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Der entscheidende Faktor fur die Verbesserung der Lebensqualitat bei Colitis-ulcerosa-Patienten ist die Resektion des erkrankten Kolons und Rektums. Hierdurch gewinnen Colitis-ulcerosa-Patienten signifikant an Lebensqualitat und konnen sogar Werte erreichen, die denen eines gesunden Kontrollkollektivs vergleichbar sind. Die Kontinenz wiederherstellende ileoanale Pouchoperation ermoglicht einen weiteren Zugewinn an Lebensqualitat, wenn eine vollstandige anale Kontinenzleistung und gute Funktion besteht, denn diese verbessern die korperliche Aktivitat und Attraktivitat der in der Regel jungen Patienten. Dieses Ziel kann jedoch nur erreicht werden, wenn keine Komplikationen auftreten, oder aber wenn auftretende Komplikationen in einer fachlich qualifizierten Nachsorge fruhzeitig detektiert, einer spezifischen (chirurgischen) Therapie zugefuhrt und beherrscht werden. Auch wenn mehrere Operationen zur Beherrschung der Pouchkomplikation erforderlich sind, weisen Pouchrevisionen eine sehr hohe Erfolgsquote von 94% auf. Colitis-ulcerosa-Patienten ohne Komplikationen wie auch Patienten mit beherrschten Komplikationen erreichen Lebensqualitatswerte eines gesunden Kontrollkollektivs. Ein gut funktionierender Pouch garantiert dem Patienten eine gute Lebensqualitat im Langzeitverlauf. Morbus-Crohn-Patienten profitieren von einer Resektion bzw. Strikturoplastik, welche die klinische Stenosesymptomatik behebt. Ein chronisch-aktiver Morbus Crohn und das postoperative Crohn-Rezidiv zeigen einen stark negativen Einfluss auf die postoperative Lebensqualitat, ebenso wie postoperativ auftretende Komplikationen. Die Beherrschung dieser Komplikationen resultiert in einem deutlichen Zugewinn an Lebensqualitat.

The pathogenesis of pouchitis, major complication after restorative proctocolectomy, and ileal J pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC) is still unclear. Changes in intraluminal bacterial colonization and correlated changes of pouch mucosa are thought to play an important role. Toll-like receptors (TLRs) as part of the innate immune system are capable of recognizing bacterial antigens. Their activation can lead to secretion of proinflammatory mediators. In this study, TLR2, 3, 4, and 5 expression profiles in the pouch mucosa of patients with UC and IPAA were analyzed and correlated with pouchitis. Clinical symptoms, endoscopy, and histology were assessed in 35 patients using the Heidelberg Pouchitis Activity Score to classify patients as either having pouchitis or not. TLR mRNA expression in normal ileal mucosa and pouch mucosa was investigated by performing semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). The results of RT-PCR were associated with the pouchitis score. In the analysis of all patients, TLR3 expression was decreased significantly whereas TLR5 expression was increased significantly in pouch mucosa compared to normal ileal mucosa (p-values 0.0076 and 0.016, respectively). A more detailed analysis upon dividing the patients into patients with and without pouchitis showed decreased TLR3 expression in the pouch mucosa only of patients without pouchitis (p-value=0.0067). TLR5 expression was increased in the pouch mucosa only of patients with pouchitis (p-value=0.023). No differences in TLR2 and 4 expression were found in either group. Differential expression of TLR3 and 5 suggests bacterial involvement in the pathogenesis of pouchitis in patients with UC.

Die Indikation zur Proktokolektomie und ileoanalen Pouchoperation (IAP) wegen einer Colitis ulcerosa (CU) wird im Kindesalter nur zogernd gestellt, obwohl sie hinsichtlich deren Kolonmanifestation kurativ wirkt. Diverse technische und indikatorische Modifikationen der letzten Jahre fuhrten zu einem deutlichen Abfall der Komplikationsraten. Der vorliegende Beitrag berichtet uber die aktuelle Operationstechnik, die Indikationsstellung, die strategische Vorgehensweise und die Ergebnisse nach IAP im Kindesalter. Eine Langzeitnachsorge ist dabei wichtig, um evtl. auftretende Komplikationen rechtzeitig erkennen und erfolgreich behandeln zu konnen. Auf diese Weise konnen Kinder nach IAP eine Lebensqualitat erreichen und behalten, die gesunden Kontrollen entspricht.

Background and aims: Restorative proctocolectomy with construction of an ileoanal pouch (IPAA) is the surgical treatment of choice for patients with ulcerative colitis (UC) or familial adenomatous polyposis (FAP). This procedure imposes an essential change in function on the terminal ileal mucosa and pouch mucosa. Glutamine is one of the major nutrients for the small-bowel mucosa; it is metabolized into glutamate and subsequently alanine in the human enterocyte. In a prospective clinical trial we compared glutamine distribution in patients with UC to that in patients with FAP before and after restorative proctocolectomy. Methods and patients: Concentrations of glutamine, glutamate, and alanine were measured pre- and postoperatively in the terminal ileal mucosa, pouch mucosa, skeletal muscle and venous blood of patients undergoing IPAA for UC or FAP. Healthy individuals served as controls for skeletal muscle glutamine concentration. Results: After IPAA the glutamine concentration in UC patients was decreased in skeletal muscle. In the mucosa glutamine remained unaltered while glutamate and alanine concentrations increased. In plasma the glutamine concentration increased, the glutamate level fell, and the alanine level increased. In FAP patients the glutamine level was unchanged in skeletal muscle after IPAA. In mucosa the glutamine level did not change, but glutamate and alanine increased. In plasma the glutamine level remained unaltered, glutamate decreased, and alanine increased. Conclusion: Patients with UC or FAP before surgical therapy do not suffer from glutamine depletion. IPAA resulted in changes in the distribution of glutamine and its metabolites in skeletal muscle, plasma, and ileal pouch mucosa, particularly in patients with UC. Further studies should investigate whether characteristics in the glutamine distribution have any impact for the long-term outcome after IPAA.

BackgroundDespite the wide range of surgical approaches for pouch salvage, septic complications are among the main causes of pouch failure.MethodsThis study analysed the mode and outcome of various therapeutic approaches for pouch salvage and the impact of time of diagnosis, localization and form of septic complications on the risk of pouch failure in 131 patients with septic complications of a total of 706 patients undergoing a J pouch procedure.ResultsSeptic complications consisted of 76·3 per cent fistulas, 15·3 per cent anastomotic breakdowns and 8·4 per cent pelvic abscesses. A total of 107 patients (81·7 per cent) with septic complications required a mean of 2·2 surgical procedures. The frequency of permanent defunctioning and excision of the pouch in the 131 patients with septic complications was 23·7 and 6·1 per cent respectively. The estimated cumulative 3-, 5- and 10-year rate of pouch failure in patients with septic complications was 19·6, 31·1 and 39·2 per cent respectively. The risk of pouch failure was significantly affected by the site of origin of septic complications (P = 0·02). The 5-year pouch failure rate increased in a subgroup of patients with septic complications at the pouch–anal anastomosis when the anal sphincter was involved (50·1 versus 29·2 per cent; P = 0·18).ConclusionPouch failure as a result of septic complications may occur several years after ileal pouch–anal anastomosis. For prevention of pouch failure, surgery for septic complications is required in a high percentage of patients and repeated attempts are justified. Follow-up studies are required for further analysis of pouch failure.

To analyze the association between pre- and perioperative factors and pouch-related septic complications (PRSC) in ulcerative colitis (UC) and in familial adenomatous polyposis (FAP) after ileal pouch-anal anastomosis (IPAA).For patients with UC and FAP, IPAA is the surgical therapy of choice, but in some patients the outcome is compromised by PRSC.A total of 706 consecutive patients (494 UC, 212 FAP) were assessed in a study aimed at identifying subgroups of patients who were at high risk for PRSC. The rate of PRSC was analyzed as a time-dependent function (Kaplan-Meier estimation). Patients with UC and FAP were stratified separately according to associated factors (age, sex, surgeon's experience, temporary ileostomy, colectomy before IPAA, anastomotic tension, and several factors specific for UC).In all, 131 (19.2%) patients had PRSC (23.4% UC, 9.4% FAP). In patients with UC, the estimated 1-year PRSC rate was 15.6% and the estimated 3-year PRSC rate was 24.2%. In patients with FAP, the estimated 1-year and 3-year PRSC rates were 9.2%. The difference between the estimated rates of PRSC was significant (P.001). In the univariate analysis, patients with UC younger than 50 years, with severe proctitis, with preoperative hemoglobin levels less than 10 g/L, or receiving corticoid medication had a significantly higher risk for PRSC (P =.039, P =.037, P =.047, P =.003, respectively). Multivariate analysis showed that patients with UC receiving a systemic prednisolone-equivalent corticoid medication of more than 40 mg/day had a significantly greater risk of developing pouch-related complications than patients with UC receiving 1 to 40 mg/day and patients with UC who were not receiving corticoid medication (RR: 3.78, 2.25, 1, respectively, P.001). Patients with FAP proved to have a significantly higher risk for PRSC in the univariate and multivariate analyses if anastomotic tension had occurred (RR 3.60, P =.0086).Pouch-related septic complications occur as late complications and should therefore be considered in regular, specific long-term follow-up examinations. The authors identified significant risk factors for PRSC specific to patients with UC and FAP; these must be considered for each individual surgical strategy.

Emergency Indications and Surgical Therapies in Patients with Toxic Colitis ulcerosa Patients suffering from severe toxic ulcerative colitis should be stabilized by intensive care

PURPOSE: Inflammation of the ileoanal pouch (pouchitis) is one of the main complications after restorative proctocolectomy, yet its cause remains poorly understood. A standardized definition and diagnostic procedures in pouchitis are lacking. METHOD: We analyzed all cases of pouchitis occurring in a group of 308 patients (210 with ulcerative colitis, 98 with familial adenomatous polyposis) who took part in a prospective long-term follow-up program. The severity of pouchitis was measured using a pouchitis activity score (Heidelberg Pouchitis Activity Score). An algorithm for the classification and management of pouchitis was established which enables the clinician: 1) to determine theseverity of pouchitis, 2) to differentiate betweenprimary pouchitis and pouchitis caused by surgical complications (secondary pouchitis), and 3) to evaluate the course (acute vs. chronic (>3 months)). RESULTS: The median duration of follow-up was 48 (range, 13–119) months. At least one episode of pouchitis was diagnosed in 29 percent of patients with ulcerative colitis and in 2 percent of familial adenomatous polyposis patients. Secondary pouchitis occurred in 6 percent of ulcerative colitis patients and was cured by surgical treatment in 13 (87 percent) of 15 cases. Primary pouchitis was diagnosed in 23 percent of ulcerative colitis patients, including 6 percent of all ulcerative colitis patients with chronic primary pouchitis. The latter showed poor response to medical treatment. In one case multifocal high-grade dysplasia occurred. Histologic examination of the excised pouch identified a carcinoma originating from the ileal mucosa. CONCLUSIONS: Ulcerative colitis patients after restorative proctocolectomy face a high risk of developing pouchitis. The algorithm used in this study was highly efficient in identifying patients with a secondary pouchitis who require surgical treatment and patients with chronic primary pouchitis. For the latter, long-term surveillance seems mandatory because of the risk of malignant transformation of the pouch mucosa.

The ileoanal pouch procedure (IAPP) was the most remarkable breakthrough in the surgical therapy of ulcerative colitis (UC) and familial adenomatous polyposis (FAP) in the last 20 years. The underlying disease is under control, the function preserved and the quality of life markedly improved. Alternative procedures (terminal ileostomy, ileorectal anastomosis) are only indicated in special cases. In the last 16 years we have operated on 662 patients (n = 493 UC; n = 169 FAP) with an ileoanal J-pouch, short rectal cuff, complete mucosectomy and hand-sewn anastomosis. Normally there is a good function for UC and FAP patients after IAPP. Surgical experience, technical modifications concerning the pouch design and the pouch-anal anastomosis, and a differentiated indication lead to a further improvement of these complex procedures with consecutive reduction of complications. Specific complications concerned mainly the pouch-anal anastomosis (fistulas, abscesses, consecutive stenosis) and inflammation of the pouch mucosa (pouchitis). A multivariate analysis showed, that increasing experience of the specialized center is a significant factor reducing inflammatory problems at the anastomosis. The cumulative incidence of pouchitis was 29%. In general there is no problem in successful treatment. But patients with chronic pouchitis are a problematic group (6.2%). Chronic pouchitis is difficult to treat. It is likely that there exists an inflammation dysplasia carcinoma sequence for the ileal pouch mucosa, analogous to the colorectum. Recently we diagnosed the first case of a real ileum pouch carcinoma with associated epithelial dysplasias following chronic pouchitis. Therefore patients with chronic pouchitis must be followed up by endoscopy and random biopsies in a surveillance program. Patients with UC and FAP can gain the life quality of healthy controls, if postoperative complications can be avoided or treated successfully. For the further development of the procedure and the individual long-term success a qualified follow-up and therapy of complications is essential. Both can be carried out only by a specialized center.

Die Lebensqualitat stellt nach ileoanaler Pouchoperation bei Patienten mit Colitis ulcerosa (CU) und familiarer adenomatoser Polyposis (FAP), neben postoperativer Morbiditat und funktionellen Parametern, eine relevante Grose zur Beurteilung des Operationserfolges dar. In den Jahren 1982 bis 1997 wurden an der Chirurgischen Universitatsklinik Heidelberg 602 Patienten (CU: n = 424; FAP: n = 178) mit einer Proktocolektomie und kontinenzerhaltenden ileoanalen Pouchanlage versorgt. Bei 27 CU- und 7 FAP-Patienten fuhrten wir eine prospektive Verlaufsbe-obachtung zur pra- und postoperativen Lebensqualitat – vor restaurativer Proktocolektomie, vor Ileostomaruckverlagerung, ein Jahr nach Ileostomaruckverlagerung – durch. CU-Patienten zeigten praoperativ eine sehr schlechte Lebensqualitat. Der entscheidende therapeutische Schritt war die Proktocolektomie. Durch die Ruckverlagerung der protektiven Ileostomie konnte die Lebensqualitat nicht mehr signifikant gesteigert werden. FAP-Patienten besasen vor Proktocolektomie eine gute Lebensqualitat, Aktivitat und Funktion, entsprechend der einer gesunden Kontrollgruppe. Durch die Proktocolektomie zeigten sie deutliche Verluste. Diese wurden durch Ileostomaruckverlagerung teilweise wieder ausgeglichen. Wichtigstes Ergebnis ist, das bei CU- und FAP-Patienten durch die restaurative Proktocolektomie eine gute Lebensqualitat und Aktivitat, vergleichbar einer gesunden Kontrollgruppe, erreicht werden kann.

Nach ileoanaler Pouchoperation wegen Colitis ulcerosa (CU) oder familiarer adenomatoser Polyposis (FAP) stellt die Lebensqualitat, neben postoperativer Morbiditat und funktionellen Parametern, eine relevante Grose zur Beurteilung des Operationserfolges dar. In den Jahren 1982 bis 1995 wurden an der Chirurgischen Universitatsklinik Heidelberg 453 Patienten (CU: n = 332; FAP: n = 121) mit einer Proktocolektomie und kontinenzerhaltenden ileoanalen Pouchanlage versorgt. An diesem Krankengut fuhrten wir eine Langzeitnachbeobachtung zur postoperativen Lebensqualitat (mediane Nachbeobachtungszeit 43,2 Monate) durch. Im Langzeitverlauf (mindestens 1 Jahr nach Ileostomaruckverlagerung; J-Pouch: n = 243, davon CU: n = 185, FAP: n = 58) waren Nachbeobachtungszeit, Grunderkrankung (CU vs. FAP) und beherrschte Komplikationen ohne Einflus auf die Lebensqualitat. Den starksten Einflus auf die Lebensqualitat hatten das Patientenalter (p < 0,01) und aktuelle, nicht beherrschte Komplikationen (p < 0,0001). Es zeigte sich ein deutlicher Zusammenhang zwischen Funktionsindex und Lebensqualitatsindex (Korrelationskoeffizient r = –0,714). Nach Proktocolektomie und J-Pouch konnen Lebensqualitatswerte vergleichbar einer gesunden Kontrollgruppe erreicht werden. Entscheidend ist die Vermeidung und Beherrschung von postoperativen Komplikationen.

Die restaurative Proktocolektomie gilt heute als Standardverfahren in der chirurgischen Therapie der Colitis ulcerosa. Alternative Verfahren (terminale- oder Kock-Ileostomie) sind auf Sonderindikationen beschrankt. Der entscheidende Vorteil der ileoanalen Pouchoperation liegt im Funktionserhalt. Dieser kann jedoch nicht einfach mit Lebensqualitat gleichgesetzt werden. Lebensqualitat ist ein multidimensionaler Begriff, der schwierig zu definieren und zu messen ist. Lebensqualitat kann nur mit geeigneten standardisierten und validierten Lebensqualitats-Mesinstrumenten erfast werden. Patienten mit Colitis ulcerosa haben, abhangig von ihrer Krankheitsintensitat, eine deutlich eingeschrankte praoperative Lebensqualitat. Der heilende Eingriff ist die Proktocolektomie. Dies schlagt sich in der Verbesserung der Lebensqualitat nieder. Bezuglich der erreichbaren Lebensqualitat ist es von untergeordneter Bedeutung, ob die Patienten mit einer terminalen Ileostomie oder einem kontinenzerhaltenden ileoanalen Pouch versorgt werden. Der Vorteil der restaurativen Proktocolektomie liegt in der Verbesserung von – speziell fur junge Patienten – wichtigen Teilbereichen, wie z. B. der Sexualitat und der korperlichen Aktivitat. Dies beeinflust auch bei Messung mit geeigneten Instrumenten nicht die Gesamtlebensqualitat. Patienten sollten praoperativ daruber aufgeklart werden, das der Funktionserhalt durch die ileoanale Pouchoperation gegenuber der terminalen Ileostomie mit einer deutlich erhohten postoperativen Morbiditat einhergeht. Treten postoperative, langfristig nicht beherrschbare Komplikationen auf, so resultiert eine wesentlich eingeschrankte Lebensqualitat. Unter Umstanden kann dann die Pouchexstirpation mit terminaler Ileostomie die sinnvollere Alternative sein. Andererseits kann der Patient mit einem gut funktionierenden, nicht komplikationsbehafteten ileoanalen Pouch evtl. in allen Teilbereichen Lebensqualitatswerte fast vergleichbar einer gesunden Kontrollgruppe erreichen. Diese Risiko-Nutzen-Relation mus dem Patienten praoperativ bewust gemacht und von ihm mitgetragen werden.

Die Coltis ulcerosa (CU) ist eine Krebsrisikoerkrankung. Bekannte Risikofaktoren sind die Erkrankungsdauer, der ausgedehnte Colonbefall, eine primar sklerosierende Cholangitis (PSC) und fraglich der fruhe Beginn im Kindesalter. Epitheldysplasien gelten im Sinne einer Entzundungs-Dysplasie-Carcinom-Sequenz als Vorlauferlasionen des Carcinoms, entstehen meist multifocal und sind coloskopisch oft nur schwer identifizierbar. Ebenso ist die histomorphologische Dysplasiediagnostik nicht ohne Schwierigkeiten. Uberwachungsprogramme nutzen die Moglichkeit der Dysplasiediagnose mittels Coloskopie und Stufenbiopsien bei CU-Patienten mit Risikofaktoren. Die Effizienz dieser Programme kann unter Berucksichtigung verschiedener Richtlinien deutlich gesteigert werden. Ziel mus es sein, Colitis-Patienten mit Risikofaktoren vor Entwicklung eines manifesten Carcinoms prophylaktisch zu proktocolektomieren. Manifeste Carcinome konnen bis auf wenige Ausnahmen erfolgreich durch eine restaurative Proktocolektomie therapiert werden. Okkulte Carcinome und synchrone Mehrfachcarcinome sind relativ haufig, weswegen Colonteilresektionen unbedingt vermieden werden sollten. Es gibt erste Hinweise, das auch fur die Ileummucosa ein malignes Entartungsrisiko besteht. Die Risikogruppe stellen nach ileoanalem Pouch die Patienten mit chronischer Pouchitis dar. Wie hoch dieses Entartungsrisiko im ileoanalen Pouch letztendlich ist, kann zum heutigen Zeitpunkt aufgrund zu kurzer Nachbeobachtungszeit noch nicht abschliesend beurteilt werden. Dennoch mus empfohlen werden, das alle Patienten nach ileoanaler Pouchoperation wegen einer CU lebenslang pouchoskopisch-bioptisch nachgesorgt werden.

Nowadays, restorative proctocolectomy is considered the "gold standard" in the surgical therapy of ulcerative colitis. Alternative procedures such as Brooke ileostomy or Kock pouch are limited to special indications. Preservation of function is the decisive advantage of the ileoanal pouch, but preservation of function is not equal to quality of life. Quality of life is a multidimensional concept that is difficult to define and measure. Quality of life can only be assessed by standardized and validated quality-of-life questionnaires. Preoperatively, patients with ulcerative colitis have a restricted quality of life, depending on the intensity of their disease. Proctocolectomy is the curative therapy and improves quality of life. When evaluating quality of life it is not essential if patients are treated by Brooke ileostomy or restorative proctocolectomy. The advantage of restorative proctocolectomy is the improvement in some aspects such as sexuality and physical activity. The "Total Quality-of-Life Index" is not improved. Preoperatively, patients should be informed that preservation of function by restorative proctocolectomy is accompanied by an increased postoperative morbidity in comparison to other procedures. Decreased quality-of-life results when complications occur postoperatively that cannot be controlled over a long period of time. In some cases excision of the ileoanal pouch may be the most sensible way of solving the problems. On the other hand, patients without complications and good function after ileoanal pouch procedure may achieve a quality of life comparable to that of healthy controls. Preoperatively, patients should be aware of this risk-benefit relationship and should share the responsibility of the decision for or against restorative proctocolectomy.

PURPOSE: Pouchitis represents a serious threat to patients with ulcerative colitis after restorative proctocolectomy with ileal pouch-anal anastomosis. The frequency of pouchitis is high, and it implies the risk of pouch failure and the risk of malignant mucosal transformation in the pouch. Early detection and precise classification of the inflammatory process are required for adequate therapy, which might be facilitated using a scoring system. The aim of the present study was to validate two existing scoring systems in routine outpatient practice. METHOD: The Heidelberg Pouchitis Activity Score and the Pouchitis Disease Activity Index developed at the Mayo Clinic were simultaneously prospectively applied in a consecutive series of 103 outpatient consultations of 41 patients at our hospital and comparatively validated against the diagnosis of pouchitis or no pouchitis concurrently made by a physician and a surgeon. RESULTS: The median score of examinations in which the clinicians' diagnosis was consistent with pouchitis were significantly higher than those of examinations inconsistent with pouchitis in both scoring systems (Heidelberg Pouchitis Activity Score, 17 (interquartile range, 14-21) and 8 (interquartile range, 5-10), respectively, P < 0.001; Pouchitis Disease Activity Index, 7 (interquartile range, 5-8) and 2.5 (interquartile range, 1-4), respectively, P < 0.001). The sensitivity and specificity in the two total scores were 84 and 79.5 percent, respectively (Heidelberg Pouchitis Activity Score), and 60 and 96.2 percent, respectively (Pouchitis Disease Activity Index); in the field clinical manifestations 44 and 73.1 percent, respectively (Heidelberg Pouchitis Activity Score), and 20 and 87.2 percent, respectively (Pouchitis Disease Activity Index); in the field endoscopic manifestations 88 and 83.3 percent, respectively (Heidelberg Pouchitis Activity Score), and 60 and 89.7 percent, respectively (Pouchitis Disease Activity Index); and in the field histologic manifestations 72 and 76.9 percent, respectively (Heidelberg Pouchitis Activity Score), and 44 and 96.2 percent, respectively (Pouchitis Disease Activity Index). Lowering the cutoff point for diagnosis of pouchitis in the Pouchitis Disease Activity Index by 2 points (pouchitis: score ≥ 5) would result in an 88 percent sensitivity and a 67 percent specificity. CONCLUSIONS: Specificity and sensitivity of the Heidelberg Pouchitis Activity Score were satisfactory. The cutoff point for diagnosing pouchitis in the Pouchitis Disease Activity Index would have to he lowered to reach an acceptable sensitivity and specificity. The very poor validity of the field clinical manifestations in diagnosing pouchitis emphasizes the need for endoscopic and histologic examination for detection of pouchitis. The issue of whether the diagnosis of pouchitis should be based on endoscopic and histologic features alone, instead of additionally taking clinical features into account, should be addressed in future studies.

Abstract. To define mediator profiles in inflamed and noninflamed areas in inflammatory bowel disease (IBD) we analyzed the expression of 35 messenger-RNAs (mRNAs) encoding cytokines, chemokines, and some related molecules in transmural gut tissues (n=138) from patients with ulcerative colitis (UC), Crohn's disease (CD), and inflammatory and normal controls by real-time quantitative reverse transcription polymerase chain reaction. Using sample collectives with a comparable degree of inflammation, most parameters investigated showed similarly increased mRNA expression levels in both active UC and CD. This included proinflammatory cytokines, but also interferon (IFN) γ and several IFN-γ inducible chemokines. Only macrophage inflammatory protein (MIP)-2α mRNA was expressed at higher levels in inflamed UC vs. CD. IH revealed that MIP-2α protein was produced mainly by intestinal epithelial cells. Importantly, in histologically noninflamed/inactive IBD samples mRNAs for several mediators were significantly enhanced, accompanied by elevated levels of migration-inhibition factor related protein (MRP) 14 transcripts. CD14 positive macrophages were found especially in noninflamed/inactive UC, many of which coexpressed the RFD-7 antigen. Our results indicate a substantial overlap in cytokine/chemokine mRNA expression in UC and CD. Elevated mediator expression is evident in noninflamed/inactive areas in both diseases. Local recruitment of MRP-14 positive leukocytes might contribute to this phenomenon. In inactive UC a phenotypically altered population of macrophages expressing CD14 might play an additional role.

The ileo-anal pouch procedure: Complications, quality of life, and long-term results. Restorative proctocolectomy with construction of an ileal pouch-anal anastomosis (IPAA) has evolved as the surgical therapy of choice for patients with ulcerative colitis (UC) and patients with familial adenomatous polyposis (FAP). 662 patients (493 UC, 169 FAP) consecutively received IPAA. Marked differences were observed between UC and FAP patients regarding the rates of overall complications (33.1 % vs. 12.5 %), pouchitis (29 % vs. 2 %), and pouch extirpation (3.2 % vs. 0.6 %). Pouchitis occurred as primary (79 %) and secundary (21 %) form, with acute (67.2 %) or chronic (32.8 %) course. Each form and course required specific therapy. Chronic pouchitis implies the risk of malignant transformation of the pouch mucosa. Quality of life improves significantly after IPAA in patients with UC and is equal to that in normal individuals, in UC and FAP, if postoperative complications are either prevented or under control.

Die Indikation zur Kolektomie wird von Padiatern nur sehr zuruckhaltend gestellt. Bei Kindern stellt die IAP noch kein Standardverfahren dar und wird nur an wenigen Zentren in sehr kleinen Fallzahlen durchgefuhrt. Entsprechend sparlich sind Literaturangaben. Material und Methode:Von 1986 bis 12/2000 wurden an der Chirurg. Univ.-Klinik HD 50 Kinder (CU n = 34; FAP n = 16) restaurativ proktokolektomiert. Alle Kinder wurden prospektiv erfast. Die Nachsorge erfolgte standardisiert (med. NBZ 4,9 J. (0,5-14 J.)). Die Lebensqualitat (LQ) wurde mit einem kindgerecht modifizierten LQ-Score gemessen. Ergebnisse:Die Indikation zur IAP wurde bei CU-Kindern in 88,2% wegen Wachstumsretardierung, in 55,9% wegen schwerer Medikamenten-NW, in 23,5% wegen therapierefraktarem Verlauf und in 2,9% wegen Dysplasien gestellt (Mehrfachnennung). Die FAP-Kinder wurden in allen Fallen wegen ausgepragter Symptomatik (Blutung, Tenesmen) operiert, zusatzlich bestanden bei 2 Kindern Epithelatypien (Tabelle 1).

Surgical treatment is indicated in a certain number of patients with ulcerative colitis (UC), either as emergency treatment for acute complications or electively for a variety of reasons. 1 Total proctocolectomy with construction of an ileal pouch–anal anastomosis (IPAA) offers the chance of eliminating the underlying disease 2–5 and preserving anal continence. This procedure has, therefore, evolved as the therapy of choice for patients with UC requiring surgical treatment. 6–11 However, the early and late outcomes of IPAA may be compromised by several pouch-related complications, among which pouch-related septic complications (PRSCs) 12–15 and pouchitis 16–19 are most frequent. Hence, there is an ongoing debate on whether the results of IPAA may be influenced by different technical procedures 20–28 and strategies 1,29–31 for IPAA. Of these strategies, the choice between the one-stage or the two-stage procedure for performing IPAA has the most apparent implications for patients and has been the subject of comparative studies in the literature. 31–43 In the two-stage procedure, a defunctioning ileostomy is established to divert the fecal stream until the ileoanal anastomosis and the reservoir are securely healed. 31–33 In our experience, a number of patients are principally suitable for both the one- and the two-stage procedure under certain favorable conditions. However, a clear framework for choosing between the alternatives is lacking in the literature. Therefore, we compared the outcome between the one- and the two-stage procedure in a matched control study of a large series of consecutive patients. This retrospective study followed the hypothesis that patients fulfilling certain conditions allow the choice between the two procedures and might profit from the less extensive one because the outcome is either equal or superior, the duration of the operation and total hospital stay are shorter, and the overall risk of intra- and postoperative complications is equal or lower.

Restorative proctocolectomy and ileal pouch-anal anastomosis is the surgical treatment of choice for patients with ulcerative colitis. As a long-term complication of this procedure, chronic pouchitis impairs the outcome in a number of patients. Aneuploidia and dysplasia have been observed after long-lasting inflammation of ileal mucosa. The question arises whether chronic inflammation of ileal mucosa predisposes to malignant transformation similar to the situation in the chronically inflamed colon. Cancer of the ileal mucosa has been reported in patients with Brooke's ileostomy and in patients with Kock pouch but not as yet in those with an ileoanal pouch. We report a patient with carcinoma in an ileoanal pouch originating from terminal ileal mucosa who had been suffering from pancolitis with long-term backwash ileitis before, and from chronic pouchitis after, restorative proctocolectomy. This case demonstrates the importance of regular follow-up with pouchoscopy and random biopsies in all patients with long-standing inflammation of the ileal mucosa.

Commonly accepted risk factors for colorectal carcinoma (CRC) in ulcerative colitis are duration and extent of disease. By identifying still unknown risk factors, surveillance strategies may be improved further. We investigated whether backwash ileitis is also a factor associated with CRC in ulcerative colitis.Five hundred ninety consecutive patients with ulcerative colitis who received restorative proctocolectomy were classified into 3 groups: (1) pancolitis with backwash ileitis, (2) pancolitis without backwash ileitis, and (3) left-sided colitis. The association with CRC was analyzed in these 3 groups of patients. As further risk factors, we investigated disease duration, dysplasia, primary sclerosing cholangitis, age at diagnosis of disease, disease activity, and gender. Univariate and multivariate logistic regression were used for analysis.CRC was diagnosed in 11.2% of all patients. CRC was found in 29.0% of 107 patients in group 1, compared with 9.0% of 369 patients in group 2, and in 1.8% of 114 patients in group 3 (P0.001). Cancer patients in group 1 showed significantly more multiple tumor growth (45.2%) than patients in group 2 (24.2%) and group 3 (0%) (P = 0.041). Estimating the relative risk for CRC in the multivariate analysis, patients in group 1 showed a significantly higher odds ratio than patients in groups 2 and 3 (odds ratio: 19.36 vs. 9.58 vs. 1; P0.001). High-grade dysplasia, low-grade dysplasia, disease duration of more than 10 years, and disease duration of less than 10 years in patients older than 45 years were further factors with significantly increased risk (odds ratios: 21.69, 6.36, 3.63, 4.37), but primary sclerosing cholangitis was not (P = 0.080). However, primary sclerosing cholangitis was strongly associated with backwash ileitis.There is a strong association of backwash ileitis with CRC in patients with ulcerative colitis who undergo proctocolectomy. The predictive value of backwash ileitis for CRC and premalignant dysplasia in patients with ulcerative colitis should be investigated in future studies based on colonoscopic surveillance.

Background: Restorative proctocolectomy as the surgical treatment of choice for patients with ulcerative colitis (UC) and those with familial adenomatous polyposis coli (FAP) imposes an essential change of function on the terminal ileal mucosa. Glutamine is one of the major nutrients for the small-bowel mucosa; it is metabolized into glutamate and subsequently alanine in the human enterocyte. In a prospective clinical trial we compared glutamine distribution in patients with ulcerative colitis to that in patients with familial adenomatous polyposis coli before and after restorative proctocolectomy, as well as in healthy individuals. Method: Concentrations of glutamine, glutamate and alanine were measured pre- and postoperatively in the terminal ileal mucosa, pouch mucosa, skeletal muscle (in median mmol/kg wet weight) and venous blood (in median mmol/l plasma) of patients undergoing total colectomy and construction of an ileoanal pouch for ulcerative colitis (UC, n = 27) or familial adenomatous polyposis coli (FAP; n = 17). Healthy individuals served as controls for skeletal muscle glutamine concentration. Results: Glutamine concentration in the skeletal muscle of healthy individuals, patients with UC and patients with FAP before IPAA did not show a significant difference (9.56, 8.55, 8.11, p = 0.82), nor did the glutamine sequence profile in terminal ileal mucosa and blood of UC and FAP patients, respectively. After IPAA, glutamine concentrations in UC patients decreased significantly in skeletal muscle (8.55, 7.24, p = 0.034). In the mucosa, glutamine increased nonsignificantly (0.70, 0.88, p = 0.10), while glutamate and alanine concentrations increased significantly (2.72, 4.13, p < 0.001; 0.76, 1.36, p = 0.003). In plasma, glutamine concentrations increased significantly (0.52, 0.58, p = 0.017). In FAP patients, glutamine levels did not change in skeletal muscle (7.14, 7.08, p = 0.31) after IPAA. In mucosa, glutamine levels increased non-significantly (0.64, 0.80, p = 0.73), whereas glutamate (2.18, 3.96, p< 0.001) and alanine (0.86, 1.20, p = 0.011) increased significantly. In plasma, glutamine levels remained unaltered (0.57, 0.56, p = 0.59). After IPAA, glutamine concentration in the pouch mucosa was significantly higher in UC than in FAP patients (p = 0.029). Conclusion: Glutamine concentrations in the store skeletal muscle of UC patients and FAP patients before surgical therapy were equal to that in healthy individuals. Restorative proctocolectomy resulted in changes in the glutamine sequence profile in ileal mucosa of both groups of patients, but resulted in significant decrease of glutamine concentrations in the store skeletal muscle only in UC patients, indicating redistribution and increased consumption of glutamine by the ileal pouch mucosa. Investigations into possible associations between characteristics of glutamine metabolism and the occurrence of pouchitis in patients with UC are required.

Backwash Ileitis (BWI) wurde als potentieller Risikofaktor fur das kolorektale Karzinom (KRK) bei Colitis ulcerosa (CU) untersucht in 590 konsekutiven Patienten, die eine restaurative Proktokolektomie erhielten. Ergebnisse: Ein kolorektales Karzinom wurde in 11,2% aller Patienten, bzw. 29,0% von 107 Patienten mit BWI diagnostiziert. Bei den letztgenannten Patienten fand sich eine signifikant erhohte Haufigkeit multiplen Tumorwachstums (45%). In der multivariaten Analyse war das relative Risiko fur eine KRK significant erhoht bei Patienten mit BWI im Vergleich zu Patienten mit Pankolitis ohne BWI und zu Patienten mit linksseitiger Kolitis (19,36 vs. 9,58 vs. 1, p

The ileoanal pouch procedure (IAPP) was the most remarkable breakthrough in the surgical therapy of ulcerative colitis (UC) and familial adenomatous polyposis (FAP) in the last 20 years. The underlying disease is under control, the function preserved and the quality of life markedly improved. Alternative procedures (terminal ileostomy, ileorectal anastomosis) are only indicated in special cases. In the last 16 years we have operated on 662 patients (n = 493 UC; n = 169 FAP) with an ileoanal J-pouch, short rectal cuff, complete mucosectomy and hand-sewn anastomosis. Normally there is a good function for UC and FAP patients after IAPP. Surgical experience, technical modifications concerning the pouch design and the pouch-anal anastomosis, and a differentiated indication lead to a further improvement of these complex procedures with consecutive reduction of complications. Specific complications concerned mainly the pouch-anal anastomosis (fistulas, abscesses, consecutive stenosis) and inflammation of the pouch mucosa (pouchitis). A multivariate analysis showed, that increasing experience of the specialized center is a significant factor reducing inflammatory problems at the anastomosis. The cumulative incidence of pouchitis was 29%. In general there is no problem in successful treatment. But patients with chronic pouchitis are a problematic group (6.2%). Chronic pouchitis is difficult to treat. It is likely that there exists an inflammation dysplasia carcinoma sequence for the ileal pouch mucosa, analogous to the colorectum. Recently we diagnosed the first case of a real ileum pouch carcinoma with associated epithelial dysplasias following chronic pouchitis. Therefore patients with chronic pouchitis must be followed up by endoscopy and random biopsies in a surveillance program. Patients with UC and FAP can gain the life quality of healthy controls, if postoperative complications can be avoided or treated successfully. For the further development of the procedure and the individual long-term success a qualified follow-up and therapy of complications is essential. Both can be carried out only by a specialized center.

After ileal pouch-anal anastomosis in patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP), in addition to postoperative morbidity and functional outcome quality of life is a relevant factor for assessment of the operation's success. Between 1982 and 1997 restorative proctocolectomy was performed in 602 patients (UC: n = 424; FAP: n = 178) at the Department of Surgery, University of Heidelberg. The assessment of pre- and postoperative quality of life was done through a prospective study (before restorative proctocolectomy, before and 1 year after closure of ileostomy). This study (UC: n = 27; FAP: n = 7) revealed a poor preoperative quality of life in patients with ulcerative colitis. Proctocolectomy is the decisive factor for the improvement of quality of life in the surgical treatment in UC. Quality of life could not be further significantly improved by ileostomy closure. Before proctocolectomy, FAP patients showed a quality of life, activity and function similar to that of healthy controls. In FAP patients proctocolectomy led to a significant loss of quality of life. This loss could only partly be regained by ileostomy closure. Quality of life and activity comparable to that of healthy controls can be achieved in UC patients by restorative proctocolectomy.

The restorative proctocolectomy with ileoanal pouch is a sophisticated operative procedure with considerable postoperative complications. The main problems are postoperative ileus (11%), anastomotic stricture (9%), local septic complications (13%) and pouchitis (29%). A variety of other complications also occur. Most of the problems can be successfully managed by conservative or surgical treatment. In only 2.5% (n = 15/593) was final pouch extirpation necessary. Postoperative function showed elevated stool frequency (6 per day) and slightly compromised stool continence. Most patients confirm good quality of life.

The expression of alternatively spliced CD44 adhesion molecules has been implicated in the pathogenesis and metastasis of colorectal cancer. Using a new set of primers for exon-specific reverse transcription-polymerase chain reaction (RT-PCR) we delineated the exact exon composition of CD44 mRNAs in normal colorectal mucosa, including isolated colonic crypts, in colorectal carcinomas and in their hepatic metastases. In addition, the surface expression of CD44 isoforms was analysed by immunohistochemistry. We identified by RT-PCR eight variant transcripts expressed in colorectal carcinomas and their metastases, but also constitutively in normal colorectal epithelia. In the normal colorectal epithelium, the surface expression of CD44 standard and variant molecules was restricted to proliferating cells at the bottom of the crypts. Despite expression of these transcripts in colorectal cancers and their metastases, monoclonal antibodies specific for standard or variant epitopes encoded by exons v5 and v6 stained only a few neoplastic lesions. These data point to a differentiation-specific CD44 expression and splicing pattern in proliferating colorectal epithelia. However, they do not support a cancer- or metastasis-specific CD44 splicing pattern. Instead, cell surface availability of CD44 epitopes was reduced rather than increased in primary tumours and particularly in liver metastases.

After ileal pouch-anal anastomosis in patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP), quality of life is a relevant factor for the assessment of the operation's success, in addition to postoperative morbidity and functional outcome. Between 1982 and 1995 restorative proctocolectomy was performed in 453 patients (UC: n = 332; FAP: n = 121) at the Department of Surgery, University of Heidelberg. We studied postoperative quality of life through a long-term follow-up study (median follow-up time 43.2 months). This study 1 year or more following ileostomy closure of persons who had undergone J-pouch anastomosis (n = 243 total; UC n = 185, FAP n = 58) revealed that at the time of follow-up, the underlying disease (UC versus FAP) and successfully treated complications are without influence on the quality of life. The patient's age (P0.01) and the presence of unsuccessfully treated complications (P0.0001) showed a significant influence on the quality of life. There was a distinct relation between the functional index and the quality of life index (coefficient of correlation r = -0.714). However, quality of life, comparable to that of healthy controls, can be achieved with UC and FAP patients by restorative proctocolectomy only if postoperative complications can be avoided or are successfully treated.

Patients with ulcerative colitis (UC) are at higher risk for cancer. Risk factors are duration of disease, extent of colitis, associated primary sclerosing cholangitis and possibly early onset of UC in childhood. Epithelial dysplasias are considered as precursors of colorectal cancer within the concept of an inflammation-dysplasia-carcinoma sequence. Dysplasia originates multifocally and is difficult to identify by colonoscopy. Histomorphological diagnosis can also be problematical. Surveillance programs utilize colonoscopy with random biopsies to diagnose dysplasia in patients with risk factors. The efficiency of these programs can be markedly increased when certain rules are applied. The ultimate aim must be to perform a proctocolectomy in patients at higher risk before invasive cancer develops. With only a few exceptions, colorectal cancer in UC can be treated by restorative proctocolectomy. Partial resection of the colon should be avoided because of the high frequency of occult carcinomas and multifocal carcinogenesis. There are first results that indicate a higher risk for malignant deterioration in the terminal ileum. After an ileoanal pouch procedure patients with chronic pouchitis seem to have a higher risk for dysplasia. At the moment the risk for malignancy cannot be calculated because of the relatively short follow-up time after ileoanal pouch procedures. However, it is recommended that after restorative proctocolectomy patients be followed by endoscopy and random biopsies for the rest of their lives.

Primary sclerosing cholangitis (PSC) is generally associated with ulcerative colitis (UC). The disease typically progresses slowly, but ultimately, and leads to cirrhosis, liver failure or bile duct cancer. PSC patients with simultaneous ulcerative colitis are also at higher risk for colorectal cancer. At the present time, there is no effective treatment for PSC, although preliminary data show encouraging results after treatment with ursodeoxycholic acid. However, there are no data concerning the delay or prevention of progress of the disease with this drug, because follow-up time is not yet long enough. Isolated bile duct strictures should be treated endoscopically. The possible effect of proctocolectomy on the course of PSC is controversial. Liver transplantation is the therapy of choice for PSC in its final stage. The 5-year survival rate (89%) is significantly better than after transplantation for other indications. Patients with ulcerative colitis have to be followed up by lifelong colonoscopy. Although the course of UC after transplantation is mostly asymptomatic, these patients are at higher risk for colorectal cancer.

Nowadays, restorative proctocolectomy is considered the "gold standard" in the surgical therapy of ulcerative colitis. Alternative procedures such as Brooke ileostomy or Kock pouch are limited to special indications. Preservation of function is the decisive advantage of the ileoanal pouch, but preservation of function is not equal to quality of life. Quality of life is a multidimensional concept that is difficult to define and measure. Quality of life can only be assessed by standardized and validated quality-of-life questionnaires. Preoperatively, patients with ulcerative colitis have a restricted quality of life, depending on the intensity of their disease. Proctocolectomy is the curative therapy and improves quality of life. When evaluating quality of life it is not essential if patients are treated by Brooke ileostomy or restorative proctocolectomy. The advantage of restorative proctocolectomy is the improvement in some aspects such as sexuality and physical activity. The "Total Quality-of-Life Index" is not improved. Preoperatively, patients should be informed that preservation of function by restorative proctocolectomy is accompanied by an increased postoperative morbidity in comparison to other procedures. Decreased quality-of-life results when complications occur postoperatively that cannot be controlled over a long period of time. In some cases excision of the ileoanal pouch may be the most sensible way of solving the problems. On the other hand, patients without complications and good function after ileoanal pouch procedure may achieve a quality of life comparable to that of healthy controls. Preoperatively, patients should be aware of this risk-benefit relationship and should share the responsibility of the decision for or against restorative proctocolectomy.

Die Colitis ulcerosa (CU) stellt bekanntermasen eine Risikoerkrankung fur colorektale Karzinome dar. Allgemein anerkannte Risikofaktoren sind: die Ausdehnung der CU, die Dauer der Erkrankung und der Beginn im Kindesalter [1–4]. Dysplastische Epithelveranderungen gelten im Sinne einer Colitis-Dysplasie-Karzinom-Sequenz als prakanzerose Lasionen [5–7]. Aus onkologischer Sicht ware es daher wunschenswert, wenn eine chirurgische Therapie nicht erst bei einem manifesten Colitis-Karzinom, sondern prophylaktisch durchgefuhrt wurde. Durch eine prophylaktische Proktokolektomie mit ileoanaler Pouchoperation konnen wir dem Patienten ein Verfahren anbieten, mit dem sich 3 Ziele verwirklichen lassen [8, 9]: 1. Sanierung der colorektalen Colitis ulcerosa-Manifestation. 2. Beseitigung des Entartungsrisikos im Colorektum. 3. Kontinenzerhalt mit guter Lebensqualitat.

Die ileoanale Pouchoperation (IAP) ist heute das Standardverfahren in der chirurgischen Behandlung der Colitis ulcerosa und der familiaren adenomatosen Polyposis (FAP). Obwohl die direkte End-zu-End-Anastomose des Ileums nach Proktokolektomie mit Praservation des analen Schliesapparates moglich ist, sind die funktionellen Ergebnisse unbefriedigend. Die Mehrzahl der Patienten ist zum Zeitpunkt der Operation erwachsen und nur bei Kindern ist durch die hohe Adaptationsfahigkeit ein noch befriedigendes Ergebnis der direkten ileoanalen Anastomose zu erwarten. Erst die Vorschaltung eines Neostuhlreservoirs aus dem terminalen Ileum brachte hier den entscheidenden Durchbruch. Parks und Nicholls publizierten 1987 [5] erstmals den erfolgreichen Einsatz dieses Verfahrens unter Anwendung des sog. S-Pouches. An unserer Klinik wurden von 1982 bis August 1997 575 Patienten mit einer ileoanalen Pouchoperation versorgt (Colitis ulcerosa n = 433, FAP n = 142). Zahlreiche Arbeitsgruppen haben sich intensiv mit der chirurgischen Durchfuhrung beschaftigt. Auch wir haben uber die Jahre unser chirurgisches Vorgehen sukzessive modifiziert.

Die Colitis ulcerosa verlauft im Kindesalter haufig schwerer als im Erwachsenenalter. 90% der Kinder zeigen eine mittlere oder schwere Entzundungsaktivitat. Chronische Entzundung und hochdosierte immunsuppressive medikamentose Therapie bedingen gerade im Kindesalter schwerwiegende, z. T. irreversible korperliche, aber auch psychosoziale Folgeschaden. Mit der ileoanalen Pouchoperation wurde seit den fruhen 80iger Jahren ein Verfahren eingefuhrt und weiterentwickelt, durch das nach Proktokolektomie die Kontinenz mit guten funktionellen Ergebnisse erhalten bleibt [1]. Trotzdem wird die Indikation zur Proktokolektomie und kontinenzerhaltenden ileoanalen Pouchoperation im Kindesalter von den behandelnden Padiatern nur sehr zogerlich gestellt. Gros ist die Angst vor Mangelzustanden, Gedeihstorungen und korperlichen Behinderungen nach einer Proktokolektomie. Die Darstellung unserer langjahrigen Erfahrungen wird zeigen, das diese Bedenken unbegrundet sind, und das vielmehr eine verzogerte Indikationsstellung mit langjahriger medikamentoser Therapie schweren Schaden anrichten kann.

Die restaurative Proktokolektomie mit ileoanalem Pouch ist ein komplexes operatives Verfahren, mit einer wesentlichen Rate an postoperativen Komplikationen. Die vier haufigsten sind der postoperative Ileus (11%), die Anastomosenstenose (9%), lokalseptische Probleme im kleinen Becken (13%) und Pouchitis (29%). Daneben wird eine ganze Reihe seltenerer Komplikationen beobachtet. Die uberwiegende Mehrzahl der postoperativen Probleme kann erfolgreich beherrscht werden und eine definitive Pouchexstirpation war nur in 2,5% der Falle (n= 15/593) notwendig. Die postoperative Funktion ist gekennzeichnet durch eine bleibend erhohte Stuhlfrequenz (f= 6/die) und eine partiell eingeschrankte Kontinenz. Die postoperative Lebensqualitat wird von den Betroffenen weit uberwiegend als positiv beurteilt.