Die EU-Verordnung für In-vitro-Diagnostika (IVDR) in der Praxis: Umsetzung und Anwendung - Ergebnisse einer öffentlichen Veranstaltung der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) im März 2023.

In order to discuss first experiences with the implementation of the EU Regulation on In Vitro Diagnostic Medical Devices (IVDR) about one year after its entry into force, the German Association of the Scientific Medical Societies (AWMF e.V.) organized a full-day public webinar. Overall, it became clear that the implementation of the IVDR still poses significant challenges for laboratory medicine and pathology. Corrections at the political level and implementation with a sense of proportion are required. Before the long-term goal of the IVDR, i.e. the increase in patient safety, can be realized, the prevention of disadvantages for patients due to gaps in care must be strived for in the medium term by all parties involved.

Hydatid Disease of the Liver.

Background: Echinococcosis also known as hydatid disease is a zoonotic parasitic disease caused by a tapeworm. It has a worldwide distribution. For long, it was thought to be a problem of the poorly sanitized "third world" and not given the importance it deserved. However, its occurrence in countries like Australia and New Zealand and recently in countries in Central Europe has meant that it is included in a WHO list of neglected diseases, has recently been the subject of extensive epidemiological studies, and has been the recipient of increased research funding. Summary: The diagnosis is still based on clinical presentation in an endemic area corroborated with typical findings on imaging which routinely include ultrasound and CT scan. Serological tests have been used in some centers to support the diagnosis. Treatment depends on the site of involvement and can vary from wait and watch to extensive radical surgical procedures. The common element of all treatments is the addition of albendazole which forms an essential cornerstone of all treatment protocols. Inspite having been used for a fairly long time, there is still no consensus on the dose, duration, and timing of therapy with albendazole. Key Message: Hydatid disease continues to be a significant global health problem inspite of a good understanding of its life cycle and rising standards of public sanitation. Though diagnosis is straightforward and not expensive, treatment can sometimes be complicated. The addition of albendazole to all treatment protocols is an important advance, but firm guidelines on duration of its use are still awaited.

Conservative therapy of severe acute pancreatitis is a safe option - results of a 15-year long-term follow-up cohort study.

Treatment of severe acute pancreatitis can be challenging with high mortality. In 2012 we reported a significantly reduced in-hospital mortality if these patients are treated conservatively for at least the first 3 weeks in the course of the disease as compared to early necrosectomy. We performed a long-term follow-up and compared the outcome of these two study groups (group 1 - early necrosectomy, n=20 versus group 2 - primary conservative treatment, n=24). Materials and methods: Follow-up of the study patients by personal contact, phone survey, or data from primary care physician. Median follow-up was 15 years (range 10-22 years). This trial is registered at: Research Registry UIN researchregistry8697. Results: Eleven survivors of group 1 and 22 survivors of group 2 were discharged after initial treatment. Ten of 11 surviving patients of group 1 (90.9%) and 20 of 22 surviving patients of group 2 (90.9%) were included in this study. Between groups, there were no statistical differences in the rate of resubmission (P=0.23), development of diabetes (P=0.78), or development of exocrine insufficiency (P=1.0). However, long-term survival in group 2 was significantly better than that of group 1 (P=0.049). Conclusion: Primary conservative treatment of severe acute pancreatitis without early necrosectomy does not lead to early complications and even shows an advantage in long-term survival. Therefore conservative treatment of severe acute pancreatitis is safe and there is no absolute need for necrosectomy in severe acute pancreatitis.

Acute Mesenteric Ischemia: Preexisting Comorbidity Determines Short-Term Outcome and Quality of Life in Long-Term Survivors.

Introduction: Acute mesenteric ischemia (AMI), either arterial or venous, is still a devastating disease with poor prognosis. It is unknown, whether AMI is associated with impaired quality of life (QoL) in long-term survivors. Material and Methods: This retrospective analysis includes 64 patients with occlusive arterial or venous mesenteric ischemia treated operatively between 2008 and 2016 at the University Medical Center Rostock. Short-term outcome with focus on comorbidities was measured by the Charlson comorbidity index (CCI) an instrument that operationally measures comorbidity based on 17 clinical parameters including age. Operative outcome in view of enterostomy placement and long-term outcome measured as QoL by the EQ-5D in the long-term survivors were evaluated. The EQ-5D is a standardized, self-reported five-dimension QoL questionnaire built to provide a simple and generic measure of health. Results: Thirty-day mortality was 60.9%, and in-hospital mortality was 70.3% (n = 45). No patient was discharged with a stoma. Patients with a primary anastomosis after the initial operation for AMI had a high leak rate of 27% (4/15 patients) compared to no dehiscence in the group of patients who had secondary anastomosis during second or third laparotomy. The long-term survivors had significantly lower CCI compared to the 45 nonsurvivors (median 4 [3, 4, 5, 6] vs. 6 [4, 5, 6, 7]). All long-term survivors had QoL assessment. QoL score was significantly impaired compared to an age- and sex-matched reference population. This impairment was not due to disease-specific sequelae such as presence of stool deviation or intestinal failure but due to preexisting risk factors as shown by an inverse relation between the CCI and QoL score. Conclusion: Herein, we show for the first time that long-term QoL in patients with AMI is impaired but this impairment is not due to disease-specific aspects but rather general risk factors underlying the presence of a higher level of comorbidities at the time of AMI.

Acute Mesenteric Ischemia.

BACKGROUND: Despite constant improvements in diagnostic as well as interventional and surgical techniques, acute mesenteric ischemia (AMI) remains a life-threatening emergency with high mortality rates. The time to diagnosis of AMI is the most important predictor of patients' outcome; therefore, prompt diagnosis and intervention are essential to reduce mortality in patients with AMI. The present review was performed to analyze potential risk factors and to help find ways to improve the outcome of patients with AMI. SUMMARY: Whereas AMI only applies to approximately 1% of all patients with an "acute abdomen," its incidence is rising up to 10% in patients >70 years of age. The initial clinical stage of AMI is characterized by a sudden onset of strong abdominal pain followed by a painless interval. Depending on the extent of disease, the symptoms of nonocclusive mesenteric ischemia (NOMI) and patients with a venous thrombosis can be very different from those of acute occlusive ischemia. Biphasic contrast-enhanced CT represents the gold standard for the diagnosis of arterial and venous occlusion. In case of a central occlusion of the superior mesenteric artery or signs of peritonitis, immediate surgery should be performed. If major bowel resection becomes necessary, critical residual intestinal length limits must be kept in mind. Endovascular techniques for arterial occlusion have taken on a much greater importance today. For stable patients with NOMI, interventional catheter angiography is recommended because it enables diagnosis and treatment with selective application of vasodilators. Depending on its degree, interventional treatment with a transhepatic catheter lysis should be considered for acute and chronic portal vein thrombosis. KEY MESSAGE: The prompt and targeted use of the appropriate diagnostics and interventions appears to be the only way to reduce the persistently high mortality rates for AMI.

Quality of Life after Complex Abdominal Wall Reconstruction.

BACKGROUND: Component separation (CS) for tension-free approximation of fascial edges is the established technique for the repair of large ventral hernias mostly regarding midline defects. Recent studies suggest lower complication rates following a modified version of this technique using a partially endoscopic-assisted approach, whereas little is known about the quality of life (QoL) in the long-term evaluation of these patients. METHODS: A retrospective study and analysis of patients undergoing hernia repair using an open CS (OCS) and endoscopically assisted CS (ECS) technique, respectively, from 2011 to 2016 at the Rostock University Medical Center. Patients underwent a mesh-based sublay reinforcement following a distinct CS with closure of the linea alba. Patient characteristics, technical details, and short-term postoperative outcomes were determined by a physician chart review. A health-related QoL survey (EQ-5D) including a pain assessment was evaluated at a median of 19.5 months postoperatively. RESULTS: Thirty-five patients had a CS: 25 OCS and 10 ECS. Perioperative variables were comparable except for the median defect size (169 cm2 OCS vs. 86 cm2 ECS; p < 0.05) and maximum width of hernia (25 vs. 13 cm). Hospitalization lasted 16.6 days in the OCS group and 7.9 days in the endoscopic group (p = 0.04). Wound complications occurred in 24% of OCS and 10% of ECS patients. CONCLUSIONS: Patients in the ECS group had a shorter hospital stay and less minor and major wound complications. These advantages led to a faster recovery directly affecting the QoL in the ECS group. This effect diminishes in the long-term follow-up with a positive trend towards the OCS technique.

Comparison Between Endoscopic Vacuum Therapy and Conventional Treatment for Leakage After Rectal Resection.

BACKGROUND: Anastomotic leakage after rectal resection represents a severe complication for the patient and requires an early and appropriate management. Endoscopic vacuum therapy (EVT) has become the treatment of choice for anastomotic leakage after rectal resection in several institutions in Germany, and commercially available systems are currently distributed in approximately 30 countries worldwide. However, there is no evidence that EVT is superior to any other treatment for anastomotic leakage after rectal resection. METHODS: Twenty-one patients treated with EVT for anastomotic leakage after rectal resection were retrospectively compared to a historical cohort of 41 patients that received conventional treatment. Primary endpoints were death, treatment success and long-term preservation of intestinal continuity. Secondary endpoints were length of hospital stay and duration of treatment. RESULTS: There was no difference in mortality (p = 0.624). The intention-to-treat analysis showed a significantly higher success rate of EVT compared to conventional treatment (95.2% vs. 65.9%, p = 0.011). EVT was associated with preservation of intestinal continuity in a significant higher percentage of patients than patients undergoing conventional treatment (86.7% vs. 37.5%, p = 0.001). Conventional treatment tended to a shorter length of hospital stay (31.1 vs. 42.2 days, p = 0.066) but with no difference in overall duration of treatment. Time until closing of a diverting stoma did not differ between groups (10.2 months in the EVT group vs. 9.4 months in the conventional treatment group, p = 0.721). CONCLUSION: According to this retrospective study, conventional therapy and EVT are both options for the treatment of anastomotic leakage after rectal resection. EVT might be more effective in terms of definite healing and preservation of intestinal continuity.

The slow releasing hydrogen sulfide donor GYY4137 reduces neointima formation upon FeCl3 injury of the carotid artery in mice.

INTRODUCTION: Neointima formation is closely linked to vascular stenosis and occurs after endothelial damage. Hydrogen sulfide is an endogenous pleiotropic mediator with numerous positive effects on the cardio vascular system. OBJECTIVE: This study evaluates the effect of the slow releasing hydrogen sulfide donor GYY4137 (GYY) on neointimal formation in vivo. METHODS: The effect of GYY on neointimal formation in the carotid artery was studied in the FeCl3 injury model in GYY- or vehicle-treated mice. The carotid arteries were studied at days 7 and 21 after treatment by means of histology and immunohistochemistry for proliferating cell nuclear antigen (PCNA) and alpha smooth muscle actin (α-SMA). RESULTS: GYY treatment significantly reduced the maximal diameter and the area of the newly formed neointima on both days 7 and 21 when compared to vehicle treatment. GYY additionally reduced the number of PCNA- and α-SMA-positive cells within the neointima on day 21 after FeCl3 injury of the carotid artery. CONCLUSIONS: Summarizing, single treatment with the slow releasing hydrogen sulfide donor GYY reduced the extent of the newly formed neointima by affecting the cellular proliferation at the site of vascular injury.

The Water-Holding Procedure for Ensuring Postoperative Continence Prior Restoring Intestinal Continuity.

BACKGROUND: A defunctioning stoma can become necessary in a relevant number of patients undergoing gastrointestinal surgery. As a matter of course, patients seek an early closure of the stoma. However, preoperative management of these patients varies and the prediction of continence after stoma removal can become challenging. Patients might be fully continent despite low manometric pressures and vice versa. An easy and reliable way to predict continence after stoma reversal would improve patients' management and outcome. Although frequently performed in various surgical centers in Germany, there is no published data on the water-holding test. Hence, this is the first study evaluating the role of the test in clinical practice. METHOD: We performed a prospective pilot study to evaluate the role of anorectal manometry and the water-holding procedure as a predictor of postoperative continence prior to stoma reversal. Inclusion criteria were a successfully passed water-holding test, any type of fecal diversion and the possibility of restoring intestinal continuity. Preoperative low manometric pressure levels were not an exclusion criteria for stoma reversal. Fifty-two patients with ostomy were consecutively enrolled in this study between October 2013 and February 2016. Anorectal manometry was performed in all patients prior to stoma reversal. After stoma removal, patients were followed-up for 6 months. Postoperative incontinence was determined using the Wexner incontinence score. RESULTS: A total of 52 patients (38 males, 14 females) were included at an average age of 59 (range 33-83) years. Most frequent indications for intestinal diversion were rectal cancer surgery, IBD-related surgery, or surgery for diverticular disease. Low anterior rectal resection was performed in 17 patients (32.7%), followed by a proctocolectomy in 9 (17.3%), colectomy in 9 (17.3%), and recto-sigmoid resection in 7 patients (13.5%). Median time from stoma creation to reversal was 206 days (range 48-871 days). All patients had successfully passed the standardized water-holding test. At the same time, the majority of patients had low preoperative manometric pressure values and would normally not have been reversed at that point. The median postoperative Wexner incontinence score was at 1.5 (range 0-20), 0.5 (range 0-14), and 0 (range 0-11) at 14, 60, and 180 days after stoma reversal. Low preoperative manometric squeeze and/or resting pressure levels were not associated with a higher postoperative incontinence score at 14, 60, or 180 days after stoma reversal. CONCLUSION: A standardized water-holding test can function as an easy and reliable method before stoma reversal to predict sufficient postoperative fecal continence. In case of a sufficient water-holding test despite low manometric pressure levels, the risk for postoperative anal incontinence seems to be low. Preoperative manometric pressure levels do not appear to predict postoperative continence.

No need for surgery? Patterns and outcomes of blunt abdominal trauma.

INTRODUCTION: The management of a patient suffering from blunt abdominal trauma (BAT) remains a challenge for the emergency physician. Within the last few years, the standard therapy for hemodynamically stable patients with BAT has transitioned to a non-operative approach. The purpose of this study is to evaluate the outcome of patients with BAT and to determine the reasons for failure of non-operative management (NOM). MATERIALS AND METHODS: Analysis of 176 consecutive patients treated for BAT was conducted in a German level 1 trauma center from 2004 to 2011. Abdominal injuries were classified according to the American Association for the Surgery of Trauma (AAST). Patients included were demonstrated to have objective abdominal trauma with either free fluid on focused assessment with sonography for trauma (FAST) or computed tomography (CT), or proven organ injury. RESULTS: Patients, 142 of 176 (80.7%), with BAT were initially managed non-operatively, with a success rate of 90%. The rates of NOM success were higher among those with less severe injuries; 100% with Abbreviated Injury Scale (AIS) of 1. In total, 125 patients (71.0%) were managed non-operatively, and 51 (29.0%) required surgical intervention. NOM failure occurred in 9.2% of the patients, the most common reason being initially undiagnosed intestinal perforation (46.2%). Positive correlation was identified (r = 0.512; p < 0.001) between the ISS (injury severity score) and the NACA (National Advisory Committee of Aeronautics) score. The delay in operation in NOM failure was 6 h in patients with underlying hepatic or splenic rupture and 34 h with intestinal perforation. The overall mortality of 5.1% was attributed especially to old age (p = 0.016), high severity of injury (p < 0.001), and greater need for blood transfusion (p < 0.001). CONCLUSION: NOM was successful for the vast majority of blunt abdominal trauma patients, especially those with less severe injuries. NOM failure and operative delay were most commonly due to occult hollow viscus injury (HVI), the detection of which was achieved by close clinical observation and abdominal ultrasound in conjunction with monitoring for rising markers of infection and by multidetector computed tomography (MDCT) if additionally indicated. Based on this concept, the delay in operation in patients with NOM failure was short. This study underscores the feasibility and benefit of NOM in BAT.

Integrated Biobanking and Tumor Model Establishment of Human Colorectal Carcinoma Provides Excellent Tools for Preclinical Research.

Over the time period from 2006 to 2017, consecutive patients operated on at the University Medical Center Rostock participated in the comprehensive biobanking and tumor-modelling approach known as the HROC collection. Samples were collected using strict standard operating procedures including blood (serum and lymphocytes), tumor tissue (vital and snap frozen), and adjacent normal epithelium. Patient and tumor data including classification, molecular type, clinical outcome, and results of the model establishment are the essential pillars. Overall, 149 patient-derived xenografts with 34 primary and 35 secondary cell lines were successfully established and encompass all colorectal carcinoma anatomic sites, grading and staging types, and molecular classes. The HROC collection represents one of the largest model assortments from consecutive clinical colorectal carcinoma (CRC) cases worldwide. Statistical analysis identified a variety of clinicopathological and molecular factors associated with model success in univariate analysis. Several of them not identified before include localization, mutational status of K-Ras and B-Raf, MSI-status, and grading and staging parameters. In a multivariate analysis model, success solely correlated positively with the nodal status N1 and mutations in the genes K-Ras and B-Raf. These results imply that generating CRC tumor models on the individual patient level is worth considering especially for advanced tumor cases with a dismal prognosis.

Neoadjuvant radio-chemotherapy prolongs healing of anastomotic leakage after rectal resection treated with endoscopic vacuum therapy.

BACKGROUND: Neoadjuvant radiochemotherapy (nRCT) is an important component in the treatment of advanced rectal cancer. Endoscopic vacuum therapy (EVT) has become the treatment of choice for anastomotic leakage after rectal resection in many institutions in Germany. Published case series report on average success and stoma reversal rates of more than 80%. However, so far, there is no distinct report on the potential influence of nRCT on EVT. METHODS: A total of 11 patients treated with EVT for anastomotic leakage after nRCT and rectal resection were retrospectively compared with a cohort of eight patients with rectal anastomotic leakage without neoadjuvant treatment. Primary endpoints were death, treatment success, and long-term preservation of intestinal continuity. Secondary endpoint was the duration of treatment. Statistical analysis was performed using Statistical Package for Social Science (SPSS) version 23.0. RESULTS: There was no difference in mortality (0%), success rate (90.9% versus 100%, p = 0.381), or long-term preservation of continuity (63.6% versus 62.5%, p = 0.960). After nRCT, patients showed a significant longer duration of EVT (31.1 days versus 15.9 days, p = 0.040) which was associated with a significantly higher number of sponge applications (9.6 versus 5.0, p = 0.042). CONCLUSIONS: In our analysis, EVT showed success in over 90% of patients with anastomotic leakage after rectal resection for colorectal cancer, regardless of neoadjuvant treatment. However, in case of anastomotic leakage, nRCT seems to be associated with the need for a significant longer duration of EVT.

Evaluation of peripheral artery disease with the TIVITA® Tissue hyperspectral imaging camera system.

BACKGROUND: Objective, reliable and easy screening for peripheral artery disease (PAD) is essential to confirm the diagnosis and initiate the respective treatment. Therefore, a new non-invasive hyperspectral camera (TIVITA® Tissue) was tested in patients with and without PAD. OBJECTIVE: It was hypothesized that the oxygenation parameters of the TIVITA® Tissue correlate to established modalities for detection of PAD and allow differentiation between individuals with and without PAD. METHODS: Evaluation of tissue oxygenation was performed in the angiosome of the medial plantar artery in 25 healthy young people and in 24 patients with and 25 patients without PAD in comparable age. Thereby, superficial oxygenation (StO2) and near-infrared (NIR) perfusion index were measured with the TIVITA® Tissue. Additionally, the ankle-brachial-index (ABI), the complaint free walking distance and the vascular quality of life were assessed and demographic data were obtained from all participants. RESULTS: TIVITA® Tissue analysis revealed significantly reduced StO2 and NIR perfusion index in PAD compared to healthy young participants and patients without PAD. StO2 and NIR perfusion index positively correlated with ABI, the complaint free walking distance and the vascular quality of life score. CONCLUSIONS: In summary, this new hyperspectral imaging camera bears great potential for PAD screening as well as for follow up.

Targeting Immune-Related Molecules in Cancer Therapy: A Comprehensive In Vitro Analysis on Patient-Derived Tumor Models.

This study investigated the impact of immune-related pathway inhibition, among them indolamine 2,3-dioxygenase (IDO), alone and together with immune cells on growth and viability of colorectal cancer (CRC) cells. A panel of patient-derived CRC cell lines with different molecular characteristics (CpG island methylator phenotype, chromosomal, and microsatellite instability) was included. Initial phenotyping of CRC cell lines (n=17) revealed high abundance of immunosuppressive checkpoint-molecules in general, but an individual profile for IDO. Presence of immune-related molecules was independent of the molecular subtype. Selective treatment of CRC cell lines showing high or low IDO expression (n=2 cell lines each) was performed with single agents and combinations of Indoximod, Curcumin, and Gemcitabine with and without the addition of peripheral blood lymphocytes (PBL) in an allogeneic setting. All substances affected CRC cell growth in a cell line specific manner. The combination of Curcumin and Gemcitabine proved to be most effective in tumor cell elimination. Functional read-out analyses identified cellular senescence, after both single and combined treatment. Curcumin alone exerted strong cytotoxic effects by inducing early and late apoptosis. Necrosis was not detectable at all. Addition of lymphocytes generally boosted antitumoral effects of all IDO-inhibitors, with up to 80 % cytotoxicity for the Curcumin treatment. Here, no obvious differences became apparent between individual cell lines. Combined application of Curcumin and low-dose chemotherapy is a promising strategy to kill tumor target cells and to stimulate antitumoral immune responses.

Villus Growth, Increased Intestinal Epithelial Sodium Selectivity, and Hyperaldosteronism Are Mechanisms of Adaptation in a Murine Model of Short Bowel Syndrome.

BACKGROUND: Short bowel syndrome results from extensive small bowel resection and induces adaptation of the remaining intestine. Ileocecal resection (ICR) is the most frequent situation in humans. Villus hypertrophy is one hallmark of mucosal adaptation, but the functional mechanisms of mucosal adaptation are incompletely understood. AIMS: The aim of the study was to characterize a clinically relevant model of short bowel syndrome but not intestinal failure in mice and to identify outcome predictors and mechanisms of adaptation. METHODS: Male C57BL6/J mice underwent 40% ICR and were followed for 7 or 14 days. Small bowel transection served as control. All mice underwent autopsy. Survival, body weight, wellness score, stool water content, plasma aldosterone concentrations, and paracellular permeability were recorded. RESULTS: Unlike controls, resected mice developed significant diarrhea with increased stool water. This was accompanied by sustained weight loss throughout follow-up. Villus length increased but did not correlate positively with adaptation. Plasma aldosterone concentrations correlated inversely with body weight at day 14. After ICR, intestinal epithelial (i.e., tight junctional) sodium permeability was increased. CONCLUSIONS: 40% ICR results in moderate to severe short bowel syndrome. Successful adaptation to the short bowel situation involves villus elongation but does not correlate with the degree of villus elongation alone. In addition, increased intestinal epithelial sodium permeability facilitates sodium-coupled solute transport. Hyperaldosteronism correlates with the severity of weight loss, indicates volume depletion, and counterregulates water loss.

Establishment, functional and genetic characterization of three novel patient-derived rectal cancer cell lines.

AIM: To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens. METHODS: Establishment of cell lines was conducted by direct in vitro culturing and in vivo xenografting with subsequent in vitro culturing. Cell lines were in-depth characterized concerning morphological features, invasive and migratory behavior, phenotype, molecular profile including mutational analysis, protein expression, and confirmation of origin by DNA fingerprint. Assessment of chemosensitivity towards an extensive range of current chemotherapeutic drugs and of radiosensitivity was performed including analysis of a combined radio- and chemotherapeutic treatment. In addition, glucose metabolism was assessed with 18F-fluorodeoxyglucose (FDG) and proliferation with 18F-fluorothymidine. RESULTS: We describe the establishment of ultra-low passage rectal cancer cell lines of three patients suffering from rectal cancer. Two cell lines (HROC126, HROC284Met) were established directly from tumor specimens while HROC239 T0 M1 was established subsequent to xenografting of the tumor. Molecular analysis classified all three cell lines as CIMP-0/ non-MSI-H (sporadic standard) type. Mutational analysis revealed following mutational profiles: HROC126: APCwt , TP53wt , KRASwt , BRAFwt , PTENwt ; HROC239 T0 M1: APCmut , P53wt , KRASmut , BRAFwt , PTENmut and HROC284Met: APCwt , P53mut , KRASmut , BRAFwt , PTENmut . All cell lines could be characterized as epithelial (EpCAM+) tumor cells with equivalent morphologic features and comparable growth kinetics. The cell lines displayed a heterogeneous response toward chemotherapy, radiotherapy and their combined application. HROC126 showed a highly radio-resistant phenotype and HROC284Met was more susceptible to a combined radiochemotherapy than HROC126 and HROC239 T0 M1. Analysis of 18F-FDG uptake displayed a markedly reduced FDG uptake of all three cell lines after combined radiochemotherapy. CONCLUSION: These newly established and in-depth characterized ultra-low passage rectal cancer cell lines provide a useful instrument for analysis of biological characteristics of rectal cancer.

Establishment, functional and genetic characterization of a colon derived large cell neuroendocrine carcinoma cell line.

AIM: To establish cell line and patient-derived xenograft (PDX) models for neuroendocrine carcinomas (NEC) which is highly desirable for gaining insight into tumor development as well as preclinical research including biomarker testing and drug response prediction. METHODS: Cell line establishment was conducted from direct in vitro culturing of colonic NEC tissue (HROC57). A PDX could also successfully be established from vitally frozen tumor samples. Morphological features, invasive and migratory behavior of the HROC57 cells as well as expression of neuroendocrine markers were vastly analyzed. Phenotypic analysis was done by microscopy and multicolor flow cytometry. The extensive molecular-pathological profiling included mutation analysis, assessment of chromosomal and microsatellite instability; and in addition, fingerprinting (i.e., STR analysis) was performed from the cell line in direct comparison to primary patient-derived tissues and the PDX model established. Drug responsiveness was examined for a panel of chemotherapeutics in clinical use for the treatment of solid cancers. RESULTS: The established cell line HROC57 showed distinct morphological and molecular features of a poorly differentiated large-cell NEC with KI-67 > 50%. Molecular-pathological analysis revealed a CpG island promoter methylation positive cell line with microsatellite instability being absent. The following mutation profile was observed: KRAS (wt), BRAF (mut). A high sensitivity to etoposide, cisplatin and 5-FU could be demonstrated while it was more resistant towards rapamycin. CONCLUSION: We successfully established and characterized a novel patient-derived NEC cell line in parallel to a PDX model as a useful tool for further analysis of the biological characteristics and for development of novel diagnostic and therapeutic options for NEC.

[Medical Device Regulation as current challenge for the legally safe introduction of new technologies]. / Medical Device Regulation als aktuelle Herausforderung für die rechtssichere Einführung neuer Technologien.

The main goal of the Medical Device Regulation (MDR) is the improvement of patient safety by laying down rules concerning the approval of medical devices for human use in the European Union. The MDR contains an extension of the conformity assessment procedure for products in the higher risk categories IIb and III. The clinical testing and assessment are regulated more strictly by e.g. the scrutiny process conducted by expert panels following the technical certification. The demand for documentation is vastly increasing due to more detailed registration (UDI) and an extension of post-market surveillance. The German Society of Surgery (DGCH) and the German Society for Biomedical Engineering have already defined a staged concept for innovation testing and clinical assessment during finalization of the MDR that contains the highest level of patient safety while simultaneously maintaining the potential for innovation. Essential elements are present in the MDR and can be implemented in a targeted way. The 3­year phase of national MDR-implementation must be used for a proactive adaptation. The DGCH is represented in the advisory council of the Federal Ministry of Health (BMG) by the Association of the Scientific Medical Societies in Germany (AWMF). The aim is a responsible harmonization of national structures with the regulations of the MDR by the construction of specific registries which should be the responsibility of medical societies. The early integration of health technology assessment will be of importance during the planning phase of product development to facilitate a positive decision on reimbursement.