C. Langelotz

The COP9 Signalosome Mediates β-Catenin Degradation by Deneddylation and Blocks Adenomatous Polyposis coli Destruction via USP15

The Wnt/beta-catenin signalling pathway has important roles in normal cellular proliferation, development and angiogenesis. Many malignant transformations, including sporadic colorectal tumours, are caused by constitutive activation of the Wnt route due to mutations in the tumour suppressor protein adenomatous polyposis coli (APC) or the beta-catenin oncogene, ultimately resulting in reduced beta-catenin degradation by the ubiquitin (Ub) proteasome system (UPS). The COP9 signalosome (CSN) regulates the UPS by controlling cullin-RING Ub ligases (CRLs). We show here that the CSN and the beta-catenin destruction complex cooperate in targeting beta-catenin for degradation by the UPS. Together with the CRL that ubiquitinates beta-catenin, they form a supercomplex responsible for beta-catenin degradation. Wnt3A, glycogen synthase kinase 3beta inhibitors or mutation of CSN-mediated deneddylation induce the disassembly of the supercomplex and the accumulation of beta-catenin. Likewise, downregulation of the CSN in HeLa cells leads to retarded degradation of beta-catenin. Additionally, we found that the knockdown of the CSN causes accelerated proteolysis of APC, an essential component of the beta-catenin destruction complex, which is degraded by the UPS as beta-catenin. We show here that APC is stabilised by the Ub-specific protease 15 (USP15) associated with the CSN. This is demonstrated by over-expression of siRNA oligonucleotides against USP15 or by over-expression of an USP15 mutant, which is unable to degrade poly-Ub chains. Thus, the CSN controls the Wnt/beta-catenin signalling by assisting the assembly of beta-catenin-degrading supercomplexes by deneddylation and, simultaneously, by stabilising APC via CSN-associated USP15. The CSN regulates the balance between beta-catenin and APC. Disturbance of this balance can cause cancer by driving cell transformation, tumour angiogenesis and metastasis. A model is provided that proposes a role of CSN-mediated deneddylation in the formation of the beta-catenin-degrading supercomplex and the protection of complex-bound APC via CSN-associated USP15.

Stress and Heart Rate Variability in Surgeons During a 24-Hour Shift

OBJECTIVE To determine the specific effects of working long hours in surgery and potential cardiac stress in the individual surgeon by measuring heart rate variability (HRV). DESIGN, SETTING, AND PARTICIPANTS This prospective study measured HRV before, during, and after a 24-hour shift in a standardized resting period of 10 minutes. Measurements were repeated over 10 shifts for each participant. Eight surgeons from a high-volume inner-city surgery department took part in the study. MAIN OUTCOME MEASURES Time and frequency domain parameters of HRV as parameters of cardiac stress and correlations with perceived stress and fatigue on a visual analog scale. RESULTS Perceived fatigue increased over 24 hours (P < .001), whereas stress levels decreased slightly (P = .06). Time domain parameters of HRV increased from before the shift to after the shift (standard deviation of normal to normal intervals, square root of the mean normal to normal interval, and percentage of adjacent pairs of normal to normal intervals differing by more than 50 milliseconds: all P < .01), denoting more cardiac relaxation. Both the low- and high-frequency components increased (P = .04 and P < .001, respectively), showing a heightened activity of the autonomic nervous system. CONCLUSIONS Measurements of HRV during a 24-hour surgical shift did not show an increase in cardiac stress concerning time domain parameters despite intense workloads for a median of 20 hours. Frequency components increased in parallel, though, suggesting alterations in sympathovagal balance. Perceived stress levels correlated with HRV, whereas fatigue did not. Further studies on occupational stress and its cardiac effects in surgeons are needed.

Fast-track-rehabilitation in surgery, a multimodal concept

Abstract The rates of postoperative local surgical complications (e.g. wound-infection, abscess, anastomotic leakage) and the postoperative mortality have markedly decreased over the past decades. However the occurrence of general medical complications (e.g. cardio-pulmonary or renal dysfunction, nosocomial infections, thromboembolism) after abdominal surgery is still frequent with an incidence of 20–60% (1–6). “Fast-track”-surgery, also called “Fast-track”-rehabilitation or “ERAS” (enhanced recovery after surgery) programme, is a combination of different pre-and intraoperative measures, which have been mainly validated in elective colonic surgery, but they can be principally employed in all surgical settings. With this approach it is possible to accelerate the postoperative convalescence and reduce the rate of general complications markedly (4, 7–10).

Initial Results after Implementation of a Multimodal Treatment for Peritoneal Malignancies

Abstract Introduction : Peritoneal carcinomatosis represents a clinical condition with a limited perspective concerning long term survival. The combination of surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) represents a complex multimodal therapeutic management concept with promising results for prolongation of survival. For the identification of pitfalls during implementation of the HIPEC procedure into clinical practice an observational study was conducted. Methods : Between 2005 and 2009 data from all patients treated with cytoreductive surgery and HIPEC for peritoneal carcinomatosis was prospectively collected and analysed. Results : During the observational interval a total of 42 patients underwent surgical treatment for peritoneal carcinomatosis. In 34 patients the complete procedure with surgical cytoreduction and HIPEC was performed. Perioperative mortality (6%) and morbidity (35%) was similar to other reported series. Twenty-five patients (76%) survived the 18 months follow-up period after complete procedure. Conclusion : The multimodal therapeutic treatment concept of surgical cytoreduction and following HIPEC leads to promising results for patients suffering from peritoneal carcinomatosis. However this treatment concept is afflicted with a relevant risk of postoperative complications.

An International Collaborative Standardizing a Comprehensive Patient-Centered Outcomes Measurement Set for Colorectal Cancer

Importance Global health systems are shifting toward value-based care in an effort to drive better outcomes in the setting of rising health care costs. This shift requires a common definition of value, starting with the outcomes that matter most to patients. Objective The International Consortium for Health Outcomes Measurement (ICHOM), a nonprofit initiative, was formed to define standard sets of outcomes by medical condition. In this article, we report the efforts of ICHOM’s working group in colorectal cancer. Evidence Review The working group was composed of multidisciplinary oncology specialists in medicine, surgery, radiation therapy, palliative care, nursing, and pathology, along with patient representatives. Through a modified Delphi process during 8 months (July 8, 2015 to February 29, 2016), ICHOM led the working group to a consensus on a final recommended standard set. The process was supported by a systematic PubMed literature review (1042 randomized clinical trials and guidelines from June 3, 2005, to June 3, 2015), a patient focus group (11 patients with early and metastatic colorectal cancer convened during a teleconference in August 2015), and a patient validation survey (among 276 patients with and survivors of colorectal cancer between October 15, 2015, and November 4, 2015). Findings After consolidating findings of the literature review and focus group meeting, a list of 40 outcomes was presented to the WG and underwent voting. The final recommendation includes outcomes in the following categories: survival and disease control, disutility of care, degree of health, and quality of death. Selected case-mix factors were recommended to be collected at baseline to facilitate comparison of results across treatments and health care professionals. Conclusions A standardized set of patient-centered outcome measures to inform value-based health care in colorectal cancer was developed. Pilot efforts are under way to measure the standard set among members of the working group.

Influence of pre-operative fluid infusion on volume status during oesophageal resection – a prospective trial

Background: Perioperative fluid therapy is controversially debated in surgery. In malnourished and hypovolaemic patients, a restrictive fluid regimen may lead to hypoperfusion and increased incidence of complications. The present prospective cohort study was performed to assess whether pre‐operative i.v. fluid administration improves intraoperative cardiac preload in patients undergoing oesophageal resection.

Mitarbeiterzufriedenheit im Arbeitszeitmodell: Längsschnittstudie zu Praxistauglichkeit und Gesetzeskonformität in einer chirurgischen Klinik der Maximalversorgung

Background Between the conflicting requirements of clinic organisation, the European Working Time Directive, patient safety, an increasing lack of junior staff, and competitiveness, the development of ideal duty hour models is vital to ensure maximum quality of care within the legal requirements. To achieve this, it is useful to evaluate the actual effects of duty hour models on staff satisfaction. Materials and Methods After the traditional 24-hour duty shift was given up in a surgical maximum care centre in 2007, an 18-hour duty shift was implemented, followed by a 12-hour shift in 2008, to improve handovers and reduce loss of information. The effects on work organisation, quality of life and salary were analysed in an anonymous survey in 2008. The staff survey was repeated in 2014. Results With a response rate of 95% of questionnaires in 2008 and a 93% response rate in 2014, the 12-hour duty model received negative ratings due to its high duty frequency and subsequent social strain. Also the physical strain and chronic tiredness were rated as most severe in the 12-hour rota. The 18-hour duty shift was the model of choice amongst staff. The 24-hour duty model was rated as the best compromise between the requirements of work organisation and staff satisfaction, and therefore this duty model was adapted accordingly in 2015. Conclusion The essential basis of a surgical department is a duty hour model suited to the requirements of work organisation, the Working Time Directive and the needs of the surgical staff. A 12-hour duty model can be ideal for work organisation, but only if augmented with an adequate number of staff members, the implementation of this model is possible without the frequency of 12-hour shifts being too high associated with strain on surgical staff and a perceived deterioration of quality of life. A staff survey should be performed on a regular basis to assess the actual effects of duty hour models and enable further optimisation. The much criticised 24-hour duty model seems to be much better than its reputation, if augmented by additional staff members in the evening hours.

Ökonomische Analyse des Behandlungsverlaufs bei über 80-jährigen Patienten an einer Klinik der chirurgischen Maximalversorgung

BACKGROUND The demographic change in Germany with an aging population and the resulting necessity of adequate surgical care for older patients was lately discussed with concern. One major aspect is the estimated higher treatment costs in the care of the elderly. MATERIALS AND METHODS InEK data from all cases of patients over the age of 80, who were treated and discharged from 2008 to 2012 as inpatients at the Department of General, Visceral, Vascular and Thoracic Surgery at the Charité - Universitätsmedizin Berlin, Campus Mitte, were analysed. Of a total of 13,612 patients 626 patients were over the age of 80. Their lengths of stay, mode of discharge and discharge management as well as costs and reimbursements according to the relevant diagnosis-related groups were analysed. RESULTS Cases of elderly patients amounted to a stable 5 % of all cases from 2008 until 2012. Their mean length of stay was 14 (median, 9), range, 1-129 days. 80 % of patients could be regularly discharged, 9 % died, 8 % were transferred to another hospital, 2 % discharged into a nursing home and 1 % into a rehabilitation centre. The elderly patients had a patient clinical complexity level of mean 2.84. Costs per day amounted to a mean 778 (median: 627) €, range: 306-7740 €, total costs to 10,686 (median: 5140) €, range: 368-186,059 €. The mean deficit was 491 (median: 176) € per patient, range: - 30,470-75,144 €. The discharge management was significantly different in comparison to patients under the age of 80 with respect to avoidance of discharge at the weekend. CONCLUSION Patients over the age of 80 are a relevant group in surgery. They have an increased perioperative risk, but patients should not be denied surgery solely because of their age. The perioperative management of the elderly has to be of maximum standardised quality. From an economic perspective it can be stated that elderly patients currently pose no exceptional financial risk to a surgical department, but contribute relevantly to the turnover, whereby special attention has to be paid to an early structured discharge management.

Magenresektion bei benignen Erkrankungen

Maßnahme Zeitpunkt Diagnostik/Prämedikation Prästationär Aufnahme 1. präoperativer Tag Intensivstation Nein Verlegung auf Normalstation OP-Tag Rehabilitationsziel »Normalkost« 4 Trinken am OP-Tag 4 Flüssige Kost ab 1. postoperativen Tag 4 Normalkost ab 3. postoperativen Tag Rehabilitationsziel »Mobilisation aus dem Bett« 4 1–2 h am OP-Tag 4 8 h am 1. postoperativen Tag 4 >8 h ab 2. postoperativen Tag Entlassung Ab 6. postoperativen Tag nach Patientenwunsch Ambulante Kontrolle 8.–10. postoperativer Tag

Klinische Ergebnisse der Fast-track-Rehabilitation

Angesichts der grosen Zahl weltweit erscheinender wissenschaftlicher Journale ist es schwierig, alle Publikationen klinischer Erfahrungen mit der Fast-track-Rehabilitation aufzulisten. Der Aufwand einer systematischen Literaturrecherche der Weltliteratur zu diesem Thema ware unter Einsatz der elektronischen Literaturdatenbanken zwar prinzipiell moglich, allerdings wurde dieser Versuch durch die uneinheitliche Nomenklatur auf diesem Gebiet erschwert. Wahrend Fast-track-Chirurgie oder Fast-track-Rehabilitation in Deutschland inzwischen weit verbreitete und vielen Operateuren durchaus bekannte Bezeichnungen sind, finden sich im deutschsp rachigen und internationalen Schrifttum auch zahlreiche alternative Bezeichnungen, von denen »ERAS« (»enhanced recovery after surgery«—»beschleunigte Erholung nach Chirurgie«), »optimised surgery« oder »multimodale Chirurgie« nur eine kleine Auswahl darstellen. Zudem publizieren zahlreiche Autoren Erfahrungen mit einem multimodalen, interdisziplinaren und evidenzbasierten perioperativen Behandlungskonzept auch ohne diesen klinischen Behandlungspfad als Fast-track-Rehabilitation oder »ERAS« zu benennen.