Impact of Borderline Resectability in Pancreatic Head Cancer on Patient Survival: Biology Matters According to the New International Consensus Criteria

Background: International consensus criteria (ICC) have redefined borderline resectability for pancreatic ductal adenocarcinoma (PDAC) according to three dimensions: anatomical (BR-A), biological (BR-B), and conditional (BR-C). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumour and vessels but that biological and conditional dimensions also are important. Methods: Patients’ tumours were retrospectively defined b

Novel diagnostic strategies for the diagnosis of initial graft function after liver transplantation

Die Lebertransplantation ist ein etabliertes Therapieverfahren zur Behandlung terminaler Lebererkrankungen. Problematisch ist allerdings die Tatsache, dass eine valide Einschätzung der Transplantatfunktion bisher erst nach einigen Tagen möglich ist, so dass in der Frühphase nach Operation noch kein optimales Therapiemanagement erfolgen kann. Ziel dieser Arbeit war es, verschiedene (dynamische) Leberfunktionstests, darunter einen in der Charité neu entwickelten Test (LiMAx-Test), sowie den bekannten Indocyaningrün (ICG)-Test, auf ihre diagnostische Wertigkeit (insbesondere die prädiktiven Werte für postoperative Komplikationen) nach Lebertransplantation im Vergleich zu konventionellen laborchemischen Parametern prospektiv zu untersuchen. Hierzu wurden mehrere, darunter vorbereitende klinische Studien mit insgesamt 433 Patienten und 46 freiwilligen Probanden durchgeführt. Es zeigte sich, dass der LiMAx-Test als einziger unter den analysierten Parametern den postoperativen Verlauf nach Lebertransplantation individuell prognostizieren kann. Bei einem Trennwert von 64 µg/kg/h konnte eine Re-Operation mit einer Sensitivität von 100% und einer Spezifität von 92% direkt nach der Transplantation vorhergesagt werden. Eine initiale Nichtfunktion der transplantierten Leber und somit die Notwendigkeit einer Retransplantation konnte anhand des LiMAx-Tests am ersten postoperativen Tag mit identischer Genauigkeit vorhergesagt werden. Außerdem konnte der wesentliche Einfluss der Transplantatfunktion auf die Pharmakokinetik des Standardimmunsuppressivums Tacrolimus dargestellt werden. Basierend auf den Ergebnissen der ersten Auswertung wurde eine neue Definition der schlechten Transplantatfunktion anhand der postoperativen LiMAx-Werte entwickelt. Durch diese verbesserte Diagnostik kann die Behandlung in der Frühphase nach Lebertransplantation deutlich verbessert werden. Zusammengenommen konnte der neu entwickelte LiMAx-Test erstmals zeigen, dass eine direkte (dynamische) Messung der initialen Transplantatfunktion nach Lebertransplantation möglich ist und wichtige Informationen für die weitere Behandlung liefern kann.Liver transplantation is a well established therapy for end stage liver disease. The valid assessment of initial graft function somehow remains a relevant clinical problem. The aim of this work was to evaluate different dynamic liver function tests, including the novel LiMAx test that had been developed at the Charité recently. The diagnostic performance of different liver function tests for postoperative complications was prospectively evaluated clinical studies. A total of 433 patients and 46 healthy volunteers were included. It was demonstrated that the LiMAx test provides the single reliable parameter for individual prognosis after liver transplantation. The need for a postoperative re-operation due to severe complications was predicted at a cut-off LiMAx of 64 µg/kg/h with 100% sensitivity and 92% specificity directly after surgery. Primary nonfunction and need for urgent retransplantation was diagnosed with equal precision at the first postoperative day. In addition, the strong relationship between graft function and metabolism of immunosuppressive drugs such as tacrolimus was demonstrated. The LiMAx was able to predict postoperative trough levels and thus might augment pharmacotherapy after liver transplantation. Finally, a new functional definition of initial poor function was developed based on postoperative LiMAx values. In conclusion, the LiMAx test provides important diagnostic information after liver transplantation that might improve the postoperative management and cannot be provided by any other present test

Defining the scope of antimicrobial stewardship interventions on the prescription quality of antibiotics for surgical intra-abdominal infections

Background: The aim of this study was to assess the impact of antimicrobial stewardship interventions on surgical antibiotic prescription behavior in the management of non-elective surgical intra-abdominal infections, focusing on postoperative antibiotic use, including the appropriateness of indications. Methods: A single-center quality improvement study with retrospective evaluation of the impact of antimicrobial stewardship measures on optimizing antibacterial use in intra-abdominal infections requiring emergency surgery was performed. The study was conducted in a tertiary hospital in Germany from January 1, 2016, to January 30, 2020, three years after putting a set of antimicrobial stewardship standards into effect. Results: 767 patients were analyzed (n = 495 in 2016 and 2017, the baseline period; n = 272 in 2018, the antimicrobial stewardship period). The total days of therapy per 100 patient days declined from 47.0 to 42.2 days (p = 0.035). The rate of patients receiving postoperative therapy decreased from 56.8% to 45.2% (p = 0.002), comparing both periods. There was a significant decline in the rate of inappropriate indications (17.4% to 8.1 %, p = 0.015) as well as a significant change from broad-spectrum to narrow-spectrum antibiotic use (28.8% to 6.5%, p ≤ 0.001) for postoperative therapy. The significant decline in antibiotic use did not affect either clinical outcomes or the rate of postoperative wound complications. Conclusions: Postoperative antibiotic use for intra-abdominal infections could be significantly reduced by antimicrobial stewardship interventions. The identification of inappropriate indications remains a key target for antimicrobial stewardship programs

Assessment of hepatic detoxification activity: proposal of an improved variant of the (13)c-methacetin breath test.

Breath tests based on the administration of a (13)C-labeled drug and subsequent monitoring of (13)CO2 in the breath (quantified as DOB - delta over baseline) liberated from the drug during hepatic CPY-dependent detoxification are important tools in liver function diagnostics. The capability of such breath tests to reliably indicate hepatic CYP performance is limited by the fact that (13)CO2 is not exclusively exhaled but also exchanged with other compartments of the body. In order to assess this bias caused by variations of individual systemic CO2 kinetics we administered intravenously the test drug (13)C-methacetin to 25 clinically liver-healthy individuals and monitored progress curves of DOB and the plasma concentration of (13)C-methacetin. Applying compartment modelling we estimated for each individual a set of kinetic parameters characterizing the time-dependent exchange of the drug and of CO2 with the liver and non-hepatic body compartments. This analysis revealed that individual variations in the kinetics of CO2 may account for up to 30% deviation of DOB curve parameters from their mean at otherwise identical (13)C-methacetin metabolization rates. In order to correct for this bias we introduced a novel detoxification score which ideally should be assessed from the DOB curve of a 2-step test ("2DOB") which is initialized with the injection of a standard dose of (13)C-labeled bicarbonate (in order to provide information on the actual CO2 status of the individual) followed by injection of the (13)C-labeled test drug (the common procedure). Computer simulations suggest that the predictive power of the proposed 2DOB breath test to reliably quantity the CYP-specific hepatic detoxification activity should be significantly higher compared to the conventional breath test

Retrospective Cohort Analysis of the Effect of Antimicrobial Stewardship on Postoperative Antibiotic Therapy in Complicated Intra-Abdominal Infections: Short-Course Therapy Does Not Compromise Patients’ Safety

Background: Recent evidence suggests that short-course postoperative antibiotic therapy (PAT) of intra-abdominal infections is non-inferior considering clinical outcomes. The aim of this study was to compare the outcome of short vs. long PAT in complicated intra-abdominal infections (cIAIs) without sepsis. Methods: We performed a single center-quality improvement study at a 1500 bed sized university hospital in Bavaria, Germany, with evaluation of the length of antibiotic therapy after emergency surgery on cIAIs with adequate source control during 2016 to 2018. We reviewed a total of 260 cases (160 short duration vs. 100 long duration). The antibiotic prescribing quality was assessed by our in-house antimicrobial stewardship team (AMS). Results: No significant differences of patient characteristics were observed between short and long PAT. The frequency of long PAT declined during the observation period from 48.1% to 26.3%. Prolongation of PAT was not linked with any clinical benefits, on the contrary clinical outcome of patients receiving longer regimes were associated with higher postoperative morbidity. AMS identified additional educational targets to improve antibiotic prescribing quality on general wards like unnecessary postoperative switches of antibiotic regimes, e.g., unrequired switches to oral antibiotics as well as prolongation of PAT due to elevated CRP. Conclusion: Short-course antibiotic therapy after successful surgical source control in cIAIs is safe, and long-duration PAT has no beneficial effects

Does concurrent cholestasis alter the prognostic value of preoperatively elevated CA19-9 serum levels in patients with pancreatic head adenocarcinoma?

Background Pancreatic adenocarcinoma (PDAC) patients with preoperative carbohydrate antigen 19-9 (CA19-9) serum levels higher than 500 U/ml are classified as biologically borderline resectable (BR-B). To date, the impact of cholestasis on preoperative CA19-9 serum levels in these patients has remained unquantified. Methods Data on 3079 oncologic pancreatic resections due to PDAC that were prospectively acquired by the German Study, Documentation and Quality (StuDoQ) registry were analyzed in relation to preoperative CA19-9 and bilirubin serum values. Preoperative CA19-9 values were adjusted according to the results of a multivariable linear regression analysis of pathologic parameters, bilirubin, and CA19-9 values. Results Of 1703 PDAC patients with tumor located in the pancreatic head, 420 (24.5 %) presented with a preoperative CA19-9 level higher than 500 U/ml. Although receiver operating characteristics (ROC) analysis failed to determine exact CA19-9 cut-off values for prognostic indicators (R and N status), the T, N, and G status; the UICC stage; and the number of simultaneous vein resections increased with the level of preoperative CA19-9, independently of concurrent cholestasis. After adjustment of preoperative CA19-9 values, 18.5 % of patients initially staged as BR-B showed CA19-9 values below 500 U/ml. However, the postoperative pathologic results for these patients did not change compared with the patients who had CA19-9 levels higher than 500 U/ml after bilirubin adjustment. Conclusions In this multicenter dataset of PDAC patients, elevation of preoperative CA19-9 correlated with well-defined prognostic pathologic parameters. Bilirubin adjustment of CA19-9 is feasible but does not affect the prognostic value of CA19-9 in jaundiced patients

Cefazolin might be adequate for perioperative antibiotic prophylaxis in intra-abdominal infections without sepsis: a quality improvement study

Background: The adequate choice of perioperative antibiotic prophylaxis (PAP) could influence the risk of surgical site infections (SSIs) in general surgery. A new local PAP guideline was implemented in May 2017 and set the first-generation cefazolin (CFZ) instead the second-generation cefuroxime (CXM) as the new standard prophylactic antibiotic. The aim of this study was to compare the risk of SSIs after this implementation in intra-abdominal infections (IAIs) without sepsis. Methods: We performed a single center-quality improvement study at a 1500 bed sized university hospital in Germany analyzing patients after emergency surgery during 2016 to 2019 (n = 985), of which patients receiving CXM or CFZ were selected (n = 587). Propensity score matching was performed to ensure a comparable risk of SSIs in both groups. None-inferiority margin for SSIs was defined as 8% vs. 4%. Results: Two matched cohorts with respectively 196 patients were compared. The rate of SSIs was higher in the CFZ group (7.1% vs. 3.6%, p = 0.117) below the non-inferiority margin. The rate of other postoperative infections was significantly higher in the CFZ group (2.0% vs. 8.7%, p = 0.004). No other differences including postoperative morbidity, mortality or length-of-stay were observed. Conclusion: Perioperative antibiotic prophylaxis might be safely maintained by CFZ even in the treatment of intra-abdominal infections

Cefazolin Might Be Adequate for Perioperative Antibiotic Prophylaxis in Intra-Abdominal Infections without Sepsis: A Quality Improvement Study

Background: The adequate choice of perioperative antibiotic prophylaxis (PAP) could influence the risk of surgical site infections (SSIs) in general surgery. A new local PAP guideline was implemented in May 2017 and set the first-generation cefazolin (CFZ) instead the second-generation cefuroxime (CXM) as the new standard prophylactic antibiotic. The aim of this study was to compare the risk of SSIs after this implementation in intra-abdominal infections (IAIs) without sepsis. Methods: We performed a single center-quality improvement study at a 1500 bed sized university hospital in Germany analyzing patients after emergency surgery during 2016 to 2019 (n = 985), of which patients receiving CXM or CFZ were selected (n = 587). Propensity score matching was performed to ensure a comparable risk of SSIs in both groups. None-inferiority margin for SSIs was defined as 8% vs. 4%. Results: Two matched cohorts with respectively 196 patients were compared. The rate of SSIs was higher in the CFZ group (7.1% vs. 3.6%, p = 0.117) below the non-inferiority margin. The rate of other postoperative infections was significantly higher in the CFZ group (2.0% vs. 8.7%, p = 0.004). No other differences including postoperative morbidity, mortality or length-of-stay were observed. Conclusion: Perioperative antibiotic prophylaxis might be safely maintained by CFZ even in the treatment of intra-abdominal infections

Predicting the prognosis in acute liver failure: results from a retrospective pilot study using the LiMAx test

Background. Acute liver failure (ALF) is a rare but potentially life-threatening condition and liver transplantation (LTX) remains frequently the only effective therapy. Nevertheless, some patients recover without LTX but the individual indication for or against LTX remains difficult.Aim. To evaluate maximal liver function capacity (LiMAx) for predicting the prognosis of ALF.Material and methods. Clinic data of 12 patients was retrospectively analyzed to compare the different liver function test results with the patients’ clinical outcome. Patients were assessed by the LiMAx test, a non-invasive breath test determining cytochrome P450 1A2 capacity using intravenous 13C-methacetin. Statistical analysis compared patients with spontaneous recovery versus non-recovery (LTX or death).Results. Twelve patients (6 male, 6 female; 49 [11–72] years) with viral hepatitis (n = 2), toxic liver injury (n = 3), or cryptogenic liver failure (n = 7) were analyzed. Seven patients fully recovered from ALF and were discharged without LTX. Three patients died and two underwent LTX. The King’s College Criteria (KCC) was fulfilled in only one out of five patients without recovery. The LiMAx was 19 ± 19 (16–62) for non-recovery vs. 94 ± 119 (39–378) μg/kg/h for recovery (P = 0.018). In contrast, all biochemical parameters [bilirubin (P = 0.106), creatinine (P = 0.343), AST (P = 0.53), ALT (P = 0.876) and INR (P = 0.876) were statistically indistinct. Also the Model for End-Stage Liver Disease (MELD) score did not show a difference [35 ± 4.3 (29–40) vs. 30 ± 11.5 (6–40); P = 0.27].Conclusions. Maximal liver function capacity determined by LiMAx test is severely impaired in patients with ALF. The LiMAx test might be effective in predicting the individual prognosis and the need for LTX in ALF