High-dimensional profiling reveals Tc17 cell enrichment in active Crohn's disease and identifies a potentially targetable signature.

The immune-pathology in Crohn's disease is linked to dysregulated CD4+ T cell responses biased towards pathogenic TH17 cells. However, the role of CD8+ T cells able to produce IL-17 (Tc17 cells) remains unclear. Here we characterize the peripheral blood and intestinal tissue of Crohn's disease patients (n = 61) with flow and mass cytometry and reveal a strong increase of Tc17 cells in active disease, mainly due to induction of conventional T cells. Mass cytometry shows that Tc17 cells express a distinct immune signature (CD6high, CD39, CD69, PD-1, CD27low) which was validated in an independent patient cohort. This signature stratifies patients into groups with distinct flare-free survival associated with differential CD6 expression. Targeting of CD6 in vitro reduces IL-17, IFN-γ and TNF production. These results identify a distinct Tc17 cell population in Crohn's disease with proinflammatory features linked to disease activity. The Tc17 signature informs clinical outcomes and may guide personalized treatment decisions.

[COVID-19 associated pneumonia despite repeatedly negative PCR-analysis from oropharyngeal swabs]. / COVID-19-assoziierte Pneumonie trotz persistierend negativen PCR-Tests aus oropharyngealen Abstrichen.

PATIENT HISTORY AND CLINICAL FINDINGS: A 46-year old construction worker presented at the emergency department with two orthostatic syncopes. The patient complained of prolonged fever and coughs for 7 days which had not improved after oral treatment with sultamicillin for 5 days, prescribed by the patient's general practitioner. Physical examination showed high blood pressure due to previously known hypertension. Other vital signs without pathological findings. Pulmonary auscultation showed basal soft crackling noises of the left lung. FINDINGS AND DIAGNOSIS: Laboratory examination showed increased values for LDH, pro-BNP and CRP and normal values for leucocytes and procalcitonin. Conventional X-Ray of the chest showed bipulmonal lateral atypical infiltrates. After the first PCR turned in negative another PCR-analysis for SARS-CoV-2 of a deep oral swab-sample was performed since the clinical, laboratory and radiological findings were typical for COVID-19. Again, SARS-CoV-2-RNA was not detected. A CT-scan of the chest showed bipulmonal lateral ground-glass attenuation, again typical for COVID-19 associated pneumonia. After a third attempt for a PCR-analysis of a deep oral swab-sample was negative, analysis of a sputum was performed which finally confirmed the diagnosis of COVID-19 associated pneumonia. THERAPY AND COURSE OF EVENTS: The patient was admitted for evaluation of syncopes and suspect of COVID-19 associated pneumonia. The patient was prophylactically isolated while the result of SARS-CoV-2-PCR from a deep oral swab was pending. Suspecting a possible secondary bacterial infection at the beginning, intravenous antibiotic treatment with ampicillin/sulbactam was initiated. While further examinations showed no indication for bacterial infection, antibiotics were discontinued after 3 days. Due to clinical recovery antiviral therapy was not performed after confirming the diagnosis. The patient was discharged 17 days after onset of first symptoms without any requirements for further isolation. CONCLUSION: This casuistic describes a case of COVID-19 associated pneumonia presenting with typical clinical features, laboratory and radiological findings. Detection of viral RNA was not successful from deep oral swab-samples despite repeated attempts. Finally, PCR-analysis of sputum confirmed the diagnosis. Analysis of deeper airway samples (sputum, bronchoalveolar lavage, tracheal secretions) or stool for SARS-CoV-2 should be performed in cases of evident clinical suspicion of COVID-19 and negative PCR results from deep oral swabs.

Treatment with proton pump inhibitors is associated with increased mortality in patients with pyogenic liver abscess.

BACKGROUND: Proton pump inhibitors (PPI) are often used in patients with gastro-esophageal reflux and peptic ulcer disease. A higher risk for infectious diseases and for pyogenic liver abscess has been reported in patients with prolonged PPI intake. Although many patients have ongoing PPI treatment after diagnosis of liver abscess, there are no data available that focus on the prognostic impact of PPI treatment in these patients. AIM: To analyse the effect of PPI treatment on mortality in patients with pyogenic liver abscesses. METHODS: Between January 2005 and March 2017, one hundred and eighty-one patients with pyogenic liver abscess were retrospectively included in this analysis. Medical records including PPI treatment, microbiological and imaging data were reviewed. The primary endpoint was index mortality and predictive factors were analysed using uni- and multivariate logistic regression models. RESULTS: One hundred patients with pyogenic liver abscess (55.2%) were treated with PPI compared to 81 patients (44.8%) without PPI treatment. In both patient cohorts, enterococcus spp. and streptococcus of the anginous group were the most common pathogens identified. Patients with PPI treatment had significantly higher index mortality compared to patients without PPI treatment (30.0% vs 11.1%, P = 0.003). After adjusting for comorbidities PPI remained an independent predictive factor with an OR of 2.56 (1.01-6.46, P = 0.036). CONCLUSIONS: PPI treatment is associated with higher index mortality in patients with pyogenic liver abscess. Therefore, critical evaluation of the indication for PPI treatment is particularly important in patients at high risk for pyogenic liver abscess.

First report of invasive liver abscess syndrome with endophthalmitis caused by a K2 serotype ST2398 hypervirulent Klebsiella pneumoniae in Germany, 2016.

We report a case of severe infection with liver abscess and endophthalmitis caused by a hypervirulent Klebsiella pneumoniae strain in an immunocompetent German male patient without travel history to Asia. Phenotypic and molecular characterization showed high similarity to the reference genome NTUH-K2044 isolated in Asia. The isolate was assigned as ST2398 (clonal complex 66). The findings underline global spread of hypervirulent Klebsiella pneumoniae strains to Europe.

On-target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: a multi-centre, prospective study.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and has high mortality despite treatment. While sorafenib has a survival benefit for patients with advanced HCC, clinical response is highly variable. AIM: To determine whether development of sorafenib toxicity is a prognostic marker of survival in HCC. METHODS: In this prospective multicentre cohort study, patients with advanced-stage HCC receiving sorafenib were recruited from five international specialist centres. Demographic and clinical data including development and grade of sorafenib toxicity during treatment, radiological response to sorafenib and survival time (months) were recorded prospectively. RESULTS: A total of 634 patients with advanced-stage HCC receiving sorafenib were recruited to the study, with a median follow-up of 6692.3 person-months at risk. The majority of patients were male (81%) with Child-Pugh A stage liver disease (74%) and Barcelona Clinic Liver Cancer stage C HCC (64%). Median survival time was 8.1 months (IQR 3.8-18.6 months). 94% experienced at least one sorafenib-related toxicity: 34% diarrhoea, 16% hypertension and 37% hand-foot syndrome (HFS). Twenty-one per cent ceased sorafenib due to toxicity and 59% ceased treatment due to progressive disease or death. On multivariate analysis, sorafenib-related diarrhoea (HR 0.76, 95% CI 0.61-0.95, P = 0.017), hypertension (HR 0.531, 95% CI 0.37-0.76, P < 0.0001) and HFS (HR 0.65, 95% CI 0.51-0.81, P < 0.0001) were all significant independent predictors of overall survival after adjusting for age, severity of liver disease, tumour stage and sorafenib dose. CONCLUSION: Development of sorafenib-related toxicity including diarrhoea, hypertension and hand-foot syndrome is associated with prolonged overall survival in patients with advanced-stage HCC on sorafenib.

The albumin-bilirubin grade improves hepatic reserve estimation post-sorafenib failure: implications for drug development.

BACKGROUND: Drug development in hepatocellular carcinoma (HCC) is limited by disease heterogeneity, with hepatic reserve being a major source of variation in survival outcomes. The albumin-bilirubin (ALBI) grade is a validated index of liver function in patients with HCC. AIM: To test the accuracy of the ALBI grade in predicting post-sorafenib overall survival (PSOS) in patients who permanently discontinued treatment. METHODS: From a prospectively maintained international database of 447 consecutive referrals, we derived 386 eligible patients treated with sorafenib within Barcelona Clinic Liver Cancer C stage (62%), 75% of whom were of Child class A at initiation. Clinical variables at sorafenib discontinuation were analysed for their impact on post-sorafenib overall survival using uni- and multivariable analyses. RESULTS: Median post-sorafenib overall survival of the 386 eligible patients was 3.4 months and median sorafenib duration was 2.9 months, with commonest causes of cessation being disease progression (68%) and toxicity (24%). At discontinuation, 92 patients (24%) progressed to terminal stage, due to worsening Child class to C in 40 (10%). Median post-sorafenib overall survival in patients eligible for second-line therapies (n = 294) was 17.5, 7.5 and 1.9 months according respectively to ALBI grade 1, 2 and 3 (P < 0.001). CONCLUSIONS: The ALBI grade at sorafenib discontinuation identifies a subset of patients with prolonged stability of hepatic reserve and superior survival. This may allow improved patient selection for second-line therapies in advanced HCC.

Perspectives of immunotherapy in hepatocellular carcinoma (HCC).

Immunotherapy is considered a new treatment option for many tumor entities, as decades of research into cancer immunotherapy have recently yielded promising results. Indeed, impressive clinical results of checkpoint blockade inhibitors in malignant melanoma and non-small cell lung cancer indicate the therapeutic potential of tumor-specific immune restoration. Over the years, different immunotherapeutic approaches have been evaluated for the treatment of hepatocellular carcinoma (HCC) with some respectable results. In this review article, we will summarize the key studies of the past 30 years and will elucidate in which direction the dynamic field of HCC immunotherapy is currently moving.

Procedural and shunt-related complications and mortality of the transjugular intrahepatic portosystemic shunt (TIPSS).

BACKGROUND: The implantation of a transjugular intrahepatic portosystemic shunt (TIPSS) is a complex angiographic procedure performed in patients with end-stage liver disease. Numerous case reports and narrative reviews have been published so far; however, studies systematically investigating procedural and shunt-related complications are lacking. AIM: To systematically investigate complications and mortality occurring during the index hospital stay and the early (4-week) period after TIPSS implantation. METHODS: The study includes 389 patients who received a TIPSS implantation between 2004 and 2014. Data were obtained from the clinical records and technical reports of the TIPSS implantation. RESULTS: During the index hospital stay, procedure-related complications occurred in 42 patients (10.8%) with intraperitoneal bleeding in 8 patients (2.1%) and infections in 14 patients (3.6%). Shunt- and disease-related complications consisted of hepatic encephalopathy (1-year incidence 29%), non-procedural infections (8.7%) and acute hepatic decompensation (4.1%). Nine patients (2.3%) died during the index hospital stay from procedure-related (two patients, 0.5%), shunt-related (four patients, 1%) or disease-related causes (three patients, 0.8%). 23 patients (5.9%) died during 4 weeks after TIPSS implantation. The 1-year probability of survival was 67.7% and was negatively associated with severe hepatic encephalopathy and acute hepatic decompensation. CONCLUSIONS: Except hepatic encephalopathy, severe procedure- and shunt-related complications are rare and early mortality is low.

[Full thickness resection device (FTRD). Experience and outcome for benign neoplasms of the rectum and colon]. / Full-Thickness-Resection-Device (FTRD). Die endoskopische Vollwandresektion für das Rektum und Kolon.

BACKGROUND: The diagnostic validity of a full-thickness resection is higher compared to endoscopic mucosal resection (EMR) or endoscopic mucosal dissection (ESD). Whereas transanal endoscopic microsurgery techniques (TEM, TAMIS) are established therapeutic procedures in the rectum no established and safe minimally invasive or endoscopic procedure exists in the colon. AIM: In this study the novel endoscopic full thickness resection device (FTRD, Ovesco, Germany) was investigated concerning success rates with histologically proven full thickness resections, R0 status as well as patient and device safety for the rectum and colon. METHOD: In the period from November 2014 to June 2015 full thickness resections in the rectum and colon were performed with the FTRD in 20 patients. Data on technical success, R0 resection rate and histologically confirmed full thickness resections were retrospectively analyzed. RESULTS: The following indications were treated in the rectum (n = 11) and colon (n = 9): T1 carcinoma (n = 6) and neuroendocrine tumors (n = 2), untreated and nonlifting adenomas (n = 3) and incomplete resection of adenomas with low and high grade dysplasia (n = 9). The technical success rate was 75 %, 3 technical failures made a conventional polypectomy necessary in 2 patients and in 1 patient an operative resection of the duplicated intestinal wall had to be performed. The median endoscopic follow-up time was 61.5 days (n = 10) and in 7 patients the clip had dislodged at the first follow-up. A thermal perforation in one case of conventional polypectomy gave rise to indications for a partial resection of the colon. In one patient the lesion in the cecum could be reached but not treated for technical reasons. The histological R0 rate was 80 %, whereas the full thickness resection rate was 60 % (85.7 % in the colon and 54.6 % in the rectum). In two patients with carcinoma and incomplete FTRD, surgical treatment was performed. The median size of the resection specimen was 5  cm(2) (range 1.6-12.9  cm(2)). CONCLUSION: The results show that FTRD is a safe and effective instrument for use in the lower gastrointestinal tract. Limitations of the FTRD system concerning full thickness resection are scarring, fibrosis and thickness of the intestinal wall, especially in the lower rectum; therefore, it is suggested that a simulation with a tube similar in size to the FTRD should be performed during the screening colonoscopy in order to establish whether an endoscopic resection with FTRD is possible.

The transcription factor c-JUN/AP-1 promotes HBV-related liver tumorigenesis in mice.

Hepatocellular carcinoma (HCC) develops as a consequence of chronic inflammatory liver diseases such as chronic hepatitis B virus (HBV) infection. The transcription factor c-Jun/activator protein 1 (AP-1) is strongly expressed in response to inflammatory stimuli, promotes hepatocyte survival during acute hepatitis and acts as an oncogene during chemically induced liver carcinogenesis in mice. Here, we therefore aimed to characterize the functions of c-Jun during HBV-related liver tumorigenesis. To this end, transgenic mice expressing all HBV envelope proteins (HBV(+)), an established model of HBV-related HCC, were crossed with knockout mice lacking c-Jun specifically in hepatocytes and tumorigenesis was analyzed. Hepatic expression of c-Jun was strongly induced at several time points during tumorigenesis in HBV(+) mice, whereas expression of other AP-1 components remained unchanged. Importantly, formation of premalignant foci and tumors was strongly reduced in HBV(+) mice lacking c-Jun. This phenotype correlated with impaired hepatocyte proliferation and increased expression of the cell cycle inhibitor p21, whereas hepatocyte survival was not affected. Progression and prognosis of HBV-related HCC correlates with the expression of the cytokine osteopontin (Opn), an established AP-1 target gene. Opn expression was strongly reduced in HBV(+) livers and primary mouse hepatocytes lacking c-Jun, demonstrating that c-Jun regulates hepatic Opn expression in a cell-autonomous manner. These findings indicate that c-Jun has important functions during HBV-associated tumorigenesis by promoting hepatocyte proliferation as well as progression of dysplasia. Therefore, targeting c-Jun may be a useful strategy to prevent hepatitis-associated tumorigenesis.

Efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPSS) in 40 patients with hepatocellular carcinoma.

BACKGROUND: Portal hypertension and hepatocellular carcinoma (HCC) are major complications of advanced liver cirrhosis. Thus, patients are often affected by both complications. Transjugular intrahepatic portosystemic shunt (TIPSS) is an effective treatment for portal hypertension and its complications. However, no established guidelines for the treatment of symptomatic portal hypertension in HCC patients are currently available. In addition, only limited information exists about the consequence of TIPSS implantation in patients with HCC. AIM: To evaluate the efficacy, safety and overall survival in HCC patients who underwent TIPSS implantation. METHODS: Forty HCC patients with portal hypertension who were treated with TIPSS between 1995 and 2012 were included in the analysis. Medical records and imaging studies were analysed. The indication for TIPSS implantation, procedure-related complications, treatment success and overall survival were assessed. RESULTS: TIPSS implantation was performed in 23 patients (57.5%) due to treatment refractory ascites, in 14 patients (35.0%) due to recurrent variceal bleeding and in three patients (7.5%) due to ascites and variceal bleeding. Primary technical success was assessed in all patients. After TIPSS implantation, no variceal bleeding reoccurred and ascites was controlled in 74.1%. No severe procedure-related complications and no deterioration of liver function were observed. Post-TIPSS hepatic encephalopathy occurred in 40.0% of all patients. 30-day, 90-day-, 1-year- and 5-year survival rates were 97.5%, 75.0%, 42.5% and 7.5%, respectively. Median overall survival after TIPSS implantation was 180 days. CONCLUSION: Transjugular intrahepatic portosystemic shunt implantation is an effective and safe treatment for portal hypertension in patients with HCC.

Transfusion-transmitted hepatitis E in Germany, 2013.

The reported IgG seroprevalence against hepatitis E virus (HEV) in German blood donations is 6.8%, and HEV RNA detected in 0.08%, but documented evidence for HEV transmission is lacking. We identified two donations from a single donor containing 120 IU HEV RNA/mL plasma and 490 IU/mL. An infectious dose of 7,056 IU HEV RNA was transmitted via apheresis platelets to an immunosuppressed patient who developed chronic HEV. Further, transmission was probable in an immunocompetent child.