Prediction of long-term clinical outcome in a diverse chronic hepatitis B population: Role of the PAGE-B score.

An abundance of noninvasive scores have been associated with fibrosis and hepatocellular carcinoma (HCC) development. We aimed to compare the prognostic ability of these scores in relation to liver histology in chronic hepatitis B (CHB) patients. Liver biopsies from treatment-naïve CHB patients at one tertiary care centre were scored by a single hepato-pathologist. Laboratory values at liver biopsy were used to calculate the PAGE-B, REACH-B, GAG-HCC, CU-HCC and FIB-4 scores. Any clinical event was defined as HCC development, liver failure, transplantation and mortality. HCC and mortality data were obtained from national database registries. Of 557 patients, 40 developed a clinical event within a median follow-up of 10.1 (IQR 5.7-15.9) years. The PAGE-B score predicted any clinical event (C-statistic.86, 95% CI: 0.80-0.92), HCC development (C-statistic .91) and reduced transplant-free survival (C-statistic .83) with good accuracy, also when stratified by ethnicity, antiviral therapy after biopsy or advanced fibrosis. The C-statistics (95% CI) of the REACH-B, GAG-HCC, CU-HCC and FIB-4 scores for any event were .70 (0.59-0.81), .82 (0.75-0.89), .73 (0.63-0.84) and.79 (0.69-0.89), respectively. The PAGE-B event risk assessment improved modestly when combined with the Ishak fibrosis stage (C-statistic .87, 95% CI: 0.82-0.93). The PAGE-B score showed the best performance in assessing the likelihood of developing a clinical event among a diverse CHB population over 15 years of follow-up. Additional liver histological characteristics did not appear to provide a clinically significant improvement.

Peginterferon add-on results in more HBsAg decline compared to monotherapy in HBeAg-positive chronic hepatitis B patients.

It is unknown whether peginterferon (PEG-IFN) add-on to entecavir (ETV) leads to more HBsAg decline compared to PEG-IFN monotherapy or combination therapy, and whether ETV therapy may prevent HBsAg increase after PEG-IFN cessation. We performed a post hoc analysis of 396 HBeAg-positive patients treated for 72 weeks with ETV + 24 weeks PEG-IFN add-on from week 24 to 48 (add-on, n = 85), 72 weeks with ETV monotherapy (n = 90), 52 weeks with PEG-IFN monotherapy (n = 111) and 52 weeks PEG-IFN + lamivudine (combination, n = 110) within 2 randomized trials. HBsAg decline was assessed at the end of PEG-IFN (EOP) and 6 months after PEG-IFN (EOF) discontinuation. Differences in baseline characteristics were accounted for using inversed probability of treatment weights. At EOP, a HBsAg reduction of ≥1log10 IU/mL was more frequently achieved for patients in the add-on or combination therapy arms (both 36%), compared to PEG-IFN mono (20%) or ETV (8%) (add-on vs PEG-IFN mono P = 0.050). At EOF, the HBsAg reduction ≥1log10 IU/mL was only sustained in patients treated with ETV consolidation (add-on vs combination and PEG-IFN mono: 40% vs 23% and 18%, P = 0.029 and P = 0.003, respectively). For add-on, combination, PEG-IFN mono and ETV, the mean HBsAg-level change at EOF was -0.84, -0.81, -0.68 and -0.33 log10 IU/mL, respectively (P > 0.05 for PEG-IFN arms). HBeAg loss at EOF was 36%, 31%, 33% and 20%, respectively (P > 0.05). PEG-IFN add-on for 24 weeks results in more on-treatment HBsAg decline than does 52 weeks of PEG-IFN monotherapy. ETV therapy may maintain the HBsAg reduction achieved with PEG-IFN.

CMV Primary Infection Is Associated With Donor-Specific T Cell Hyporesponsiveness and Fewer Late Acute Rejections After Liver Transplantation.

Viral infections, including cytomegalovirus (CMV), abrogate transplantation tolerance in animal models. Whether this also occurs in humans remains elusive. We investigated how CMV affects T cells and rejection episodes after liver transplantation (LT). Phenotype and alloreactivity of peripheral and allograft-infiltrating T cells from LT patients with different CMV status were analyzed by flow cytometry. The association of CMV status with early and late acute rejection was retrospectively analyzed in a cohort of 639 LT patients. CMV-positivity was associated with expansion of peripheral effector memory T cell subsets after LT. Patients with CMV primary infection showed donor-specific CD8(+) T cell hyporesponsiveness. While terminally differentiated effector memory cells comprised the majority of peripheral donor-specific CD8(+) T cells in CMV primary infection patients, they were rarely present in liver allografts. Retrospective analysis showed that R(-) D(+) serostatus was an independent protective factor for late acute rejection by multivariate Cox regression analysis (hazard ratio [HR] = 0.18, 95% CI = 0.04-0.86, p = 0.015). Additionally, CMV primary infection patients showed the highest Vδ1/Vδ2 γδ T cell ratio, which has been shown to be associated with operational tolerance after LT. In conclusion, our data suggest that CMV primary infection may promote tolerance to liver allografts, and CMV status should be considered when tapering or withdrawing immunosuppression.

Loss of intrahepatic HBsAg expression predicts sustained response to peginterferon and is reflected by pronounced serum HBsAg decline.

There is a lack of knowledge regarding the effect of peginterferon (PEG-IFN) on the expression of intrahepatic hepatitis B core and surface antigen (HBcAg and HBsAg) in chronic hepatitis B (CHB) and its relation with response to therapy. Fifty-two HBeAg-positive and 67 HBeAg-negative CHB patients with paired liver biopsies taken at baseline and after 1 year of PEG-IFN therapy were studied. After PEG-IFN therapy, HBeAg-negative patients showed a significant reduction in both intrahepatic HBcAg (P = 0.04) and HBsAg expression (P < 0.001). In contrast, a reduction in intrahepatic HBcAg expression was not observed in HBeAg-positive patients, while a trend in reduction of intrahepatic HBsAg staining was found (P = 0.09). Post-treatment, 7 (13%) HBeAg-positive and 9 (14%) HBeAg-negative patients had no expression of intrahepatic HBsAg. Patients without any intrahepatic HBsAg expression post-treatment were more likely to achieve a combined response (HBeAg loss with hepatitis B virus (HBV) DNA <2000 IU/mL for HBeAg -positive and HBV DNA <2000 IU/mL and normal alanine aminotransferase for HBeAg-negative CHB): 71% vs 5% for HBeAg-positive (P < 0.001) and 60% vs 16% for HBeAg-negative patients (P = 0.004), respectively. Moreover, a more profound decline of serum HBsAg was observed in patients with absence of intrahepatic HBsAg staining (3.1 vs 0.4 log IU/mL, P < 0.001 and 1.7 vs 0.4 log IU/mL, P = 0.005 for HBeAg-positive and HBeAg-negative CHB, respectively). In conclusion, PEG-IFN reduces expression of intrahepatic HBsAg. Loss of HBsAg as assessed by immunohistochemistry from the liver predicts a sustained response and is reflected in a pronounced serum HBsAg decline.

The number needed to treat to prevent mortality and cirrhosis-related complications among patients with cirrhosis and HCV genotype 1 infection.

Cirrhotic patients with chronic hepatitis C virus (HCV) infection remain at risk for complications following sustained virological response (SVR). Therefore, we aimed to evaluate treatment efficacy with the number needed to treat (NNT) to prevent clinical endpoints. Mortality and cirrhosis-related morbidity were assessed in an international multicentre cohort of consecutively treated patients with HCV genotype 1 infection and cirrhosis. The NNT to prevent death or clinical disease progression (any cirrhosis-related event or death) in one patient was determined with the adjusted (event-free) survival among patients without SVR and adjusted hazard ratio of SVR. Overall, 248 patients were followed for a median of 8.3 (IQR 6.2-11.1) years. Fifty-nine (24%) patients attained SVR. Among patients without SVR, the adjusted 5-year survival and event-free survival were 94.4% and 80.0%, respectively. SVR was associated with reduced all-cause mortality (HR 0.15, 95% CI 0.05-0.48, P = 0.002) and clinical disease progression (HR 0.16, 95% CI 0.07-0.36, P < 0.001). The NNT to prevent one death in 5 years declined from 1052 (95% CI 937-1755) at 2% SVR (interferon monotherapy) to 61 (95% CI 54-101) at 35% SVR (peginterferon and ribavirin). At 50% SVR, which might be expected with triple therapy, the estimated NNT was 43 (95% CI 38-71). The NNT to prevent clinical disease progression in one patient in 5 years was 302 (95% CI 271-407), 18 (95% CI 16-24) and 13 (95% CI 11-17) at 2%, 35% and 50% SVR, respectively. In conclusion, the NNT to prevent clinical endpoints among cirrhotic patients with HCV genotype 1 has declined enormously with the improvement of antiviral therapy.

Serum level of Ca 19-9 increases ability of IgG4 test to distinguish patients with autoimmune pancreatitis from those with pancreatic carcinoma.

BACKGROUND: Autoimmune pancreatitis (AIP) is often difficult to distinguish from pancreatic carcinoma or other pancreatobiliary diseases. High serum levels of carbohydrate antigen 19-9 (Ca 19-9) are indicative of malignancies, whereas high levels of immunoglobulin (Ig)G4 (>1.4 g/l) are characteristic of AIP. We investigated whether serum levels of these proteins can differentiate between these diseases. METHODS: We measured levels of Ca 19-9 and IgG4 in serum samples from 33 patients with AIP, 53 with pancreatic carcinoma, and 145 with other pancreatobiliary disorders. We determined cut-off levels for each assay. Logistic regression analysis was used to evaluate combined data on Ca 19-9, IgG4, and bilirubin levels. RESULTS: Low levels of Ca 19-9 were independently associated with AIP, compared with pancreatic adenocarcinoma [odds ratio (OR) 0.28; 95% confidence interval (CI) 0.13-0.59; p = 0.0001]. Using an upper level of 74 U/ml, the assay for Ca 19-9 identified patients with AIP with 73% sensitivity and 74% specificity. Using a lower level of 2.6 g/l, the assay for IgG4 identified these patients with 70% sensitivity and 100% specificity. Combining data, levels of Ca 19-9 < 74 U/ml and IgG4 > 1.0 g/l identified patients with AIP with 94% sensitivity and 100 % specificity. CONCLUSIONS: Patients with AIP have lower levels of Ca 19-9 than those patients with pancreatic carcinoma. Measurement of either the Ca 19-9 or the IgG4 level alone are not accurate enough for diagnosis. However, the combination of Ca 19-9 < 74 U/ml and IgG4 > 1.0 g/l distinguishes patients with AIP from those patients with pancreatic carcinoma with 94% sensitivity and 100% specificity.

Precore and core promoter mutants are associated with higher HBeAg seroconversion but low disease remission rates in HBV patients treated with nucleos(t)ide analogues.

HBeAg seroconversion in HBV patients is considered an important event. We determined precore (PC) and base core promoter (BCP) mutations in 137 HBeAg-positive nucleos(t)ide analogues (NA) treated patients by INNO-LiPA HBV PreCore assay (Innogenetics). The majority of patients with nongenotype A had PC/BCP mutants present at baseline (P = 0.02). During 29 months of therapy, 45 patients achieved HBeAg seroconversion. Probability of HBeAg seroconversion was higher in patients with PC and/or BCP mutants (P = 0.01). After HBeAg seroconversion, patients with BCP mutants had more HBeAg relapse (P = 0.07), and PC mutants less often achieved HBV DNA < 2000 IU/mL (P = 0.07).

Sensitive detection of hepatocellular injury in chronic hepatitis C patients with circulating hepatocyte-derived microRNA-122.

As chronic hepatitis C patients with progressive disease can present themselves with normal ALT levels, more sensitive biomarkers are needed. MicroRNAs are newly discovered small noncoding RNAs that are stable and detectable in the circulation. We aimed to investigate the association between hepatocyte-derived microRNAs in serum and liver injury in patients with chronic hepatitis C. The hepatocyte-derived miR-122 and miR-192 were analysed in sera of 102 chronic HCV-infected patients and 24 healthy controls. Serum levels of miR-122 and miR-192 correlated strongly with ALT (R = 0.67 and R = 0.65, respectively, P < 0.001 for both). Median levels of miR-122 and miR-192 in HCV-infected patients were 23 times and 8 times higher as in healthy controls (P < 0.001 for both). Even within the HCV-infected patients with a normal ALT (n = 38), the levels of miR-122 and miR-192 were 12 times and 4 times higher compared with healthy controls (P < 0.001 for both). Multivariate logistic regression analyses showed that only miR-122 was a significant predictor of the presence of chronic HCV infection (P = 0.026). Importantly, miR-122 was also superior in discriminating chronic HCV-infected patients with a normal ALT from healthy controls compared with the ALT level (AUC = 0.97 vs AUC = 0.78, P = 0.007). In conclusion, our study confirmed that liver injury is associated with high levels of hepatocyte-derived microRNAs in circulation and demonstrated that in particular miR-122 is a sensitive marker to distinguish chronic hepatitis C patients from healthy controls. More sensitive blood markers would benefit especially those patients with minor levels of hepatocellular injury, who are not identified by current screening with ALT testing.

Systematic review and meta-analysis of the association between diabetes mellitus and incidence and mortality in breast and colorectal cancer.

BACKGROUND: Increasing evidence suggests that diabetes mellitus (DM) is associated with increased cancer incidence and mortality. Several mechanisms involved in diabetes, such as promotion of cell proliferation and decreased apoptosis, may foster carcinogenesis. This study investigated the association between DM and cancer incidence and cancer-specific mortality in patients with breast and colorectal carcinoma. METHODS: A meta-analysis of controlled trials, prospective cohort studies and pooled cohort studies published after 2007 was conducted. Embase, PubMed and the Cochrane Library were searched. Summary hazard ratios (HRs) were calculated using a random-effects model. Sensitivity and subgroup analyses were performed to adjust for confounders, mode of DM assessment and follow-up time. RESULTS: Twenty studies were included to investigate the association between DM and breast and colorectal cancer incidence and cancer-specific mortality. The studies predominantly comprised patients with type II DM. The overall HR for breast cancer incidence was 1·23 (95 per cent confidence interval 1·12 to 1·34) and that for colorectal cancer was 1·26 (1·14 to 1·40) in patients with DM compared with those without diabetes. The overall HR was 1·38 (1·20 to 1·58) for breast cancer- and 1·30 (1·15 to 1·47) for colorectal cancer-specific mortality in patients with DM compared with those without diabetes. CONCLUSION: This meta-analysis indicated that DM is a risk factor for breast and colorectal cancer, and for cancer-specific mortality.

Genetic polymorphisms in innate immunity receptors do not predict the risk of bacterial and fungal infections and acute rejection after liver transplantation.

INTRODUCTION: We studied the influence of a broad range of genetic variants in recipient and donor innate immunity receptors on bacterial and fungal infections and acute rejection after liver transplantation (LT). METHODS: Seventy-six polymorphisms in TLR 1-10, NOD2, LBP, CD14, MD2, SIGIRR, Ficolins 1, -2, and -3, MASP 1, -2, and -3, and the complement receptor C1qR1 were determined in 188 LT recipients and 135 of their donors. Associations with clinically significant infections and acute rejection were analyzed for 50 polymorphisms. Significant associations were validated in an independent cohort of 181 recipients and 167 donors. RESULTS: Three recipient polymorphisms and 3 donor polymorphisms were associated with infections in the identification cohort, but none of these associations were confirmed in the validation cohort. Three donor polymorphisms were associated with acute rejection in the identification cohort, but not in the validation cohort. CONCLUSION: In contrast to their effect in the general population, 50 common genetic variations in innate immunity receptors do not influence susceptibility to bacterial/fungal infections after LT. In addition, no reproducible associations with acute rejection after LT were observed. Likely, transplant-related factors play a superior role as risk factors for bacterial/fungal infections and acute rejection after LT.

Barrett's esophagus and esophageal adenocarcinoma are common after treatment for achalasia.

BACKGROUND: Achalasia is characterized by esophageal aperistalsis and impaired relaxation of the lower esophageal sphincter (LES). This contrasts with an insufficient LES, predisposing to gastro-esophageal reflux and Barrett's esophagus. The co-incidence of achalasia and BE is rare. Pneumatic dilatation (PD) may lead to gastro-esophageal reflux, Barrett's esophagus development, and esophageal adenocarcinoma. AIMS: To determine the incidence of Barrett's esophagus and esophageal adenocarcinoma in achalasia patients treated with PD. METHODS: We performed a single-center cohort follow-up study of 331 achalasia patients treated with PD. Mean follow-up was 8.9 years, consisting of regular esophageal manometry, timed barium esophagram, and endoscopy. RESULTS: Twenty-eight (8.4%) patients were diagnosed with Barrett's esophagus, one at baseline endoscopy. This corresponds with an annual incidence of Barrett's esophagus of 1.00% (95% CI 0.62-1.37). Hiatal herniation was present in 74 patients and 21 developed Barrett's esophagus compared to seven of 257 patients without a hiatal hernia. Statistical analysis revealed a hazard ratio of 8.04 to develop Barrett's esophagus if a hiatal hernia was present. Post-treatment LES pressures were lower in patients with Barrett's esophagus than in those without (13.9 vs. 17.4 mmHg; p = 0.03). Two (0.6%) patients developed esophageal adenocarcinoma during follow-up. CONCLUSIONS: Barrett's esophagus is incidentally diagnosed in untreated achalasia patients despite high LES pressures, but is more common after successful treatment, especially in the presence of hiatal herniation. Patients treated for achalasia should be considered for GERD treatment and surveillance of development of Barrett's esophagus, in particular, when they have low LES pressures and a hiatal herniation.

Psychiatric side effects and fluctuations in serotonergic parameters in the treatment of chronic hepatitis C infection.

INTRODUCTION: Treatment of hepatitis C with peginterferon induces psychiatric side effects. These might include changes in serotonergic function. METHODS: Twenty-two hepatitis C patients were treated with peginterferon. At different time points, psychometric assessment was performed using the profile of mood states. Plasma samples were taken to study serotonergic parameters. RESULTS: Anger and depression increased compared to baseline, starting with anger (from week 3 onwards), followed by depression (from week 7 onwards). Other scores did not show consistent changes. No consistent changes were observed in tryptophan, tryptophan/large neutral amino acids ratio, biopterin and 5-hydroxyindoleacetic acid. The tyrosine/large neutral amino acids ratio, neopterin, phenylalanine/tyrosine ratio, and prolactin concentrations increased compared to baseline. Prolactin levels were associated with the occurrence of depression and anger. DISCUSSION: Particularly anger and depression increased during treatment. Neither a decrease in tryptophan and tryptophan availability was seen, nor a relationship between these parameters and the development of psychopathology. Therefore, other mechanisms in the induction of psychopathology should be considered. The observed increases in neopterin and phenylalanine/tyrosine ratio are indicative of changes in tetrahydrobiopterin, which is involved in the metabolism of serotonin, noradrenaline and dopamine, and possibly mediating the increase in prolactin. The increase in prolactin levels and its relationship with depression and anger needs further exploration.

The HLA-DP2 protein binds the immunodominant epitope from myelin basic protein, MBP85-99, with high affinity.

Myelin basic protein (MBP) is a candidate autoantigen in multiple sclerosis (MS). The immunodominant epitope for T-cell responses is assigned to the amino acid sequence MBP84-102, which binds to human leukocyte antigen (HLA)-DR2a (DRB5*0101) and HLA-DR2b (DRB1*1501) of the HLA-DR2 haplotype carrying the strongest genetic association with MS. In contrast with HLA-DR and -DQ molecules, HLA-DP molecules are poorly characterized with respect to the binding of self-peptides. We show here that HLA-DP2 binds MBP85-99 with high affinity, and that the amino acid residues in position MBP91, MBP92 and MBP93 are influencing the binding, as shown by alanine scans. We further used a series of truncated peptides to identify the core of the binding. Moving the frame along the peptide from residues 87-97 to 89-99 progressively decreased the binding affinity for HLA-DP2, while moving further towards the C-terminal completely abrogated the binding of peptides to HLA-DP2. The data suggest that the docking of the MBP85-99 peptide into the HLA-DP2 groove is dependent on MBP88V and MBP89V and may use either of them as primary anchor for the p1 position. HLA-DP2 might thus present the MBP85-99 peptide in the same register as the HLA-DRB1*1501, where the MBP89V is preferred as the p1 anchor. Notably, full-length MBP was able to compete for peptide binding with an affinity similar to that seen for the high-affinity binding peptides, DRα170-83 and IIP53-65. In summary, the HLA-DP2 molecule binds the immunodominant epitope in MS, MBP85-99, possibly in more than one register.

Frequency and clinical outcomes of flares related to nucleos(t)ide analogue therapy in patients with chronic hepatitis B.

Flares in chronic hepatitis B are often detrimental but sometimes lead to sustained immune control and disease remission. The aim of this study was to estimate the frequency of hepatitis flares which occur during and/or after cessation of nucleos(t)ide analogue (NA) therapy, and to assess their outcomes. In a single centre cohort study we investigated 227 patients who received a total of 351 NA treatment courses. NA therapy was discontinued after 149 treatment courses. In total, 27 flares were observed during 9779 on-treatment patient-months. The frequency was estimated as 3.2 per 100 person-years (95% CI 2.2-4.7). Lamivudine (LAM)-treated patients demonstrated the highest frequency (4.9/100 person-years, 95% CI 3.2-7.4). Twenty (74%) of 27 on-therapy flares were associated with development of genotypic resistance, which all occurred during LAM therapy. NA withdrawal flares occurred after a median post-treatment follow-up of 3.5 months in 17 (11%) of 149 treatment discontinuations. No flares were observed in patients who switched to another antiviral agent (n = 51). None of the on-therapy and withdrawal flares related to NA therapy were associated with sustained disease remission, and seven flares resulted in decompensated liver disease. In this study, flares related to NA therapy never led to immune control and sustained disease remission, and sometimes resulted in decompensated liver disease.

Long-term survival after perforated diverticulitis.

AIM: Short-term survival after emergency surgery for perforated diverticulitis is poor. Less is known about long-term survival. The aims of this study were to evaluate long-term survival after discharge from hospital and to identify factors associated with prognosis. METHOD: All patients who underwent emergency surgery for perforated diverticulitis in five hospitals in Rotterdam, the Netherlands, between 1990 and 2005, were included. The association between type of surgery (Hartmann's procedure or primary anastomosis) and long-term survival was analysed using multivariate Cox regression analysis, taking into account age American Society of Anesthesiology (ASA) classification, Hinchey score, Mannheim Peritonitis Index (MPI) and surgeon's experience. In addition, survival of the patients was compared with that of the matched general Dutch population. RESULTS: Of 340 patients included in the study, 250 were discharged alive from hospital. The overall 5-year survival was 53%. Survival was significantly impaired compared with the expected matched gender-, age- and calendar time-specific survival. Overall survival was significantly related to age and ASA classification. Hinchey score, MPI, number of re-interventions, the surgeon's experience and type of procedure did not influence long-term survival, although a trend was found for Hartmann's procedure to be a risk factor for poorer survival compared with primary anastomosis (hazard ratio for mortality: 1.88; 95% confidence interval, 0.96-3.67; P = 0.07). CONCLUSION: Long-term survival of patients after perforated diverticulitis is limited and mainly caused by the poor general condition of the patients, rather than by the severity of the primary disease or calendar-time and type of procedure.

Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85-99 complex.

Susceptibility to multiple sclerosis (MS) is associated with the human histocompatibility leukocyte antigen (HLA)-DR2 haplotype, suggesting that major histocompatibility complex class II-restricted presentation of central nervous system-derived antigens is important in the disease process. Antibodies specific for defined HLA-DR2-peptide complexes may therefore be valuable tools for studying antigen presentation in MS. We have used phage display technology to select HLA-DR2-peptide-specific antibodies from HLA-DR2-transgenic mice immunized with HLA-DR2 molecules complexed with an immunodominant myelin basic protein (MBP) peptide (residues 85-99). Detailed characterization of one clone (MK16) demonstrated that both DR2 and the MBP peptide were required for recognition. Furthermore, MK16 labeled intra- and extracellular HLA-DR2-MBP peptide complexes when antigen-presenting cells (APCs) were pulsed with recombinant MBP. In addition, MK16 inhibited interleukin 2 secretion by two transfectants that expressed human MBP-specific T cell receptors. Analysis of the structural requirement for MK16 binding demonstrated that the two major HLA-DR2 anchor residues of MBP 85-99 and the COOH-terminal part of the peptide, in particular residues Val-96, Pro-98, and Arg-99, were important for binding. Based on these results, the antibody was used to determine if the HLA-DR2-MBP peptide complex is presented in MS lesions. The antibody stained APCs in MS lesions, in particular microglia/macrophages but also in some cases hypertrophic astrocytes. Staining of APCs was only observed in MS cases with the HLA-DR2 haplotype but not in cases that carried other haplotypes. These results demonstrate that HLA-DR2 molecules in MS lesions present a myelin-derived self-peptide and suggest that microglia/macrophages rather than astrocytes are the predominant APCs in these lesions.

On-treatment monitoring of adefovir therapy in chronic hepatitis B: virologic response can be assessed at 24 weeks.

Patients with chronic hepatitis B (CHB) who will and those who will not respond to adefovir (ADV) monotherapy need to be identified at an early stage in order to adjust treatment and prevent future development of antiviral resistance. In a single-centre cohort study, we investigated 76 CHB patients [50% hepatitis B e antigen (HBeAg)-positive] treated with long-term ADV monotherapy. During a median follow-up of 122 (24-185) weeks, 42 (55%) patients achieved virologic response (VR), defined as HBV-DNA levels <10(3) copies/mL, and 10 patients (13%) developed genotypic ADV resistance. Independent baseline predictors of VR were HBeAg negativity [hazard ratio (HR) 2.98; 95% confidence interval (CI) 1.24-7.19; P = 0.02], high alanine aminotransferase (ALT) levels (HR 1.11; 95% CI 1.05-1.18; P = 0.001), and low HBV-DNA levels (HR 0.56; 95% CI 0.41-0.75; P < 0.001). HBV-DNA at week 24 demonstrated a higher predictive value for VR than HBV-DNA at week 48. Important predictors of genotypic resistance were presence of cirrhosis (HR 6.54; 95% CI 1.39-30.9; P = 0.018), and not achieving VR during treatment (HR 6.60; 95% CI 1.35-32.4; P = 0.008). Patients without VR at week 24 already demonstrated a trend towards the emergence of ADV resistance (P = 0.07). HBV-DNA at week 24 was a better on-treatment predictor of VR than HBV-DNA at week 48, and ADV-resistant mutations developed more frequently in patients without VR at week 24. Therefore, our study suggests that virologic response to ADV therapy can be assessed at 24 weeks, instead of the generally recommended 48 weeks.

ALT and viral load decline during PEG-IFN alpha-2b treatment for HBeAg-positive chronic hepatitis B.

BACKGROUND: Alanine aminotransferase (ALT) is one of the main indicators for inflammatory activity in chronic hepatitis B. During interferon-based therapy, approximately 25%-40% of patients exhibit an ALT flare. OBJECTIVES AND STUDY DESIGN: To analyze the relation between ALT and HBV-DNA during pegylated interferon alpha-2b (PEG-IFN) treatment and compare different patterns of on-treatment viral load decline with the occurrence of ALT flares. RESULTS: Of the 123 patients included in this study 31 (25%) exhibited an ALT flare during treatment or follow-up. Six out of 8 (75%) host-induced flares, i.e. ALT flares which were followed by a HBV-DNA decrease associated with a favorable treatment outcome, occurred in patients with a delayed HBV-DNA decline pattern (delayed vs. non-delayed decline, p=.022); 5 of these 8 patients exhibited HBeAg loss and 4 even HBsAg loss at the end of follow-up. The prediction of ALT normalization was possible using on-treatment viral load. Based on the difference from baseline, the evolution of viral load and ALT level were strongly interrelated during treatment and follow-up. With a joint model we estimated a correlation coefficient of 0.38 (p<0.001) during the first 4 weeks of the treatment and of 0.72 (p<0.0001) thereafter. CONCLUSION: There was a strong relation between ALT and viral load in HBeAg-positive chronic hepatitis B patients treated with PEG-IFN alpha-2b, especially after 4 weeks of treatment. Patients with a delayed decline in viral load often exhibited a host-induced flare associated with a favorable outcome.

Epidemiological trends of pre-malignant gastric lesions: a long-term nationwide study in the Netherlands.

BACKGROUND: The pre-malignant gastric lesions atrophic gastritis (AG), intestinal metaplasia (IM) and dysplasia (DYS) have long been identified as principal risk factors for gastric cancer. OBJECTIVE: To evaluate epidemiological time trends of pre-malignant gastric lesions in the Netherlands. METHODS: Patients with a first diagnosis of AG, IM or DYS between 1991 and 2005 were identified in the Dutch nationwide histopathology registry. The number of new diagnoses per year were evaluated relative to the total number of patients with a first gastric biopsy. Time trends were evaluated with age-period-cohort models using logistic regression analysis. RESULTS: In total, 23 278 patients were newly diagnosed with AG, 65 937 patients with IM, and 8517 patients with DYS. The incidence of AG declined similarly in men and women with 8.2% per year [95% CI 7.9% to 8.6%], and DYS with 8.1% per year [95% CI 7.5% to 8.6%]. The proportional number of new IM cases declined with 2.9% per year [95% CI 2.7% to 3.1%] in men and 2.4% [95% CI 2.2% to 2.6%] in women. With age-period-cohort models a cohort phenomenon was demonstrated for all categories of pre-malignant gastric lesions in men and in women with IM and DYS. Period phenomena with a larger decline in number of diagnoses after 1996 were also demonstrated for AG and IM. CONCLUSIONS: The incidence of pre-malignant gastric lesions is declining. Period and cohort phenomena were demonstrated for diagnoses of AG and IM. These findings imply that a further decrease of at least 24% in the incidence of gastric cancer in the coming decade may be anticipated in Western countries without specific intervention.