Combined regression score predicts outcome after neoadjuvant treatment of oesophageal cancer.

BACKGROUND: Histopathologic regression following neoadjuvant treatment (NT) of oesophageal cancer is a prognostic factor of survival, but the nodal status is not considered. Here, a score combining both to improve prediction of survival after neoadjuvant therapy is developed. METHODS: Seven hundred and fifteen patients with oesophageal squamous cell (SCC) or adenocarcinoma (AC) undergoing NT and esophagectomy were analysed. Histopathologic response was classified according to percentage of vital residual tumour cells (VRTC): complete response (CR) without VRTC, major response with <10% VRTC, minor response with >10% VRTC. Nodal stage was classified as ypN0 and ypN+. Kaplan-Meier and Cox regression were used for survival analysis. RESULTS: Survival analysis identified three groups with significantly different mortality risks: (1) low-risk group for CR (ypT0N0) with 72% 5-year overall survival (5y-OS), (2) intermediate-risk group for minor/major responders and ypN0 with 59% 5y-OS, and (3) high-risk group for minor/major responders and ypN+ with 20% 5y-OS (p < 0.001). Median survival in AC and SCC cohorts were comparable (3.8 (CI 95%: 3.1, 5.3) vs. 4.6 years (CI 95%: 3.3, not reached), p = 0.3). CONCLUSIONS: Histopathologic regression and nodal status should be combined for estimating AC and SCC prognosis. Poor survival in the high-risk group highlights need for adjuvant therapy.

Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group.

BACKGROUND: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). PATIENTS AND METHODS: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. RESULTS: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. CONCLUSIONS: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).

Predicting complicated appendicitis based on clinical findings: the role of Alvarado and Appendicitis Inflammatory Response scores.

PURPOSE: The pre-interventional differentiation between complicated and uncomplicated appendicitis is decisive for treatment. In the context of conservative therapy, the definitive diagnosis of uncomplicated appendicitis is mandatory. This study investigates the ability of clinical scoring systems and imaging to differentiate between the two entities. METHODS: This is a retrospective analysis of two cohorts from two tertiary referral centers in Switzerland and Germany. All consecutive patients underwent appendectomy between January 2008 and April 2013 (in the first cohort) or between January 2017 and June 2019 (the second cohort). Exclusion criteria did not apply as all patients found by the database search and received an appendectomy were included. Diagnostic testing and calculation of a receiver operating curve were performed to identify a cutoff for clinical scores that resulted in a minimum sensitivity of 90% to detect complicated appendicitis. The cutoff was combined with additional diagnostic imaging criteria to see if diagnostic properties could be improved. RESULTS: Nine hundred fifty-six patients were included in the analysis. Two hundred twenty patients (23%) had complicated appendicitis, and 736 patients (77%) had uncomplicated appendicitis or no inflammation. The complicated appendicitis cohort had a mean Alvarado score of 7.03 and a mean AIR of 5.21. This compared to a mean Alvarado of 6.53 and a mean AIR of 4.07 for the uncomplicated appendicitis cohort. The highest Alvarado score with a sensitivity of > 90% to detect complicated appendicitis was ≧ 5 (sensitivity = 95%, specificity 8.99%). The highest AIR score with a sensitivity of > 90% to detect complicated appendicitis was ≧ 3 (sensitivity 91.82%, specificity 18.53). The analysis showed that additional CT information did not improve the sensitivity of the proposed cut-offs. CONCLUSION: AIR and Alvarado scores showed limited capability to distinguish between complicated and uncomplicated appendicitis even with additional imaging in this retrospective cohort. As conservative management of appendicitis needs to exclude patients with complicated disease reliably, appendectomy seems until now to remain the safest option to prevent undertreatment of this mostly benign disease.

R0 resection following chemo (radio)therapy improves survival of primary inoperable pancreatic cancer patients. Interim results of the German randomized CONKO-007± trial.

PURPOSE: Chemotherapy with or without radiotherapy is the standard in patients with initially nonmetastatic unresectable pancreatic cancer. Additional surgery is in discussion. The CONKO-007 multicenter randomized trial examines the value of radiotherapy. Our interim analysis showed a significant effect of surgery, which may be relevant to clinical practice. METHODS: One hundred eighty patients received induction chemotherapy (gemcitabine or FOLFIRINOX). Patients without tumor progression were randomized to either chemotherapy alone or to concurrent chemoradiotherapy. At the end of therapy, a panel of five independent pancreatic surgeons judged the resectability of the tumor. RESULTS: Following induction chemotherapy, 126/180 patients (70.0%) were randomized to further treatment. Following study treatment, 36/126 patients (28.5%) underwent surgery; (R0: 25/126 [19.8%]; R1/R2/Rx [n = 11/126; 6.1%]). Disease-free survival (DFS) and overall survival (OS) were significantly better for patients with R0 resected tumors (median DFS and OS: 16.6 months and 26.5 months, respectively) than for nonoperated patients (median DFS and OS: 11.9 months and 16.5 months, respectively; p = 0.003). In the 25 patients with R0 resected tumors before treatment, only 6/113 (5.3%) of the recommendations of the panel surgeons recommended R0 resectability, compared with 17/48 (35.4%) after treatment (p < 0.001). CONCLUSION: Tumor resectability of pancreatic cancer staged as unresectable at primary diagnosis should be reassessed after neoadjuvant treatment. The patient should undergo surgery if a resectability is reached, as this significantly improves their prognosis.

CONKO-006: A randomised double-blinded phase IIb-study of additive therapy with gemcitabine + sorafenib/placebo in patients with R1 resection of pancreatic cancer - Final results.

BACKGROUND: CONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib (GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles. PATIENTS AND METHODS: This randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment. RESULTS: 122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%). By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021). CONCLUSION: CONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients. CLINICAL TRIAL INFORMATION: German Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242.

Consensus in determining the resectability of locally progressed pancreatic ductal adenocarcinoma - results of the Conko-007 multicenter trial.

BACKGROUND: One critical step in the therapy of patients with localized pancreatic cancer is the determination of local resectability. The decision between primary surgery versus upfront local or systemic cancer therapy seems especially to differ between pancreatic cancer centers. In our cohort study, we analyzed the independent judgement of resectability of five experienced high volume pancreatic surgeons in 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer. METHODS: Pretherapeutic CT or MRI scans of 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer were evaluated by 5 independent pancreatic surgeons. Resectability and the degree of abutment of the tumor to the venous and arterial structures adjacent to the pancreas were reported. Interrater reliability and dispersion indices were compared. RESULTS: One hundred ninety-four CT scans and 6 MRI scans were evaluated and all parameters were evaluated by all surgeons in 133 (66.5%) cases. Low agreement was observed for tumor infiltration of venous structures (κ = 0.265 and κ = 0.285) while good agreement was achieved for the abutment of the tumor to arterial structures (interrater reliability celiac trunk κ = 0.708 P < 0.001). In patients with vascular tumor contact indicating locally advanced disease, surgeons highly agreed on unresectability, but in patients with vascular tumor abutment consistent with borderline resectable disease, the judgement of resectability was less uniform (dispersion index locally advanced vs. borderline resectable p < 0.05). CONCLUSION: Excellent agreement between surgeons exists in determining the presence of arterial abutment and locally advanced pancreatic cancer. The determination of resectability in borderline resectable patients is influenced by additional subjective factors. TRIAL REGISTRATION: EudraCT:2009-014476-21 (2013-02-22) and NCT01827553 (2013-04-09).

Quantitative spleen and liver volume changes predict survival of patients with primary sclerosing cholangitis.

AIM: To assess the value of quantitative spleen and liver volume changes in predicting the survival of patients with primary sclerosing cholangitis (PSC). MATERIALS AND METHODS: This institutional review board-approved single-centre study included 89 PSC patients with baseline and follow-up liver imaging studies and laboratory data between 2000 and 2018. Change in spleen, total and lobar liver volumes, and lobar-to-total liver volume ratio was compared between patients with and without adverse outcome (liver transplantation, transplant waiting list, and death). Receiver operating characteristic (ROC) and Kaplan-Meier analysis were performed to identify the volumetric threshold for prediction of outcome and show how these thresholds predict survival, respectively. A p-value of <0.05 was considered statistically significant. RESULTS: The present cohort included 53 men (60%), with mean age of 42 years at baseline. The only volumetric parameters with significant differences in change between patients with and without adverse outcome were spleen volume (p<0.001) and left-to-total liver volume ratio (L/T; p=0.025). The probability of transplant-free survival at 36 months was 59.1% versus 11.9% for patients with spleen volume change <50 ml versus ≥50 ml, respectively (AUC=0.731); and 61.3% versus 13.8% for patients with L/T change <0.04 versus ≥0.04, respectively (AUC=0.638). The patients with changes below the cut-off in both spleen volume and L/T, had a higher probability of transplant-free survival at 36 months (76.8%), compared to those with change at or below the cut-offs in one or both of these two parameters (36.7%, 15%, respectively; p=0.001). CONCLUSION: Spleen volume change and L/T change might be useful biomarkers for prediction of transplant-free survival in patients with PSC.

[Systematic surgery of retroperitoneal sarcomas : Imaging-guided planning of surgical strategy]. / Systematische Chirurgie retroperitonealer Sarkome : Bildgestützte Planung des Resektionsausmaßes.

Abdominal and retroperitoneal sarcomas (RPS) represent approximately 25-30% of all soft tissue sarcomas, if besides typical retroperitoneal tumors gastrointestinal stromal tumors (GIST) are also included. The surgical R0 en bloc resection with histopathologically free margins is basically the only potentially curative treatment procedure. When planning the surgical strategy, the histopathological subtype and tumor localization are pivotal. The extent of resection should be guided by the goal to reach an en bloc resection with histopathologically negative margins. Due to the frequently found vast dimensions of RPS and ultimately topographic proximity to vital structures at primary diagnosis, R0 resections are not always achievable. Despite the introduction of multimodal treatment regimens and the development of standardized extended surgical procedures, such as systematic retroperitoneal compartmental resection (SRCR), local recurrences remain the most common cause of tumor-associated death. Finally, the results of the transatlantic RPS working group (TARPSWG) could show that treatment of RPS in specialized high-volume centers contributes to better long-term survival. Particularly in Germany there is an urgent demand for centralization of sarcoma patient treatment.

Impact of age on the efficacy of oxaliplatin in the preoperative chemoradiotherapy and adjuvant chemotherapy of rectal cancer: a post hoc analysis of the CAO/ARO/AIO-04 phase III trial.

Background: The German rectal cancer trial CAO/ARO/AIO-04 has shown a significant benefit in 3-year disease-free survival (DFS) of adding oxaliplatin to a standard preoperative 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) and adjuvant chemotherapy in patients with locally advanced rectal cancer. The use of oxaliplatin as adjuvant treatment in elderly patients with colon cancer is controversial. We therefore investigated the impact of age on clinical outcome in the CAO/ARO/AIO-04 phase III trial. Patients and methods: We carried out a post hoc analysis of the CAO/ARO/AIO-04 phase III trial evaluating primary and secondary end points according to age. Patient and tumor characteristics, NCI CTC adverse events grades 3-4 (version 3.0), dose intensities as well as survival and recurrence data were analyzed in three specified age groups (<60, 60-70, and ≥70 years). The influence of age as a continuous variable on DFS was modeled using a subpopulation treatment effect pattern plot (STEPP) analysis. Results: A total of 1232 patients were assessable. With the exception of Eastern Cooperative Oncology Group status (P < 0.001), no differences in patient and tumor characteristics were noticed between age groups. Likewise, toxicity pattern, dose intensities of CRT and surgical results were similar in all age groups. After a median follow-up of 50 months, in patients aged <60 years a significant benefit of adding oxaliplatin to 5-FU-based CRT and adjuvant chemotherapy was observed for local (P = 0.013) and systemic recurrences (P = 0.023), DFS (P = 0.011), and even overall survival (OS; P = 0.044). The STEPP analysis revealed improved hazard ratios for DFS in patients aged 40-70 years compared with elderly patients treated with oxaliplatin. Conclusion: The addition of oxaliplatin significantly improved DFS and OS in younger patients aged <60 years with advanced rectal cancer. Patients aged ≥70 years had no benefit. Clinical Trials Number: NCT00349076.

Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial.

Background: Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial. Patients and methods: Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS. Results: After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106-7.020; P < 0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P = 0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4. Conclusion: Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.

Long-term prognostic impact of surgical complications in the German Rectal Cancer Trial CAO/ARO/AIO-94.

BACKGROUND: The influence of postoperative complications on survival in patients with locally advanced rectal cancer undergoing combined modality treatment is debatable. This study evaluated the impact of surgical complications on oncological outcomes in patients with locally advanced rectal cancer treated within the randomized CAO/ARO/AIO-94 (Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society) trial. METHODS: Patients were assigned randomly to either preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) or postoperative CRT between 1995 and 2002. Anastomotic leakage and wound healing disorders were evaluated prospectively, and their associations with overall survival, and distant metastasis and local recurrence rates after a long-term follow-up of more than 10 years were determined. Medical complications (such as cardiopulmonary events) were not analysed in this study. RESULTS: A total of 799 patients were included in the analysis. Patients who had anterior or intersphincteric resection had better 10-year overall survival than those treated with abdominoperineal resection (63·1 versus 51·3 per cent; P < 0·001). Anastomotic leakage was associated with worse 10-year overall survival (51 versus 65·2 per cent; P = 0·020). Overall survival was reduced in patients with impaired wound healing (45·7 versus 62·2 per cent; P = 0·009). At 10 years after treatment, patients developing any surgical complication (anastomotic leakage and/or wound healing disorder) had impaired overall survival (46·6 versus 63·8 per cent; P < 0·001), a lower distant metastasis-free survival rate (63·2 versus 72·0 per cent; P = 0·030) and more local recurrences (15·5 versus 6·4 per cent; P < 0·001). In a multivariable Cox regression model, lymph node metastases (P < 0·001) and surgical complications (P = 0·008) were the only independent predictors of reduced overall survival. CONCLUSION: Surgical complications were associated with adverse oncological outcomes in this trial.

Tacrolimus interaction with oral oestrogen in kidney transplant recipients: A case-control study.

WHAT IS KNOWN AND OBJECTIVE: Oestrogens could inhibit the metabolism of drugs, such as calcineurin inhibitors, that are substrates for cytochrome P-450 microsomal enzymes. This study assessed the potential tacrolimus interaction with oral conjugated oestrogen in kidney transplant recipients who received conjugated oestrogen as prophylaxis against bleeding, before kidney biopsy. METHODS: In this case-control study, 13 kidney transplant recipients who received oral conjugated oestrogen as prophylaxis against uraemic bleeding before allograft biopsy were considered as cases. Thirteen matched kidney transplant recipients with similar immunosuppressive regimen served as controls. In this study, comparisons were made between the groups regarding daily dose, blood trough concentrations and calculated concentration corrected for dose of tacrolimus at three time points of the study. RESULTS AND DISCUSSION: All patients in the case group received conjugated oestrogen at a dose of 3.75 mg/day for 4.78 ± 0.83 days. Without any change in tacrolimus dose, the blood concentration of tacrolimus increased during concomitant administration of conjugated oestrogen (from 8.10 ± 2.85 to 12.35 ± 4.62 ng/mL; P = .11) and decreased after cessation of conjugated oestrogen (6.07 ± 2.18 ng/mL; P = .015). The calculated concentration corrected for dose of tacrolimus increased from 127.04 ± 79.23 to 211.40 ± 146.38 ngmLmgkg/d after conjugated oestrogen administration (P = .036). Thereafter, it decreased to 108.55 ± 78.61 ngmLmgkg/d after cessation of oestrogen (P = .003). Only one patient experienced nausea while taking oestrogen without any change in her liver enzymes. WHAT IS NEW AND CONCLUSION: Concomitant administration of oral oestrogen increased tacrolimus blood concentration. Hence, it is necessary to monitor tacrolimus blood levels during concomitant oestrogen therapy and for several days after oestrogen withdrawal.

[Recruiting and Personal Development in Surgical Departments of Large Referral Centers - Current Practice and Options for Improvement from Industry and Service Business]. / Personalgewinnung und -entwicklung in viszeralchirurgischen Kliniken von Großkrankenhäusern ­ derzeitiger Stand und Möglichkeiten der Optimierung aus Industrie und Dienstleistungsgewerbe.

Background Cut-throat competition, cost pressure, generation Y, shortage of qualified staff and feminisation influence human resources management in visceral surgery. The assessment of the current situation by chief surgeons (CS) as well as proof of transferability of strategies from industry and service business (ISB) have not yet been investigated. Material and Methods The CS of university hospitals and large referral centres (> 800 beds) were interviewed (n = 100) on the basis of a standardised questionnaire including 43 items. Closed questions were designed with a 5-point Likert scale and their analysis was presented as means (MW) and standard deviations (±). Ten human resources manager (HMR) of ISB were invited to participate in 45-minute telephone interviews. Results Thirty-seven CS participated in the survey, 15 of whom were full professors. Unsolicited applications (100%), job advertisements (78%) and direct approaches to final year students (78%) were the most common ways of recruitment. Only 17% of CS used a standardised form for preparation. Professional expertise (MW 2.2 ± 0.9), social skills (MW 1.9 ± 0.6) and excellent German language skills (MW 1.8 ± 0.8) were named as important qualifications for employment, while references and certificates were regarded as being less important (MW 3.2 ± 0.9). Personal development was regarded as important (MW 1.1 ± 0.2), but a defined period for residency was not guaranteed (MW 3.0 ± 1.5). Transparent selection criteria for career opportunities (MW 2.5 ± 1.1) and different career models (MW 2.7 ± 1.2) were only rarely available. Six HRM participated in the interviews. Active head-hunting (75%), Internet platforms (75%), presentations at conferences (75%), as well as hiring trainees (50%), job advertisements (50%) and social media (50%) were established options to find qualified employees. Professional and management careers were often separate career paths, while social expertise was regarded as being crucial for filling management positions. Conclusion In visceral surgery, unsolicited applications, job advertisements and direct approaches to final year students are the most common ways for recruitment. Diversified professional and management careers are not yet established. Recruiting strategies that are successful in ISB - such as active scouting and use of social media - should be evaluated for visceral surgery, as well as diversified career models.

[Management of acute appendicitis : Evidence for prompt surgical treatment?] / Management der akuten Appendizitis : Evidenz für eine zeitnahe chirurgische Therapie?

BACKGROUND: Acute appendicitis is a common disease which requires immediate surgical treatment of the focus of inflammation. So far there are no reliable data on how much time can pass between hospitalization, indications for surgery and initiating surgery without an increased risk of morbidity and mortality for the patient. OBJECTIVE: The aim of this study was to investigate how much time can lapse between admission and initiation of surgery for acute appendicitis while still providing patient safety and no increase in complication rates. MATERIAL AND METHODS: This retrospective analysis investigated the management of all patients who underwent appendectomy under the suspicion of acute appendicitis. Besides the time span between hospital admittance and beginning of the operation (admission to incision time, AIT), anamnestic, diagnostic, technical and perioperative data were assessed and statistically analyzed (mean ± SD). RESULTS: From January 2008 to April 2013 a total of 655 patients underwent appendectomy. The mean AIT was 7 h and the rate of negative appendectomy was 9.8 %. The mean hospitalization period was 5.9 ± 8.7 days with a postoperative stay of 5.2 ± 7.1 days. A comparison of the subgroups stratified by increasing AIT showed that there was no increased probability for perforation or postoperative complications with an AIT of up to 8 h. DISCUSSION: This retrospective cohort study showed that appendectomy should be performed within the first 8 h after hospitalization of the patient.

[Undergraduate Medical Students "On Call" to Assist in Theatre: Analysis of the Financial Aspects and a Mixed-Method Study Exploring Their Motives for Working]. / Studentische Hilfskräfte im "Operativen Rufdienst": Mixed-Method-Studie zur Analyse des finanziellen Aspekts und der Motive der Studierenden.

Background/Purpose: Surgical patient care has grown in complexity, as hospital workload has continuously increased. We therefore established a pool of "undergraduate medical students on call" to assist in the theatre outside working hours. We aimed to recruit talented students to reduce the burden on physicians and to motivate students into entering surgery. Methods: An exploratory mixed-method study was performed. In a qualitative study, guided interviews were conducted with five students about their reasons for working in the theatre and the results were used to construct an online questionnaire using EvaSys®. This was presented to 16 current and former students in a subsequent quantitative study. Furthermore, the cost of student employment was calculated and compared with physicians' salaries. Results: In 2013 and 2014, 8-9 students worked a total of 1063 and 1211 hours in the theatre, respectively. The difference in salaries between the students and surgical residents was € 28.37 per hour. We calculated that the annual savings were approximately € 60,000. When questioned on their motives during the interview, only a few students emphasised the financial aspects, whereas the majority emphasised the gain in experience. The analysis was based on comparison of the mean values (online survey) with a 4-point Likert scale (1 = high acceptance; 4 = no acceptance). We defined the motives with a mean ≤ 1.3 as primary. Based on this selection, gathering experience, fun/enjoyment, interest in surgery, and the change from studying were considered as distinct motives. In the interviews, students clearly pointed out that teaching and learning opportunities in the theatre were not commonly taken advantage of and that interaction with the surgeons should be improved. Conclusion: Students actively chose to work as assistants in the theatre, for a variety of motives. The financial aspects were subordinate. The concept of students assisting in the theatre is favourable for both employers and students. However, the results also reveal that there is room for improvement in the implementation of the concept.

[Implementation of Robot-Assisted Surgery]. / Aufbau eines Roboterprogramms.

The implementation of robot-assisted surgery requires a multi disciplinary approach with appropriate training and cooperation of surgical, anesthetic and technical staff. Besides acquiring the technical skills and getting used to complex technique, patient selection and an appropriate frequency of procedures are required to avoid complications.

[Lymph node metastases in ypT1/2 rectal cancer after neoadjuvant chemoradiotherapy : The Achilles heel of organ-preserving operative procedures?]. / Lymphknotenmetastasen beim ypT1/2-Rektumkarzinom nach neoadjuvanter Radiochemotherapie : Die Achillesferse organerhaltender Operationsverfahren?

BACKGROUND: For patients with rectal cancer and complete remission (ypT0) or with good response and residual tumor restricted only to the bowel wall (ypT1-2) after neoadjuvant chemoradiotherapy (CRT), local excision has been suggested as an alternative to avoid the significant morbidity and functional deficits associated with total mesorectal excision (TME). The aim of this investigation was to investigate the incidence, distribution and tumor-related localization of mesorectal lymph node (LN) metastases in TME specimens with complete remission (ypT0), intramural (ypT1-2) and extramural (ypT3-4) residual tumor tissue. PATIENTS AND METHODS: Specimens of TME from 81 patients with locally advanced rectal cancer (UICC II-III) undergoing neoadjuvant CRT within the phase III German rectal cancer trial CAO/ARO/AIO-04 were prospectively evaluated. The entire mesorectal compartment was microscopically screened after complete paraffin embedding. The number and localization of all detectable LN metastases were documented in relation to the primary tumor. RESULTS: Whereas 50 patients (62 %) had ypT3-4 rectal cancer after neoadjuvant CRT, 20 patients (25 %) presented with residual tumor within the bowel wall (ypT1-2), 11 patients (14 %) had pathological complete remission (ypT0), an average of 28 ± 13.7 LN were detected per specimen and 25 patients (31 %) had residual LN metastases after CRT. Although the incidence of LN metastases was higher in the ypT3-4 group (40 %), 25 % of patients in the ypT1-2 group with intramural residual tumor had a mean number of 2.2 residual LN metastases of which 55 % were located far from the primary lesion in the proximal mesorectum. None of the patients with ypT0 status (complete response) had residual LN metastases. CONCLUSION: Even in patients with good response and post-CRT tumor tissue restricted only to the bowel wall (ypT1-2), there is still a considerable risk for residual LN metastases. Local excision of residual rectal cancer was accompanied by a higher rate of local failure and radical surgery with TME should remain the standard treatment in these patients. To date, valid selection criteria for patients eligible for organ-sparing surgery are still lacking.

[General principles of tumour biology in visceral surgery]. / Allgemeine Grundlagen der Tumorbiologie in der Viszeralchirurgie.

Within the last decade, there has been a tremendous progress in understanding the molecular basis of cancer. In particular, the development and the characteristic features of cancer cells are being increasingly understood. The understanding of these molecular characteristics is mandatory for the development of novel, targeted therapeutic strategies and their integration into clinical practice. In addition, tumour genetics play a critically important role for hereditary cancer syndromes, with respect to both diagnostics and clinical decision-making. The aim of this review is to highlight general principles of tumour genetics from a visceral surgeon's point of view, although a comprehensive summary of all aspects would be beyond the scope of this article due to the complexity of the topic.

[Advance Directives - Not a Lot of Margin for Error - The Surgeon's View of a Complex Medical-Legal Topic]. / Patientenverfügungen - welchen Spielraum erlauben sie? - Chirurgische Sicht auf ein komplexes medizinjuristisches Thema.

Since September 1st, 2009, the most recent version of the German "Betreuungsrechtsänderungsgesetz" has been validated by the legislators. It precisely sets out how physicians and nursing staff have to deal with a written declaration of a patient's will. This new law focuses in a special way on advance directives, describes the precise rules for the authors of an advance directive and shows both its sphere of action and its limitations. This article aims to give an overview on the legal scope of advance directives, and to illustrate potential limitations and conflicts. Furthermore, it shows the commitments and rights of the medical team against the background of an existing advance directive.

UDP glucuronosyltransferase 1A expression levels determine the response of colorectal cancer cells to the heat shock protein 90 inhibitor ganetespib.

HSP90 inhibition represents a promising route to cancer therapy, taking advantage of cancer cell-inherent proteotoxic stress. The HSP90-inhibitor ganetespib showed benefit in advanced clinical trials. This raises the need to identify the molecular determinants of treatment response. We tested the efficacy of ganetespib on a series of colorectal cancer (CRC)-derived cell lines and correlated their sensitivities with comprehensive gene expression analysis. Notably, the drug concentration required for 50% growth inhibition (IC50) varied up to 70-fold (from 36 to 2500 nM) between different cell lines. Correlating cell line-specific IC50s with the corresponding gene expression patterns revealed a strong association between ganetespib resistance (IC50>500 nM) and high expression of the UDP glucuronosyltransferase 1A (UGT1A) gene cluster. Moreover, CRC tumor samples showed a comparable distribution of UGT1A expression levels. The members of the UGT1A gene family are known as drug-conjugating liver enzymes involved in drug excretion, but their function in tumor cells is hardly understood. Chemically unrelated HSP90 inhibitors, for example, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), did not show correlation of drug sensitivities with UGT1A levels, whereas the ganetespib-related compound NVP-AUY922 did. When the most ganetespib-resistant cell line, HT29, was treated with ganetespib, the levels of HSP90 clients were unaffected. However, HT29 cells became sensitized to the drug, and HSP90 client proteins were destabilized by ganetespib upon siRNA-mediated UGT1A knockdown. Conversely, the most ganetespib-sensitive cell lines HCT116 and SW480 became more tolerant toward ganetespib upon UGT1A overexpression. Mechanistically, ganetespib was rapidly glucuronidated and excreted in resistant but not in sensitive CRC lines. We conclude that CRC cell-expressed UGT1A inactivates ganetespib and other resorcinolic Hsp90 inhibitors by glucuronidation, which renders the drugs unable to inhibit Hsp90 and thereby abrogates their biological activity. UGT1A levels in tumor tissues may be a suitable predictive biomarker to stratify CRC patients for ganetespib treatment.