Middle ear cholesteatoma in two cats diagnosed with the aid of video-otoscopy.

Case series summary: The present report describes middle ear cholesteatoma in two cats and also the use of video-otoscopy and flushing to assist with the diagnosis. CT and video-otoscopic examination and flushing were performed in two cats, a 13-year-old mixed breed spayed female cat and a 1-year-old mixed breed male cat, with middle ear cholesteatomas. During the procedure, keratinous material from the middle ears was collected for histopathological evaluation, demonstrating findings consistent with cholesteatoma, and the middle ears were flushed extensively. Relevance and novel information: There is little information about middle ear cholesteatoma in cats, and to the authors' knowledge, there are no reports in cats investigating the use of video-otoscopy to aid in the diagnosis of aural cholesteatoma, and this report demonstrates that it can aid in the diagnosis of this condition in cats. In addition, one of the cats had a concurrent otic polyp, which has not been previously reported in cats with cholesteatoma. Additionally, this is the first report of cholesteatoma in a young cat. The access to the cholesteatoma material was via ventral bulla osteotomy in one cat and via external canal without video-otoscopy in the other. More information regarding cholesteatoma in cats will help identify potential similarities and differences of this condition in cats compared with humans and dogs.

Assembly of infectious Kaposi's sarcoma-associated herpesvirus progeny requires formation of a pORF19 pentamer.

Herpesviruses cause severe diseases particularly in immunocompromised patients. Both genome packaging and release from the capsid require a unique portal channel occupying one of the 12 capsid vertices. Here, we report the 2.6 Å crystal structure of the pentameric pORF19 of the γ-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) resembling the portal cap that seals this portal channel. We also present the structure of its ß-herpesviral ortholog, revealing a striking structural similarity to its α- and γ-herpesviral counterparts despite apparent differences in capsid association. We demonstrate pORF19 pentamer formation in solution and provide insights into how pentamerization is triggered in infected cells. Mutagenesis in its lateral interfaces blocked pORF19 pentamerization and severely affected KSHV capsid assembly and production of infectious progeny. Our results pave the way to better understand the role of pORF19 in capsid assembly and identify a potential novel drug target for the treatment of herpesvirus-induced diseases.

Cost evaluation of PAGE-B risk score guided HCC surveillance in patients with treated chronic hepatitis B.

BACKGROUND: The PAGE-B score (Platelet Age GEnder-HBV) selects chronic hepatitis B (cHB) patients showing no relevant 5-year risk for hepatocellular carcinoma (HCC). We, therefore, explored potential cost reduction following the introduction of a PAGE-B tailored ultrasound screening in a single center cohort of cHB patients receiving stable antiviral therapy. METHODS: cHB patients attending throughout the year 2018 were documented. Patients eligible for PAGE-B score were classified into high (≥18 points), intermediate (10-17 points) and low (≤9 points) HCC risk groups. Patients of the low HCC risk group could postpone HCC screening to reduce HCC screening expenses. Full costs for hepatic ultrasound were assessed. RESULTS: Throughout the year cHB patients (n = 607) attended our clinic, which included PAGE-B eligible patients (n = 227, 37.4%) of whom n = 94 (15.8%) were allocated to the low HCC risk group. Sonographic HCC screening during a median exam time of 12.4 min (IQR 9.2-17.2) resulted in total costs of 22.82 Euro/exam. Additional opportunistic expenses caused by patient's lost earnings or productivity were 15.6-17.5 €/exam and 26.7 €/exam, respectively. Following a PAGE-B tailored HCC screening at our institution annual full costs for cHB patients could be reduced by 15.51%, which equals a cost reduction by 1.91% for our total sonography unit. In comparison, 1.35% up to 7.65% of HBV-infected patients of Caucasian descent could postpone HCC screening according to population-based estimates from Germany. CONCLUSIONS: PAGE-B risk score adapted screening for HCC is an efficient and cost neutral tool to reduce costs for sonography in Caucasian patients with chronic hepatitis B receiving antiviral treatment.

High pretreatment static and dynamic alpha-fetoprotein values predict reduced overall survival in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is one of the most lethal cancers worldwide. Novel prognostic and/or predictive biomarkers are urgently needed to improve patient management. Alpha-fetoprotein (AFP) is a well-established and widely used biomarker for hepatocellular carcinoma. However, diagnostic accuracy of static AFP values is limited and the clinical potential is a matter of ongoing scientific discussion. OBJECTIVE: We here evaluated the prognostic impact of pretreatment static and dynamic AFP variables on overall survival of hepatocellular carcinoma patients in a Western cohort. METHODS: Patients with confirmed hepatocellular carcinoma (n = 809) treated at the Johannes Gutenberg University Mainz between 1998 and 2014 and two available pretreatment AFP-values (AFP-slope) were retrospectively analysed. Clinicopathological baseline parameters, pretreatment static values and AFP-slope were assessed. Prognostic impact was determined by Kaplan-Meier analyses and Cox regression models. RESULTS: High static and dynamic AFP variables prior to therapy were associated with reduced survival rates of hepatocellular carcinoma patients. Several known clinical parameters such as Child-Pugh B (p < 0.01) and C stage (p < 0.001), portal vein thrombosis (p < 0.001) and extrahepatic spread (p < 0.001) were confirmed as independent predictors for overall survival. Addition of static and/or dynamic AFP variable resulted in higher time-dependent area under the curves. Notably, in patients with more favourable prognosis, AFP-slope prior to therapy was a slightly stronger predictor for overall survival compared with static AFP values. CONCLUSION: Static and dynamic AFP variables prior to therapy are predictive for overall survival of hepatocellular carcinoma patients. Addition of AFP-slope to established prognostic parameters might improve prognostic classification for a subgroup of hepatocellular carcinoma patients with preserved liver function and without portal vein tumour thrombosis.

High pre-treatment static and dynamic alpha-fetoprotein values predict reduced overall survival in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is one of the most lethal cancers worldwide. Novel prognostic and/or predictive biomarkers are urgently needed to improve patient management. Alpha-fetoprotein is a well-established and widely used biomarker for hepatocellular carcinoma. However, diagnostic accuracy of static alpha-fetoprotein values is limited and the clinical potential is a matter of ongoing scientific discussion. OBJECTIVE: We here evaluated the prognostic impact of pre-treatment static and dynamic alpha-fetoprotein variables on overall survival of hepatocellular carcinoma patients in a Western cohort. METHODS: Patients with confirmed hepatocellular carcinoma (n = 809) treated at the Johannes Gutenberg-University Mainz between 1998 and 2014 and two available pre-treatment alpha-fetoprotein-values (AFP-slope) were retrospectively analysed. Clinico-pathological baseline parameters, pre-treatment static values and AFP-slope were assessed. Prognostic impact was determined by Kaplan-Meier analyses and Cox regression models. RESULTS: High static and dynamic alpha-fetoprotein variables prior to therapy were associated with reduced survival rates of hepatocellular carcinoma patients. Several known clinical parameters such as Child-Pugh B (p < 0.01) and C stage (p < 0.001), portal vein thrombosis (p < 0.001) and extrahepatic spread (p < 0.001) were confirmed as independent predictors for overall survival. Addition of static and/or dynamic alpha-fetoprotein variable resulted in higher time-dependent area under the curves. Notably, in patients with more favourable prognosis, AFP-slope prior to therapy was a slightly stronger predictor for overall survival compared with static alpha-fetoprotein values. CONCLUSION: Static and dynamic alpha-fetoprotein variables prior to therapy are predictive for overall survival of hepatocellular carcinoma patients. Addition of AFP-slope to established prognostic parameters might improve prognostic classification for a subgroup of hepatocellular carcinoma patients with preserved liver function and without portal vein tumour thrombosis.

Validation of prognostic accuracy of MESH, HKLC, and BCLC classifications in a large German cohort of hepatocellular carcinoma patients.

BACKGROUND AND AIM: The Barcelona Clinic Liver Cancer (BCLC) staging system is commonly used to classify hepatocellular carcinoma (HCC) patients. However, other staging classification schemes have been proposed. We aimed to compare the prognostic accuracy of the Hong Kong Liver Cancer Staging (HKLC), the Model to Estimate Survival for HCC (MESH), and the BCLC staging systems using a Western cohort of HCC patients. METHODS: We retrospectively analyzed 918 patients diagnosed with HCC treated at the University Medical Center of Mainz between 2005 and 2014. We compared the predictive power of survival time of the BCLC, HKLC, and MESH. Predictive ability was tested using the integrated Brier score (IBS) and Harrell's C index. RESULTS: Kaplan-Meier analyses showed significant differences in survival between stages defined by the BCLC, HKLC, and MESH. The HKLC classification demonstrated a more robust classification concordance and lower prediction error compared to the BCLC and MESH. In addition, we found that the BCLC offers superior predictive ability to the MESH in the first four years, whereas the MESH is superior for long-term predictions. CONCLUSION: Our analyses confirm the prognostic value of three different HCC scoring systems. When compared, the HKLC provides superior prognostication ability.

Patulous Eustachian tube and palatine defect in a Dachshund with chronic unilateral otitis externa and otitis media.

BACKGROUND: Patulous Eustachian tube (pET) is a rare dysfunction of the Eustachian tube described in humans. It is characterized by failure of the ET to close, resulting in unrestricted passage of air, sound and material between the nasopharynx and the middle ear. OBJECTIVE: To report a case of pET associated with otitis in a dog. ANIMAL: A 6-year old-female spayed Dachshund dog. METHODS AND MATERIALS: Otoscopic examination, cytological evaluation, culture and susceptibility, computerized tomography (CT), video-otoscopic flushing and surgery. RESULTS: Left ear otoscopic examination revealed erythema, purulent frothy discharge, ceruminous gland hyperplasia, stenosis and a partial tear of the tympanum. Cytological evaluation from the left external canal showed neutrophils, macrophages, rods and cocci. Aerobic culture showed predominantly multidrug-resistant Pseudomonas aeruginosa. The CT findings of the left ear included chronic changes in the external canal, marked lysis of the tympanic bulla and marked dilation of the ET. During video-otoscope flushing, saline drained through the mouth. Bilateral incomplete hypoplasia of the soft palate was noted. Total ear canal ablation and bulla osteotomy with ET dissection were curative. Histopathological findings were compatible with chronic otitis externa (OE) and media. CONCLUSION AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first case of pET described in animals. The ET dysfunction and palatine defect were likely the cause of the otitis in this dog. Clinicians should investigate pET in animals with signs of OE characterized by frothy liquid and food fragments in the ear canal in addition to sneezing after drinking water.

Targeting Kaposi's Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical Use.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of three human malignancies: Kaposi's sarcoma, primary effusion lymphoma, and the plasma cell variant of multicentric Castleman disease. Previous research has shown that several cellular tyrosine kinases play crucial roles during several steps in the virus replication cycle. Two KSHV proteins also have protein kinase function: open reading frame (ORF) 36 encodes a serine-threonine kinase, while ORF21 encodes a thymidine kinase (TK), which has recently been found to be an efficient tyrosine kinase. In this study, we explore the role of the ORF21 tyrosine kinase function in KSHV lytic replication. By generating a recombinant KSHV mutant with an enzymatically inactive ORF21 protein, we show that the tyrosine kinase function of ORF21/TK is not required for the progression of the lytic replication in tissue culture but that it is essential for the phosphorylation and activation to toxic moieties of the antiviral drugs zidovudine and brivudine. In addition, we identify several tyrosine kinase inhibitors, already in clinical use against human malignancies, which potently inhibit not only ORF21 TK kinase function but also viral lytic reactivation and the development of KSHV-infected endothelial tumors in mice. Since they target both cellular tyrosine kinases and a viral kinase, some of these compounds might find a use in the treatment of KSHV-associated malignancies.IMPORTANCE Our findings address the role of KSHV ORF21 as a tyrosine kinase during lytic replication and the activation of prodrugs in KSHV-infected cells. We also show the potential of selected clinically approved tyrosine kinase inhibitors to inhibit KSHV TK, KSHV lytic replication, infectious virion release, and the development of an endothelial tumor. Since they target both cellular tyrosine kinases supporting productive viral replication and a viral kinase, these drugs, which are already approved for clinical use, may be suitable for repurposing for the treatment of KSHV-related tumors in AIDS patients or transplant recipients.

Improved Prediction of Survival by a Risk Factor-Integrating Inflammatory Score in Sorafenib-Treated Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Inflammation affects progression of hepatocellular carcinoma (HCC). We therefore postulate that systemic inflammatory markers could help to predict prognosis in HCC patients receiving sorafenib therapy. METHODS: Overall survival (OS) of HCC patients receiving palliative sorafenib treatment was correlated with the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), C-reactive protein to albumin ratio (CAR), Glasgow prognostic score (GPS) and the modified GPS (mGPS) along with clinicopathological parameters. Predictors of OS were assessed by multivariable Cox regression and receiver operating characteristics and area under the curve (ROC-AUC) analyses. RESULTS: Patients receiving sorafenib (n = 120) for advanced HCC (Barcelona Clinic Liver Cancer stage C) were explored by retrospective analysis. Findings were subsequently validated by a second HCC cohort (n = 113) receiving sorafenib at two independent treatment centers. Multivariable assessment across these HCC cohorts confirmed a stable association of CAR (p ≤ 0.001), GPS (p ≤ 0.01) and mGPS (p ≤ 0.004) with OS. This study also identified Eastern Cooperative Oncology Group (ECOG) performance score (p < 0.001) and portal thrombosis (p = 0.002) as prognostic factors and uncovered an inconsistent OS association of NLR and PLR in HCC patients. Additional combined analysis of ECOG, portal thrombosis and GPS within an extended score (GPS-EP) was associated with OS (p = 0.021), which was confirmed within the validation cohort (p = 0.001). In sorafenib-treated HCC, the ROC-AUC value for the prediction of 12-month survival was 0.761 (CAR >/≤0.37 cut-off, p < 0.001), 0.766 (GPS, p < 0.001) and 0.754 (mGPS, p < 0.001), respectively. In comparison to this, GPS-EP achieved a higher AUC of 0.826 (0.746-0.907) for the 12-month survival prediction, resulting in a 64.4% sensitivity and 83.3% specificity at a > 2 point cut-off. CONCLUSIONS: Inflammatory scores obtained before sorafenib treatment initiation are associated with OS in advanced HCC. Their combination with other risk factors improves prediction of 3- and 12-month survival, which could guide treatment decisions in selected patient subgroups.

Kaposi's sarcoma-associated herpesvirus vIRF2 protein utilizes an IFN-dependent pathway to regulate viral early gene expression.

Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) belongs to the subfamily of Gammaherpesvirinae and is the etiological agent of Kaposi's sarcoma as well as of two lymphoproliferative diseases: primary effusion lymphoma and multicentric Castleman disease. The KSHV life cycle is divided into a latent and a lytic phase and is highly regulated by viral immunomodulatory proteins which control the host antiviral immune response. Among them is a group of proteins with homology to cellular interferon regulatory factors, the viral interferon regulatory factors 1-4. The KSHV vIRFs are known as inhibitors of cellular interferon signaling and are involved in different oncogenic pathways. Here we characterized the role of the second vIRF protein, vIRF2, during the KSHV life cycle. We found the vIRF2 protein to be expressed in different KSHV positive cells with early lytic kinetics. Importantly, we observed that vIRF2 suppresses the expression of viral early lytic genes in both newly infected and reactivated persistently infected endothelial cells. This vIRF2-dependent regulation of the KSHV life cycle might involve the increased expression of cellular interferon-induced genes such as the IFIT proteins 1, 2 and 3, which antagonize the expression of early KSHV lytic proteins. Our findings suggest a model in which the viral protein vIRF2 allows KSHV to harness an IFN-dependent pathway to regulate KSHV early gene expression.

Programmed cell death protein-1 (PD-1)-targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real-world cohort.

BACKGROUND: Programmed cell death protein-1-targeted immunotherapy has shown promising results in phase II studies of hepatocellular carcinoma. AIM: To evaluate safety and efficacy of nivolumab and pembrolizumab in an international, multicentre, real-world cohort of patients with advanced hepatocellular carcinoma. METHODS: Sixty-five patients treated with nivolumab (n = 34) or pembrolizumab (n = 31) between July 10, 2015 and December 31, 2018 (data cut-off) across six centres in Austria and Germany were retrospectively analysed. RESULTS: Child-Pugh class A/B/C was 32 (49%)/28 (43%)/5 (8%). Immunotherapy was used as systemic first-/second-/third-/fourth-line treatment in 9 (14%)/27 (42%)/26 (40%)/3 (5%) patients. Fifty-four patients had at least one follow-up imaging and were, therefore, available for radiological response assessment. The overall response and disease control rates were 12% and 49% respectively. Of 52 evaluable patients, four (8%) had hyperprogressive disease. Median time to progression was 5.5 (95% CI, 3.5-7.4) months, median progression-free survival was 4.6 (95% CI, 3.0-6.2) months, and median overall survival was 11.0 (95% CI, 8.2-13.8) months. Most common adverse events were infections (n = 7), rash (n = 6), pruritus (n = 3), fatigue (n = 3), diarrhoea (n = 3) and hepatitis (n = 3). Efficacy and safety results were comparable between Child-Pugh A and B patients; however, median overall survival (OS) was shorter in Child-Pugh B patients (16.7 vs 8.6 months; P = 0.065). There was no difference in terms of efficacy and adverse events between patients who received immunotherapy as first-/second-line and third-/fourth-line respectively. CONCLUSIONS: Programmed cell death protein-1-targeted immunotherapy with nivolumab or pembrolizumab showed promising efficacy and safety in patients with advanced hepatocellular carcinoma, including subjects with Child-Pugh stage B and patients with intensive pretreatment.

Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Nutrition- and life style-associated risk factors are increasingly prevalent. Metformin, the mainstay of type 2 diabetes mellitus (T2DM)-treatment, reduces the risk of hepatocarcinogenesis. However, its influence on the prognosis of patients with HCC has not been investigated on a large scale, yet. METHODS: Five thousand and ninety-three patients treated for HCC between 2000 and 2016 at three referral centres were included in this retrospective multicentre study. The aim of this study was to assess whether treatment with metformin for T2DM is associated with a prolonged overall survival (OS) in patients diagnosed with HCC. RESULTS: Among 5093 patients with HCC, 1917 patients (37.6%) were diagnosed with T2DM, of which 338 (17.6%) received treatment with metformin. Compared to diabetic patients not treated with metformin, patients on metformin had a significantly better hepatic function (Child-Pugh-Score A: 69.2% vs 47.4%, P < 0.001) and underwent significantly more often tumour resection (22.1% vs 16.5%, P = 0.024). Patients on metformin had a significantly longer median OS (mOS) compared to diabetic patients not treated with metformin (22 vs 15 months, P = 0.019). The prolongation of survival was most significant in patients treated with surgery. Using a propensity score match (PSM), patients were adjusted for hepatic function and initial therapy. In the matched cohorts, mOS remained significantly longer in metformin-treated patients (22 vs 16 months, P = 0.021). Co-treatment of metformin and sorafenib was associated with a survival disadvantage. CONCLUSION: Treatment with metformin was associated with an improved survival in patients with T2DM and HCC. This effect was most pronounced in patients at potentially curative tumour stages.

Extent of portal vein tumour thrombosis in patients with hepatocellular carcinoma: The more, the worse?

BACKGROUND & AIMS: Portal vein tumour thrombosis (PVTT) has a significant impact on the prognosis of patients with hepatocellular carcinoma (HCC). The degree of PVTT varies from sub-/segmental invasion to complete occlusion of the main trunk. Aim of this study was to evaluate whether the degree of PVTT correlates with prognosis. METHODS: A total of 1317 patients with HCC treated at our tertiary referral centre between January 2005 and December 2016 were included. PVTT was diagnosed by contrast-enhanced computed tomography or magnetic resonance imaging. The extent of PVTT was documented according to the Liver Cancer Study Group of Japan classification: Vp0 = no PVTT, Vp1 = segmental portal vein invasion, Vp2 = right anterior/posterior portal vein, Vp3 = right/left portal vein and Vp4 = main trunk. Median overall survival (OS) was calculated for each group. RESULTS: Portal vein tumour thrombosis was present in 484 (36.8%) patients. Median OS without PVTT was 35.7 months, significantly longer than in patients with PVTT (7.2 months, P < 0.001). The patients with PVTT were subclassified as follows: 103 Vp1, 87 Vp2, 143 Vp3 and 151 Vp4. The corresponding median OS yielded 14.6, 9.4, 5.8 and 4.8 months for Vp1-Vp4, respectively (P < 0.001). CONCLUSIONS: Portal vein tumour thrombosis in patients with HCC is associated with a dismal prognosis. The results indicate an association between the extent of PVTT and OS. However, the extent of PVTT is not that decisive, as even minor PVTT leads to a very poor prognosis. Therefore, meticulous evaluation of cross-sectional imaging is crucial for the clinical management of patients with HCC.

Validation of insulin-like growth factor-1 as a prognostic parameter in patients with hepatocellular carcinoma in a European cohort.

BACKGROUND: In hepatocellular carcinoma (HCC), the third leading cause of cancer-related mortality worldwide, the Child-Turcotte-Pugh score (CTP) is one of the most established tools to assess hepatic reserve and determine survival. Serum levels of insulin-like growth factor-1 (IGF-1) are decreased in patients with chronic liver disease or HCC. A modified score combining circulating IGF-1 with the CTP score (IGF-CTP) was recently proposed. METHODS: IGF-CTP scoring was evaluated in 216 patients diagnosed with HCC between 2007 and 2017 to assess the predictive value of serum IGF-1 levels for patient risk stratification and overall survival (OS). RESULTS: Liver cirrhosis was identified in 80.1% of the study cohort, and alcohol-induced liver disease was the most frequent underlying cause of HCC (44.4%). Serum IGF-1 levels were significantly lower in patients with HCC in cirrhosis compared with non-cirrhotic HCC (p < 0.01). A lower serum level of IGF-1 was associated with more advanced stages of liver cirrhosis (p < 0.05) and cancer stages (p < 0.001). Median OS in the cohort was 11.4 months (range 0.5-118.2 months). OS was significantly higher (10.9 vs. 7.9 months; p < 0.05) in patients with a serum IGF-1 level above the median of 43.4 ng/mL. Patient reassignment using IGF-CTP scoring reclassified 35.6% of patients. Through reassignment, stratification regarding OS was comparable to CTP. CONCLUSIONS: This study is the first to investigate IGF-1 and the IGF-CTP classification in a European cohort of HCC patients. Serum IGF-1 correlates with OS in patients with HCC. However, the IGF-CTP classification was not superior compared to CTP score regarding OS.

Probable cutaneous adverse drug reaction to piroxicam in a cat.

CASE SUMMARY: A 9-year-old male neutered Devon Rex cat presented with bilaterally symmetrical ulcerative lesions with mucopurulent exudate that developed rapidly. The lesions were apparent on the axillae, ventral abdomen and inguinal areas. The cat was systemically well. Piroxicam was being administered for palliative treatment of a previously diagnosed salivary adenocarcinoma. Histopathology revealed severe extensive epidermal ulceration with focal dyskeratotic keratinocytes in the stratum granulosum without lymphocyte satellitosis. Resolution of skin lesions was observed after discontinuing piroxicam. Similar lesions developed after previous piroxicam administration, further suggesting a possible adverse reaction to this drug. In addition, the Naranjo score indicated that piroxicam was a probable cause for the ulcerative skin lesions. RELEVANCE AND NOVEL INFORMATION: This is the first report of piroxicam, a non-steroidal anti-inflammatory drug, as a probable cause of ulcerative skin lesions in a cat.

Validation of the SNACOR clinical scoring system after transarterial chemoembolisation in patients with hepatocellular carcinoma.

BACKGROUND: Transarterial chemoembolisation is the standard of care for intermediate stage (BCLC B) hepatocellular carcinoma, but it is challenging to decide when to repeat or stop treatment. Here we performed the first external validation of the SNACOR (tumour Size and Number, baseline Alpha-fetoprotein, Child-Pugh and Objective radiological Response) risk prediction model. METHODS: A total of 1030 patients with hepatocellular carcinoma underwent transarterial chemoembolisation at our tertiary referral centre from January 2000 to December 2016. We determined the following variables that were needed to calculate the SNACOR at baseline: tumour size and number, alpha-fetoprotein level, Child-Pugh class, and objective radiological response after the first transarterial chemoembolisation. Overall survival, time-dependent area under receiver-operating characteristic curves, Harrell's C-index, and the integrated Brier score were calculated to assess predictive ability. Finally, multivariate analysis was performed to identify independent predictors of survival. RESULTS: The study included 268 patients. Low, intermediate, and high SNACOR scores predicted a median survival of 31.5, 19.9, and 9.2 months, respectively. The areas under the receiver-operating characteristic curve for overall survival were 0.641, 0.633, and 0.609 at 1, 3, and 6 years, respectively. Harrell's C-index was 0.59, and the integrated Brier Score was 0.175. Independent predictors of survival included tumour size (P < 0.001), baseline alpha-fetoprotein level (P < 0.001) and Child-Pugh class (P < 0.004). Objective radiological response (P = 0.821) and tumour number (P = 0.127) were not additional independent predictors of survival. CONCLUSIONS: The SNACOR risk prediction model can be used to identify patients with a dismal prognosis after the first transarterial chemoembolisation who are unlikely to benefit from further transarterial chemoembolisation. However, Harrell's C-index showed only moderate performance. Accordingly, this risk prediction model can only serve as one of several components used to make the decision about whether to repeat treatment.

Impact of Individual Components of the Metabolic Syndrome on the Outcome of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib.

BACKGROUND/AIM: Individual components of the metabolic syndrome (MS) such as obesity or diabetes mellitus impair the prognosis of patients with hepatocellular carcinoma (HCC) following curative treatment approaches or transarterial therapies. The aim of this retrospective study was to assess the impact of these factors on the overall survival (OS) of patients with advanced HCC treated with sorafenib. METHODS: Univariate and multivariate analyses were performed to assess the impact of individual components of the MS on the OS of 152 consecutive patients with advanced HCC treated with sorafenib. RESULTS: The presence of overweight/obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and of the MS itself did not impair the median OS. Multivariate analysis showed that Eastern Cooperative Oncology Group Performance Status ≥1 (hazards ratio [HR] 2.03), presence of macrovascular invasion (HR 1.71), Child-Pugh score B/C (HR 2.19), tumor grading G3 (HR 2.17), no prior HCC treatment (HR 2.34), and the presence of 2 or more out of 5 individual components of the MS (HR 0.65) were independent prognostic factors regarding the median OS. CONCLUSIONS: Our investigations do not confirm a negative prognostic role of individual components of the MS or the MS itself for patients with advanced HCC treated with sorafenib.

Kaposi sarcoma herpesvirus pathogenesis.

Kaposi sarcoma herpesvirus (KSHV), taxonomical name human gammaherpesvirus 8, is a phylogenetically old human virus that co-evolved with human populations, but is now only common (seroprevalence greater than 10%) in sub-Saharan Africa, around the Mediterranean Sea, parts of South America and in a few ethnic communities. KSHV causes three human malignancies, Kaposi sarcoma, primary effusion lymphoma, and many cases of the plasmablastic form of multicentric Castleman's disease (MCD) as well as occasional cases of plasmablastic lymphoma arising from MCD; it has also been linked to rare cases of bone marrow failure and hepatitis. As it has colonized humans physiologically for many thousand years, cofactors are needed to allow it to unfold its pathogenic potential. In most cases, these include immune defects of genetic, iatrogenic or infectious origin, and inflammation appears to play an important role in disease development. Our much improved understanding of its life cycle and its role in pathogenesis should now allow us to develop new therapeutic strategies directed against key viral proteins or intracellular pathways that are crucial for virus replication or persistence. Likewise, its limited (for a herpesvirus) distribution and transmission should offer an opportunity for the development and use of a vaccine to prevent transmission.This article is part of the themed issue 'Human oncogenic viruses'.

[EXIT - A Possible Intervention for New- and Earlyborn Babies with Severe Hydrops Fetalis and Hydrothoraces on Both Sides]. / Die EXIT-Prozedur ­ eine Option bei der Erstversorgung von Kindern mit schwerem Hydrops fetalis und beidseitigem Hydrothorax.

The EXIT (ex utero intrapartum treatment) procedure is an established method of respiratory protection, originally used in the delivery of fetuses with congenital obstructive airway diseases (tumors in the throat area, hygromas, so-called congenital high airway obstruction syndrome (CHAOS)). Meanwhile, the procedure is also carried out in large perinatal centers for pronounced diaphragmatic hernia or other special indications (EXIT to ECMO, congenital lung airway malformations (CCAM), pulmonary atresia). We present our experience with adapted EXIT procedures in 5 preterm infants with secondary generalized hydrops fetalis and pronounced bilateral hydrothoraces.

Kaposi Sarcoma Herpesvirus (KSHV) Latency-Associated Nuclear Antigen (LANA) recruits components of the MRN (Mre11-Rad50-NBS1) repair complex to modulate an innate immune signaling pathway and viral latency.

Kaposi Sarcoma Herpesvirus (KSHV), a γ2-herpesvirus and class 1 carcinogen, is responsible for at least three human malignancies: Kaposi Sarcoma (KS), Primary Effusion Lymphoma (PEL) and Multicentric Castleman's Disease (MCD). Its major nuclear latency protein, LANA, is indispensable for the maintenance and replication of latent viral DNA in infected cells. Although LANA is mainly a nuclear protein, cytoplasmic isoforms of LANA exist and can act as antagonists of the cytoplasmic DNA sensor, cGAS. Here, we show that cytosolic LANA also recruits members of the MRN (Mre11-Rad50-NBS1) repair complex in the cytosol and thereby inhibits their recently reported role in the sensing of cytoplasmic DNA and activation of the NF-κB pathway. Inhibition of NF-κB activation by cytoplasmic LANA is accompanied by increased lytic replication in KSHV-infected cells, suggesting that MRN-dependent NF-κB activation contributes to KSHV latency. Cytoplasmic LANA may therefore support the activation of KSHV lytic replication in part by counteracting the activation of NF-κB in response to cytoplasmic DNA. This would complement the recently described role of cytoplasmic LANA in blocking an interferon response triggered by cGAS and thereby promoting lytic reactivation. Our findings highlight a second point at which cytoplasmic LANA interferes with the innate immune response, as well as the importance of the recently discovered role of cytoplasmic MRN complex members as innate sensors of cytoplasmic DNA for the control of KSHV replication.