the like, we identified papers published in peer-review journals and reporting data on the brain structure of patients with panic disorder. Included papers were used comparatively to speculate about the nature of reported brain structural alterations. Results: Anxiety, which is the core feature of the disorder, correlates with the function of the amygdala, which showed a smaller volume in patients, as compared to healthy subjects. Data also showed a volumetric decrease of the anterior cingulate along with increased fractional anisotropy, and increase of some brainstem nuclei, particularly of the rostral pons. Other structures with reported volumetric correlates of panic disorder are the hippocampus and the parahippocampal cortices, the insula, the putamen, and the pituitary gland. Volumetric changes in the anterior cingulate, frontal, orbitofrontal, insular, and temporal cortices have also been described in structural neuroimaging studies. Major methodological limitations are considered in context. Conclusions: Several data point to the existence of structural neuroanatomical alterations in panic disorder, consisting in significant volumetric reductions or increases in different brain areas. White matter alterations were shown also in the only diffusion tensor imaging study performed to date. Available data do not allow us to conclude about the possible progression of these alterations