Anja Victor

Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma

Criteria to select patients with hepatocellular carcinoma (HCC) for liver transplantation (LT) are based on tumor size and number of nodules rather than on tumor biology. The present study was undertaken to assess the role of transarterial chemoembolization (TACE) in selecting patients with tumors suitable for LT. Ninety‐six consecutive patients with HCC were treated by repeatedly performed TACE, 62 of them exceeding the Milan criteria. Patients meeting the Milan criteria were immediately listed, and patients beyond the listing criteria were listed upon downstaging of the tumor following successful TACE. Fifty patients were finally transplanted. Of these 50 patients, 34 exceeded the Milan criteria. In these 96 patients, overall 5‐year survival was 51.9%. However, it was 80.9% for patients undergoing LT and 0% for patients without transplantation (P < 0.0001). Tumor recurrence was primarily influenced by the control of the disease through continued TACE during the waiting time. Freedom from recurrence after 5 years was 94.5% in patients (n = 39) with progress‐free TACE during the waiting time. Tumor recurrence was significantly higher in patients (n = 11) who after initial response to TACE progressed again before LT (freedom from recurrence 35.4%; P = 0.0017). Progress‐free course of TACE during the waiting time (P = 0.006; risk ratio, 8.95), and a limited number of tumor nodules as assessed in the surgical specimen (P = 0.025; risk ratio, 0.116) proved to be significant predictors for freedom from recurrence in the multivariate analysis. Milan criteria were without impact on recurrence. Our data suggest that sustained response to TACE is a better selection criterion for LT than the initial assessment of tumor size or number. Liver Transpl 12:1260‐1267, 2006.

Impact of Infectious Burden on Progression of Carotid Atherosclerosis

Background and Purpose— Recent findings suggest a causative role of infections in the pathogenesis of atherosclerosis. The extent of atherosclerosis and the prognosis of patients with atherosclerosis seem to be increased by the number of infections to which an individual has been exposed. In a prospective study, we evaluated the effect of 8 pathogens and the aggregate pathogen burden on the progression of carotid atherosclerosis. Methods— In 504 patients (74.9% men; age, 62.9±10 years), we measured intima-media thickness and prevalence of carotid artery stenosis. Follow-up measurements after a mean of 2.5 years were available in 427 patients (85%). Blood samples were taken, and IgG or IgA antibodies to Chlamydia pneumoniae, Helicobacter pylori, Haemophilus influenzae, Mycoplasma pneumoniae, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus types 1 and 2 were measured. Statistical evaluation was performed with logistic regression procedures. Results— Elevated IgA antibodies against C pneumoniae (P <0.04) and IgG antibodies against Epstein-Barr virus (P <0.01) and herpes simplex virus type 2 (P <0.04) were associated with progression of atherosclerosis (increase of intima-media thickness ≥0.1 mm/y or progression of carotid stenosis) after adjustment for age, sex, cardiovascular risk factors, highly sensitive C-reactive protein, and statin intake. Infectious burden, divided into 0 to 3, 4 to 5, and 6 to 8 seropositivities, was significantly associated with progression of atherosclerosis, with odds ratios of 1.8 (95% confidence interval, 1.1 to 2.9) for 4 to 5 and 3.8 (95% CI, 1.6 to 8.8) for 6 to 8 compared with 0 to 3 seropositivities after adjustment. Conclusions— Our results support the hypothesis that the number of infectious pathogens to which an individual has been exposed independently contributes to the progression of carotid atherosclerosis.

C4A deficiency and nonresponse to hepatitis B vaccination

BACKGROUND/AIMS Hepatitis B vaccination failure has been linked to the presence of certain human leukocyte antigen class II alleles. However, the functional background of these associations has remained unclear. Complement component C 4 is encoded within the major histocompatibility complex and is essential for classical pathway activation. METHODS Healthy individuals (n=4269) were vaccinated in a prospective trial with Engerix B. Nonresponse was classified as anti-HBs<10 U/l after the last vaccination. Seventy-three nonresponders (NR) (1.7%) were identified. For comparison 53 responders (R) (anti-HBs>10 IU/l) were drawn randomly from the same cohort. C4 allotyping was carried out by high-voltage agarose gel electrophoresis and C4alpha-chain typing using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. C4 gene deletions (C4Del) were studied by Southern blot. RESULTS C4AQ0 alleles were observed in 45/73 (62%) NR compared to 17/53 (32%) R (P=0.001). C4ADel was observed in 24/73 (33%) NR and in 6/52 (12%) R (P=0.006). C4AQO alleles were present in 21/49 (43%) NR without C4Del compared to 10/46 (22%) in R without C4Del (P=0.031). In a logistic regression with DRB1*0301, DRB1*07, DRB1*1301 and C4AQ0 all except for DRB1*0301 showed a significant association. CONCLUSIONS C4AQ0 shows a DRB1*0301 independent association with vaccine failure. C4AQ0 alleles probably contribute to inefficient complement activation and failure of B cells to secrete anti-HBs.

Intratympanic dexamethasone and hyaluronic acid in patients with low-frequency and Ménière's-associated sudden sensorineural hearing loss.

Background: Steroids are widely used for the treatment of cochleovestibular disorders. Direct steroid application in the middle ear cavity, when combined with a round window membrane permeability-modulating substance, increases the level of the steroid reaching the target cells. We measured hearing in patients with idiopathic isolated low-frequency sensorineural hearing loss and in patients with sudden sensorineural hearing loss and a history of Ménières disease. Contradictory reports about effectiveness of intratympanic steroid therapy on vertigo control and hearing improvement in patients with Ménières disease exist in the literature. Methods: Eighteen patients with isolated low-frequency idiopathic sudden sensorineural hearing loss and 21 patients with sudden sensorineural hearing loss and a history of Ménières disease were prospectively evaluated. The acute effect of the intratympanic application of dexamethasone with hyaluronic acid on hearing outcome after failure of an initial standard treatment with intravenous steroid and vasoactive substances was assessed. Evaluation was based on standard pure-tone audiometry findings. Results: After intratympanic injection of dexamethasone and hyaluronic acid, 14 of the 18 patients with isolated low-frequency sensorineural hearing loss showed a significant improvement in hearing. After intratympanic therapy, 15 patients with a previous history of Ménières disease and idiopathic isolated low-frequency sensorineural hearing loss showed an improvement in hearing on pure-tone audiometry, four remained unchanged, and two showed a tendency toward a slight deterioration. Conclusion: Intratympanic combined dexamethasone/hyaluronic acid application provides a reliable and safe therapeutic option for improvement of hearing in patients with isolated low-frequency idiopathic sudden sensorineural hearing loss or sensorineural hearing loss resulting from Ménières disease who have failed intravenous steroid and vasoactive treatments.

Expression of multiple epigenetically regulated cancer/germline genes in nonsmall cell lung cancer

Cancer/germline (CG) antigens represent promising targets for widely applicable mono‐ and multiantigen cancer vaccines for nonsmall cell lung cancer (NSCLC). Since little is known about their composite expression in this tumor type, we analyzed 7 CG genes (MAGE‐A3, NY‐ESO‐1, LAGE‐1, BRDT, HOM‐TES‐85, TPX‐1 and LDHC) in 102 human NSCLC specimens. About 81% of NSCLC express at least 1 and half of the specimen at least 2 CG genes. Activation of most of these genes occurs more frequently in squamous cell cancer than in adenocarcinomas. Even though we found all genes but one to be regulated by genomic methylation, not all of them are co‐expressed. In particular, combining CG genes not localized on the X‐chromosome may provide effective treatment for an extended number of patients.

Interaction between gene variants of the serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT) in borderline personality disorder.

Borderline personality disorder (BPD) is characterized by a heterogeneous symptomatology with instability in impulse control, interpersonal relationships and self‐image. BPD patients display repeated self‐injury, chronic suicidal tendencies and emotional dysregulation, mainly dysregulation of negative affect. In its etiology, genetic and environmental factors have been suggested. Recently, an investigation in male healthy volunteers found gene–gene effects of the catechol‐O‐methyl‐transferase (COMT) low‐activity (Met158) and the low‐expression allele of the deletion/insertion (short/long or S/L, respectively) polymorphism in the serotonin transporter‐linked promoter region (5‐HTTLPR) on the central processing of aversive stimuli. The purpose of the present study was to test for association between BPD and the COMT Val158Met single nucleotide polymorphism (SNP), the 5‐HTTLPR S/L variant and the interaction of these two gene variants. One hundred sixty one well‐defined Caucasian BPD patients and 156 healthy controls were recruited from central Germany. In BPD patients, the genotype COMT Met158Met was over‐represented compared to healthy controls (P = 0.0085; adjusted P = 0.034). We observed no differences in 5‐HTTLPR genotypes between BPD and controls (P = 0.286). Additionally, the COMT Met158Met genotype was significantly over‐represented in BPD patients carrying at least one 5‐HTTLPR S allele (P = 0.0007; adjusted P = 0.028). Logistic regression analysis confirmed an interaction of the COMT Met158 and the 5‐HTTLPR S allele (P = 0.001). These data suggest an involvement of altered dopaminergic and/or noradrenergic neurotransmission as well as an interactive effect of COMT and 5‐HTTLPR gene variants in the etiology of BPD, and underline the usefulness of analyses of gene–gene effects in diseases of complex inheritance with multiple genes involved.

A genetic basis for IFN-γ production and T-bet expression in humans

Th1 and Th2 cytokines secreted by polarized effector T cells play a pivotal role in the development of autoimmune and allergic diseases. However, the genetic basis of cytokine production by T lymphocytes in humans is poorly understood. In this study, we investigated the genetic contribution to cytokine production and regulation of T cell-specific transcription factors in a prospective twin study. We found a substantial genetic contribution to the production of Th1 cytokines such as IFN-γ and TNF-α with heritabilities of 0.85 (95% confidence intervals, 0.74–0.95) and 0.72 (0.50–0.93), respectively, whereas no genetic influence on production of the Th2 signature cytokine IL-4 was observed. Furthermore, the intrapair variability in IFN-γ production by isolated T cells was lower in monozygotic than in dizygotic twins. In contrast to GATA-3, NFAT, and NF-κB, intrapair variability of T-bet, the master transcription factor of Th1 cells, was very low among monozygotic and high among dizygotic twins, indicative of a strong genetic influence on T-bet (heritability 0.93, 95% confidence interval, 0.84–1.0). Our data provide novel insights into the genetic regulation of human Th cell polarization. These data suggest that signature cytokines and cytokine signaling events of Th1 rather than Th2 cells are genetically determined and implicate that Th2-associated diseases in humans might be due to genetic variations in Th1 cytokine regulation via T-bet. This concept is highlighted by the recent finding that inactivation of the T-bet gene in mice results in development of clinical hallmark features of asthma.

Incidence of HAV and HBV Infections and Vaccination Rates in Patients With Autoimmune Liver Diseases

OBJECTIVES:Hepatitis A virus (HAV) or hepatitis B virus (HBV) superinfection is associated with an increased mortality in patients with chronic liver diseases (CLD). Despite official recommendations, it was reported that the vaccination rate against HAV is low in patients with chronic hepatitis C infection. To evaluate the situation in patients with autoimmune liver diseases, we conducted a retrospective cohort study.METHODS:Susceptibility to HAV and HBV infections, course of HAV and HBV infections, vaccination rates against HAV and HBV, and efficacy of hepatitis A/B vaccines were evaluated by antibody testing in 225 patients with autoimmune liver diseases during 1,677 person-years.RESULTS:Susceptibility to HAV/HBV infection was 51/86%. Incidence of HAV/HBV infection was 1.3/1.4 per 1,000 person-years. One HAV infection occurred, but the patient recovered spontaneously. Two patients were HBV-infected after receiving an anti-HBc-positive (antibody to hepatitis B core antigen) donor graft during orthotopic liver transplantation, and one of them developed chronic HBV infection. Vaccination rates were 11% (HBV) and 13% (HAV), respectively. Seventy-six percent of the vaccinated patients (HBV vaccine) developed anti-HBs (antibody to hepatitis surface antigen) ≥10 UI/L. Ten out of 13 vaccinated patients, showing a low or nonresponse to hepatitis B vaccine, had concomitant immunosuppressive therapy. Anti-HAV was detectable in all patients after administration of HAV vaccine.CONCLUSIONS:Patients with autoimmune liver diseases have a high susceptibility to HAV and HBV infections. Vaccination rates are low in this patient cohort and efficacy of hepatitis B vaccine is reduced due to immunosuppressive therapy. Improving adherence to vaccine recommendations is essential to prevent HAV and HBV infections in patients with autoimmune liver diseases.

Cochlear Origin of Early Hearing Loss in Vestibular Schwannoma

Objective: To test whether early hearing loss (HL) is cochlear in origin in patients with vestibular schwannoma (VS).

Manifestationen der Atherosklerose in verschiedenen GefäßregionenGemeinsamkeiten und Unterschiede hinsichtlich Epidemiologie, Ätiologie und Prognose

ZusammenfassungAus pathologischen Untersuchungen ist bekannt, dass es sich bei der Atherosklerose um eine Erkrankung handelt, die den gesamten Gefäßbaum betrifft. In der Framingham-Studie wurden Risikofaktoren der Atherosklerose ermittelt, die für die Lokalisation der Atherosklerose in verschiedenen Gefäßprovinzen eine unterschiedliche Wertigkeit besitzen. Patienten mit Manifestationen der Atherosklerose in Herz-, Hals- und Beinschlagadern haben im Vergleich zu einem Normalkollektiv eine schlechtere Prognose. Außerdem liegt eine hohe Koinzidenz von atherosklerotischen Läsionen in den verschiedenen Gefäßregionen vor. Besonders ungünstig ist die Prognose für Patienten, die zum Zeitpunkt der Untersuchung bereits relevante Stenosen in mehreren Gefäßgebieten haben. So konnten wir in einer eigenen Untersuchung an 804 Patienten zeigen, dass Patienten, die zusätzlich zu einer koronaren Herzkrankheit (KHK) noch periphere Stenosen (Beinarterien, Karotiden) aufwiesen, nach einem Beobachtungszeitraum von im Mittel 3,2 Jahren signifikant häufiger kardiovaskuläre Ereignisse (Tod, Myokardinfarkt, Schlaganfall) erlitten als Patienten mit KHK ohne zusätzliche Gefäßmanifestationen. Die Stabilität einer atherosklerotischen Läsion wird durch lokale und systemische inflammatorische Mechanismen bestimmt. Man geht davon aus, dass neben der symptomatischen Läsion multiple stabile oder instabile Läsionen im gesamten Gefäßbaum vorhanden sind, was für die Gesamtprognose des Patienten entscheidend ist. Möglicherweise spielt eine chronische Infektion mit verschiedenen Keimen (sog. Infektionslast) eine prognostisch wichtige Rolle als Trigger der Inflammation.Zur Behandlung von Patienten mit Atherosklerose sind daher systemische Therapieansätze gefordert. Prognostisch günstige Effekt haben die Thrombozytenaggregationshemmer. Ein weiterer interessanter Therapieansatz sind die Statine, denen neben der Lipidsenkung eine Rolle bei der Plaquestabilisation zuzukommen scheint.AbstractPathological studies have demonstrated that atherosclerosis involves the whole arterial vessel tree. In the Framingham study, cardiovascular risk factors could be defined with different prognostic value for the development of atherosclerosis in various vascular regions. The prognosis of patients with atherosclerosis in coronary, carotid or leg arteries is worse comapred to a normal population. Moreover, patients with symptomatic lesions in one vascular bed often have additional asymptomatic atherosclerosis lesions in other vascular regions. Patients with atherosclerosis in multiple vascular regions have a worse prognosis than patients with atherosclerosis in one vascular bed only. In a study of 804 patients, we could show a significantly higher incidence of cardiovascular events (death, myocardial infarction, stroke) in patients with coronary artery disease (CAD) and additional lesions in peripheral arteries (leg, carotid) during a 3.2-year-follow-up compared to thos with CAD only. Local and systemic inflammatory processes in the arterial vessel wall are considered to play an important role with regard to plaque instability. It has been suggested, that besides the symptomatic atherosclerotic lesion, multiple stable or unstable lesions are present in the whole arterial vessel tree predicting the patients prognosis. Chronic infections with multiple pathogens (ldquo;concept of infectious burden”) probably play an important role by triggering these inflammatory processes.Therefore, systemic therapeutic regimes are necessary for the treatment of patients with atherosclerosis. The platelet aggregation inhibitors improve the prognosis of patients with atherosclerosis in all vascular areas. Another important therapeutic regime is the use of statins, which seem to be not only effective in lipid lowering but also in plaque stabilization.