Klinikum Magdeburg

BACKGROUND: Guidelines on the management of Helicobacter pylori, which cover indications for management and treatment strategies, were produced in 2000. AIMS: To update the guidelines at the European Helicobacter Study Group (EHSG) Third Maastricht Consensus Conference, with emphasis on the potential of H pylori eradication for the prevention of gastric cancer. RESULTS: Eradication of H pylori infection is recommended in (a) patients with gastroduodenal diseases such as peptic ulcer disease and low grade gastric, mucosa associated lymphoid tissue (MALT) lymphoma; (b) patients with atrophic gastritis; (c) first degree relatives of patients with gastric cancer; (d) patients with unexplained iron deficiency anaemia; and (e) patients with chronic idiopathic thrombocytopenic purpura. Recurrent abdominal pain in children is not an indication for a "test and treat" strategy if other causes are excluded. Eradication of H pylori infection (a) does not cause gastro-oesophageal reflux disease (GORD) or exacerbate GORD, and (b) may prevent peptic ulcer in patients who are naïve users of non-steroidal anti-inflammatory drugs (NSAIDs). H pylori eradication is less effective than proton pump inhibitor (PPI) treatment in preventing ulcer recurrence in long term NSAID users. In primary care a test and treat strategy using a non-invasive test is recommended in adult patients with persistent dyspepsia under the age of 45. The urea breath test, stool antigen tests, and serological kits with a high accuracy are non-invasive tests which should be used for the diagnosis of H pylori infection. Triple therapy using a PPI with clarithromycin and amoxicillin or metronidazole given twice daily remains the recommended first choice treatment. Bismuth-containing quadruple therapy, if available, is also a first choice treatment option. Rescue treatment should be based on antimicrobial susceptibility. CONCLUSION: The global burden of gastric cancer is considerable but varies geographically. Eradication of H pylori infection has the potential to reduce the risk of gastric cancer development.

IMPORTANCE: The prognosis for patients with pancreatic cancer is poor, even after resection with curative intent. Gemcitabine-based chemotherapy is standard treatment for advanced pancreatic cancer, but its effect on survival in the adjuvant setting has not been demonstrated. OBJECTIVE: To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival. DESIGN, SETTING, AND PATIENTS: CONKO-001 (Charité Onkologie 001), a multicenter, open-label, phase 3 randomized trial to evaluate the efficacy and toxicity of gemcitabine in patients with pancreatic cancer after complete tumor resection. Patients with macroscopically completely removed pancreatic cancer entered the study between July 1998 and December 2004 in 88 hospitals in Germany and Austria. Follow-up ended in September 2012. INTERVENTIONS: After stratification for tumor stage, nodal status, and resection status, patients were randomly assigned to either adjuvant gemcitabine treatment (1g/m2 d 1, 8, 15, q 4 weeks) for 6 months or to observation alone. MAIN OUTCOMES AND MEASURES: The primary end point was disease-free survival. Secondary end points included treatment safety and overall survival, with overall survival defined as the time from date of randomization to death. Patients lost to follow-up were censored on the date of their last follow-up. RESULTS: A total of 368 patients were randomized, and 354 were eligible for intention-to-treat-analysis. By September 2012, 308 patients (87.0% [95% CI, 83.1%-90.1%]) had relapsed and 316 patients (89.3% [95% CI, 85.6%-92.1%]) had died. The median follow-up time was 136 months. The median disease-free survival was 13.4 (95% CI, 11.6-15.3) months in the treatment group compared with 6.7 (95% CI, 6.0-7.5) months in the observation group (hazard ratio, 0.55 [95% CI, 0.44-0.69]; P < .001). Patients randomized to adjuvant gemcitabine treatment had prolonged overall survival compared with those randomized to observation alone (hazard ratio, 0.76 [95% CI, 0.61-0.95]; P = .01), with 5-year overall survival of 20.7% (95% CI, 14.7%-26.6%) vs 10.4% (95% CI, 5.9%-15.0%), respectively, and 10-year overall survival of 12.2% (95% CI, 7.3%-17.2%) vs 7.7% (95% CI, 3.6%-11.8%). CONCLUSIONS AND RELEVANCE: Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN34802808.

BACKGROUND: Intravenous bolus fluorouracil plus leucovorin is the standard adjuvant treatment for colon cancer. The oral fluoropyrimidine capecitabine is an established alternative to bolus fluorouracil plus leucovorin as first-line treatment for metastatic colorectal cancer. We evaluated capecitabine in the adjuvant setting. METHODS: We randomly assigned a total of 1987 patients with resected stage III colon cancer to receive either oral capecitabine (1004 patients) or bolus fluorouracil plus leucovorin (Mayo Clinic regimen; 983 patients) over a period of 24 weeks. The primary efficacy end point was at least equivalence in disease-free survival; the primary safety end point was the incidence of grade 3 or 4 toxic effects due to fluoropyrimidines. RESULTS: Disease-free survival in the capecitabine group was at least equivalent to that in the fluorouracil-plus-leucovorin group (in the intention-to-treat analysis, P<0.001 for the comparison of the upper limit of the hazard ratio with the noninferiority margin of 1.20). Capecitabine improved relapse-free survival (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99; P=0.04) and was associated with significantly fewer adverse events than fluorouracil plus leucovorin (P<0.001). CONCLUSIONS: Oral capecitabine is an effective alternative to intravenous fluorouracil plus leucovorin in the adjuvant treatment of colon cancer.

IMPORTANCE: The GeparSixto trial provided evidence that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline, taxane, and bevacizumab increases pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Whether BRCA1 and BRCA2 germline mutation status affects treatment outcome remains elusive. OBJECTIVE: To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a randomized clinical trial used archived DNA samples and cancer family history of 315 patients with TNBC enrolled between August 1, 2011, and December 31, 2012, in the GeparSixto trial. In all, 291 participants (92.4%) were included in this multicenter prospective investigation. DNA samples were analyzed for germline mutations in BRCA1, BRCA2, and 16 other cancer predisposition genes. The pCR rates between the carboplatin and noncarboplatin arms were compared. Genetic analyses were performed at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany; data analysis, November 1 through December 31, 2015. MAIN OUTCOMES AND MEASURES: Proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status. For pCR rates, the ypT0/is ypN0 definition was used as a primary end point. RESULTS: Of the 291 patients with TNBC, all were women; the mean (SD) age was 48 (11) years. The pCR rate in the carboplatin group was 56.8% (83 of 146) and 41.4% (60 of 145) in the noncarboplatin group (odds ratio [OR], 1.87; 95% CI, 1.17-2.97; P = .009). Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients (17.2%). In the noncarboplatin arm, the pCR rate was 66.7% (16 of 24) for patients with BRCA1 and BRCA2 mutations and 36.4% (44 of 121) for patients without (OR, 3.50; 95% CI, 1.39-8.84; P = .008). The high pCR rate observed in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) was not increased further by adding carboplatin (17 of 26 [65.4%]). In contrast, carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations: 66 of the 120 patients (55%) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients (36.4%) in the noncarboplatin arm (OR, 2.14; 95% CI, 1.28-3.58; P = .004). Patients without pathogenic BRCA1 and BRCA2 alterations showed elevated disease-free survival rates when carboplatin was added (without carboplatin, 73.5%; 95% CI, 64.1%-80.8% vs with carboplatin, 85.3%; 95% CI, 77.0%-90.8%; hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04). CONCLUSIONS AND RELEVANCE: Under the nonstandard GeparSixto polychemotherapy regimen, patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01426880.

PURPOSE Anaplastic thyroid carcinoma is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options for patients with BRAF-wild type disease. As part of a phase I/II study in patients with advanced/metastatic solid tumors, patients with anaplastic thyroid carcinoma were treated with spartalizumab, a humanized monoclonal antibody against the programmed death-1 (PD-1) receptor. METHODS We enrolled patients with locally advanced and/or metastatic anaplastic thyroid carcinoma in a phase II cohort of the study. Patients received 400 mg spartalizumab intravenously, once every 4 weeks. The overall response rate was determined according to RECIST v1.1. RESULTS Forty-two patients were enrolled. Adverse events were consistent with those previously observed with PD-1 blockade. Most common treatment-related adverse events were diarrhea (12%), pruritus (12%), fatigue (7%), and pyrexia (7%). The overall response rate was 19%, including three patients with a complete response and five with a partial response. Most patients had baseline tumor biopsies positive for PD-L1 expression (n = 28/40 evaluable), and response rates were higher in PD-L1–positive (8/28; 29%) versus PD-L1–negative (0/12; 0%) patients. The highest rate of response was observed in the subset of patients with PD-L1 ≥ 50% (6/17; 35%). Responses were seen in both BRAF-nonmutant and BRAF-mutant patients and were durable, with a 1-year survival of 52.1% in the PD-L1–positive population. CONCLUSION To our knowledge, this is the first clinical trial to show responsiveness of anaplastic thyroid carcinoma to PD-1 blockade.

The controversy as to whether Doppler ultrasonic methods should play a role in clinical decision-making in the prevention of stroke is attributable to reported disagreement between angiographic and ultrasonic results and the lack of internationally accepted ultrasound criteria for describing the degree of stenosis. Foremost among the explanations for both is the broad scatter of peak systolic velocities in the stenosis, the criterion that has so far received most attention. Grading based on a set of main and additional criteria can overcome diagnostic errors. Morphological measurements (B-mode images and color flow imaging) are the main criteria for low and moderate degrees of stenosis. Increased velocities in the stenosis indicate narrowing, but the appearance of collateral flow and decreased poststenotic flow velocity prove a high degree stenosis (≥70%), additionally allowing the estimation of the hemodynamic effect in the category of high-degree stenosis. Additional criteria refer to the effect of a stenosis on prestenotic flow (common carotid artery), the extent of poststenotic flow disturbances, and derived velocity criteria (diastolic peak velocity and the carotid ratio). This multiparametric approach is intended to increase the reliability and the standard of reporting of ultrasonic results for arteriosclerotic disease of the carotid artery.

BACKGROUND: Low-grade B-cell lymphomas arising in mucosa-associated lymphoid tissue (MALT) are most frequently localized in the gastrointestinal tract. More than 90% of gastric MALT lymphomas are diagnosed in patients with chronic, Helicobacter pylori-associated gastritis. High remission rates for these lymphomas have been observed after the cure of H. pylori infection. Data are lacking, however, with regard to the duration of the remissions. To address this question of remission duration, we have followed 50 patients in whom H. pylori infections were eradicated, and we determined whether the patients in complete remission displayed evidence of residual monoclonal B cells during follow-up. METHODS: Patients were treated with amoxycillin and omeprazole for 2 weeks in an attempt to cure H. pylori infections. Follow-up included endoscopic investigations with biopsy sampling. Monoclonal B cells in biopsy specimens were detected by means of a polymerase chain reaction (PCR)-based assay. RESULTS: H. pylori infections were cured in all 50 patients. The median follow-up for the 50 patients is currently 24 months (729 days; range, 135-1411 days). Forty patients achieved complete remission of their lymphomas, but five have subsequently relapsed. The median time of continuous complete remission for the 40 patients was 15.4 months (468 days; range, 0-1198 days). Among six patients whose Iymphomas did not respond to H. pylori eradication, four revealed high-grade lymphomas upon surgery. PCR indicated the presence of monoclonal B cells during follow-up in 22 of 31 assessable patients in complete remission. CONCLUSIONS: Complete remissions of low-grade gastric MALT Iymphomas after the cure of H. pylori infection appear to be stable, although most patients display evidence of monoclonal B cells during follow-up. Whether these patients are truly cured of their Iymphomas remains to be determined.

A lipoxygenase has been purified from rabbit reticulocyte-rich anaemic blood cells. It possesses a molecular weight of 78 000 and an isoelectric point of 5.5 and contains 5% neutral sugars and two iron atoms per enzyme molecule. The lipoxygenase has proved to be identical with the inhibitors of respiratory proteins described formerly. The actions of the lipoxygenase on linoleic acid, phospholipids, mitochondrial and erythrocyte membranes and electron transfer particles were studied. A special feature of the reticulocyte lipoxygenase is the suicidal character of its action on lipids. With electron transfer particles the reticulocyte lipoxygenase causes a loss of acid-labile sulfur which accompanies respiratory inhibition; the strong respiratory inhibition is not exerted by soybean lipoxygenase. The reticulocyte lipoxygenase acts preferably on mitochondrial membranes as compared with cell membranes of the erythrocyte; erythrocyte cytosol moderates the action on mitochondrial membranes. Furthermore, the lipoxygenase reaction can concomitantly and irreversibly inactivate sulfhydryl enzymes as demonstrated with muscle glyceraldehyde-3-phosphate dehydrogenase. The occurrence of the lipoxygenase here described is restricted to reticulocytes; very low amounts were observed in bone marrow and no lipoxygenase was detectable in normal blood. During the course of an experimental anaemia the lipoxygenase is produced owing to superinduction in large amounts, which may persist for a long time since they escape inactivation. Preliminary evidence was obtained for the occurrence of other lipoxygenases in tissues of lung, spleen, kidney and also epithelial tumours.

To explore mechanisms contributing to the clinical heterogeneity of systemic mastocytosis (SM) and to suboptimal responses to diverse therapies, we analyzed 39 KIT D816V mutated patients with indolent SM (n = 10), smoldering SM (n = 2), SM with associated clonal hematologic nonmast cell lineage disorder (SM-AHNMD, n = 5), and aggressive SM (n = 15) or mast cell leukemia (n = 7) with (n = 18) or without (n = 4) AHNMD for additional molecular aberrations. We applied next-generation sequencing to investigate ASXL1, CBL, IDH1/2, JAK2, KRAS, MLL-PTD, NPM1, NRAS, TP53, SRSF2, SF3B1, SETBP1, U2AF1 at mutational hotspot regions, and analyzed complete coding regions of EZH2, ETV6, RUNX1, and TET2. We identified additional molecular aberrations in 24/27 (89%) patients with advanced SM (SM-AHNMD, 5/5; aggressive SM/mast cell leukemia, 19/22) whereas only 3/12 (25%) indolent SM/smoldering SM patients carried one additional mutation each (U2AF1, SETBP1, CBL) (P < .001). Most frequently affected genes were TET2, SRSF2, ASXL1, CBL, and RUNX1. In advanced SM, 21/27 patients (78%) carried ≥3 mutations, and 11/27 patients (41%) exhibited ≥5 mutations. Overall survival was significantly shorter in patients with additional aberrations as compared to those with KIT D816V only (P = .019). We conclude that biology and prognosis in SM are related to the pattern of mutated genes that are acquired during disease evolution.

We evaluated 29 knees with a minimum follow-up of 2 years after anterior cruciate ligament (ACL) reconstruction using doubled autogenous semitendinosus tendons. On the femoral side, a 5-mm Mersilene tape (Ethicon, Norderstedt, Germany) with an Endobutton (Acufex Microsurgical, Mansfield, MA) was used. The tendon was fixed on the tibial side with two staples. Regarding the IKDC score, 66% of the patients were graded as normal or nearly normal. The anterior laxity side-to-side difference (KT 1000, man-max-drawer) was under 3 mm in 55% and under 5 mm in 90%. Radiographs taken in the lateral and anteroposterior projections of the knee showed sclerotic bone tunnel margins. The diameter of the bone tunnels were measured, corrected for magnification, then compared with the original reamed diameter to determine any change in size. Enlargement of at least 2 mm was identified in 72% of the femoral tunnels and 38% of the tibial tunnels. No correlation was found concerning the enlargement of the tunnel and the IKDC score or the residual joint laxity. We conclude that using an Endobutton-Mersilene construct in ACL reconstruction leads to femoral and tibial bone tunnel enlargement at follow-up of 2 years.

Bei diesem Dokument handelt es sich um die aktualisierte Fassung der 2006 erstmals erstellten S3-Leitlinie zum exokrinen Pankreaskarzinom.

The control theory of Kacser and Burns [in: Rate Control of Biological Processes (Davies, D.D. ed) pp. 65-104, Cambridge University Press, London, 1973] and Heinrich and Rapoport [Eur. J. Biochem. (1974) 42, 97-105] has been used to quantify the amount of control exerted by different steps on mitochondrial oxidative phosphorylation in rat-liver mitochondria. Inhibitors were used to manipulate the amount of active enzyme. The control strength of the adenine nucleotide translocator was measured by carrying out titrations with carboxyatractyloside. In state 4, the control strength of the translocator was found to be zero. As the rate of respiration was increased by adding hexokinase, the control strength of the translocator increased to a maximum value of approximately 30% at approximately 80% of state 3 respiration. In state 3, control of respiration is distributed between a number of steps, including the adenine nucleotide translocator, the dicarboxylate carrier and cytochrome c oxidase. The measured values for the distribution of control agree very well with those calculated with the aid of a model for mitochondrial oxidative phosphorylation developed by Bohnensack et al. [Biochim. Biophys. Acta (1982) 680, 271-280].

BACKGROUND: FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined. PATIENTS AND METHODS: In this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan-Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method. RESULTS: CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n = 592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P = 0.051), PFS (P < 0.001), and OS (P < 0.001). Within the RAS wild-type population, OS observed in CMS4 significantly favored FOLFIRI cetuximab over FOLFIRI bevacizumab. In CMS3, OS showed a trend in favor of the cetuximab arm, while OS was comparable in CMS1 and CMS2, independent of targeted therapy. CONCLUSIONS: CMS classification is prognostic for mCRC. Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS3 and CMS4. CMS classification provides deeper insights into the biology to CRC, but at present time has no direct impact on clinical decision-making.The FIRE-3 (AIO KRK-0306) study had been registered at ClinicalTrials.gov: NCT00433927.

The kinetics of in vivo regulation of mitochondrial respiration by ADP was studied in rat heart, slow-twitch skeletal muscle (soleus) and fast-twitch skeletal muscle (gastrocnemius, plantaris, quadriceps and tibialis anterior) by means of saponin-skinned fibres. Mitochondrial respiratory parameters were determined in the absence and presence of creatine (20 mM), and the effect of proteolytic enzymes (trypsin, chymotrypsin or elastase) on these parameters was investigated in detail. The results of these experiments confirm the observation of Veksler et al. [Veksler, V.I., Kuznetsov, A. V., Anflous, K., Mateo, P., van Deursen, J., Wieringa, B. & Ventura-Clapier, R. (1995) J. Biol. Chem. 270, 19921-19929], who studied muscle fibres from normal and transgenic mice, that the kinetics of respiration regulation in muscle cells is tissue specific. We found that in rat cardiac and soleus muscle fibres the apparent K(m) for respiration regulation was 300-400 microM and decreased to 50-80 microM in the presence of creatine. In contrast, in skinned fibres from gastrocnemius, plantaris, tibialis anterior and quadriceps muscles, this value was initially very low, 10-20 microM, i.e. the same as that is in isolated muscle mitochondria, and the effect of creatine was not observable under these experimental conditions. Treatment of the fibres with trypsin, chymotrypsin or elastase (0.125 micrograms/ml) for 15 min decreased the apparent K(m) for ADP in cardiac and soleus muscle fibres to 40-98 microM without significant alteration of Vmax or the intactness of outer mitochondrial membrane, as assessed by the cytochrome c test. In fibres from gastrocnemius, trypsin increased the apparent K(m) for ADP transiently. The effects of trypsin and chymotrypsin were studied in detail and found to be concentration dependent and time dependent. The effects were characterised by saturation phenomenon with respect to the proteolytic enzyme concentration, saturation being observed above 1 microM enzyme. These results are taken to show that in cardiac and slow-twitch skeletal muscle, the permeability of the outer mitochondrial membrane to adenine nucleotides is low and controlled by a cytoplasmic protein that is sensitive to trypsin and chymotrypsin. This protein may participate in feedback signal transduction by a mechanism of vectorial-ligand conduction. This protein factor is not expressed in fast-twitch skeletal muscle, in which cellular mechanism of regulation of respiration is probably very different from that of slow-twitch muscles.

We conducted a prospectively randomised clinical trial to investigate the role of adjuvant outpatient immunochemotherapy administered postoperatively in high-risk patients with renal cell carcinoma. In total, 203 renal carcinoma patients' status post radical tumour nephrectomy were stratified into three risk groups: patients with tumour extending into renal vein/vena cava or invading beyond Gerota's fascia (pT3b/c pN0 or pT4pN0), patients with locoregional lymph node infiltration (pN+), and patients after complete resection of tumour relapse or solitary metastasis (R0). Patients were randomised to undergo either (A) 8 weeks of outpatient subcutaneous interleukin-2 (sc-rIL-2), subcutaneous interferon-alpha2a (sc-rIFN-alpha2a), and intravenous 5-fluorouracil (iv-5-FU) according to the standard Atzpodien regimen (Atzpodien et al, 2004) or (B) observation. Two-, 5-, and 8-year survival rates were 81, 58, and 58% in the treatment arm, and 91, 76, and 66% in the observation arm (log rank P=0.0278), with a median follow-up of 4.3 years. Two, 5-, and 8-year relapse-free survival rates were calculated at 54, 42, and 39% in the treatment arm, and at 62, 49, and 49% in the observation arm (log rank P=0.2398). Stage-adapted subanalyses revealed no survival advantages of treatment over observation, as well. Our results established that there was no relapse-free survival benefit and the overall survival was inferior with an adjuvant 8-week-outpatient sc-rIL-2/sc-rIFN-alpha2a/iv-5-FU-based immunochemotherapy compared to observation in high-risk renal cell carcinoma patients following radical tumour nephrectomy.

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, and Switzerland).

BACKGROUND: Cetuximab plus FOLFIRI improved overall survival compared with bevacizumab plus FOLFIRI in KRAS wild-type metastatic colorectal cancer (mCRC) in FIRE-3, but no corresponding benefit was found for progression-free survival. This analysis aimed to determine whether cetuximab improves response and survival versus bevacizumab among response-evaluable patients receiving first-line FOLFIRI for RAS wild-type mCRC and the effect of primary tumour side on outcomes. METHODS: The intent-to-treat population included 593 patients with KRAS exon 2 wild-type mCRC. Further testing identified 400 patients with extended RAS wild-type disease; of these, 352 (88%) who received ≥3 cycles of therapy and had ≥1 post-baseline scan were evaluable for response and constituted the per-protocol population (169 cetuximab and 183 bevacizumab). Patients received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) with either weekly cetuximab or biweekly bevacizumab given on day 1 of each 14-day cycle until response, progression or toxicity occurred. The primary endpoint was the objective response rate (ORR) in the per-protocol population. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). The effect of primary tumour location was evaluated. RESULTS: Median OS in the RAS wild-type population was 31 vs 26 months in the cetuximab and bevacizumab groups, respectively (HR 0.76, P = 0.012). In the per-protocol population, outcomes favoured cetuximab for ORR (77% vs 65%, P = 0.014) and median OS (33 vs 26 months, HR 0.75, P = 0.011), while PFS was comparable between groups. The advantage of cetuximab over bevacizumab occurred only in patients with left-sided primary tumours. CONCLUSIONS: FOLFIRI plus cetuximab resulted in a significantly higher ORR and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumours. The superior response associated with cetuximab may particularly benefit patients with symptomatic tumours or borderline-resectable metastases. CLINICALTRIALS. GOV IDENTIFIER: NCT00433927.

A chip-based system mimicking the transport function of the human cardiovascular system has been established at minute but standardized microsystem scale. A peristaltic on-chip micropump generates pulsatile shear stress in a widely adjustable physiological range within a microchannel circuit entirely covered on all fluid contact surfaces with human dermal microvascular endothelial cells. This microvascular transport system can be reproducibly established within four days, independently of the individual endothelial cell donor background. It interconnects two standard tissue culture compartments, each of 5 mm diameter, through microfluidic channels of 500 μm width. Further vessel branching and vessel diameter reduction down to a microvessel scale of approximately 40 μm width was realised by a two-photon laser ablation technique applied to inserts, designed for the convenient establishment of individual organ equivalents in the tissue culture compartments at a later time. The chip layout ensures physiological fluid-to-tissue ratios. Moreover, an in-depth microscopic analysis revealed the fine-tuned adjustment of endothelial cell behaviour to local shear stresses along the microvasculature of the system. Time-lapse and 3D imaging two-photon microscopy were used to visualise details of spatiotemporal adherence of the endothelial cells to the channel system and to each other. The first indicative long-term experiments revealed stable performance over two and four weeks. The potential application of this system for the future establishment of human-on-a-chip systems and basic human endothelial cell research is discussed.

AIM: The objective of this study was to find out the effects of anastomotic leakage (AL) following resection of colon cancer upon perioperative outcome and long-term oncological result. PATIENTS AND METHODS: Using the database of a country-wide quality assurance study "Quality Assurance in Primary Colorectal Carcinoma" we analysed the data from the complete sub-population of 844 patients who had AL after resection of colon cancer. These were compared with corresponding data from 27 427 similar patients without AL. Hospital mortality, AL-associated post-operative morbidity and long-term outcome were investigated. RESULTS: Hospital mortality after AL was 18.6%, compared with 2.6% for patients without AI. AL-related secondary complications occurred in 62.7% cases, while patients without AL had a corresponding rate of 19.9%. Those with AL had a poorer long-term oncological result, with a five-year survival rate of 51.0% (p<0.001) and a five-year tumour-free survival rate of 63.0% (compare 74.6% without AL; p<0.001). CONCLUSIONS: Post-operative AL after resection of colon cancer is associated with significant morbidity and hospital mortality rates and with a greater risk of a poor oncological outcome.

The use of anti-thymocyte globulin (ATG) has represented the standard of care in graft-versus-host disease (GVHD) prophylaxis in patients undergoing a mismatched unrelated donor (MMUD) transplant. The safety and feasibility of posttransplant cyclophosphamide (PTCY) in this setting have been reported recently, but no study has compared the outcomes of PTCY vs ATG in 9/10 MMUD transplants. Using the registry data of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we performed a matched-pair analysis comparing those 2 strategies in a 9/10 MMUD setting. Ninety-three patients receiving PTCY were matched with 179 patients receiving ATG. A significantly lower incidence of severe acute GVHD was observed with PTCY compared with ATG. Recipients of the former also showed higher leukemia-free survival and GVHD/relapse-free survival (GRFS). When performing a subgroup analysis including patients receiving peripheral blood stem cells, being in complete remission, or receiving the same associated immunosuppressive agents, superiority of PTCY over ATG was confirmed. Similar to the haploidentical setting, use of PTCY is an effective anti-GVHD prophylaxis in the 9/10 MMUD transplant. Use of PTCY may also provide better outcomes in long-term disease control. These results need confirmation in large prospective randomized trials.