[Implementation of a fast track program : Challenges and solution approaches]. / Implementierung eines Fast-Track-Programmes : Herausforderungen und Lösungsansätze.

BACKGROUND: For more than a decade the evolving concept of fast track surgery has been implemented, predominantly in colorectal surgery. The practice of fast track surgery has yielded excellent results concerning reduction of postoperative complications and hospital stay and has been shown to increase patient satisfaction; however, several studies have shown a sometimes alarmingly low rate of implementation of the individual fast track measures and the rate is a maximum of 44%. OBJECTIVE: In this review, obstacles for implementation of fast track surgery are investigated. Advice is given on possible solutions to circumvent obstacles and facilitate successful establishment of multimodal recovery protocols in individual institutions. MATERIAL AND METHODS: The current international literature is critically evaluated and discussed with a particular focus on prospective clinical trials and expert recommendations. RESULTS: The reasons for a lack of adherence to fast track surgery principles have been shown to be multifactorial. Time-consuming expenditure, logistic difficulties, lack of support by colleagues as well as limitations in the healthcare system and patient-dependent factors appear to complicate implementation of fast track programs. CONCLUSION: Successful implementation and long-term perpetuation can be achieved only by an interdisciplinary team with a low level hierarchy, continuous training and a positive feedback culture. An early inclusion and clarification of personnel and patients should be firmly integrated into the fast track concept. This results in a higher satisfaction of patients and personnel and subsequently stronger adherence to the fast track concept.

[Obstacles and facilitators of conducting studies - the perspective of colorectal cancer centers' coordinators]. / Hemmende und fördernde Faktoren bei der Durchführung von Studien - Die Sicht von Darmkrebszentrumskoordinatorinnen und -koordinatoren.

INTRODUCTION: Clinical trials and health services research are crucial pillars for improving patient care. This paper examines factors inhibiting and promoting the study activity and the knowledge and use of trial registries (e. g. DRKS, StudyBox) as an opportunity to learn about existing studies. MATERIAL AND METHODS: The coordinators of 274 cancer center sites certified according to the requirements of the German Cancer Society were surveyed using a standardized online questionnaire. Data were analyzed using descriptive and bivariate statistics to identify associations with characteristics of the sites (e. g. patient volume, ownership, teaching status). RESULTS: 176 sites participated in the survey (64.2 %). The central obstacle to study participa-tion from the centers' view is the low number of existing studies. General knowledge of the population about studies was considered low. Trial registries are known to almost all respondents, but are rarely used. DISCUSSION: The results of the survey suggest that comprehensive measures are needed to sustainably increase the study activity. These include, for example, better information about studies, for example through appropriate databases, and (industry-independent) research funding. One possible way to sensitize patients for studies could be the comprehensive education of the population about the purpose of studies.

[Certified stomach cancer centres as seen by their directors: results of a questionaire to key personnel]. / Zertifizierte Darmkrebszentren aus Sicht der Zentrumsleitungen: Ergebnisse einer Schlüsselpersonenbefragung.

Since 2003 the German Cancer Society (Deutsche Krebsgesellschaft, DKG) has been certifying specific organ cancer centers in Germany. After 8 years activity, there are now more than 600 certified cancer centres that, as required by the national cancer plan, enable "oncological management at an assured quality level" in Germany. Anmong them are more than 200 certified centres for stomach cancer, that treat about 25 % of all newly diagnosed cases of stomach cancer. In this article we have examined the question as to what changes the certification concept has caused in the centres.

Neuroendocrine tumours (carcinoids) of the appendix.

Neuroendocrine tumours (NETs) of the appendix (formerly 'carcinoids') are rare and are usually detected incidentally after appendectomy. Histopathologically they derive from a subepithelial cell population, which is different from NETs in other sites. They are preferentially located at the tip of the appendix. Tumours <1 cm hardly ever metastasize and are treated by appendectomy. Tumours >2 cm require right hemicolectomy because of a significant risk of metastatic spread. Treatment for lesions 1-2 cm is controversial and needs further characterization of the tumour (i.e. mesoappendiceal invasion, vascular invasion, mitotic activity, proliferation markers) and careful patient risk evaluation. Goblet-cell carcinoids have features resembling both carcinoid and adenocarcinoma and should be treated by hemicolectomy. Overall prognosis of small appendiceal NET is excellent in all ages.

Antibiotic prophylaxis influences cardiovascular stability in complicated surgery.

OBJECTIVE: Antibiotic prophylaxis is used in many surgical procedures but there are frequent cardiovascular instabilities following antibiotics in perioperative period. A clinic modelling randomised trial (CMRT) in pigs was developed to compare the effects of 2 commonly used antibiotic combinations on cardiovascular stability during major surgery. MATERIALS AND METHODS: Thirty pigs (both sexes) were randomised into 3 groups, receiving either saline (placebo), co-amoxiclav or cefuroxime/metronidazole in clinically relevant doses as antibiotic prophylaxis. A laparotomy was performed and the abdomen remained open. Surgical complications were simulated by removing one third of the blood volume. For fluid resuscitation, 500 ml hetastarch (HAES(TM)) were infused rapidly (therapy of complication) and polymyxin B (15 mg/kg bodyweight) was applied for induction of histamine release reactions (complication of therapy). The main end points were histamine release reactions, these were classified by 2 blinded investigators. RESULTS: Neither cardiovascular changes nor histamine release reactions were detected immediately after the administration of antibiotics or placebo alone. Plasma histamine concentrations increased after bleeding in the co-amoxiclav group (p < 0.05). After fluid resuscitation and induction of anaphylactoid reactions, the median histamine release and cardiovascular changes were not significantly different between the groups. However, the incidence of typical histamine release related reactions differed significantly between the groups: 8/10 for the controls, 6/10 in the co-amoxiclav and 2/10 in the cefuroxime/metronidazole group (p < 0.05). CONCLUSIONS: The stability and reproducibility of this model clearly demonstrated the concept of a 'clinic modelling randomised trial' as a useful tool. Antibiotic prophylaxis influences the organism's capability to cope with intraoperative bleeding and fluid resuscitation problems. Indeed antibiotic prophylaxis may be beneficial. These effects of antibiotics could only be demonstrated in complex surgical models. Thus new antibiotics should be investigated in complex animal models prior to prospective randomised clinical trials or usage in clinical practice.

Early and late histamine release induced by albumin, hetastarch and polygeline: some unexpected findings.

OBJECTIVE: The perioperative use of colloidal plasma substitutes is still under discussion. We therefore conducted a prospective randomised study with three commonly used plasma substitutes to examine their histamine releasing effects in 21 volunteers. MATERIAL OR SUBJETS: 21 male volunteers were enrolled in this prospective, randomised, controlled clinical study. Endpoints were the incidence of early and late histamine release and the time course of the release kinetics. Normovolemic hemodilution technique was used with hydroxyethyl starch (n = 6), human albumin (n = 6) and polygeline (n = 9). Measurement and observation period was 240 min after the start of the plasma substitute infusion. Heart rate, blood pressure, SaO(2), clinical symptoms/signs and plasma histamine were measured during the observation period. RESULTS: The incidence of histamine release over the whole observation period in all three groups was 100%. Histamine release occurred frequently in all three groups until 30 min (50%-78%) and up to 240 min (late release reaction: 67%-83%) after the start of infusion. Surprisingly even hydroxyethyl starch, which is regarded as a generally safe and effective plasma substitute, caused high incidences of late histamine release (67%). Histamine release is a well known side effect of polygeline and - to a lesser extent - also of albumin, but was a novel finding for hydroxyethyl starch. CONCLUSIONS: We demonstrated for the first time histamine releasing effects of hydroxyethyl starch over a long period of time after administration. This perioperatively and for intensive care possibly relevant finding should make clinicians aware of late side effects not yet connected with the clinical use of these colloidal plasma substitutes.

Granulocyte colony-stimulating factor but not peritoneal lavage increases survival rate after experimental abdominal contamination and infection.

BACKGROUND: The value of peritoneal lavage for intra-abdominal contamination and infection has never been proven scientifically. In contrast, the stimulation of host defence mechanisms with cytokines such as granulocyte colony-stimulating factor (G-CSF) has appeared promising in recent clinical trials. METHODS: Clinic modelling randomized trials (CMRTs), which model the complexity of the clinical reality, were used in rats in which peritoneal contamination and infection (PCI) was produced with human stool bacteria. The following groups were compared: trial 1, intraoperative peritoneal lavage with saline versus taurolin (18 rats per group); trial 2, no lavage versus saline lavage versus saline lavage plus subcutaneous administration of G-CSF (18 rats per group); trial 3, lavage with saline versus no lavage (30 rats per group). The primary endpoint was mortality at 120 h. Secondary endpoints were the phagocytic activity of granulocytes, and systemic and peritoneal cytokine levels. RESULTS: In trial 1 lavage with taurolin was not superior to that with saline (five of 18 versus eight of 18 animals survived; P = 0.32). In trial 2, six of 18 animals having no lavage and three of 18 receiving saline lavage survived. The combination of lavage and G-CSF increased the number of animals surviving to 11 of 18 (P < 0.05). Lavage combined with G-CSF stimulated granulocyte phagocytic activity (P < 0.01) and reduced the levels of interleukin (IL) 6 (P < 0.01) and tumour necrosis factor alpha (P < 0.05) in peritoneal fluid, as well as plasma levels of IL-6 (P < 0.05) and IL-10 (P < 0.01). In trial 3, survival was not significantly different in animals having lavage (14 of 30) and no lavage (19 of 30) (P = 0.14). CONCLUSION: In these CMRTs of intra-abdominal contamination and infection, peritoneal lavage was not beneficial, but when lavage was combined with subcutaneous administration of G-CSF mortality was reduced and the local and systemic cytokine response was downgraded. Results from these CMRTs were used directly to define the trial conditions of a randomized clinical trial with G-CSF. Peritoneal lavage is not recommended.

Quality of life profile: from measurement to clinical application.

Quality of life (QoL) can be assessed in an accurate, valid and reliable way by means of standardized QoL questionnaires and is an important endpoint in clinical trials today. The aim of this study is to implement quality of life as a diagnostic tool for problem-oriented follow-up care of cancer patients. This is done in the framework of an intervention study in the area of regional health care research using qualitative analysis and the methodological concept of barrier analysis. We developed the diagnostic tool by generating individual, graphic QoL profiles based on patients' responses to the EORTC QLQ-C30 and the corresponding disease-specific modules BR23 for breast cancer and CR38 for rectal cancer. The clinical application is investigated by assessing physicians' responses. The QoL profile is judged as a useful diagnostic tool by all participating physicians. It enables physicians to assess the QoL of the patient and incorporate the knowledge they gain in their daily practice. Especially in breast cancer follow-up care QoL profiles give added value to both patients and doctors. The next implementation steps have to extend the concept of QoL to larger groups of patients and physicians by overcoming the restraining factors as identified in the barrier analysis.

Nasogastric tube versus gastrostomy tube for gastric decompression in abdominal surgery: a prospective, randomized trial comparing patients' tube-related inconvenience.

BACKGROUND: Perioperative decompression of the stomach is still a common procedure and can be achieved using either nasogastric tubes (NTs) or gastrostomy tubes (GTs). While both procedures appear to be equally effective, some authors believe that NTs are less convenient for patients than GTs. However, to date, no reliable prospective data are available on this issue. METHODS: We conducted a prospective, randomized trial comparing NTs versus GTs with a total of 110 patients undergoing elective colon surgery. The primary outcome measure was the patient's tube-related inconvenience and pain, assessed in a standardized interview on day 2 after surgery and quantified by means of a visual-analog scale (VAS). A questionnaire including the EORTC QLQ-C30 and additional items regarding retrospective tube-related judgements was administered on the day of discharge and 4 weeks after discharge. Secondary endpoints were the therapy-related morbidity and general complications. RESULTS: When patients were asked which of their drainage tubes (all patients had three or four drainage tubes, such as decompression drains, urinary drains, central venous line) was most inconvenient, 43% (CI 33-53%) in the NT group reported that the NT was most inconvenient, while only 4% (CI 1-10%) of the GT patients judged the GT most inconvenient ( P<0.001, Chi(2) test). This effect was also found in VAS ratings of inconvenience and discomfort ( P<0.01). Also postoperatively (p.o.), NT patients evidenced less preference for their tube system (day 2 p.o.: 71%, CI 61-80%; 4 weeks p.o.: 66%, CI 56-75%) than did GT patients (day 2 p.o.: 94%, CI 88-98%; 4 weeks p.o.: 91% CI 84-96%); again, these differences were statistically significant ( P<0.02; Chi(2) test). No differences between groups emerged regarding global quality of life or conventional clinical outcomes. CONCLUSION: This prospective randomized trial supports the clinical observation that NT causes more subjective inconvenience than GT. In cases when a prolonged postoperative ileus is expected, decisions for a prophylactic decompressing tube system have to weigh up the possibilities of different averse clinical as well as subjective outcomes. It is then preferable to include patients' preferences in the individual decision making process (shared-decision making).

Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). Protocol of a controlled clinical trial developed by consensus of an international study group. Part three: individual patient, complication algorithm and quality manage.

GENERAL DESIGN: Presentation of a new type of a study protocol for evaluation of the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and of sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). A randomised, placebo controlled, double-blinded, single-centre study is performed at an University Hospital (n = 40 patients for each group). This part presents the course of the individual patient and a complication algorithm for the management of anastomotic leakage and quality management. OBJECTIVE: In part three of the protocol, the three major sections include: The course of the individual patient using a comprehensive graphic display, including the perioperative period, hospital stay and post discharge outcome. A center based clinical practice guideline for the management of the most important postoperative complication--anastomotic leakage--including evidence based support for each step of the algorithm. Data management, ethics and organisational structure. CONCLUSIONS: Future studies with immune modifiers will also fail if not better structured (reduction of variance) to achieve uniform patient management in a complex clinical scenario. This new type of a single-centre trial aims to reduce the gap between animal experiments and clinical trials or--if it fails--at least demonstrates new ways for explaining the failures.

Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). Protocol for a controlled clinical trial developed by consensus of an international study group. Part two: design of the study.

GENERAL DESIGN: Presentation of a new type of a study protocol for evaluation of the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and of sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). This part describes the design of the randomised, placebo controlled, double-blinded, single-centre study performed at an university hospital (n = 40 patients for each group). OBJECTIVE: The trial design includes the following elements for a prototype protocol: * The study population is restricted to patients with colorectal cancer, including a left sided resection and an increased perioperative risk (ASA 3 and 4). * Patients are allocated by random to the control or treatment group. * The double blinding strategy of the trial is assessed by psychometric indices. * An endpoint construct with quality of life (EORTC QLQ-C30) and a recovery index (modified Mc Peek index) are used as primary endpoints. Qualitative analysis of clinical relevance of the endpoints is performed by both patients and doctors. * Statistical analysis uses an area under the curve (AUC) model for improvement of quality of life on leaving hospital and two and six months after operation. A confirmatory statistical model with quality of life as the first primary endpoint in the hierarchic test procedure is used. Expectations of patients and surgeons and the negative affect are analysed by social psychological scales. CONCLUSION: This study design differs from other trials on preoperative prophylaxis and postoperative recovery, and has been developed to try a new concept and avoid previous failures.

Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). Protocol of a controlled clinical trial developed by consensus of an international study group. Part one: rationale and hypothesis.

GENERAL DESIGN: Presentation of a novel study protocol to evalue the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). The rationale and hypothesis are presented in this part of the protocol of the randomised, placebo controlled, double-blinded, single-centre study performed at an university hospital (n = 40 patients for each group). OBJECTIVE: Part one of this protocol describes the concepts of three major sections of the study: Definition of optimum and sub-optimal recovery after operation. Recovery, as an outcome, is not a simple univariate endpoint, but a complex construction of mechanistic variables (i. e. death, complications and health status assessed by the surgeon), quality of life expressed by the patient, and finally a weighted outcome judgement by both the patient and the surgeon (true endpoint). Its conventional early assessment within 14-28 days is artificial: longer periods (such as 6 months) are needed for the patient to state: "I am now as well as I was before". Identification of suitable target patients: the use of biological response modifiers (immune modulators) in addition to traditional prophylaxes (i. e. antibiotics, heparin, volume substitutes) may improve postoperative outcome in appropriate selected patients with reduced host defence and increased immunological stress response, but these have to be defined. Patients classified as ASA 3 and 4 (American Society for Anaesthesiologists) and with colorectal cancer will be studied to prove this hypothesis. Choice of biological response modifier: Filgrastim has been chosen as an example of a biological response modifier because it was effective in a new study type, clinic-modelling randomised trials in rodents, and has shown promise in some clinical trials for indications other than preoperative prophylaxis. It has also enhanced host defence and has been anti-inflammatory in basic research. CONCLUSION: The following hypothesis will be tested in patients with operations for colorectal cancer and increased preoperative risk (ASA 3 and 4): is the outcome as evaluated by the hermeneutic endpoint (quality of life expressed by the patient) and mechanistic endpoints (mortality rate, complication rate, relative hospital stay, assessed by the doctor) improved in the group receiving filgrastim prophylaxis in comparison with the placebo group? Quality of life will be the first primary endpoint in the hierarchical, statistical testing of confirmatory analysis.

Expression and NNK reducing activities of carbonyl reductase and 11beta-hydroxysteroid dehydrogenase type 1 in human lung.

The tobacco specific nitrosamine 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), which is found in high amounts in tobacco products, is believed to play an important role in lung cancer induction in smokers. NNK requires metabolic activation by cytochrome P450 mediated alpha-hydroxylation to exhibit its carcinogenic properties. On the other hand, NNK is inactivated by carbonyl reduction to its alcohol-equivalent 4-methylnitrosamino-1-(3-pyridyl)-1-butanol (NNAL) followed by glucuronidation and final excretion into urine or bile. Carbonyl reduction and alpha-hydroxylation are the predominant pathways in man, and it has been postulated that the extent of these competing pathways determines the individual susceptibility to lung cancer. Moreover, only a minor part of all habitual smokers develop lung cancer, suggesting the existence of susceptibility genes. Microsomal 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) (EC 1.1.1.146) and cytosolic carbonyl reductase (CR) (EC 1.1.1.184) have been shown to be mainly responsible for NNAL formation in liver and lung. In the present study, we performed comparative investigations of human lung tissue samples from several patients with respect to the expression and activity of 11beta-HSD 1 and carbonyl reductase. We observed varying levels in 11beta-HSD 1 and carbonyl reductase expression in these patients, as revealed by RT-PCR and ELISA. Also, the tissue samples showed a different activity and inhibitor profile for both enzymes. According to our results, variations in the expression and activity of NNK carbonyl reducing enzymes may constitute a major determinant in the overall NNK detoxification capacity and thus may be linked to the great differences observed in the individual susceptibility of tobacco-smoke related lung cancer.

[Surgical therapy of rectal carcinoma. Portrayal of the current health care status within the scope of a district quality assurance study]. / Chirurgische Therapie des Rectumcarcinoms. Abbildung der realen Versorgungssituation im Rahmen einer kreisbezogenen Qualitätssicherungsstudie.

UNLABELLED: In an era of economic pressure, patient's participation in decision-making and evidence-based medicine, the need for quality assurance of medical processes in daily routine becomes increasingly important. The aim of this quality assessment study is to demonstrate the real state of surgical care of patients with rectal carcinoma in the context of a field study on quality management in oncology. METHODS: Prolective cohort-study, small-area-analysis. Between 01.01.1997 and 31.12.1998, all patients with newly diagnosed rectal carcinoma and treatment in the county of Marburg-Biedenkopf (252.975 inhabitants, 3 hospitals) were included in the study. Documentation included all variables (n = 82) relevant for primary surgical therapy according to guidelines and standards. RESULTS: 146 consecutive patients fulfilled the inclusion criteria. 93% underwent resection of the tumor. In 6.6% of these cases rigid rectoscopy for determination of the tumor's distance from the anal verge was not performed. In 16.9% the colon was not examined completely. In 98.5% the state of distant metastases was documented preoperatively. 93% of the patients with tumors in the upper/middle third of the rectum and curative-intent surgery (n = 68) received a sphincter-saving operation. For all curative-intent procedures negative resection margins were confirmed histologically. Complication rates were 31.6% for anterior resection and 46.9% for abdominoperineal extirpation. CONCLUSIONS: Comparative analysis of quality indicators revealed a predominantly good quality of care. Improving efforts can now be concentrated on few areas of suboptimal quality in the setting of internal quality management. Critical results require detailed analysis of the single cases. Thus, conditions requiring deviation from guidelines become apparent.

Parathyroid xenotransplantation without immunosuppression in experimental hypoparathyroidism: long-term in vivo function following microencapsulation with a clinically suitable alginate.

Permanent hypoparathyroidism is one of the most difficult of all endocrine disorders to treat medically. Because this deficiency syndrome rarely is a life-threatening condition, systemic immunosuppression for recipients of transgenic transplants is not justified. An alternative would be protecting the tissue to be transplanted from the immunologic response (immunoisolation) by coating it with a semipermeable membrane- microencapsulation. Unfortunately, prior to the first clinical use, further analysis of the coating substance (alginate) demonstrated that it has potential cancerogenic properties. Using a purified amitogenic alginate suitable for clinical use, we accomplished allotransplantation in a long-term animal model and reported the first clinical cases without postoperative immunosuppression recently. In view of the potential clinical use, we investigated the ability of the microencapsulation technology with the novel amitogenic alginate in experimental hypoparathyroidism (80 parathyroidectomized rats) to enable transgenic transplantation across the highest immunologic barrier (xenotransplantation: human to rat) to ensure intact transplant function without immunosuppression. In a controlled, long-term animal study, the effect of microencapsulation on xenotransplanted human parathyroid tissue was evaluated over a period of 30 weeks (microencapsulated and naked hyperplastic parathyroid tissue, respectively). Functionally, human parathyroid tissue was able to replace that of rats. More than 6 months after xenotransplantation 32 of 40 animals that had received microencapsulated transplants were normocalcemic. In contrast, serum calcium concentrations dropped to postparathyroidectomy levels within 3 weeks in the animals that had received naked tissue only. Correspondingly, normocalcemic animals showed vital parathyroid tissue inside the microcapsules, which were surrounded by a small rim of fibroblasts. When combining microencapsulation with an improved tissue culture method, xenotransplantation of human parathyroid tissue and maintenance of its physiologic function is reproducibly achieved over the highest transplantation barrier. Using the amitogenic alginate may be a crucial step toward the first clinical use of this technique for parathyroid xenotransplantation without immunosuppression.

Are covered stents really effective at closing esophagotracheal fistulas? Results of an animal study.

PURPOSE: To determine whether covered self-expanding metal stents successfully exclude experimentally created esophagotracheal fistulas. METHODS: Esophagotracheal fistulas were surgically created in the upper third of the esophagus in 12 minipigs and immediately sealed by implantation of a covered self-expanding metal stent (20 mm expanded diameter) in the esophagus. Before the animals were killed, after 3, 7, 14, 28, 30, and 36 days, the position of the stent and the sealing of the fistula were monitored fluoroscopically. The esophagus, trachea, and both lungs were examined histologically. RESULTS: Creation of an esophagotracheal fistula was successful in all cases. All fistulas were widely patent at autopsy. The technical success rate for stent deployment and initial sealing of the fistula was 100%. During follow-up, five stents migrated distally, but none into the stomach. Therefore, the fistula was no longer excluded in five animals. In seven animals the stent sealed the fistula until the death of the animal. Tracheal narrowing necessitated additional tracheal stenting in three animals. Two minipigs died due to aspiration of food. Histologic examination showed signs of aspiration in all animals with stents in place for longer than 2 weeks. CONCLUSION: This experimental animal study revealed worse results for sealing of esophagotracheal fistulas with covered self-expanding metal stents than have been reported for the clinical use of these devices.

Carbonyl reduction of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by cytosolic enzymes in human liver and lung.

The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen, independent of the route and type of administration. There are competing metabolic activation and detoxification pathways. NNK is activated by alpha-hydroxylation at either the methyl or methylene carbonyl adjacent to the N-nitroso group to yield intermediates that methylate and pyridyloxobutylate DNA. Detoxification of NNK in humans usually occurs via carbonyl reduction to its hydroxy product NNAL, which undergoes glucuronosylation and final excretion. In vitro studies on NNK metabolism have usually been performed with tissue homogenates, microsomal fractions and/or purified microsomal enzymes, but cytosolic metabolism of NNK has been ignored until today. The results of this study demonstrate that cytosolic fractions of human liver and lung also participate in NNK metabolism. We provide evidence that a substantial degree of NNK carbonyl reduction occurs by cytosolic enzymes and that these enzymes may contribute to NNK detoxification in human liver and lung. The relative contribution of cytosolic vs. microsomal NNK carbonyl reduction is nearly identical in liver, whereas it is more than 3-fold higher in lung microsomes compared to lung cytosol. The inhibition profile suggested that mainly carbonyl reductase (EC 1.1.1.184) was active in cytosol of both organs. The expression of carbonyl reductase mRNA in liver and lung was proven by reverse transcription-(RT)-PCR. In conclusion, the results of this study provide the first data on cytosolic enzymes participating in NNK detoxification in human liver and lung.

Platelet aggregation during abdominal surgery in an experimental pig model: the effects of presurgical antibiotic protocols and volume replacement with hydroxyethyl starch.

The effect of presurgical antibiotic protocols in combination with hemodilution on platelet aggregation was studied. Thirty pigs were randomly assigned to three groups. Group 1 received amoxicillin/clavulanic acid, group 2 metronidazole+cefuroxime, and group 3, as a control, sodium chloride. They underwent laparotomy, massive blood loss, and volume replacement with hydroxyethyl starch 200, followed by an anaphylactoid reaction. Platelet aggregation was measured by the turbidometric method. Neither antibiotic protocols had any effect on platelet aggregation as compared with the control group. In all three groups, aggregation to ADP and collagen was significantly reduced after volume replacement with hydroxyethyl starch. In contrast, the sensitivity to the aggregating effects of collagen was increased as assessed by a higher frequency of responses to low concentrations of collagen and a shortened latency of the aggregation response after collagen addition. Further in vitro studies revealed that dilution of plasma with hydroxyethyl starch specifically induced the changes seen after in vivo volume replacement. The results suggest that the plasma substitute hydroxyethyl starch 200 increases the sensitivity to low doses of collagen, an effect never described before and considered of clinical relevance.