Evidence-Based Medicine in Daily Surgical Decision Making: A Survey-Based Comparison between the UK and Germany

Background: Evidence-based medicine (EbM) is a vital part of reasonable and conclusive decision making for clinicians in daily clinical work. To analyze the knowledge and the attitude of surgeons towards EbM, a survey was performed in the UK and Germany. Methods: A web-based questionnaire was distributed via mailing lists from the Royal College of Surgeons of England (RCSE) and the Berufsverband Deutscher Chirurgen (BDC). Our primary aim was to get information about knowledge of EbM amongst German and British surgeons. Results: A total of 549 individuals opened the questionnaire, but only 198 questionnaires were complete and valid for analysis. In total, 40,000 recipients were approached via the mailing lists of the BDC and RCSE. The response rate was equally low in both countries. On a scale from 1 (unimportant) to 10 (very important), all participants rated EbM as very important for daily clinical decision making (7.3 ± 1.9) as well as for patients (7.8 ± 1.9) and the national health system (7.8 ± 1.9). On a scale from 1 (unimportant) to 5 (very important), systematic reviews (4.6 ± 0.6) and randomized controlled trials (4.6 ± 0.6) were identified as the highest levels of study designs to enhance evidence in medicine. British surgeons considered EbM to be more important in daily clinical work when compared to data from German surgeons (7.9 ± 1.6 vs. 6.7 ± 2.1, p < 0.001). Subgroup analysis showed different results in some categories; however, a pattern to explain the differences was not evident. Personal requirements expressed in a free text field emphasized the results and reflected concerns such as broad unwillingness and lack of interdisciplinary approaches for patients (n = 59: 25 in the UK and 34 in Germany). Conclusion: The overall results show that EbM is believed to be important by surgeons in the UK and Germany. However, perception of EbM in the respective health system (UK vs. Germany) may be different. Nonetheless, EbM is an important tool to navigate through daily clinical problems although a discrepancy between the knowledge of theoretical abstract terms and difficulties in implementing EbM in daily clinical work has been detected. The provision of infrastructure, courses and structured education as a permanent instrument will advance the knowledge, application and improvement of EbM in the future

FSP1 is a glutathione-independent ferroptosis suppressor

Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been believed to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants5,6. However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis7 is critical to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been identified that account for the resistance of cells to ferroptosis. Here we used an expression cloning approach to identify genes in human cancer cells that are able to complement the loss of GPX4. We found that the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2) is a previously unrecognized anti-ferroptotic gene. AIFM2, which we renamed ferroptosis suppressor protein 1 (FSP1) and which was initially described as a pro-apoptotic gene11, confers protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that the suppression of ferroptosis by FSP1 is mediated by ubiquinone (also known as coenzyme Q10 (CoQ10)): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ10 using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, the FSP1–CoQ10–NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma : A Randomized, Multicenter, Open-Label Phase 3 Trial

Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age 60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.Peer reviewe

Resektion im Vergleich zu Transplantation als kurative Behandlungsoption für das Hepatozelluläre Karzinom bei Patienten mit Zirrhose - Eine systematische Analyse

Das hepatozelluläre Karzinom (HCC) stellt eine der weltweit häufigsten Tumorerkrankungen dar. Die Inzidenz ist in den letzten Dekaden stetig gestiegen. Die derzeitigen kurativen Behandlungsmethoden sind vor allem Lebertransplantation und Leber Resektion. Der vorherrschende Organmangel führt zur Diskussion, ob Patienten mit HCC in Zirrhose transplantiert werden sollten, oder ob mit der Resektion in ausgewählten Patienten vergleichbare Ergebnisse erzielt werden kann. Es wurde eine systematische Analyse von mehreren Datenbanken durchgeführt. Studien zu Lebertransplantation und/oder Leber Resektion bei Patienten mit HCC in Zirrhose im Publikationszeitraum von 1990 bis 2011 wurden analysiert. Der Primäre Endpunkt war das Gesamtüberleben (OS). Sekundäre Endpunkte waren Rezidiv freies Überleben (DFS) und prognostische Faktoren, wie z.B. Tumor Charakteristika (Tumorzahl, Tumorgröße, Gefäßeinbruch, AFP Wert, Leberfunktion, usw.). Die Datenbankanalyse ergab 2428 Treffer. Bis dato wurde keine kontrolliert randomisierte Studie mit Vergleich von Transplantation und Resektion bei HCC in Zirrhose durchgeführt. Siebzig Publikationen waren zur statistischen Auswertung geeignet. Das DFS mehr als das OS war nach Transplantation signifikant besser. Die Patienten werden nicht bei vergleichbarem Tumorstadium oder vergleichbarer Leberfunktion behandelt. Intention-to-treat Analyse wurde kaum durchgeführt. Zusammenfassend sollten basierend auf der derzeitig verfügbaren Evidenz (Level III und niedriger) als primäre Behandlung für resektable HCC die Resektion durchgeführt werden. Eine kontrolliert randomisierte Studie bei Patienten ohne Kontraindikationen für beide Therapien und mit vergleichbaren Charakteristika sollte durchgeführt werden mit der Hypothese, dass Resektion bei HCC und sekundäre Transplantation bei Rezidiv oder Leberversagen vergleichbare Ergebnisse gegenüber der primären Transplantation liefert

Extended pancreas donor program - the EXPAND study rationale and study protocol

BACKGROUND: Simultaneous pancreas kidney transplantation (SPK), pancreas transplantation alone (PTA) or pancreas transplantation after kidney (PAK) are the only curative treatment options for patients with type 1 (juvenile) diabetes mellitus with or without impaired renal function. Unfortunately, transplant waiting lists for this indication are increasing because the current organ acceptability criteria are restrictive; morbidity and mortality significantly increase with time on the waitlist. Currently, only pancreas organs from donors younger than 50 years of age and with a body mass index (BMI) less than 30 are allocated for transplantation in the Eurotransplant (ET) area. To address this issue we designed a study to increase the available donor pool for these patients. METHODS/DESIGN: This study is a prospective, multicenter (20 German centers), single blinded, non-randomized, two armed trial comparing outcome after SPK, PTA or PAK between organs with the currently allowed donor criteria versus selected organs from donors with extended criteria. Extended donor criteria are defined as organs procured from donors with a BMI of 30 to 34 or a donor age between 50 and 60 years. Immunosuppression is generally standardized using induction therapy with Myfortic, tacrolimus and low dose steroids. In principle, all patients on the waitlist for primary SPK, PTA or PAK are eligible for the clinical trial when they consent to possibly receiving an extended donor criteria organ. Patients receiving an organ meeting the current standard criteria for pancreas allocation (control arm) are compared to those receiving extended criteria organ (study arm); patients are blinded for a follow-up period of one year. The combined primary endpoint is survival of the pancreas allograft and pancreas allograft function after three months, as an early relevant outcome parameter for pancreas transplantation. DISCUSSION: The EXPAND Study has been initiated to investigate the hypothesis that locally allocated extended criteria organs can be transplanted with similar results compared to the currently allowed standard ET organ allocation. If our study shows a favorable comparison to standard organ allocation criteria, the morbidity and mortality for patients waiting for transplantation could be reduced in the future. TRIAL REGISTRATION: Trial registered at: NCT0138400

Extended Pancreas Donor Program—The EXPAND Study

Background Pancreas transplantation is the only curative treatment option for patients with juvenile diabetes. Organ shortage and restrictive allocation criteria are the main reasons for increasing waitlists, leading to severe morbidity and mortality. We designed a study to increase the donor pool with extended donor criteria (EDC) organs (donor age, 50-60 years; body mass index, 30-34 kg/m(2)). Methods Utilization of EDC organs required the implementation of a new allocation system within Eurotransplant. The study was a prospective, multicenter, 2-armed trial. The primary endpoint was pancreas function after 3 months. Rejection episodes, kidney function, and waitlist time were secondary endpoints. Patients receiving an EDC organ were study group patients; recipients of standard organs were control group patients. Follow-up was 1 year. Results Seventy-nine patients were included in 12 German centers, 18 received EDC organs and 61 received standard organs. Recipient demographics were similar. Mean EDC donor age was 51.4 5 years versus 31.7 +/- 12 in the control group. Insulin-free graft survival was 83.3% for EDC and 67.2% for standard organs (P = 0.245) after 3 months. One-year pancreas survival was 83.3% and 83.5% in the EDC versus standard group. One-year kidney allograft survival was approximately 94% in both groups. Rejection episodes and morbidity were similar. Conclusions The Extended Pancreas Donor Program (EXPAND) shows in a prospective trial that selected EDC organs of donors older than 50 years can be used with outcomes similar to standard-criteria organs, therefore showing potential to reduce organ shortage and waiting times. This study substantiates the full implementation of EDC organs in a pancreas allocation system

Sirolimus use in liver transplant recipients with hepatocellular carcinoma: A randomized, multicenter, open-label phase 3 trial

We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC).status: publishe