[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.

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.

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.

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.

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.

The rat hepatocyte plasma membrane organic anion binding protein is immunologically related to the mitochondrial F1 adenosine triphosphatase beta-subunit.

A 55-kD organic anion binding protein (OABP) was identified previously in liver cell plasma membrane sinusoidal subfractions. Although this protein was localized to the surface of hepatocytes by immunofluorescence, immunoblot analysis revealed reactivity toward both plasma membrane and mitochondrial fractions. To clarify these findings, an immunoreactive clone from a rat liver cDNA expression library was isolated, the 1,500-base pair cDNA insert was sequenced, and the corresponding beta-galactosidase fusion protein was expressed and purified. The resulting sequence corresponded to that of the rat mitochondrial F1-adenosine triphosphatase (F1-ATPase) beta-subunit. This protein and OABP are of similar size and are mutually immunologically cross-reactive. That the antigen was present on the cell surface as well as in mitochondria was suggested from studies of immunoprecipitation after cell-surface iodination, and light- and electron-microscopic immunocytochemistry. Photoaffinity labeling of bovine F1-ATPase with high-specific-activity [35S]sulfobromophthalein revealed binding only to the beta-subunit. Hepatocyte uptake of bilirubin and sulfobromophthalein requires cellular ATP and mitochondria also transport these organic anions, which at high doses inhibit respiration. The presence of an organic anion binding site on the F1-ATPase beta-subunit suggests that it may play a role in these processes.

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.

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.

Hepatitis C virus, alcoholic cirrhosis, and hepatocellular carcinoma.

We undertook a retrospective study to determine the prevalence of hepatitis C virus (HCV) and hepatitis B virus (HBV) infection in 81 Caucasian patients with confirmed hepatocellular carcinoma (HCC). Besides HBV and HCV serological markers, HCV RNA and HBV DNA were detected in serum and liver tissue by polymerase chain reaction. Overall, HCV RNA was found in 20 cases (25%), HBV DNA in 21 patients (26%), and coinfection in 3 patients (3%). HCV RNA in liver tissue was not found without virus in serum, whereas HBV DNA was found in the liver tissue of one patient without viremia. In an additional analysis, 32 patients with HCC and alcoholic cirrhosis (HCC-AC) were compared to 35 cases with AC without HCC and 35 cases with alcoholic hepatitis. The prevalence of HCV RNA in HCC-AC (19%) was significantly higher than in the other groups (AC, 3%; alcoholic hepatitis, 0%). HBV DNA was present in 19% of HCC-AC as compared to 3% of AC and 0% of alcoholic hepatitis. We conclude that the form of HCC in 50% of the patients in a Western European country is related to chronic viral hepatitis. Our data obtained from a group of patients having alcoholic liver disease with or without HCC suggest that the prevalence of HCV RNA or HBV DNA in these populations increases with the severity of hepatic injury.

Establishment of a highly specific detection system for GB virus C (GBV-C) minus-strand RNA.

Although the clinical relevance of GB virus C (GBV-C) is still elusive, this virus has been found with high prevalence in several groups of patients with liver disease. As was shown for hepatitis C virus (HCV), minus-strand RNA is supposed to function as a replicative intermediate. We have established a reliable and sensitive detection system for GBV-C minus-strand RNA based on nested RT-PCR (reverse transcription-polymerase chain reaction) with a tagged primer system. Sensitivity and specificity was extensively tested using in-vitro transcribed GBV-C sequences and genomic viral RNA. Specificity of the amplified fragments was proven by Southern blot hybridization. Using this detection system, we found the presence of GBV-C minus-strand RNA in 6/41 (14.6%) sera of GBV-C infected or GBV-C/HCV coinfected patients. No correlation with virological parameters such as amount of GBV-C plus-strand RNA, genotype or titer of HCV could be detected.

Sequence analysis of hepatitis GB virus C (GBV-C) isolates from 14 patients.

In 1995, a new human hepatitis virus belonging to the family Flaviviridae was described and designated hepatitis GBV-C. To investigate variations within the genome of GBV-C and to study the relationship of GBV-C to GBV-A/B or hepatitis C virus (HCV), we established a detection system using reverse transcriptase polymerase chain reaction (RT-PCR) of the putative helicase region (NS3). So far, isolates derived from 14 different GBV-C-positive sera were analyzed (GBV-C/S3-36), showing 80.1-89.4% (mean: 85%) identical nucleotides. The deduced amino acid sequences revealed 97.3% homology. Nucleotide sequences of GBV-C/S3-36 revealed about 60% identity to GBV-A as well as to HCV, but only 56% identity to GBV-B. Amino acid sequences revealed 73.4 and 68.6% similarity to GBV-A and GBV-B, respectively, but a slightly higher percentage of 78.5% to HCV sequences. Thus, according to the putative GBV-C helicase sequence, a subtyping of GBV-C into different genotypes may be necessary.

A rapid and highly specific technique to detect hepatitis C RNA in frozen sections of liver.

AIMS: To develop a polymerase chain reaction (PCR) based technique that would permit the rapid and highly specific detection of hepatitis C virus (HCV) RNA extracted from frozen liver tissue. METHODS: Samples of liver tissue from 18 patients undergoing orthotopic liver transplantation were studied. Nine patients were HCV positive. Total RNA was extracted from between one and 10 sections, 10 microns thick, from each tissue sample. HCV RNA was amplified by (1) conventional, multistep reverse transcription PCR (RT-PCR) and by (2) combined, single step RT-PCR using coupled oligonucleotide primers based on the sequence of the 5' untranslated region of the viral genome. Positive results were confirmed by dot blot analysis using a digoxigenin labelled oligoprobe (Alx 89). RESULTS: HCV RNA was detected in the nine HCV positive patients by both conventional and combined RT-PCR. HCV RNA was not detected in the HCV negative patients. As little as 500 ng total RNA was needed as the template to yield detectable amounts of amplified cDNA. The digoxigenin labelled oligoprobe hybridised with HCV RNA positive specimens only. CONCLUSIONS: The combined, single step RT-PCR is a rapid and sensitive technique for detecting HCV RNA in frozen liver tissue.

B-lymphocytes are predominantly involved in viral propagation of hepatitis C virus (HCV).

Recent reports have shown that HCV infection is not only restricted to hepatocytes. Like hepatitis B virus (HBV), which also was thought to be strictly hepatotropic in early molecular and cellular investigations, infection of lymphoid cells by HCV in vivo has been demonstrated. We showed that total peripheral blood leukocytes of chronically HCV-infected patients are infected by detection of plus- and minus-stranded HCV RNA using strand-specific oligonucleotide primers in the RT-PCR. These cells also represent extrahepatic sites for the viral replication, as demonstrated by incorporation of [3H]-uridine into nascent RNA after stimulation of the cells with a mitogen. Furthermore, total PBML from an uninfected person could be infected in vitro using an HCV-positive serum. It could be shown that replication of HCV RNA takes place in these cells. Examination of different subsets of PBML showed predominant infection of B-lymphocytes during HCV disease. Additionally, infection of T-lymphocytes was detected in about 50% of all chronically HCV-infected patients.

Follow-up of patients with hepatitis non-A, non-B: incidence and persistence of anti-HCV depend on route of transmission.

Of 32 patients with non-A, non-B hepatitis, 10 (31%) were still anti-HCV-positive 12.8 years after the acute phase of the disease. Seven of the patients (21.9%) still had elevated ALT levels, and among these, 5 out of 5 patients who had been subject to parenteral risk were anti-HCV-positive. In contrast, none of the patients who had not been subject to parenteral risks were positive.

Therapy of chronic viral hepatitis.

Interferon is currently the only established therapeutical option for chronic viral hepatitis. Sustained response can be achieved in approximately 25% of patients with chronic HBV or HCV infection. Results in chronic HDV infection are disappointing. Whether combination of interferon with other lymphokines or antiviral drugs will lead to higher response rates, remains to be established. The argument that interferon will only place spontaneous seroconversion on an earlier date has not been disproved yet. Long-term follow-ups are necessary to show that therapy with interferon will improve survival and reduce the incidence of hepatocellular carcinoma in patients with chronic viral hepatitis.

[The hydro-MRT of chronic inflammatory bowel diseases]. / Hydro-MRT chronisch entzündlicher Darmerkrankungen.

PURPOSE: Evaluation of hydro-MRI in the diagnosis of chronic inflammatory bowel disease (IBD). MATERIAL AND METHODS: 33 patients with suspected Crohn's disease or ulcerative colitis were studied prospectively. After distension of the colon by a rectal enema, breathhold MR imaging was performed during bowel relaxation. Results were compared to the clinical diagnosis, endoscopy, barium studies and histopathology. RESULTS: 24/24 patients with active Crohn's disease were correctly diagnosed by MRI. Conversely, MRI was positive in only 2/5 patients with ulcerative colitis. In 5 patients the presence of IBD was excluded. There were no false positives. CONCLUSION: Hydro-MRI is a very reliable modality in the diagnosis of Crohn's disease. In the differentiation of Crohn's disease from ulcerative colitis, hydro-MRI seems to be a promising imaging procedure.