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ZusammenfassungNach Wirksamwerden der Verordnung (EU) Nr. 536/2014 (Clinical Trials Regulation – CTR) des Europäischen Parlaments und des Rates am 31.01.2022 hat sich das Antragsverfahren für klinische Prüfungen grundlegend geändert. In diesem Beitrag werden die grundlegenden Verfahrensänderungen und die daraus für Deutschland und insbesondere für die Ethikkommissionen folgenden Veränderungen dargestellt. Auf die Harmonisierungsbestrebungen der Ethikkommissionen auf der EU-Ebene wird eingegangen.Nach der neuen EU-Verordnung ist in Deutschland nur noch jeweils eine einzige Ethikkommission in die Genehmigung einer klinischen Arzneimittelprüfung eingebunden. Das bisherige Benehmensverfahren unter Einbeziehung mehrerer lokal zuständiger Ethikkommissionen wurde abgelöst. An dessen Stelle ist eine engere Zusammenarbeit der Ethikkommissionen mit den Bundesoberbehörden durch die Erstellung eines gemeinsamen Bewertungsberichts (Assessment-Report) sowie mit den anderen EU-Mitgliedsländern im Rahmen der Konsolidierung der jeweiligen länderspezifischen Anforderungen getreten. Der zuvor mit dem Benehmensverfahren einhergegangene regelmäßige gegenseitige Austausch der Ethikkommissionen hatte jedoch dazu beigetragen, Entscheidungskriterien, aber auch die Ermessensentscheidungen zu harmonisieren. Durch den Wegfall dieses Austauschs sind zum einen detailliertere Verfahrensempfehlungen erforderlich, aber auch regelmäßige andere Austauschmöglichkeiten, um die bereits bestehenden Harmonisierungen nicht nur beizubehalten, sondern auch weiter voranzutreiben. Der Arbeitskreis Medizinischer Ethik-Kommissionen in der Bundesrepublik Deutschland e. V. (AKEK) steht dazu als Vertretung der einzelnen Ethikkommissionen auch in intensivem Austausch mit Bundesoberbehörden, Antragstellern, anderen europäischen Ethikkommissionen und europäischen Institutionen.

Die Rolle von Ethikkommissionen bei der Bewertung klinischer Arzneimittelprüfungen hat sich im Laufe der Jahre gewandelt. Aus den kollegialen Beratungsgremien wurden Patientenschutzorganisationen mit Behördencharakter. Während das ärztliche Berufsrecht in Deutschland bei biomedizinischer Forschung am Menschen lediglich eine Beratungspflicht für Ärzte vorsieht, bei der eine ablehnende Stellungnahme in rechtlicher Hinsicht nicht zu einer Unzulässigkeit des Forschungsvorhabens führt, verlangt das Arzneimittelgesetz (AMG) eine zustimmende Bewertung durch die zuständige Ethikkommission. Das AMG definiert sowohl die durch die Ethikkommission zu prüfenden Elemente eines Antrages für eine klinische Arzneimittelprüfung als auch abschließend die Gründe, anhand derer die zustimmende Bewertung versagt werden kann. Ethikkommissionen, die Anträge gemäß AMG bewerten, müssen nach Landesrecht gebildet sein und sind interdisziplinär mit Fachärzten, Juristen und Methodikern besetzt. Wesentliche Bewertungsinhalte sind ein ärztlich vertretbares Nutzen-Risiko-Verhältnis, die Angemessenheit der verwendeten Methoden einschließlich biometrischer Aspekte, die Anforderungen an die Studienteilnehmer, wie z. B. Einwilligungsfähigkeit, die Eignung der Prüfer und Prüfeinrichtungen sowie die Angemessenheit der schriftlichen Informationen, mit denen Studienteilnehmer informiert werden und sie ihre Einwilligung erteilen sollen. Trotz der bereits jetzt hohen Regelungsdichte werden zukünftig mit der Anwendbarkeit der Verordnung (EU) Nr. 536/2014 die Anforderungen an Zusammensetzung und Arbeitsweise von Ethikkommissionen noch detaillierter gesetzlich festgelegt mit dem Ziel, die Bewertung klinischer Arzneimittelprüfungen in der EU weiter zu harmonisieren.

Die Verordnung (EU) Nr. 536/2014 und deren arzneimittelrechtliche nationale Umsetzung werden zukunftig eine enge Zusammenarbeit von Bundesoberbehorden und Ethikkommission bei der Bewertung klinischer Prufungen von Arzneimitteln am Menschen erforderlich machen. In Vorbereitung darauf wurde ein Pilotprojekt initiiert, in dem anhand aktueller Antrage die zukunftigen Prozesse der Verordnung unter Einhaltung der derzeitigen rechtlichen Vorgaben simuliert werden. Damit soll Antragstellern, Behorden und Ethikkommissionen Gelegenheit gegeben werden, sich mit den neuen Verfahren vertraut zu machen. Ziel der Arbeit war die Untersuchung aller Pilotprojektverfahren des ersten Jahres nach Start des Pilotprojekts Ende 2015. Alle 20 im ersten Jahr abgeschlossenen Pilotprojektverfahren wurden auf Fristenadharenz und Bewertungsergebnis analysiert. 17 von 20 Verfahren konnten innerhalb der von der EU-Verordnung vorgegebenen Fristen vollstandig abgeschlossen werden. In zwei Fallen uberzogen die Sponsoren geringgradig die Nachlieferungsfrist. In einem Fall zog der Sponsor den Antrag im Pilotverfahren zuruck. Alle 20 Antrage wurden gemeinsam von Bundesbehorde und Ethikkommission bearbeitet und in allen Fallen wurde erfolgreich ein abgestimmter Assessment Report fristgerecht erstellt. Alle 20 Antrage wurden genehmigt, davon in 5 Fallen unter aufschiebenden Bedingungen. Die Einhaltung der Fristen durch Bundesoberbehorde und Ethikkommissionen zeigt, dass die im Pilotverfahren etablierten technischen Infrastrukturen und Prozesse grundsatzlich funktionieren. Die Zusammenarbeit zwischen Bundesoberbehorde und Ethikkommissionen war aus Sicht der Beteiligten sehr erfolgreich.

Over the years, the role of ethics committees (ECs) in the review process of clinical trial applications (CTAs) has changed from being a collegial advisory body to a patient protection organisation with an authority character. While the law governing the medical profession in Germany only provides for an obligation for physicians to ask for an EC review in biomedical research on human beings, a negative opinion on the CTA does not lead to the inadmissibility of the research project from a legal point of view. In contrast, the German Medicinal Product Act (Arzneimittelgesetz, AMG) requires a favourable opinion as an approving assessment by the competent EC.The AMG defines both the elements of a clinical trial application to be reviewed by the EC as well as the principle grounds of non-acceptance to reject a favourable opinion. ECs that assess CTAs must be constituted in accordance with the state law and must be composed of interdisciplinary medical specialists, lawyers and methodologists. The main assessment criteria are a medically acceptable risk-benefit ratio, the appropriateness of the methods used, including biometric aspects, the requirements to be met by the study participants, such as their ability to give consent, the suitability of the investigators and trial facilities as well as the appropriateness of the written information with which the study participants are to be informed and give their consent.In spite of the already high degree of regulation, the applicability of the European Clinical Trial Regulation will result in even more detailed legal requirements for the composition and working procedures of an EC with the aim of further harmonising the assessment of CTAs in the EU.

The European Clinical Trials Regulation 536/2014 and the corresponding national legal transitions will require close cooperation between the federal higher authorities and ethics committees in the assessment of clinical trial applications involving medicinal products in humans. In preparation for this, a pilot project was launched to simulate the future processes of the regulation in line with current legal requirements and in order to give applicants, authorities and ethics committees the opportunity to familiarise themselves with the new procedures.The aim of this paper is to examine all pilot project procedures of the first year since starting the pilot project at the end of 2015.All 20 pilot projects completed in the first year were analysed for adherence to deadlines and results of the assessments.Within the time limits specified in the EU regulation, 17 of 20 procedures were fully completed. In two cases, the sponsors slightly exceeded the additional delivery period. In one case, the sponsor withdrew the application within the pilot procedure. All 20 applications were processed jointly by the federal authorities and ethics committees, and in all cases a coordinated assessment report was successfully compiled on time. All 20 applications were approved, five of which were subject to suspensive conditions.Compliance with the deadlines set by federal authorities and ethics committee shows that the technical infrastructures and processes established in the pilot procedure are fully functional. The cooperation between the federal higher authorities and ethics committees was very successful from the perspective of the parties involved.

Background: Today, humerus nails have become the surgical method of choice in the treatment of humerus shaft fractures. Whether or not the radial nerve should be intraoperatively examined by default in case of primary paresis is currently under discussion. Patients and Methods: Clinical findings from 38 patients with humeral shaft fractures surgically treated with unreamed humerus nail (UHN) at the Department of Accident Surgery, University Clinics Bonn, Germany, between 2000 and 2003 were retrospectively assessed. Constant Score was applied for evaluation of functional results. Results: In 40% of patients, primary radial nerve paresis was present. This was especially common after high energy trauma (e.g. traffic accident) and significantly increased in fractures of the middle third. In 93% of cases, spontaneous remission of motor and sensory loss was observed. No iatrogenic radial nerve impairment occurred. Conclusion: Due to the high rates of spontaneous remissions of radial nerve palsy after treatment with UHN in humerus shaft fractures, primar exploration of the radial nerve does not appear to be necessary.

BACKGROUND: Lymphatic spread is 1 of the most relevant prognostic factors for gastric carcinoma. The current International Union Against Cancer (UICC) pN staging system is based on the number of metastatic lymph nodes and does not take into consideration the characteristics of the metastatic lymph nodes itself. The aim of the current study was to examine the prognostic value of extracapsular lymph node involvement in gastric cancer and to find correlations with clinicopathological parameters. METHODS: Tissue samples were obtained from 159 gastric cancer patients who underwent gastrectomy with D2-lymphadenectomy in 142 (89.3%) cases and subtotal gastrectomy with D2-lymphadenectomy in 17 (10.7%) cases. The number of resected lymph nodes, number of metastatic lymph nodes, and number of metastatic lymph nodes with extracapsular lymph node involvement were determined. Extracapsular spread was defined as infiltration of cancer cells beyond the capsule of the metastatic lymph node. RESULTS: Ninety-six (60.4%) patients had lymph node metastasis. In 57 (35.8%) cases, extracapsular lymph node involvement was also detected. Extracapsular lymph node involvement was significantly associated with higher pN-category (P < .001), higher pM category (P = .048), and higher UICC stages (P = .001). According to the Kaplan-Meier log-rank statistical method, extracapsular lymph node involvement was significantly associated with poor survival (P = .001). In the multivariate analysis besides pT (P < .001) and R-category (P = .009), extracapsular lymph node involvement also remained as an independent prognostic factor (P = .003), whereas the UICC pN-category (P = .822) lost its prognostic value. CONCLUSIONS: Extracapsular lymph node involvement is associated with higher tumor stages and is an independent negative prognostic factor in gastric cancer. In future staging systems for gastric cancer, extracapsular lymph node involvement should be considered. Cancer 2010. © 2010 American Cancer Society.

Background Long bone fractures, particularly of the femur, are common in multiple-trauma patients, but their optimal management has not yet been determined. Although a trend exists toward the concept of “damage control orthopedics” (DCO), current literature is inconclusive. Thus, a need exists for a more specific controlled clinical study. The primary objective of this study was to clarify whether a risk-adapted procedure for treating femoral fractures, as opposed to an early definitive treatment strategy, leads to an improved outcome (morbidity and mortality). Methods/Design The study was designed as a randomized controlled multicenter study. Multiple-trauma patients with femur shaft fractures and a calculated probability of death of 20 to 60 % were randomized to either temporary fracture fixation with external fixation and defined secondary definitive treatment (DCO) or primary reamed nailing (early total care). The primary objective was to reduce the extent of organ failure as measured by the maximum sepsis-related organ failure assessment (SOFA) score. Results Thirty-four patients were randomized to two groups of 17 patients each. Both groups were comparable regarding sex, age, injury severity score, Glasgow Coma Scale, prothrombin time, base excess, calculated probability of death, and other physiologic variables. The maximum SOFA score was comparable (nonsignificant) between the groups. Regarding the secondary endpoints, the patients with external fixation required a significantly longer ventilation period (p = 0.049) and stayed on the intensive care significantly longer (p = 0.037), whereas the in-hospital length of stay was balanced for both groups. Unfortunately, the study had to be terminated prior to reaching the anticipated sample size because of unexpected low patient recruitment. Conclusions Thus, the results of this randomized study reflect the ambivalence in the literature. No advantage of the damage control concept could be detected in the treatment of femur fractures in multiple-trauma patients. The necessity for scientific evaluation of this clinically relevant question remains. Trial registration Current Controlled Trials ISRCTN10321620 Date assigned: 9 February 2007. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1162-2) contains supplementary material, which is available to authorized users.

Nicht dislozierte unkomplizierte Bruche ohne Gelenkbeteiligung konnen zum Teil konservativ versorgt werden. Doch der Vorteil einer operativen Behandlung nach einer Fraktur ist, dass der Patient nicht wochenlang mit dem Gips liegt, sondern ohne ausere Fixation rasch wieder mobil ist. Gerade bei alteren Patienten lassen sich so das Thromboembolie risiko und der Pflegeaufwand erheblich reduzieren.

Aim: The aim of this prospective study was to evaluate the clinical and prognostic impact of immunohisto-chemically assessed uPA and PAI-1 in patients with gastric cancer. Methods: This prospective study analyzed specimens obtained from 105 gastric cancer patients who underwent gastrectomy with extended lymphadenectomy. The immunohistochemical expression of uPA and PAI-1 was studied semiquantitatively in the tumor epithelium and was correlated with the clinicopathological features of each patient. Results: Univariate analysis revealed no statistically significant association of uPA levels with pT and pN category (p=0.655 and 0.053, respectively), grading (p=0.374), depth of tumor invasion (p=0.665), UICC classification (p=0.21) and the Lauren classification (p=0.578). PAI-1 expression showed no statistically significant correlation with pT, pN and M category (p=0.589, 0.414, and 0.167, respectively), grading (p=0.273), and the Lauren classification (p=0.368). Only the UICC classification was significantly correlated with PAI-1 (p=0.016). Kaplan-Meier analysis revealed no significant association of uPA and PAI-1 with overall survival (p=0.0929 and 0.0870, respectively). Conclusions: Our results could not verify any prognostic value of uPA and PAI-1 levels in patients with gastric carcinoma. Therefore, the uPA-system as a biologically defined prognostic marker to identify high-risk gastric cancers should be applied with caution. However, considering the number of patients involved and the borderline level of significance observed in this study, a larger number of events may have resulted in significant differences.

The aim of this prospective study was to analyze Ming's classification in correlation with other currently used classification systems of gastric cancer. In addition, we wanted to define the prognostic significance of the Ming classification system. The present study analyzed material of 117 patients with gastric carcinoma who underwent D2-gastrectomy with curative intent. All specimens were categorized according to International Union Against Cancer (UICC) classification, World Health Organization (WHO) classification, Borrmann classification, Lauren classification, Goseki classification, Ming classification, and tumor differentiation. For analysis of correlation between the classification systems, the correlation coefficient according to Spearman was calculated. The survival curves have been calculated according to the Kaplan-Meier method. According to the Ming classification, 38.5% of the carcinomas exhibited an expanding growth pattern, and 61.5% of specimens showed an infiltrating growth pattern. The subtypes according to the Ming and Lauren classification correlated significantly (P < 0.001). WHO classification (P < 0.001), tumor differentiation (P < 0.001), and Goseki classification (P < 0.001), as well as the macroscopic classification of Borrmann (P < 0.001) and the pT and pN categories of the UICC classification exhibited a highly significant correlation with the Ming classification (P < 0.001 and 0.001, respectively). Median overall survival was 31.3 months. In Kaplan-Meier analysis, the 3-year survival rates were lower in the infiltrative tumor type when compared to the expansive tumor type according to Ming (P = 0.0847). In multivariate analysis, only the UICC system presented as an independent prognostic factor in multivariate analysis (P < 0.001). This study shows that the Ming classification correlates significantly with the currently used classification systems for gastric cancer and with the UICC staging system, especially, the pT and pN category. The 3-year survival rates were lower in the infiltrative tumor type than in the expansive tumor type according to Ming. However, the Ming classification is not an independent prognostic factor.

BACKGROUND Skip metastasis to mediastinal lymph nodes is a prognostic factor for patients with nonsmall cell lung carcinoma (NSCLC). Little is known about the biologic behavior of tumors with noncontinuous spread to the mediastinal lymph nodes. In patients with pN2 skip metastases, micrometastases to N1 lymph nodes, which only mimic skip metastases, have not been investigated. METHODS In a retrospective study, the authors analyzed the primary tumor specimens from 45 patients with pN2 NSCLC (18 patients had squamous cell carcinomas, 23 had adenocarcinomas, and 4 had large cell carcinomas). They immunohistochemically evaluated the expression of p21, p53, MUC-1, Bcl-2, c-ErbB-2, and E-cadherin. Survival rates and biomarker expression levels were compared between patients with pN2 disease and infiltration of N1 lymph nodes (without skip metastasis [n = 28]) and patients with pN2 disease without N1 infiltration (with skip metastasis [n = 17]). To evaluate micrometastasis in the pN1 lymph nodes of 17 patients with skip metastases, lymph nodes were stained using the anticytokeratin antibody, AE1/AE3. RESULTS The 5-year survival rate of patients with skip metastases was 41%, compared with 14% for patients without skip metastases (P = 0.019). In a multivariate analysis, the incidence of skip metastases did not vary significantly according to gender, age, histology, pT status, or cM status. Three skip-positive patients (17.6%) had micrometastatic tumor involvement of pN1 lymph nodes. After adding these patients to the group of patients without skip metastases, there was still a significant difference in survival between the two groups. p53, MUC-1, c-ErbB-2, and E-cadherin expression levels in primary tumor specimens were not significantly different in patients with continuous metastasis and patients with skip metastases. Patients with skip metastases expressed lower levels of p21 (P = 0.026), whereas Bcl-2 expression levels were considerably higher (P = 0.019) compared with the corresponding levels in patients without skip metastases. CONCLUSIONS Patients with NSCLC and pN2 skip metastases have a more favorable prognosis than do patients with pN2 disease without skip metastases. Tumor specimens from these patients exhibit elevated expression of the antiapoptosis gene BCL2 and lower expression levels of p21 relative to patients with pN2 disease without skip metastases. Micrometastases occurred in 3 of 17 (17.6%) patients with pN2 disease and skip metastases diagnosed by routine histopathology. Cancer 2004. © 2004 American Cancer Society.

Expression of MMP-2 is associated with progression and lymph node metastasis of gastric carcinoma Aims: One important step in tumour invasion is the penetration of the basement membrane. Matrix metalloproteinases (MMPs) play a key role in the migration of normal and malignant cells through the basement membrane. The aim of this study was to investigate correlations between matrix metalloproteinase 2 (MMP-2) immunoreactivity and currently used classification systems and possible relationships between lymph node metastasis and MMP-2 expression. Methods and results: This prospective study analysed specimens obtained from 114 gastric cancer patients (mean age 64 years; range 33–86 years) who underwent gastrectomy with extended lymphadenectomy. All specimens were categorized according to UICC classification, WHO classification, tumour differentiation, Lauren classification, Ming classification and Goseki classification. Formalin-fixed paraffin-embedded tumour specimens were stained using an avidin–biotin complex peroxidase assay. MMP-2 expression in the tumour epithelium was studied by immunohistochemistry with semiquantitative (score 0–3) evaluation. The MMP-2 staining pattern was positive (score 1–3) in 93 (81.6%) specimens and negative (score 0) in 21 (18.4%) samples. No significant correlations were found between MMP-2 expression and other variables such as age, tumour differentiation, WHO, Lauren, Goseki, and Ming classifications. In contrast, the intensity of MMP-2 staining in tumour cells correlated significantly with depth of tumour infiltration (T-stage), lymph node metastasis (N-stage), distant metastasis (M-stage), and UICC stage. Conclusions: Expression of MMP-2 is strongly associated with tumour progression and lymph node metastasis in gastric cancer. Therefore MMP-2 staining may be clinically useful as predictor of tumour progression, especially for lymph node metastasis.

The effect of acetyl - tyrosyl-valyl-alanyl-aspartyl - chloromethylketone (ac-YVAD-cmk), an irreversible caspase-1 (IL-1beta converting enzyme, ICE) inhibitor on mortality, leukocyte and platelet counts and cytokine levels was investigated in a double-blind rat model of endotoxaemia. Intravenous (i.v.) bolus administration of lipopolysaccharide (LPS) (25-75 mg kg(-1), n=12 per group) to anaesthetized rats induced a dose dependent increase in mortality over 8 h (LD(50)=48 mg kg(-1)). During this period, animals became leukopenic and thrombocytopenic. Serum levels of IL-beta, IL-6, and TNF-alpha were highly elevated. Pretreatment of rats with ac-YVAD-cmk at a dose of 12.5 micromol kg(-1) significantly reduced mortality from 83 to 33% using Log Rank analysis. However, ac-YVAD-cmk did not modify blood cell counts or cytokine profiles as compared with the LPS-drug vehicle group. These data lay credence to the potential importance of caspase-1-inhibition in modifying the inflammatory response to endotoxin. Further investigations are warranted in understanding the relationship between caspase-1 inhibition, cytokine production and animal survival in different experimental paradigms of sepsis.

Ms Schott and colleagues concluded in their study of the influence on funding of trials with medicinal products that publications from trials initiated by the pharmaceutical companies were often distorted. Also, such trials, they say, had positive results more often than non-pharmaceutically initiated trials. This was not explained by a difference in study quality. Their cited articles, however, were not based on insights from planning or conducting of trials but from their publication. Based on our working experience at an ethics committee of a medical faculty, we can state that advice is much more urgently required for non-industrially sponsored trials. Differences in planning clinical trials also seem to be responsible for the fact that more non-industrially funded trials do not take the desired course. It is of note, for example, that among 22 clinical drug trials with non-industry funders that received advice from the ethics committee at Cologne University in 2006–2008, 5 trials had substantial difficulties in recruiting subjects (fewer than half of the subjects were recruited during the planned recruitment period). This makes it doubtful whether such trials—especially on a background of limited funding—can ever be brought to a satisfactory conclusion. Problems in conducting trials will be reflected by the published results. By reverse conclusion, this should not lead to a situation where the pharmaceutical industry receives the blame for the successful conclusion, resulting in better publication opportunities. The authors did not sufficiently consider that different objectives exist for industry-sponsored and non-industry-sponsored trials, which in turn mean that for mere entrepreneurial reasons alone, industry sponsors will initiate only those trials that have a high chance of success. We agree with the authors’ reminder to take into consideration competing interests when interpreting study results. However, their comment that industry-sponsored drug trials are reported with a positive selection bias was not supported by reliable data. In order to state this, it would have been necessary to go further than looking at individual case reports and analyze the study quality comprehensively (including the planning and conducting of the trials, not only the publication of the results).

Introduction: Matrix metalloproteinases (MMPs) can degrade type IV collagen of extracellular matrices and basal membranes and thus play a key role in the migration of malignant cells. Aim of the present study was to investigate possible correlations of MMP and TIMP genotypes on gene expression, on clinicopathological parameters and on prognosis in gastric cancer. Methods: Genomic DNA was extracted from paraffin-embedded tissues of 135 patients who were treated surgically between May 1996 and January 2005 for primary gastric carcinoma. Allelic discrimination for MMP-2−1306C>T, TIMP-2303C>T and MMP-7−181A>G was performed by quantitative real-time PCR using two allele-specific TaqMan probes in competition for amplification of each gene. MMP-2 and TIMP-2 gene expression in resected tumor tissues was immunhistochemically detected. Genotyping was correlated with expression and with histopathologic parameters. Relations to overall survival were evaluated with univariate analysis according to the Kaplan-Meier approach (log-rank test). Results: The genotype distribution and allele frequencies of the SNPs were not significantly different from the control group. A significant correlation was seen for TIMP-2303C>T with a higher pN-stage (p=0.01) and pM-stage (p=0.02) for patients with CC genotype. 25 (96.2%) patients with pN3-stage had a TIMP-2303C>T CC-genotype, whereas the portion of patients with a CC-genotype in the other pN-stages was only between 71.4% for pN0 and 79.4% for pN1. The C-allele frequency for patients with distant metastasis (pM1) was 96.2% and 87.6% for patients without distant metastasis (pM0). No significant correlation could be found between the analyzed SNPs and the immunhistochemically detected protein levels of MMP-2 (p=0.766) and of TIMP-2 (p=0.684). In the univariate analyses non of the SNPs correlated with survival. Conclusion: In contrast to previous studies with low number of patients, survival in gastric cancer was not associated with the MMP-2−1306C>T and TIMP-2303C>T with expression of MMP-2 and TIMP-2 could be demonstrated. For the first time a significant correlation of TIMP-2303C>T with pN-and pM-category could be described in the present study.

The purpose of this study was to clarify the relationship of the immunohistochemical expression of c-met, p53 and p21 with clinicopathological parameters and prognosis in gastric carcinomas. We analyzed specimens from 114 gastric cancer patients (median age 64 years, range: 33-86) who underwent gastrectomy with lymphadenectomy. Specimens were categorized according to the tumor differentiation, based on UICC, WHO, Lauren, Ming and Goseki classifications. Specimens were examined immunohistochemically with antibodies against c-met, p53 and p21. The expression was evaluated semiquantitatively and correlated with the clinicopathological parameters. The c-met staining pattern was positive in 73.7%. P53 and p21 were positive in 86.8 and 67.5%, respectively. No significant correlation between c-met or p21 expression and the clinicopathological parameters was seen. A significant increase of p53 expression was observed in stage pT3 and -4. The overexpression of c-met and p53 was significantly associated with a poor prognosis in the univariate survival analysis. In the multivariate analysis this impact was maintained for c-met. P21 proved to be a significant prognostic factor in the multivariate analysis. Our data suggest that the overexpression of c-met and p21 may represent independent prognostic factors in gastric carcinoma.

The purpose of this study was to clarify the relationship of the immunohistochemical expression of c-met, p53 and p21 with clinicopathological parameters and prognosis in gastric carcinomas. We analyzed specimens from 114 gastric cancer patients (median age 64 years, range: 33-86) who underwent gastrectomy with lymphadenectomy. Specimens were categorized according to the tumor differentiation, based on UICC, WHO, Laurén, Ming and Goseki classifications. Specimens were examined immunohistochemically with antibodies against c-met, p53 and p21. The expression was evaluated semiquantitatively and correlated with the clinicopathological parameters. The c-met staining pattern was positive in 73.7%. P53 and p21 were positive in 86.8 and 67.5%, respectively. No significant correlation between c-met or p21 expression and the clinicopathological parameters was seen. A significant increase of p53 expression was observed in stage pT3 and -4. The overexpression of c-met and p53 was significantly associated with a poor prognosis in the univariate survival analysis. In the multivariate analysis this impact was maintained for c-met. P21 proved to be a significant prognostic factor in the multivariate analysis. Our data suggest that the overexpression of c-met and p21 may represent independent prognostic factors in gastric carcinoma.

The expression of the nm23 gene has been associated with the development of metastasis. Numerous studies have shown down-regulation of nm23 expression in metastatic breast and colon cancer. The expression of the putative metastasis-suppressor gene nm23 in gastric carcinoma is controversial. The aim of this study was the analysis of nm23 expression in a large series of gastric cancer patients.In a retrospective immunohistochemical study specimens obtained from 116 gastric cancer patients (mean age 64 years; range: 33-85) who had undergone gastrectomy with extended lymphadenectomy were analyzed. Nm23 expression in the tumor epithelium was studied by immunohistochemistry followed by a semi-quantitative (score 0-3) evaluation. Statistical analysis including Chi-square test, uni- and multivariate survival analyses were performed.The nm23 staining pattern was positive (score 2-3) in 100 (86.2%) specimens and negative (score 0-1) in 16 (13.8%) samples. Lymph node metastasis was found in 65% of the patients. No significant correlations could be determined between nm23 expression and other variables such as gender, age, tumor differentiation, WHO-, Laurén-, Goseki-, or Ming-classification. The intensity of nm23 staining in the tumor cells was not significantly correlated with depth of tumor infiltration (T-stage), lymph node metastasis (N-stage), distant metastasis (M-stage), UICC-stage, or prognosis.Our series did not show a correlation of nm23 expression in terms of lymph node and distant metastasis or prognosis in gastric cancer patients.

Cancellous bone grafting is currently the most frequent method for replacement of bone material. In recent years, several alternative methods came into practice. However, up to now it remains unclear whether cancellous bone grafting is cheaper as compared to these new methods. Therefore, the aim of this study was to calculate the direct costs of cancellous bone grafting. For calculation of the direct costs operation time needed in addition to the main surgical intervention was measured and the material used recorded in a consecutive series of 50 interventions including bone grafting at the Department of Trauma Surgery at the University Hospital of Bonn Medical School. Surgical staff costs were calculated on the basis of a standard team consisting of one surgical attendant, surgical resident, surgical nurse, and nurse’s service. Cost of anaesthesia was calculated on a per minute base. Mean additional operation time was 26.3 min (range 17–35 min). Surgical staff costs per operation minute were 2.70 Euro, costs for anaesthesiological service were 4.18 Euro/min. Material additional used consisted of sutures and sterilization costs. Material costs summed up to 32.01 Euro. The total direct costs of bone grafting were 212.95 Euro. The direct costs of harvesting cancellous bone graft and the use of bone replacement material are comparable. Due to the high complication rate at the donor site the total-cost-of-illness might be higher when using autologous bone graft.

Despite improved surgical techniques and better perioperative management, postoperative complications remain a serious problem in patients undergoing esophagectomy for esophageal cancer. During the early postoperative course, infections occur in approximately 50% of patients,1–4 the majority of which relate to the lung. In larger series, pneumonia-associated postoperative mortality ranges between 5% and 10%.5–7 Possible reasons are the major surgical trauma, poor nutritional status, and reduced immune response. Impaired neutrophil function in patients with esophageal cancer has been reported as an additional putative cofactor for bacterial infections.8 Endogenous hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) enhance host defense against pathogens by mobilizing granulocytes and improving neutrophil function.9 In a recently published meta-analysis, G-CSF was shown to reduce the frequency and length of neutropenia in patients undergoing chemotherapy for malignant lymphoma10 and solid tumors.11 Currently, G-CSF is mainly used for the prevention of chemotherapy-induced neutropenia and neutropenia-associated infections, in clinical trials aimed at dose escalation of cytostatic drugs, as well as in high-dose chemotherapy and stem-cell selection. More recently, smaller studies have investigated the use of G-CSF to prevent bacterial infections in non-neutropenic patients.12–18 In a trial involving non-neutropenic postoperative/posttraumatic patients at high risk of sepsis, none of the G-CSF treated patients developed sepsis, whereas 3 patients in the control group died.14 Another trial involving patients with acute traumatic brain injury or cerebral hemorrhage reported that G-CSF was associated with a dose-dependent reduction in the frequency of bacteremia.15 One pilot study investigated the efficacy of G-CSF in preventing postoperative infections after radical vulvectomy.18 Compared with historic controls, the incidence of wound infection and wound breakdown was markedly decreased. Administration of G-CSF in these trials was safe and well tolerated. In addition, there is some evidence that G-CSF activates anti-inflammatory cytokines such as IL-1ra and soluble TNF-alpha-receptor (sTNFR) and reduces the levels of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF).19 Because G-CSF might improve impaired neutrophil function in patients undergoing esophagectomy for esophageal cancer, our group performed a phase-II study using a perioperative application schedule.20 We found a marked increase in neutrophil function despite the extensive surgical trauma as well as a low infection rate in 20 patients enrolled when compared with historic controls. To validate these data, we initiated a prospective placebo-controlled study with perioperative administration of G-CSF to reduce infection rates in patients after esophagectomy for esophageal cancer. Here, we report the results of this multicenter trial in a total of 155 randomized patients.

The aim of this prospective cohort study was to address the feasibility of measuring cytokines in serum and urine as early predictor tests for the identification of septic Intensive Care Unit (ICU) patients. The study group consisted of 10 septic and 5 non-septic patients at the onset of sepsis according to modified definitions by the American College of Chest Physicians (ACCP)/Society of Critical Care Medicine (SCCM). Serum and urine samples were taken from septic patients at the onset of sepsis and from non-septic patients, every 12 h for 3 days and thereafter every 24 h until day 10. Levels of TNF-alpha, IL-1beta, IL-6, IL-10, IL-18, IFN-gamma, MCP-1, and PCT (procalcitonin) were measured by ELISA. Apart from serum IL-18 and PCT levels, which were elevated in septic patients (p

Background Skip metastasis to mediastinal lymph nodes is a well-known phenomenon in non-small cell lung cancer (NSCLC). Little is reported in the literature about its clinical importance. It is still under discussion whether any prognostic differences exist between resected NSCLC with either skip metastases or continuous mediastinal lymph node metastases (N2). Patients and Methods We analyzed retrospectively the data of 45 patients with a pN2-stage, who underwent resection for NSCLC. Seventeen of these patients (37.8%), showing no metastatic involvement of hilar (N1) lymph nodes, were compared to the remaining 28 patients with infiltration of hilar nodes (N1) as well as N2 nodes. Results Multivariate analysis showed no statistically significant difference between the skip metastasis and the continuous N2 group regarding sex, age, histology, T- or M-status. The frequency of skip metastasis was higher in patients with a primary tumor in the upper lobe (n = 12, 71%) compared to the lower lobe (n = 5, 29%). This difference was not statistically significant. In patients with a non-continuous lymph node spread, 29 out of 119 resected mediastinal lymph nodes were infiltrated (1.7 per patient, range: 1–10). Compared to 83 metastatic involved lymph nodes out of 198 resected mediastinal nodes (three per patient, range: 1–10) in patients with involvement of N1 and N2 nodes (P = 0.034, Mann–Whitney test). The 5-year survival rate of pN2 patients with skip metastasis was 41% compared to 14% in patients with involvement of N1 and N2 nodes (P = 0.019). Conclusions pN2 patients with mediastinal lymph node skip metastasis have a more favorable prognosis compared to pN2 patients with continuous infiltration of the regional lymph nodes. Patients with a continuous lymph node involvement show an increased number of infiltrated mediastinal lymph nodes per patient compared to patients with a non-continuous spread. Skip metastasis is an independent prognostic factor of survival. The presence of skip metastasis seems to be a unique subgroup of pN2 disease in NSCLC. J. Surg. Oncol. 2003;82:256–260. © 2003 Wiley-Liss, Inc.

The stimulatory effects of different purified lipopolysaccharide (LPS) preparations from E. coli, S. typhosa, P. aeruginosa, and K. pneumoniae on cytokine and chemokine production were measured in whole blood assays by ELISA. Incubation of 0.5 ml whole blood with 10 ng/ml E. coli and S. typhosa resulted in a time-dependent production of TNF-alpha, IL-1beta, IFN-gamma, IL-10 and MCP-1. K. pneumoniae, however, showed preferential effects on IL-1beta, IL-10 and MCP-1 production with less potent effects on TNF-alpha and IFN-gamma. LPS derived from P. aeruginosa showed a similar potency to other LPS preparations on MCP-1 production, yet completely failed to elicit the production of other cytokines. To further investigate potencies of the different LPS preparations, mediator production was determined following stimulation with agonist concentrations of 0.1 ng and 1000 ng per ml over a 24 h time period. Dose-response curves were obtained with LPS derived from E. coli, S. typhosa and K. pneumoniae on all mediators apart from IL-1beta and MCP-1. Most strikingly though, was the ability of LPS derived from P. aeruginosa to selectively elicit a significant dose-response effect on MCP-1 production, despite its very weak stimulatory effects on all other cytokines. These data imply that the bacterial origin of different LPS preparations can exhibit disparate effects on inflammatory mediator production. Furthermore, the potent, selective dose-response effect of P. aeruginosa LPS on MCP-1 production could help to explain the preponderance of a relentless inflammatory cellular infiltrate in diseases such as cystic fibrosis (CF).

Der Lymphknotenstatus des Magenkarzinoms kann weder pra- noch intraoperativ zuverlassig vorhergesagt werden. Fur die Einschrankung bzw. Unterlassung der Lymphadenek-tomie im Rahmen des Sentinel-Node-Konzeptes ist eine sichere Erfassung des N-Status jedoch von entscheidender Bedeutung. Das bereits erfolgreich beim malignen Melanom und beim Mammakarzinom eingesetzte Sentinel-Node-Konzept konnte auch bei gastro-intestinalen Tumoren zu einer Planung der Lymphknotendissektion beitragen. Erste Ergebnisse aus Japan deuten darauf hin, dass dieses Konzept auch beim Magenkarzinom anwendbar ist.

Einleitung: Ziel unserer prospektiven Studie war die Evaluation der p53- und MMP-2 Immunreaktivitat in Magenkarzinomen sowie deren Korrelation zur Tumorprogression und insbesondere zur Lymphknotenmetastasierung. Methode: Die vorliegende immunhistochemische Studie analysiert den MMP-2 Status der Resektionspraparate von 115 Patienten (mean Alter 64 Jahre; Bereich: 33 — 86) mit primarem Magenkarzinom nach D2-Gastrektomie. Die immunhistochemische Analyse an Paraffinschnitten erfolgte fur p53 nach der Immunomax-Methode und fur MMP-2 nach der ABC-Methode. Die Auswertung erfolgte semiquantitativ. Alle Tumore wurden gemas der UICC-, WHO-, Lauren-, Ming- und Goseki-Klassifikation eingeodnet. Ergebnisse: Eine positive Immunreaktivitat fur MMP-2 konnte in 94 (81,7%) Tumorresektaten nachgewiesen werden. 21 Praparate (18,3%) zeigten keine MMP-2 Expression. Zwischen der MMP-2 Expression und anderen Faktoren wie dem Alter, der Tumordifferenzierung, der WHO-, der Lauren-, der Goseki-, und der Ming-Klassifikation konnte keine Korrelation gefunden werden. Im Gegensatz hierzu zeigte die MMP-2 Expression eine signifikante Korrelation zur Tumorinfiltration (T-Stadium), zur Lymphknotenmetastasierung (N-Stadium), zur Fernmetastasierung (M-Stadium) und zum UICC-Stadium. Eine Uberexpression (Anfarbung > 20%) von p53 zeigte sich in 80,7% der untersuchten Tumore. Die p53 Immunreaktivitat korrelierte dabei signifikant mit dem T- und dem N-Status sowie mit dem UICC-Stadium. Schlusfolgerungen: Die Expression von p53 und MMP-2 in Magenkarzinomen zeigt eine signifikante Korrelation zur Tumorprogression und insbesondere zur Lymphknotenmetastasierung. Die immunhistochemische Analyse von p53 und MMP-2 konnte daher in Kombination mit klinischen Parametern von klinischer Relevanz fur die Pradiktion der Tumorprogression und der Lymphknotenmetastasierung sein.

Einleitung: Die stationare Osophagusdurchzugsmanometrie hat sich inzwischen als Standard in der Diagnostik von Osophagusfunktionsstorungen etabliert. Jedoch ist die Bedeutung der einzelnen Komponenten des Manometrieprotokolls fur die Wahl der OP-Methode bei gastroosophagealer Refluxkrankheit (GERD) nicht adaquat untersucht. Ziel dieser Studie war die Evaluierung des Einflusses der verschiedenen Parameter der Osophagusmanometrie auf die chirurgischen Strategie bei GERD. Patienten und Methoden: Von Januar 1995 bis Januar 2000 wurden 123 konsekutiv zugewiesene GERD-Patienten untersucht. 97 dieser Patienten (52 Frauen und 45 Manner, mittleres Alter 48 Jahre) wurden mit einer Fundoplikatio nach Nissen in konventioneller oder laparoskopischer Technik versorgt. Praoperativ wurden bei jedem Patienten eine stationare Osophagusdurchzugsmanometrie mit Wasserperfusionskatheter, sowie Gastroduodenoskopie und 24 h-osophagus-pH-Metrie standardmasig durchgefuhrt. Unabhangig von den Ergebnissen der Osophagusmanometrie erhielt jeder Patient eine 360°-Fundoplikatio mit 2 cm langer Manschette („floppy-Nissen“). Ergebnisse: Praoperativ wiesen 85 der 97 Patienten (88%) eine Inkompetenz des unteren osophagussphinkters auf. Bei 17 (18%) Patienten wurde eine Osophagushypomotilitat diagnostiziert. Bei 2 bzw. 1 nicht operierten Patienten wurde eine amotile Achalasie bzw. ein diffuser Osophagusspasmus festgestellt. Postoperativ wurden 92% der Patienten nachuntersucht (mittlere Nachuntersuchungszeit 1,8 Jahren). 5 bzw. 8 Patienten (1 bzw. 2 davon hypomotil) entwickelten postoperativ eine persistierende Dysphagie bzw. ein Rezidiv (Relatives Risiko 1,2 bzw. 1,6). Zwei Patienten (einer hypomotil) wurden reoperiert. Schlussfolgerungen: Die praoperative Osophagusmanometrie bei GERD kann auf die Bestimmung der oberen Grenze des unteren Osophagussphinkters, sowie den Ausschluss spezieller Osophagusmotilitatsstorungen eingeschrankt werden. Die „floppy-Nissen“ Fundoplikatio kann ohne zusatzliches Dysphagierisiko bei Patienten mit hypomotilem Osophagus angewandt werden.

Einleitung: Bislang existiert eine Vielzahl von histopathologischen Klassifikationen des Magenkarzinoms. Anlehnend an die Lauren-Klassifikation wurde die Ming-Klassifikation eingefuhrt, die einen expansiven von einem infiltrativen Tumortyp unterscheidet. Aktuell liegen nur wenige Studien zur Ming-Klassifikation beim Magenkarzinom vor, die zudem kontroverse Ergebnisse aufzeigen. Ziel unserer Studie ist daher ein Vergleich der Ming-Klassifikation mit etablierten Klassifikationssystemen und die Beurteilung ihrer Relevanz fur die Einschatzung der Tumorprogression. Methode: Die vorliegende morphologische Studie analysiert die Resektionspraparate von 115 Patienten (mean 65 Jahre; Bereich: 33–86) mit primarem Magenkarzinom nach D2-Gastrektomie. Alle Tumore wurden gemas der UICC-, WHO-, Lauren-, Ming- und Goseki-Klassifikation durch 2 Pathologen unabhangig voneinander eingeteilt. Statistik: Die Korrelation zwischen den histopathologischen Klassifikationen wurde univariat nach Spearman berechnet. P-Werte < 0.05 wurden als statistisch signifikant angenommen. Ergebnisse: Nach der Ming-Klassifikation konnten 44 Patienten (38,3%) dem expansiven und 71 Patienten (61,7%) dem infiltrativen Typ zugeordnet werden. Erwartungsgemas zeigte sich eine Korrelation mit der Lauren-Klassifikation (p < 0.0001), wobei alle intestinalen Tumore dem expansiven Typ und die Karzinome vom Mischtyp bzw. vom diffusen Typ dem infiltrativen Typ zugeordnet wurden. Desweiteren ergab sich eine hochsignifikante Korrelation mit der WHO-Klassifikation, der Tumordifferenzierung und der Goseki-Klassifikation (p < 0.0001). Die makroskopische Klassifikation nach Borrmann zeigte ebenfalls eine Korrelation mit der Ming-Klassifikation, wobei 62% der Fruhkarzinome dem expansiven Typ und 95% der Bor mann IV-Karzinome dem infiltrativen Typ zugeordent wurden (p < 0.0001). Das Tumorstadium (UICC) und hier insbesondere der T- und N-Status wiesen eine hochsignifikante Korrelation zur Ming-Klassifikation auf. So waren 66% der NO-Falle dem expansiven Typ und 91% der N3-Falle dem infiltrativen Typ zuzuordnen (p < 0.0001). Schlussfolgerungen: Die Ming-Klassifikation korreliert hochsignifikant mit den etablierten histopathologischen Klassifikationssystemen. Zusatzlich besteht eine valide Korrelation mit dem Tumorstadium, insbesondere dem T- und N-Status.