[Choosing wisely - perspectives: what are the key questions?] / Klug entscheiden ­ Perspektiven: Was sind die entscheidenden Ansätze (Key Questions) für die Zukunft?

Gastroenterology offers a wide field for future "choosing wisely" recommendations (CWR). They should refer not only to an under- or overuse of diagnostic tools like laboratory or imaging tests but also to an evidence-based application of drug therapies und endoscopic interventions. Drugs like antibiotics or proton pump inhibitors are both often prescribed in the absence of clearly defined underlying diseases and not given when an indication is clear. Similar is true for the ordering of abdominal imaging methods. Computerized tomography of the abdomen too often is preferred over a qualified ultrasound study. Laboratory tests like amylase or lipase should not be ordered for asymptomatic patients since false positive values often end up with further useless and occasionally invasive examinations. Ordering both enzymes in acute pancreatitis will not provide any additional information. Similarly, CEA, ammonia or procalcitonin have either limited or no value in gastroenterology. Upper gastrointestinal endoscopy should not be performed in asymptomatic people without any risk factors. On the other hand, colonoscopy is still underused as a valuable screening tool for detection and secondary prevention of colorectal carcinomas in people over 50 years old.The dramatic rise in people suffering from obesity is paralleled by an enormous increase in severe cases of non-alcoholic fatty liver disease associated with high morbidity and mortality. This calls for CWRs addressing this causal relationship and offering not only patient centered therapeutic solutions but also calling for effective measures to regulate the marketing of highly processed food or sugar enriched soft drinks. Published guidelines in Gastroenterology will continue to be a rich source for delineating new CWRs. Nevertheless, CWRs are also needed in daily practice offering solutions for clinical problems not covered by guidelines. These, however, have to be based both on a broad interdisciplinary consent of experts in the field and on scientific evidence.

Evidence-Based Follow-up for Adults With Cancer.

BACKGROUND: The objectives of follow-up care for cancer patients include psycho- social assistance and the detection of health problems. The concept of follow-up care rests on the assumption that the early detection of cancer recurrences and disease- or treatment-related complications is beneficial to patients. In this article, we provide an overview of the scientific evidence supporting current recommen- dations for the follow-up care of patients with colorectal cancer, lung cancer, and lymphoma. METHODS: This review is based on pertinent publications that were retrieved by a selective search in PubMed, supplemented by the authors' own experience in patient care and guideline creation. RESULTS: As recurrences usually arise soon after initial treatment, the recommended follow-up interval is shorter in the first two years (3-6 months) and longer thereafter (6-12 months). The question of which particular follow-up studies should be per- formed has only been systematically analyzed in a few cases. For patients with colorectal cancer, colonoscopy is the most important study. Intensive follow-up care is associated with a statistically non-significant increase in the survival rate compared to minimal follow-up care (77.5% versus 75.8%). Intensive diagnostic follow-up studies have been found to lead to a doubling of the frequency of operations for recurrence with curative intent, yet without any effect on the average survival time. The findings in lung cancer are similar. However, after tumor resection with curative intent, regularly repeated CT scanning leads to a survival advantage. In lymphoma patients, the longer the interval from primary treatment, the greater the likelihood of treatment-related secondary illnesses. It is not yet known how follow-up care should be provided to these patients in order to help them best. CONCLUSION: The evidence supporting the efficacy of currently recommended modalities of follow-up care for cancer patients is weak. Until more data from clinical studies become available, the current guidelines should be followed.

[Long-term drug treatments to improve prognosis of patients with liver cirrhosis and to prevent complications due to portal hypertension]. / Medikamentöse Langzeittherapien zur Prognoseverbesserung bei Leberzirrhose und zur Vermeidung von Komplikationen der portalen Hypertension.

Portal hypertension in patients with liver cirrhosis can be improved, not only by surgical or interventional shunt placements, but also by drug-only treatment. Many recent studies addressed the question whether any of these substances can improve survival of patients with liver cirrhosis when administered continuously for months and years. Non-selective beta-blockers (NSBB), statins, antibiotics, enoxaparin and albumin have been shown to possess many beneficial effects in the pathophysiology of portal hypertension or on events leading to decompensation of liver cirrhosis. Accordingly, they represent candidate drugs for long-term treatment to improve patient survival. In contrast to NSBB, antibiotics and albumin, which have clearly defined indications in the treatment of complications related to portal hypertension, the role of statins and anticoagulants in the management of these patients remains to be further elucidated. Recent studies came to opposing results when a permanent treatment was tested to improve patient prognosis or to prevent liver decompensation. At present, there is no reason to change our everyday practice beyond established management proposals published in practice guidelines. This paper gives an overview of present and future indications for treatment with NSBB, antibiotics, statins, anticoagulants and albumin with special reference to studies aiming at improving prognosis of patients with liver cirrhosis.

[Updated S2k-Guideline "Complications of liver cirrhosis". German Society of Gastroenterology (DGVS)]. / Aktualisierte S2k-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) "Komplikationen der Leberzirrhose".

This guideline provides evidence-based key recommendations for diagnosis and therapy of complications of liver cirrhosis and upgrades the 2011 version. An interdisciplinary team of medical experts and patient support groups developed the guideline following the AWMF recommendations for evidence based consensus guidelines. New chapters concerning diagnosis and therapy of hepatic encephalopathy were added.

[Elevated liver enzymes]. / Erhöhte Leberwerte.

Elevated liver enzymes are a frequent finding in both symptomatic and asymptomatic patients necessitating further evaluation to clarify the underlying disease. Three different patterns of increased liver enzymes can be defined to allow for a more precise and rational further diagnostic approach. A predominant increase in transaminase activities reflects a disturbance of hepatocellular integrity which can be found in patients with viral hepatitis, genetic liver diseases like Wilson`s disease or hemochromatosis, and drug-induced liver diseases. A second pattern is characterized by high serum alkaline phosphatase and γ-glutamyltranspeptidase activities indicating cholestatic liver diseases. The next important diagnostic measure in this group is an ultrasound study discerning intra- from extrahepatic cholestasis. Intrahepatic cholestatic diseases include primary and secondary sclerosing cholangitis, genetic disturbances of canalicular membrane transporters or drug-induced liver dieseases. Extrahepatic cholestasis involves obstruction of the large bile ducts by gall stones or tumors. The third enzym pattern is defined by a predominant rise in γ-glutamyl transpeptidase which is observed in alcoholic or non-alcoholic fatty liver disease and infiltrating liver diseases. A rise in liver enzymes is not necessarily indicative of a primary hepatic origin. Extrahepatic diseases often cause similarly increased serum activities. In addition even higher values can be observed under normal conditions during pregnancy or in adolescens. Lower values in asymptomatic patients should only be controlled since more than 30% of elevated transaminases spontaneously normalize during follow-up.

[Severe dyspnea by combination of cervical spondylosis and struma]. / Lebensbedrohliche Dyspnoe durch Struma und HWS-Spondylose.

UNLABELLED: CASE HISTORY PHYSICAL EXAMINATION: A 79-years-old female suffered from cervical pain for several years which radiated in both shoulders. A nodular goiter was already known and therefore a radio iodine treatment had been planned. Eight months ago the patient noticed a progressing breathlessness. Emergency admission happened due to inspiratory stridor and severe attacks of dyspnoea. Sufficient breathing was only possible by wearing a rigid cervical collar. There were no neurological deficits. EXAMINATION: Tracheoscopy showed a mass in the dorsal cervical region. The cervical x-ray, computed tomography and magnet resonance imaging conformed a distinct spondylopathy at the leading edge of the cervical vertebral bodies including ventralisation of the oesophagus and narrowing of the trachea (>50%). THERAPY AND COURSE: Simultaneously a total thyroidectomy, including neuromonitoring of the N. vagus, and ventral microsurgical resection of the spondylopathy was performed. There was no relapse of dyspnoea in the following year. CONCLUSION: The coincidence of a goiter and ventral cervical spondylopathy accompanied by significant dyspnoea is remarkable. The order of diagnostic steps in this emergency case displays a major problem. The patient was scheduled for goiter surgery and admitted as emergency due to a stridor. The cervical spondylopathy was diagnosed by tracheoscopy and cervical x-ray. This case report emphasizes the importance to think about cervical lesions in the presence of a goiter and dyspnoea. To find out quickly whether there is a cervical lesion or not a x-ray should be obtained. Missing these lesions can result in a fatal course.

The patient with unexplained elevated serum liver enzymes.

The pattern of elevated serum liver enzymes in symptomatic or asymptomatic patients allows for an initial classification of liver diseases into cholestatic or hepatocellular diseases. A female patient with extrahepatic cholestasis due to segmental bile duct strictures and a localized mass lesion within the pancreas is presented. Although many diagnostic procedures were performed in this case the diagnosis was not obtained before surgical laparotomy was initiated with bioptic sampling from bile ducts, lymph nodes and pancreatic tissue. Microscopic examination of the specimen revealed extensive biliary and pancreatic scarring together with periductal infiltrates composed of lymphocytes and plasma cells consistent with sclerosing cholangitis in systemic autoimmune pancreatitis. The patient completely recovered upon treatment with prednisone and azathioprine. The difficult approach to the final diagnosis is discussed in light of established and modern diagnostic tools.

Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer.

PURPOSE: To compare the effectiveness and tolerability of gemcitabine plus cisplatin with single-agent gemcitabine as first-line chemotherapy for locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with advanced adenocarcinoma of the pancreas were randomly assigned to receive either gemcitabine 1,000 mg/m2 and cisplatin 50 mg/m2 given on days 1 and 15 of a 4-week cycle (GemCis arm) or gemcitabine alone at a dose of 1,000 mg/m2 on days 1, 8, and 15 of a 4-week regimen (Gem arm). The primary end point was overall survival; secondary end points were progression-free survival, response rate, safety, and quality of life. RESULTS: One hundred ninety-five patients were enrolled and showed baseline characteristics well balanced between treatment arms. Combination treatment in the GemCis arm was associated with a prolonged median progression-free survival (5.3 months v 3.1 months; hazard ratio [HR] = 0.75; P = .053). Also, median overall survival was superior for patients treated in the GemCis arm as compared with the Gem arm (7.5 v 6.0 months), an advantage which did not, however, reach statistical significance (HR = 0.80; P = .15). Tumor response rates were comparable between treatment arms (10.2% v 8.2%). The rate of stable disease was, however, greater in the combination arm (60.2% v 40.2%; P < .001). Grade 3 to 4 hematologic toxicity did not exceed 15% in both treatment arms. CONCLUSION: These results support the efficacy and safety of an every-2-weeks treatment with gemcitabine plus cisplatin. Median overall survival and progression-free survival were more favorable in the combination arm as compared with gemcitabine alone, although the difference did not attain statistical significance.

Ursodeoxycholic acid induced activation of the glucocorticoid receptor in primary rat hepatocytes.

BACKGROUND AND AIMS: Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, improves biochemical, immunopathological and histological parameters in chronic cholestatic liver diseases. The immunomodulatory properties of UDCA show interesting similarities with the effects of glucocorticoids. We investigated the activation of the glucocorticoid receptor by UDCA and the glucocorticoid receptor dependent gene expression in primary rat hepatocytes as well as binding of radiolabelled UDCA to the glucocorticoid receptor ligand binding site expressed in a glucocorticoid receptor fusion protein. METHODS: Primary rat hepatocytes in culture were co-transfected with a luciferase reporter gene construct (GRE-luc) containing a glucocorticoid receptor responsive element (GRE) and a glucocorticoid receptor expression vector (6RGR) followed by stimulation with dexamethasone or UDCA. Luciferase activity was determined and specific binding of glucocorticoid receptor to the GRE was confirmed by an electrophoretic mobility shift assay (EMSA). The glucocorticoid receptor binding site was expressed in a GR-myc fusion protein and binding of radiolabelled UDCA to the fusion protein was determined. RESULTS: Incubation of co-transfected hepatocytes with 0.1-1.000 microM dexamethasone or 0.1-1.000 microM UDCA led to an 11.9- to 20.85-fold (dexamethasone) and 2.6- to 4.3-fold (UDC) increase of luciferase activity. Mobility shift assays using nuclear extracts from transfected and stimulated hepatocytes also showed a dose dependent increase of DNA binding after stimulation with UDCA. However, incubation of the GR-myc fusion protein with radiolabelled UDCA yielded no specific binding of UDCA to the glucocorticoid receptor binding site, whereas dexamethasone showed specific binding of the fusion protein. CONCLUSIONS: UDCA activates the intracellular glucocorticoid receptor in a dose-dependent manner. Direct binding of the glucocorticoid receptor by radiolabelled UDCA at the glucocorticoid receptor binding site could be excluded as the mechanism of activation. The mechanisms involved in UDCA-mediated glucocorticoid receptor activation and possible targeted glucocorticoid receptor activation due to partial UDCA tissue specificity warrant further elucidation.

Gallbladder motility in healthy volunteers: effects of age, gender, body mass index, and hair color.

BACKGROUND/AIMS: Ultrasonographic determination of gallbladder motility is sparsely performed in clinical practice as the examination is considered to be time consuming and there is uncertainty about a number of parameters possibly influencing the results. The aims of this study were a) to establish normal values for a simple ultrasonographic test and b) to evaluate the influence of different parameters on gallbladder motility. METHODOLOGY: In 62 systematically age- and sex-matched healthy volunteers, ultrasonographic measurements of gallbladder volume (ellipsoid method, planimetry and sum-of-cylinders method) were performed fasting and 5, 10, 20, 30, 40, 50, 60, 70 and up to 75 min after stimulation with a standardized high-caloric liquid meal. RESULTS: Using the ellipsoid method, gallbladder fasting volume (V0) reached a mean value (+/- SD) of 24.6 +/- 10.0 mL with an ejection fraction of 65.9 +/- 19.1%. Age, gender and hair color did not influence parameters of gallbladder contraction. Body mass index showed a weak correlation with V0 but not with ejection fraction. There was a highly significant correlation between the ellipsoid method and longitudinal planimetry and the sum-of-cylinders method, respectively. CONCLUSIONS: Ultrasonographic measurement of gallbladder motility in healthy volunteers shows a very wide scattering of normal values. In the interpretation of gallbladder emptying, age, gender and body mass index do not have to be considered. Determination of gallbladder motility may be performed by a rather simple approach with oral stimulation and ellipsoid method or longitudinal planimetry as easily applicable ultrasonographic measurements.

[Acute liver failure]. / Das akute Leberversagen.

Acute liver failure represents a serious life-threatening event comparable to acute heart failure with cardiogenic shock or acute renal failure. Underlying acute liver diseases leading to hepatic failure differ between different geographic regions and in their incidence rates. In Europe etiological agents like viruses, drugs and toxins predominate over other much rarer causes. The different noxious agents lead to hepatocellular necrosis and/or apoptosis with loss of liver cell specific functions subsequent to a fall of functioning hepatocytes below a critical number. The syndrome is clinically characterized by the rapid onset of hepatic encephalopathy within 7 days after a first manifestation of liver disease (fulminant liver disease). Liver failure in patients with preexisting chronic liver disease is largely defined by the time which elapses between the occurrence of jaundice and encephalopathy (hyperacute, acute, subacute liver failure). The acute loss of liver specific functions is accompanied by a number of severe life-threatening complications like cerebral edema, circulatory failure, infections, renal failure and defective coagulation. Management of patients with fulminant liver disease requires a profound knowledge of hepatology and intensive care medicine. A close cooperation with a liver transplant unit is an absolute prerequisite for successful therapy. Permanent or temporary auxiliary liver replacement by a healthy human liver allows for a survival of 60 to 70% of patients selected for such a transplant procedure. Progress has been made in the temporary substitution of specific liver cell functions bridging the time period between liver failure and resumption of hepatocellular functions or availability of a donor liver. Different artificial livers have been designed and introduced into clinical trials. However, further evaluation is urgently needed.