[Abdominal pain and unclear focal liver lesion in 46-year-old female patient]. / Rechtsseitiger Oberbauchschmerz und unklare Leberraumforderung bei einer 46-jährigen Patientin.

A 46-year-old woman presented with recurrent right upper quadrant pain. Abdominal ultrasound revealed an inhomogeneous liver lesion (4â€¯× 7 cm) with complex echotexture. Since further contrast-enhanced imaging tests were inconclusive and lesion integrity remained unclear, a left hemihepatectomy was performed. Histological examination revealed a hepatic epithelioid angiomyolipoma. Hepatic epithelioid angiomyolipoma is a rare, mostly benign, mesenchymal hepatic tumor, composed of smooth muscle cells, adipose tissue, and blood vessels of varying proportions, and its correct diagnosis remains a clinical challenge.

Therapy susceptible germline-related BRCA 1-mutation in a case of metastasized mixed adeno-neuroendocrine carcinoma (MANEC) of the small bowel.

BACKGROUND: Adenocarcinomas or combined adeno-neuroendocrine carcinomas (MANEC) of small bowel usually have a dismal prognosis with limited systemic therapy options. This is the first description of a patient showing a germline-related BRCA1 mutated MANEC of his ileum. The tumor presented a susceptibility to a combined chemotherapy and the PARP1-inhibitor olaparib. CASE PRESENTATION: A 74-year old male patient presented with a metastasized MANEC of his ileum. Due to clinical symptoms his ileum-tumor and the single brain metastasis were removed. We verified the same pathogenic (class 5) BRCA1 mutation in different tumor locations. There was no known personal history of a previous malignant tumor. Nevertheless we identified his BRCA1 mutation as germline-related. A systemic treatment was started including Gemcitabine followed by selective internal radiotherapy (SIRT) to treat liver metastases and in the further course Capecitabine but this treatment finally failed after 9 months and all liver metastases showed progression. The treatment failure was the reason to induce an individualized therapeutic approach using combined chemotherapy of carboplatin, paclitaxel and the Poly (ADP-ribose) polymerase- (PARP)-inhibitor olaparib analogous to the treatment protocol of Oza et al. All liver metastases demonstrated with significant tumor regression after 3 months and could be removed. In his most current follow up from December 2017 (25 months after his primary diagnosis) the patient is in a very good general condition without evidence for further metastases. CONCLUSION: We present first evidence of a therapy susceptible germline-related BRCA1 mutation in small bowel adeno-neuroendocrine carcinoma (MANEC). Our findings offer a personalized treatment option. The germline background was unexpected in a 74-year old man with no previously known tumor burden. We should be aware of the familiar background in tumors of older patients as well.

Predicting ADR from PDR and individual adenoma-to-polyp-detection-rate ratio for screening and surveillance colonoscopies: A new approach to quality assessment.

BACKGROUND AND AIMS: Adenoma detection rate (ADR) has been established as a quality indicator for screening colonoscopy. Because ADR is cumbersome to obtain in routine practice, polyp detection rate (PDR), polypectomy rate (PR) and adenoma-to-polyp-detection-rate-ratio (APDRR) have been proposed to estimate ADR. This study aimed to evaluate APDRR in order to estimate ADR (ADRest) in different settings. METHODS: Average risk screening and surveillance colonoscopies from a community-based private practice and a tertiary academic hospital setting were retrospectively evaluated. APDRR was calculated as averaged group APDRR for all study procedures (APDRR) and for the first half of study procedures of each gastroenterologist (APDRRag) or individually for each gastroenterologist on the basis of his or her first 25, 50 and 100 colonoscopies (APDRRind). ADRest was determined from PDR by using APDRR, APDRRag, and APDRRind, respectively. RESULTS: A total of 2717 individuals were analyzed. Using APDRR, significant correlations between ADR and ADRest were observed for the entire (0.944, p < 0.001), proximal (0.854, p < 0.001), and distal (0.977, p < 0.001) colon. These correlations were lost when APDRRag was used to estimate each gastroenterologist's ADR for the second half of his or her included colonoscopies. However, ADR and ADRest correlated significantly with a root-mean-square-error of 6.8% and 5.8% when APDRRind on the basis of each gastroenterologist's first 50 and 100 colonoscopies was used for subsequent colonoscopies. CONCLUSIONS: ADR for subsequent colonoscopies of an individual endoscopist can be reliably estimated from PDR by using an individually calculated APDRR. Prospective studies are needed to verify this promising approach in different practice settings.

Economic burden of Clostridium difficile associated diarrhoea: a cost-of-illness study from a German tertiary care hospital.

PURPOSE: Clostridium difficile associated diarrhoea (CDAD) is the most common cause of health-care-associated infectious diarrhoea. In the context of the German health-care system, direct and indirect costs of an initial episode of CDAD and of CDAD recurrence are currently unknown. METHODS: We defined CDAD as presence of diarrhoea (≥3 unformed stools/day) in association with detection of Clostridium difficile toxin in an unformed faecal sample. Patients treated with metronidazole (PO or IV) and/or vancomycin (PO) were included. Comprehensive data of patients were retrospectively documented into a database using the technology of the Cologne Cohort of Neutropenic Patients (CoCoNut). Patients with CDAD were matched to control patients in a 1:1 ratio. Analysis was split in three groups: incidence group (CDAD patients without recurrence), recurrence group (CDAD patients with ≥1 recurrence) and control group (matched non-CDAD patients). RESULTS: Between 02/2010 and 12/2011, 150 patients with CDAD (114 patients in the incidence and 36 (24 %) in the recurrence group) and 150 controls were analysed. Mean length of stay was: 32 (95 %CI: 30-37), 94 (95 %CI: 76-112) and 24 days (95 %CI: 22-27; P = <0.001), resulting in mean overall direct treatment costs per patient of €18,460 (95 %CI: €14,660-€22,270), €73,900 (95 %CI: €50,340-€97,460) and €14,530 (95 %CI: €11,730-€17,330; P = <0.001). In the incidence and recurrence group, the mean cumulative number of antibiotic CDAD treatment days was 11 (95 %CI: 10-12) and 36 (95 %CI: 27-45; P = <0.001). CONCLUSIONS: Especially CDAD recurrence was associated with excessive costs, which were mostly attributable to a significantly longer overall length of stay. Innovative treatment strategies are warranted to reduce treatment costs and prevent recurrence of CDAD.

Clinical management of chronic hepatitis B infection: results from a registry at a German tertiary referral center.

PURPOSE: We studied a cohort of adult patients with chronic hepatitis B (CHB) infection, followed at a tertiary referral liver center in Germany over 12.5 years to analyze the clinical features and impact of management on disease progression and survival of CHB patients in general and of those with CHB and HCC in particular. METHODS: We retrospectively evaluated the medical records of 242 adult (age ≥ 18 years) patients. CHB was defined as positive hepatitis B surface antigen (HBsAg) and/or HBV-DNA levels >10 IU/mL for at least 6 months. Patient demographics, HBV markers, antiviral treatment, laboratory parameters, liver imaging and histology were recorded for each visit. HCC patients were divided into two groups and separately analyzed (group 1: n = 24, HCC at first visit and group 2: n = 11, HCC during surveillance). RESULTS: The mean age was 44 years in CHB patients without HCC (63% male) and about 59 years in patients with HCC (77% male). Antiviral therapy was given to 59% of patients without HCC compared to only 25% in group 1 and 18% in group 2 with comparable median HBV DNA levels of approximately 36,000 IU/mL. There was no statistically significant difference concerning the HCC stages (Milan, UCSF, BCLC) at first diagnosis. Five-year survival was 19% in group 1 vs. 64% in group 2 (p = 0.019), with LTx performed in 12 vs. 45%, respectively. CONCLUSION: Surveillance of CHB patients did not result in early stage detection of HCC but in a higher likelihood to receive potentially curative treatments.

Alisporivir with peginterferon/ribavirin in patients with chronic hepatitis C genotype 1 infection who failed to respond to or relapsed after prior interferon-based therapy: FUNDAMENTAL, a Phase II trial.

Alisporivir (ALV) is an oral, investigational host-targeting agent, with pangenotypic activity against hepatitis C virus (HCV). This randomized, double-blind, placebo-controlled, Phase II study explored the efficacy and safety of ALV with peginterferon-α2a/ribavirin (PR) in patients with chronic HCV genotype 1 infection in whom prior PR had failed (43% relapsers, 34% null responders and 23% partial responders). Four-hundred-and-fifty-nine patients were randomized (1:1:1:1) to ALV 600 mg once daily (QD), ALV 800 mg QD, ALV 400 twice daily (BID) or placebo plus PR for 48 weeks. When the global ALV trial programme was put on clinical hold, all patients in this study had received ≥31 weeks of randomized treatment; patients completed 48 weeks on PR alone. All ALV groups demonstrated superior rates of complete early virologic response (cEVR; primary endpoint) vs PR alone (P ≤ 0.0131), with highest cEVR rate seen with ALV 400 mg BID (74% vs 36% with PR alone; P < 0.0001). Respective SVR12 rates (key secondary endpoint) were 65% vs 26% in prior relapsers, 63% vs 5% in partial responders and 68% vs 3% in null responders. In patients who received >40 weeks of randomized treatment, the SVR12 rate was 89% for ALV 400 mg BID vs 30% for PR alone (P = 0.0053). Rates of viral breakthrough and relapse were lowest with ALV 400 mg BID. One case of pancreatitis (fully recovered) occurred with ALV/PR. Common AEs were headache, fatigue, anaemia, neutropenia and nausea. Hypertension was infrequent, but more common with ALV. ALV merits further investigation in interferon-free regimens in combination with direct-acting antiviral agents.

Propofol sedation for colonoscopy with a new ultrathin or a standard endoscope: a prospective randomized controlled study.

BACKGROUND AND STUDY AIMS: The majority of colonoscopies in Germany are performed under conscious sedation. Previous studies reported that pediatric colonoscopes reduce the demand for sedative drugs and may improve cecal intubation. The aim of this study was to compare a new ultrathin and a standard colonoscope in terms of propofol demand during colonoscopy. PATIENTS AND METHODS: A total of 203 patients were prospectively randomized to undergo colonoscopy with either a 9.5-mm ultrathin (UTC) colonoscope or a standard colonoscope of variable stiffness. Initially, 40 or 60 mg of propofol were administered according to body weight, followed by bolus injections of 20 mg as deemed necessary. Propofol was administered by a separate physician who was blinded to the endoscope used. Sedation levels were defined according to guidelines; pain and complaints were recorded on a numeric rating scale. RESULTS: Significantly less propofol was required to reach the cecum with the UTC (adjusted mean 94.9 mg [95 % confidence interval (CI) 85.7 - 105.0] vs. 115.3 mg [95 %CI 105.8 - 124.7]; P = 0.003). The level of sedation and pain score were lower with the UTC (sedation level 1 76 % vs. 61 %; P = 0.003; pain score adjusted mean 2.0 [95 %CI 1.7 - 2.4] vs. 2.8 [95 %CI 2.5 - 3.1]; P = 0.001). The rate of ileal and cecal intubation, time to reach the cecum, number of external compressions, withdrawal time, polyp and adenoma detection rate, and patient satisfaction were not different between the two colonoscopes. The time to intubate the ileum was longer with the UTC (1.73 minutes [95 %CI 1.42 - 2.04] vs. 1.22 minutes [95 %CI 0.91 - 1.52]; P = 0.020). CONCLUSIONS: Use of a new ultrathin colonoscope was associated with reduced propofol consumption, lower patient sedation levels, and less pain than the standard colonoscope, but ileal intubation time was longer.

Yersinia pseudotuberculosis bloodstream infection and septic arthritis: case report and review of the literature.

Yersinia pseudotuberculosis belongs to the family Enterobacteriaceae and is known to cause enterocolitis, terminal ileitis, pseudoappendicitis, erythema nodosum, reactive polyarthritis, and, occasionally, bloodstream infections. Here, we report the first case of bacteremia and septic arthritis in a patient without obvious risk factors and review all of the published cases of Y. pseudotuberculosis bloodstream infections.

Endosonographic diagnosis of solid pancreatic tumors: a retrospective analysis from a tertiary referral center.

BACKGROUND: The sensitivity of endosonography for pancreatic tumors is good, but differentiation between malignant and benign lesions remains a challenge. We, therefore, analyzed the correlation between endosonographic findings and pancreatic carcinoma in a population with a high prevalence of chronic pancreatitis. METHODS: 171 endosonographic examinations were retrospectively evaluated using 22 dichotomous criteria. Final diagnosis was defined by the results of pancreas resection or by clinical follow-up (median: 41 months). A sum score was established after multivariate analysis. RESULTS: Final diagnosis was carcinoma, chronic pancreatitis, neuroendocrine tumor and normal pancreas in 67, 65, 9, and 38 subjects (prevalence 39 %, 38 %, 5 %, 22 % respectively) After multivariate analysis, carcinoma was significantly correlated with six endosonographic criteria and age, which resulted in the following score (yes = 1, no = 0): (dilated pancreatic duct) + (vascular infiltration) + (suspicious lymph nodes) + (tumor edge with pseudopodia-like extensions) + (age > 50 years) - (increased pancreas parenchyma echogenicity) - (tumor diameter < 10 mm) + 3. After receiver operating characteristic analysis, the area under the curve was 0.85. For score values of 5 (4) or more, sensitivity was 0.63 (0.93), specificity 0.91 (0.55), positive predictive value 0.82 (0.57), negative predictive value 0.79 (0.92), positive likelihood ratio 7.24 (2.05), and negative likelihood ratio 0.41 (0.14). CONCLUSION: A simple and potentially useful score for the prediction of pancreatic cancer based on six endosonographic criteria and patient age was established. Distribution of final diagnoses in the patient population argues for the score's applicability in clinical practice of a tertiary referral center and warrants prospective validation.

[Therapy of complications of hepatic cirrhosis]. / Therapie von Komplikationen der Leberzirrhose.

Complications of liver cirrhosis are usually confined to advanced stages of the disease. Bleeding from esophageal or gastric varices may be prevented by treatment with beta-blockers or by endoscopic band ligation in case of large varices and intolerance for beta-blockers. Treatment of an acute bleeding episode from varices can efficiently be treated by endoscopic procedures, potentially in combination with drug therapy. In case of bleeding uncontrolled by endoscopy, TIPS is an effective alternative in selected patients. Treatment of ascites consists of reduction of sodium intake, aldosterone antagonists, and loop diuretics as needed. TIPS or repeated paracentesis may be necessary in refractory ascites. Spontanous bacterial peritonitis (SBP) must be sought and treated with antibiotics in conjunction with albumin administration in order to reduce mortality. Hepatorenal syndrome is characterized by a poor prognosis. Therefore, liver transplantation should be considered in appropriate patients.

Pharmacokinetics of ibuprofen sodium dihydrate and gastrointestinal tolerability of short-term treatment with a novel, rapidly absorbed formulation.

OBJECTIVE: This paper describes four studies investigating the dissolution, plasma pharmacokinetics and safety of a novel, fast-acting ibuprofen formulation, ibuprofen sodium dihydrate. MATERIAL AND METHOD: Four separate studies investigated: the in vitro dissolution rates of ibuprofen sodium dihydrate (at pH 1.2, 3.5 and 7.2); the bioavailability of ibuprofen sodium dihydrate (in two pharmacokinetic studies; combined n = 38) compared with conventional ibuprofen, ibuprofen lysinate, ibuprofen arginate and ibuprofen liquagels (all 2 x 200 mg ibuprofen); and the gastroduodenal tolerance of ibuprofen sodium dihydrate and ibuprofen arginate (both 2 x 200 mg ibuprofen t.i.d.) in an endoscopy safety study, where endoscopy was performed at baseline and at the end of each treatment period using a five-point scale to assess the integrity of the gastric and duodenal mucosa. RESULTS: Ibuprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 than conventional ibuprofen, ibuprofen lysinate and ibuprofen liquagels. Ibuprofen sodium dihydrate had similar C(max) to ibuprofen lysinate and ibuprofen liquagels and significantly higher Cmax than conventional ibuprofen (p = 0.002). The mean plasma concentration for ibuprofen sodium dihydrate was significantly higher than for conventional ibuprofen (p = 0.028) 10 minutes post-dose and the t(max) for ibuprofen sodium dihydrate was reached significantly earlier than for conventional ibuprofen (p = 0.018). All three formulations were bioequivalent according to the acceptable boundaries (90% confidence intervals). No statistically significant difference was observed between the ibuprofen formulations in terms of adverse events and specifically with respect to hemorrhagic scores; 41 (46.0%) adverse events (AEs) occurred after administration of ibuprofen sodium dihydrate, and 46 (52.9%) after ibuprofen arginate. One occurrence of an invasive ulcer was observed after administration of ibuprofen arginate. CONCLUSIONS: The new formulation of ibuprofen sodium dihydrate dissolves quickly in vitro, has the same extent of absorption as other fast-acting ibuprofen formulations, and is absorbed into plasma more rapidly than conventional ibuprofen. In addition, the present studies suggest that the tolerability and safety profile of ibuprofen sodium dihydrate is comparable to existing ibuprofen formulations.

Fulminant liver failure induced by hepatosplenic alphabeta T-cell lymphoma.

Since survival rates of fulminant liver failure are low, early consideration of liver transplantation in patients developing hepatic encephalopathy due to progressive liver failure is mandatory. Rapid diagnostic work-up is necessary to identify the underlying disease and to rule out contraindications to liver transplantation. We report the case of a 35-year-old patient presenting with fulminant hepatitis and a four-week history of biopsy-proven autoimmune hepatitis. Despite high-dose steroid-treatment liver function progressively worsened and hepatic encephalopathy rapidly developed. Histopathologic evaluation of a liver biopsy specimen revealed necrotizing hepatitis and rare atypical lymphocytes. Surgical biopsy specimens confirmed the suspicion of an aggressive hepatosplenic alphabeta T-cell lymphoma which represents a contraindication to liver transplantation.

[Therapy of hepatitis B and C. Problem situations in chronic HBV and HCV infection]. / Therapie der Virushepatitis B und C. Problemsituationen bei chronischer HBV- und HCV-Infektion.

In the most recent years, therapy of chronic hepatitis has been improved. Nonresponder to an initial treatment is the predominant group of difficult-to-treat patients. Nonresponse may be due to host specific factors and/or virus specific properties. It is essential to reconsider the indication for treatment in respect to the presumed beneficial effect before initiating therapy or retreatment in these patients. Optimally, only those patients should be treated who are at significant risk for progression of liver disease.

Combination therapy with interferon-alpha 2b and ribavirin for the treatment of relapse patients and non-responders with chronic HCV infection.

BACKGROUND: Treatment of patients with chronic hepatitis C after failure of an interferon monotherapy remains controversial. While relapse patients have a sustained response after a combination therapy with interferon-alpha 2b 3 x 3 MU/week plus ribavirin 1,000/1,200 mg daily for 24 weeks in up to 49%, the standard therapy for initial non-responders remains to be determined. METHODS: We therefore conducted a large multicenter trial to compare efficacy and safety of a combined interferon/ribavirin therapy in 327 non-responders and 181 relapse patients with chronic HCV infection outside of highly specialized institutions. RESULTS: After 6 months therapy with interferon-alpha-2b 3 MU thrice a week plus ribavirin 1,000/1,200 mg daily for 24 weeks 31% of relapse patients and 11% of initial non-responders achieved a sustained response according to an intent to treat analysis. CONCLUSIONS: These data could not confirm the high rate of sustained responders in relapse patients. In addition we were only able to induce a sustained response in every tenth non-responder. These results might reflect the realistic sustained response rates in a non-biased European population of HCV-infected patients.

Expression of apoptosis and apoptosis-related peptides in various stages of rejection in the human transplanted liver.

BACKGROUND/AIMS: In the transplanted liver, the role of apoptosis and apoptosis-related proteins are largely unknown. This study addresses the question whether hepatocyte or leukocyte apoptosis plays an important role in acute rejection of the transplanted human liver and which pathways are involved. METHODOLOGY: Cryosections from liver biopsies with acute rejection were stained with the TUNEL technique for detection of apoptosis and labeled immunohistochemically with antibodies against CD95, bcl-2, TGF-beta and iNOS. A double-labeling protocol was developed for simultaneous detection of iNOS and apoptosis. Liver tissue with chronic viral hepatitis, with hepatitis reinfection and tissue without pathological findings served as a control. RESULTS: Leukocyte apoptosis was markedly reduced in severe compared to mild or moderate acute rejection. Hepatocyte apoptosis is detected rarely in acute rejection with a slight increase from mild to severe despite a strong expression of CD95 and TGF-beta on hepatocytes. The hepatocyte expression of iNOS is weak in acute rejection but strong in control slides with hepatitis B/C reinfection. In acute rejection, simultaneous expression of iNOS and apoptosis could be demonstrated in Kupffer-cells. CONCLUSIONS: Severe acute rejection in the human transplanted liver is characterized by a lack of apoptosis of infiltrating portal lymphocytes probably caused by a reduced downregulation of lymphocyte function. Secondly, in spite of the strong expression of CD95 and TGF-alpha, hepatocyte apoptosis plays a limited role for liver damage in acute rejection. Finally, Kupffer cell apoptosis is increased in acute rejection and seems to be induced by nitric oxide.

Hepatotropism of GB virus C (GBV-C): GBV-C replication in human hepatocytes and cells of human hepatoma cell lines.

BACKGROUND/AIMS: Recently, GB virus C (GBV-C) has been identified as another virus potentially causing viral hepatitis. However, its hepatotropism and pattern of infection in humans is still unknown. To elucidate the presence and replication of GBV-C in the human liver, we investigated tissue samples of six explanted livers from five GBV-C mono- or GBV-C/HCV co-infected patients for GBV-C RNA plus- and minus-strand RNA. METHODS: These tissues were examined using nested RT-PCR followed by Southern blot hybridization as well as fluorescence in situ hybridization on liver cryosections. To further substantiate susceptibility of liver cells for GBV-C, in vitro infection of human hepatoma cells (HuH7, HepG2) with GBV-C mono-infected serum was performed. RESULTS: By reverse transcription followed by nested PCR (RT-PCR), 5 of 6 liver specimens (4/5 patients) were positive for GBV-C plus-strand RNA, and viral minus-strand RNA could be detected in 4 of 6 liver specimens (4/5 patients). One liver sample was negative for GBV-C RNA. In two specimens we could identify GBV-C infection by in situ hybridization. Virus infection appeared to be restricted to hepatocytes and detection of minus-strand RNA showed viral replication in a few highly infected liver cells. In vitro infection of HepG2 or HuH7 cells confirmed these findings by a release of virions into supernatant. CONCLUSION: In conclusion, our results establish GBV-C as a hepatotropic virus infecting human cells of hepatic origin in vivo and in vitro.