Communicative reprogramming non-curative hepatocellular carcinoma with low-dose metronomic chemotherapy, COX-2 inhibitor and PPAR-gamma agonist: a phase II trial.

Systemic therapy for advanced hepatocellular carcinoma (HCC) is still challenging. A biomodulatory therapy approach targeting the communicative infrastructure of HCC, including metronomic low-dose chemotherapy with capecitabine, pioglitazone and rofecoxib, has been evaluated in patients with non-curative HCC. Altogether 38 patients were evaluable in this one-arm, multicenter phase II trial. The primary endpoint, median progression-free survival was 2.7 months (95% CI: 1.6-3.79) for all evaluable patients and 8.4 months (95% CI: 0-18.13) for patients ≥ 6 weeks on protocol. Median overall survival (OS) was 6.7 months (95% CI: 4.08-9.31) and 9.4 months (95% CI: 4.82-13.97), respectively. Most common adverse events were edemas grade 3, which were commonly related to the advanced stage, with 66% of the patients suffering from liver cirrhosis. Exploratory data analyses showed significant impact of ECOG performance status grade 0 versus 1 and CLIP score 0/1 versus > 1 on OS, 9.8 months (95% CI: 4.24-15.35) versus 2.7 months (95% CI: 1.03-4.36; P = 0.002), and 9.8 months (95% CI: 3.23-16.37) versus 4.4 months (95% CI: 3.14-5.66; P = 0.009), respectively. Preceding tumor surgery had significant beneficial impact on survival, as well as maximal tumor diameter of < 5 cm. The correlation of C-reactive protein decrease with significantly improved OS underlines the close link between inflammation and tumor control. Biomodulatory therapy in advanced HCC may be a low toxic, efficacious treatment and principally demonstrates that such approaches should be followed further for treatment of advanced HCC.

New economic training model for installing ultrasound-guided drainages.

Abscesses and circumscribed collections of fluid are frequently found as complications of infectious diseases or surgery. Drainage is often indicated. We have established a new, economic, easy-to-make model to learn and improve competence in installing ultrasound-guided drainage. Up to fifteen water balloons (size 30 - 50 mm) were placed in a plastic box which then was filled with instant custard powder mixed with water. Spiral computed tomography (CT) of this box was performed. Experienced (n = 8) and inexperienced examiners (n = 8) drained the balloons via a direct puncture technique using either ultrasound-guidance alone or volume navigation with image fusion (ultrasound and CT) with needle tracking. Trainees filled out a questionnaire (before and after training) asking for information on their experience in ultrasound, in installing drainages and evaluating the new model. The time needed for installing the drainage was measured. None of the participants had ever attended a course on drainage installation. Only a few of the experienced examiners (n = 3) would autonomously install a drainage into a fluid collection with a size exceeding 4 cm before training. After training all participants felt more confident in ultrasound and in installing drainages into abscesses or other fluid collections. Most of the participants rated additional volume navigation with image fusion as a helpful tool. Ultrasound-guided drainage of abscesses can be trained easily with this new and economic model. Students and physicians can improve their skills and gain confidence in performing ultrasound-guided interventions.

[Spontaneous bacterial peritonitis]. / Spontan bakterielle Peritonitis.

Spontaneous bacterial peritonitis (SBP) is the most frequent infection in patients with cirrhosis during hospitalization and is associated with high acute and long-term mortality. Diagnosis is made by paracentesis with determination of neutrophil count in ascitic fluid. Empirical antibiotic therapy must be initiated immediately. The choice of drug is dependent on prior therapies. Liver transplantation has to be considered in the absence of contra-indications. Prophylaxis of SBP is indicated in patients with ascites and gastrointestinal hemorrhage, and in patients after SBP. Primary prophylaxis should be considered in high-risk patients with cirrhosis and ascites. The development of resistance to antibiotic drugs is a relevant side-effect.

[Contrast-enhanced sonographic drainage control: a feasibility study]. / Kontrastmittelsonografische Drainagenkontrolle: eine Feasibility-Studie.

Liver abscesses still represent a life-threatening disease. Interventional abscess puncture and/or drainage are often the most adequate treatment. The aim of our study was the evaluation of drainage control with contrast-enhanced sonography. We included 15 patients in our feasibility study, three of whom had infected liver cysts, three had abscesses after liver resection or transplantation, six had intrahepatic abscesses and three had abscesses of other localisations. For drainage control with contrast-enhanced sonography we administered 1 mL of the contrast agent SonoVue® (Bracco, Germany) diluted in 10 mL of 0.9 % of NaCl through the indwelling drainage or an 18-G Chiba needle. A total of 28 sonographic controlled examinations was performed. The position of the drainage, as well as the size of the abscess itself could be demonstrated in all cases. Furthermore, possible septs or the communication of different abscess regions could be seen. Drainage remained in position for an average of 13.3 days. Assessment of drainage position and size of the abscess region is of clinical relevance. The main advantages of the described examination with contrast-enhanced sonography are the lack of radiation and the low costs due to the small amount of contrast medium used.

A novel mechanism for target gene-specific SWI/SNF recruitment via the Snf2p N-terminus.

Chromatin-remodeling complexes regulate the expression of genes in all eukaryotic genomes. The SWI/SNF complex of Saccharomyces cerevisiae is recruited to its target promoters via interactions with selected transcription factors. Here, we show that the N-terminus of Snf2p, the chromatin remodeling core unit of the SWI/SNF complex, is essential for the expression of VHT1, the gene of the plasma membrane H(+)/biotin symporter, and of BIO5, the gene of a 7-keto-8-aminopelargonic acid transporter, biotin biosynthetic precursor. chromatin immunoprecipitation (ChIP) analyses demonstrate that Vhr1p, the transcriptional regulator of VHT1 and BIO5 expression, is responsible for the targeting of Snf2p to the VHT1 promoter at low biotin. We identified an Snf2p mutant, Snf2p-R(15)C, that specifically abolishes the induction of VHT1 and BIO5 but not of other Snf2p-regulated genes, such as GAL1, SUC2 or INO1. We present a novel mechanism of target gene-specific SWI/SNF recruitment via Vhr1p and a conserved N-terminal Snf2p domain.

Evaluation of the microcirculation of hepatocellular carcinomas using contrast-enhanced ultrasound with intraarterial and intravenous contrast application during transarterial chemoembolization with drug-eluting beads (DEB-TACE): preliminary data.

PURPOSE: The objective was the evaluation of microcirculation in hepatocellular carcinomas (HCC) in vivo by dynamic contrast-enhanced ultrasound (CEUS) after intravenous (i.v.) and intraarterial (i.a.) application of contrast agent during transarterial chemoembolization (TACE) using drug-eluting beads (DEB). PATIENTS AND METHODS: Eleven patients with HCC underwent CEUS directly before and immediately after DEB-TACE. The sonographic contrast agent was injected through the microcatheter intraarterially and intravenously. The grade of hypervascularization was evaluated before Bead application. The percentage of devascularization after Bead application was calculated and quantitative devascularization was carried out using time intensity curves (TIC). These results were compared to postinterventional angiography after Bead application and postprocedural computed tomography. RESULTS: The hypervascularization of HCC was marginal improved after i.a. contrast application compared to i.v. application (p = 0.163). The reduction of vascularization after Bead application correlated significant between i.a. and i.v. contrast application (p = 0.007) and decreased significant using TIC analysis (p = 0.003). Postinterventional angiography related with CEUS after i.a. sonographic contrast agent application. Extrahepatic tumor-feeding arteries were detected by a mismatch between i.a. and i.v. CEUS in one case. CONCLUSION: Quantification of the reduction of microvascularization using TIC analysis may be a valuable periinterventional tool during DEB-TACE. Intraprocedural CEUS with i.a. and i.v. ultrasound contrast agent injection may help finding extrahepatic tumor-feeding arteries.

Contrast-enhanced ultrasound in diagnosing liver malignancy.

PURPOSE: The use of contrast enhancers has widened the possibilities of sonographic imaging, and allows the differentiation of characteristic enhancement patterns leading to diagnosis in focal liver lesions. The aim of our study was to evaluate contrast ultrasound signs in diagnosing malignant liver lesions. METHODS: 86 patients with 100 solid liver lesions were enrolled. A baseline gray-scale sonogram was obtained with a multifrequency 4 C convex array probe, followed by contrast-enhanced sonography with a low mechanical index (<0.2) over 300 seconds. Final diagnosis was confirmed by histology or in case of haemangioma by CT/NMR and quantitative contrast harmonic imaging (CHI) with perfusion analysis (contrast). RESULTS: 55 malignant (6 HCC, 46 secondary malignant lesions - 3 of them lymphoma, 3 cholangiocarcinoma), and 45 benign lesions (8 FNH, 1 von Meyenburg complex, 1 granuloma, 3 adenoma, 21 hemangioma, 2 focal fat storage imbalances, 7 abscesses, one scar, and in one case normal liver) were found. 51/55 malignant (all but one filia and three HCC), but also 17/45 benign lesions showed hypoperfusion in the late phase. The ultrasound pattern in the arterial phase differed in malignant lesions: 22 lesions were initially hypervascular, 20 had rim enhancement and in 13 lesions there was a non-specific vascularisation. In all but one malignant lesion a diminishing of contrast agent in the late phase compared to the arterial phase with respect to the surrounding liver tissue was observed. Only three benign lesions with this later sign were falsely diagnosed as malignant: one adenoma, one epitheloid granuloma, and a scar. Quantitative perfusion pattern was analyzed exemplary. Diminishing of contrast agent in the late phase compared to the arterial phase with respect to the surrounding liver tissue as a sign for malignancy had a positive predictive value of 95%, a sensitivity of 98%, a negative predictive value of 98%, and a specificity of 93%. CONCLUSIONS: Diminishing of contrast agent in the late phase compared to the arterial phase with respect to the surrounding liver tissue is a helpful sign in contrast enhanced ultrasound to diagnose malignancies.

[Perianal fistulas in Crohn's disease: treatment results at an interdisciplinary unit]. / Perianale Crohn-Fisteln : Ergebnisse der Behandlung in einer interdisziplinären Sprechstunde.

BACKGROUND: Approximately one third of patients with Crohn's disease develop perianal fistulas. This study was conducted to determinate outcome predictors in patients treated at a specialized multidisciplinary unit. PATIENTS AND METHODS: Between May 2005 and May 2008, all patients with perianal Crohn's fistulas were treated by the same surgeon and a gastroenterologist specialized in managing patients with Crohn's disease. Deep fistulas were treated by fistulotomy. For high fistulas, a noncutting seton was placed followed by maintenance treatment with azathioprine and/or infliximab. "Optimal outcome" was recorded when (a) there was no need for diverting stoma, (b) complete healing was achieved by fistulotomy, or (c) fistula symptoms were under control, i.e. there was no need for treatment extension during follow-up. RESULTS: Thirty-four male and 32 female patients underwent 100 surgical interventions. The most frequent types of fistula were high trans-sphincteric (62%) and high intersphincteric (15%). Eleven of the 32 females presented with rectovaginal fistulae. At the study end, complete healing was observed in 12 patients and 32 had good control of fistula symptoms. Seven required proctectomy, fistula symptoms were not under control in 12, and three required diverting stoma. Altogether 44 patients (67%) achieved optimal outcome. The following factors were predictors of nonoptimal outcome by multivariate analysis: presence of Crohn's colitis (P=0.01), age at the onset of Crohn's disease <20 years (P=0.02), and types of fistula not suitable for fistulotomy (P=0.05). CONCLUSIONS: The multidisciplinary approach at specialized units will lead to successful outcome in >60% of patients with Crohn's perianal fistulas. The presence of Crohn's colitis, young age at disease onset, and presence of high fistulas are indicators of poor prognosis.

[Diagnostic and therapeutic consequences of abnormal ultrasound findings]. / Diagnostische und therapeutische Konsequenz von Ultraschallbefunden.

BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the diagnostic and therapeutic consequences arising from abnormal ultrasound findings in a multidisciplinary setting in the University of Regensburg Clinical Centre. PATIENTS AND METHODS: The results of 1162 randomly selected ultrasound examinations (on 671 males and 491 females) from a total of 14,301 at an interdisciplinary ultrasound unit were analysed. The investigators recorded the findings in a routinely used standardized manner. The records and discharge reports of each patient were then evaluated with regard to the diagnostic and therapeutic consequences of the findings. RESULTS: There were 1843 abnormal findings in 901 patients. In 114 patients (6.2 %) no adequate diagnostic measures had been undertaken or recommended at discharge, but the reasons for the decisions taken could not be judged (value 4). 72.1 % of all patients were recruited from departments of internal medicine. However, the highest percentage of findings without adequate consequences were found to be in patients of the departments of oral and maxillofacial surgery, dermatology and nuclear medicine. CONCLUSION: The number of ultrasound examinations that had been done without adequate consequences was comparatively low at 6.2 %. But perhaps this number can be further reduced by improved wording of the examination reports.

Endoscopic retrograde cholangiography of a hepaticojejunostomy using double balloon enteroscopy.

Examination of a biliodigestive anastomosis presents a diagnostic and therapeutic challenge. Visualization of biliodigestive anastomosis and endoscopic retrograde cholangiography with intervention is possible with a double balloon enteroscope.

Future expectations in the prophylaxis of intestinal bleeding.

Prophylaxis of gastrointestinal bleeding is attempted in widely varying situations. In NSAID-induced peptic ulcer, the advantage of selective cyclooxygenase 2 inhibitors with regard to gastrointestinal damage has yet to be translated into an advantage in overall morbidity. Strategies for primary and secondary prevention of variceal bleeding have been established. Therapy tailored to hepatic venous pressure gradient has the potential to achieve clinical relevance. Several methods have been developed to prevent postpolypectomy bleeding, but their optimal risk-tailored application has yet to be demonstrated. Although octreotide treatment seems to be beneficial in reducing the blood loss from angiodysplasias, controlled studies to determine its optimal use are awaited. Stress-ulcer prophylaxis is commonly applied in critically ill patients. Although data indicate that H2-receptor antagonists and omeprazole are effective in preventing clinically significant bleeding, evidence for an advantage with respect to length of hospital or intensive-care-unit stay, as well as mortality, is still lacking. Since there is misuse of acid-suppressing drugs on regular wards, in-house guidelines may offer the potential for saving costs and reducing inappropriate prescription.

Outcome of patients with acute, necrotizing pancreatitis requiring drainage-does drainage size matter?

AIM: To assess the outcome of patients with acute necrotizing pancreatitis treated by percutaneous drainage with special focus on the influence of drainage size and number. METHODS: We performed a retrospective analysis of 80 patients with acute pancreatitis requiring percutaneous drainage therapy for infected necroses. Endpoints were mortality and length of hospital stay. The influence of drainage characteristics such as the median drainage size, the largest drainage size per patient and the total drainage plane per patient on patient outcome was evaluated. RESULTS: Total hospital survival was 66%. Thirty-four patients out of all 80 patients (43%) survived acute necrotizing pancreatitis with percutaneous drainage therapy only. Eighteen patients out of all 80 patients needed additional percutaneous necrosectomy (23%). Ten out of these patients required surgical necrosectomy in addition, 6 patients received open necrosectomy without prior percutaneous necrosectomy. Elective surgery was performed in 3 patients receiving cholecystectomy and one patient receiving resection of the parathyroid gland. The number of drainages ranged from one to fourteen per patient. The drainage diameter ranged from 8 French catheters to 24 French catheters. The median drainage size as well as the largest drainage size used per patient and the total drainage area used per patient did not show statistically significant influence on mortality. CONCLUSION: Percutaneous drainage therapy is an effective tool for treatment of necrotizing pancreatitis. Large bore drainages did not prove to be more effective in controlling the septic focus.

Outcome of hemato-oncologic patients with and without stem cell transplantation in a medical ICU.

OBJECTIVE: To assess the outcome of a mixed population of critical ill patients with haematological malignancies with special focus on the comparison of patients who underwent stem cell transplantation with non-transplanted patients. METHODS: Retrospective, unicentric analysis of 94 critical ill cancer patients in a tertiary care centre in a period of two years time. RESULTS: We analysed different variables at admission as well as different treatment modalities during the ICU stay. We compared the outcome by using chi-square test by Pearson for categorical variables and Kaplan-Meier as well as Cox-Regression for survival analysis. The general patients characteristics did not significantly differ between transplanted and non-transplanted patients. The overall ICU and hospital mortality were 43% and 54%. Considering just patients with mechanical ventilation we found ICU and hospital mortalities of 65% and 82% in the stem cell transplantation group vs. 67% and 74% in the non-transplanted group, respectively. As risk factors for overall mortality in multivariate analysis only the Simplified Acute Physiology Scale II and the need of ventilation remained significant. Between the underlying diseases mortality did not show significant differences at all. CONCLUSIONS: The outcome and prognosis of critical ill cancer patients has generally slightly improved over the last years. Our data show no statistically significant differences regarding outcome and prognosis between stem cell transplanted and non-transplanted patients receiving ICU treatment. A stem cell transplantation should not be considered a strong contraindication for ICU treatment or artificial ventilation.

[Palliative therapy in cholangio- and gallbladder carcinoma]. / Palliative Therapie von Gallengangs- und Gallenblasenkarzinomen.

Non-resectable cholangiocarcinoma and gallbladder carcinoma have a poor prognosis. In addition to the general aspects of "best supportive care", biliary drainage is an important part of the palliative treatment of patients with malignant biliary stenosis. Photodynamic therapy has led to an improved median survival in hilar cholangiocarcinoma in two controlled studies. The survival benefit of external radiation or intraluminal brachytherapy has not yet been convincingly demonstrated. Whether or not systemic chemotherapy should be applied is still under debate. A single study including advanced biliary and pancreatic cancer patients has demonstrated a survival benefit for the combined group. In recent years, new chemotherapy protocols have been applied, some with promising results. Intra-arterial chemotherapy and chemotherapeutically coated stents have not been evaluated well enough to be recommended outside clinical studies. Ablative therapies have been used in a limited number of patients only. Further studies are necessary to clarify whether these treatment modalities are effective.

Comparison of low and high frequency transducers in the detection of liver metastases.

BACKGROUND AND AIMS: To evaluate the benefit of the additional use of a high frequency ultrasound probe (7.5 MHz) in finding suspicious liver lesions compared to the examination using a 3.5-MHz transducer only. PATIENTS AND METHODS: One hundred and fifty-seven patients with underlying malignant disease were examined with both transducers using one of three ultrasound machines (Siemens Sonoline Elegra, GE Healthcare Logic 9, or Hitachi EUB-8500). Findings on hepatic lesions were collected on a standardised documentation sheet and evaluated by descriptive statistics. RESULTS: Ninety-three patients (59.2% of all patients) showed no evident liver lesion on conventional ultrasound with the 3.5 MHz probe. In 29 patients (18.5%) new suspicious liver lesions were found by using the high frequency transducer. Thirteen of these 29 patients (44.8%) were suspected to suffer from diffuse infiltration of the liver with malignant lesions or at least 10 additional visible lesions. In 14 patients, no liver lesion had been known before high frequency ultrasound examination. The size of newly described liver lesions ranged from 2 mm to 1.5 cm. Time needed for the additional examination with the high frequency transducer ranged between 1 and 15 min with an average of 4.0 min. CONCLUSION: The additional use of a high frequency transducer in patients with underlying malignant disease slightly extends the examination time, but reveals new, potentially malignant hepatic lesions in almost every fifth patient.

[Chronic diseases after gastrointestinal surgery]. / Folgeerkrankungen nach gastrointestinalen Operationen.

Gastrointestinal surgery may not only lead to early postoperative complications but also chronic consequences. These have therapeutic implications for affected patients. The kind and extent of surgical intervention determines the spectrum of postsurgical phenomena which may occur. These chronic consequences are due to changes in gastrointestinal anatomy, the synchronization of digestive processes, or the ability to digest and absorb food. In case of transplantation surgery, adverse effects of immunosuppression have to be considered. Sometimes, chronic consequences of surgical procedures are difficult to recognize. The knowledge of typical problems associated with gastrointestinal surgery is necessary to enable early and timely diagnosis and treatment. Some negative effects can be avoided by early therapeutic interventions. This article summarizes typical chronic consequences of gastrointestinal surgery.

Analysis of intestinal haem-oxygenase-1 (HO-1) in clinical and experimental colitis.

Haem-oxygenase-1 (HO-1) has been shown to exert anti-inflammatory, anti-apoptotic and anti-proliferative effects. We investigated HO-1 expression in patients with inflammatory bowel disease (IBD) and could demonstrate a scattered expression of HO-1 in the intestinal epithelium of severely inflamed colonic mucosa of patients with IBD compared to control specimens such as diverticulitis, suggesting dysregulated expression in IBD. To further analyse potential mechanisms of HO-1 induction in the intestine we employed an in vitro epithelial cell apoptosis model and an experimental colitis model. In vitro induction of HO-1 by the HO-1 inducer cobalt protoporphyrin (CoPP) resulted in a dose-dependent down-regulation of caspase-3 activation in HT-29 cells, indicating an anti-apoptotic function of HO-1 in the intestine. In vivo, preventive HO-1 induction by CoPP in acute dextran sodium sulphate (DSS)-induced colitis led to a significant down-regulation of colonic inflammation (P < 0.01) with a concomitant reduction in interferon (IFN)-gamma - but unaffected interleukin (IL)-10-secretion by isolated mesenteric lymph nodes (P < 0.01). Additionally, TUNEL staining of colonic sections demonstrated fewer apoptotic epithelial cells in the colon of CoPP treated animals. No beneficial effects were observed if HO-1 was induced by CoPP after the onset of acute colitis or in chronic DSS-induced colitis. In conclusion, the data suggest a protective role of HO-1 if it is induced before the onset of inflammation. However, as shown by the lack of effects in established acute or in chronic colitis, the induction of HO-1 may not be a promising approach for the treatment of IBD.

[Sonographic controlled drainage of a fluid formation of the spleen in combination with pancreatitis]. / Sonographisch gesteuerte Punktion und Drainage einer Flüssigkeitsformation in der Milz bei Pankreasschwanzpankreatitis -- Milzhämatom oder in die Milz perforierte Pankreaspseudozyste?

With regard to acute or chronic pancreatitis various complications involving the spleen can occur, hematoma of the spleen being a rare complication. We describe the case of a patient in reduced general condition with elevated pancreatic enzymes and signs of inflammation. During multiple examinations, hematoma of the spleen, as well as hematomas close to the left adrenal gland and a larger hematoma close to the gastric wall were detected. In computed tomography and due to the laboratory parameters a pancreatitis was diagnosed. After CT-controlled puncture a communication between both formations was considered possible which was in retrospect CT-assisted not successful. Subsequently an ultrasound controlled drainage was performed, finally resulting in a restitutio ad integrum, thereby avoiding splenectomy. The described percutaneous puncture of a fluid formation in the splenic area represents a non-surgical option in the therapy of intrasplenic pancreatic fluid formations.