A comparison of trends in mortality from primary liver cancer and intrahepatic cholangiocarcinoma in Europe.

BACKGROUND: To update and compare mortality from primary liver cancer (PLC) and intrahepatic cholangiocarcinoma (ICC) in Europe in 1990-2010. MATERIALS AND METHODS: We used data from the World Health Organization (WHO) to compute age-standardized (world population) mortality rates, and used joinpoint analysis to identify substantial changes. RESULTS: Between 2002 and 2007, PLC rates in the European Union (EU) declined from 3.9 to 3.6/100,000 men. Around 2007, the highest male rates were in France (6.2/100,000), Spain (4.9), and Italy (4.0), while the lowest ones were in Sweden (1.1), the Netherlands (1.2), and the UK (1.8). In women, mortality was lower (0.8/100,000 in 2007 in the EU), and showed more favourable trends, with a decline of over 2% per year over the last two decades as compared with 0.4% in men, in the EU. In contrast, the EU mortality from ICC increased by around 9% in both sexes from 1990 to 2008, reaching rates of 1.1/100,000 men and 0.75/100,000 women. The highest rates were in UK, Germany, and France (1.2-1.5/100,000 men, 0.8-1.1/100,000 women). CONCLUSIONS: PLC mortality has become more uniform across Europe over recent years, with an overall decline; in contrast, ICC mortality has substantially increased in most Europe.

Palaeoenvironment and palaeoclimate of the Middle Miocene lake in the Steinheim basin, SW Germany: A reconstruction from C, O, and Sr isotopes of fossil remains

A differentiated reconstruction of palaeolimnologic, -environmental, and -climatic conditions is presented for the Middle Miocene long-term freshwater lake (14.3 to 13.5 Ma) of the Steinheim basin, on the basis of a combined C, 0, and Sr isotope study of sympatric skeletal fossils of aquatic and terrestrial organisms from the lake sediments. The oxygen isotope composition for lake water of the Steinheim basin (delta O-18(H2O) = +2.0 +/- 0.4 parts per thousand VSMOW, n = 6) was reconstructed from measurements of delta O-18(PO4) of aquatic turtle bones. The drinking water calculated from the enamel of large mammals (proboscideans, rhinocerotids, equids, cervids, suids) has delta O-18(H2O) values (delta(OH2O)-O-18 = -5.9 +/- 1.7 parts per thousand VSMOW, n = 31) typical for Middle Miocene meteoric water of the area. This delta O-18(H2O) value corresponds to a mean annual air temperature (MAT) of 18.8 +/- 3.8 degrees C, calculated using a modem-day delta(OH2O)-O-18-MAT relation. Hence, large mammals did not use the lake water as principal drinking water. In contrast, small mammals, especially the then abundant pika Prolagus oeningensis drank from O-18-enriched water sources (delta O-18(H2O) = +2.7 +/- 2.3 parts per thousand VSMOW, n = 7), such as the lake water. Differences in Sr and 0 isotopic compositions between large and small mammal teeth indicate different home ranges and drinking behaviour and support migration of some large mammals between the Swabian Alb plateau and the nearby Molasse basin, while small mammals ingested their food and water locally. Changes in the lake level, water chemistry, and temperature were inferred using isotopic compositions of ostracod and gastropod shells from a composite lake sediment profile. Calcitic ostracod valves (Ilyocypris binocularis; delta O-18 = +1.7 +/- 1.2 parts per thousand VPDB, delta C-18 = -0.5 +/- 0.9 parts per thousand, VPDB, n = 68) and aragonitic, gastropod shells (Gyraulus spp.; delta O-18 = +2.0 +/- 13 parts per thousand VPDB, delta C-13 = -1.1 +/- 1.3 parts per thousand VPDB, n = 89) have delta O-18 and delta C-13 values similar to or even higher than those of marine, carbonates. delta C-13 values:of the biogenic carbonates parallel lake level fluctuations while delta O-18 values scatter around +2 +/- 2 parts per thousand and reflect the short term variability of meteoric water inflow vs. longer term evaporation. Sr-87/Sr-86 ratios of aragonitic Gyraulus spp. gastropod shells parallel the lake level fluctuations, reflecting variable inputs of groundwater and surface waters. Using a water delta O-18(H2O) value of +2.0 parts per thousand VSMOW, water temperatures calculated from skeletal tissue delta O-18 values of ostracods are 16.7 +/- 5.0 degrees C, gastropods 20.6 +/- 5.6 degrees C, otoliths 21.8 +/- 1.4 degrees C, and fish teeth 17.0 +/- 2.7 degrees C. The calculated MAT (similar to 19 degrees C), lake water temperatures (similar to 17 to 22 degrees C) and the O-18-enriched water compositions are indicative of warm-temperate climatic conditions, possibly with a high humidity during this period. Vegetation in the area surrounding the basin was largely of the C-3-type, as indicated by carbon isotopic compositions of tooth enamel from large mammals (delta C-13 = -11.1 +/- 1.1 parts per thousand VPDB, n = 40). (c) 2006 Elsevier B.V. All rights reserved.

Double-bundle transtibial posterior cruciate ligament reconstruction with a tendon-patellar bone-semitendinosus tendon autograft: clinical results with a minimum of 2 years' follow-up.

PURPOSE: The purpose of this study was to evaluate the clinical and subjective outcomes after arthroscopic-assisted double-bundle posterior cruciate ligament (PCL) reconstruction. METHODS: A series of 15 patients with grade III isolated chronic PCL tears underwent double-bundle PCL reconstruction. Of these patients, 8 (53%) had simultaneous fractures. The mean time from accident to surgery was 10.8 months (range, 8 to 15 months). The mean age at the time of surgery was 28.2 years (range, 17 to 43 years). All of the patients reported knee insecurity during activities of daily living or light sporting activities, with associated anterior knee pain in 5 patients. Preoperatively, posterolateral or posteromedial corner injuries were ruled out through accurate clinical examination. The knees were assessed before surgery and at a mean follow-up of 3.2 years (range, 2 to 5 years) with a physical examination, 4 different rating scales, and stress radiographs obtained with a Telos device (Telos, Marburg, Germany). RESULTS: Postoperative physical examination revealed a reduction of the posterior drawer and tibial step-off in all cases, although the posterior laxity was not completely normalized. Nevertheless, the patients were subjectively better after surgery. The subjective International Knee Documentation Committee score was significantly ameliorated. With regard to the objective International Knee Documentation Committee score, 6 knees (40%) were graded as abnormal because of posterior displacement of 6 mm or greater on follow-up stress radiographs with the Telos device. On the Lysholm knee scoring scale, the score was excellent in 13% of patients and good in 87%. The mean score on the Hospital for Special Surgery knee ligament rating scale was 85.8. The Tegner activity score showed an amelioration after surgery, but no patient resumed his or her preinjury level of activities. The postoperative stress radiographs revealed an improvement in posterior instability of 50% or more in all but 3 knees (20%). CONCLUSIONS: Our technique of double-bundle PCL reconstruction produced a significant reduction in knee symptoms and allowed the patients to return to moderate or strenuous activity, although the posterior tibial translation was not completely normalized and our results appear to be no better than the results of single-bundle PCL reconstruction. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Stable isotope ecology of Miocene large mammals from Sandelzhausen, southern Germany

The carbon, oxygen, and strontium isotope composition of enamel from teeth of large Miocene herbivorous mammals from Sandelzhausen (MN5, late Early/early Middle Miocene) in the North Alpine foreland basin, were analyzed to infer diet and habitat. The mean enamel delta(13)C value of -11.4 +/- 1.0% (n = 53) for the nine taxa analyzed (including proboscideans, cervids, suids, chalicotheres, equids, rhinocerotids) indicates a pure C(3) plant diet for all mammals. (87)Sr/(86)Sr ratios of similar to 0.710 higher than those from teeth of the western Molasse Basin (0.708-0.709) seem to indicate preferential feeding of the mammals in the northeastern Molasse Basin. The sympatric herbivores have different mean delta(13)C and delta(18)O values which support diet partitioning and/or use of different habitats within a C(3) plant ecosystem. Especially the three sympatric rhinoceroses Plesiaceratherium fahlbuschi, Lartetotherium sansaniense, and Prosantorhinus germanicus show clear partitioning of plants and/or habitats. The palaeomerycid Germanomeryx fahlbuschi was a canopy folivore in moderately closed environments whereas Metaschizotherium bavaricum (Chalicotheriidae) and P. germanicus (Rhinocerotidae) were browsers in more closed forest environments. The horse Anchitherium aurelianense was probably a more generalized feeder than assumed from its dental morphology. The forest hog Hyotherium soemmeringi has the highest delta(13)C and lowest delta(18)O value of all analyzed taxa, possibly related to a frugivorous diet. Most taxa were water-dependent browsers that record meteoric water delta(18)O values of about -5.6 +/- 0.7% Vienna Standard Mean Ocean Water (VSMOW). Using a modern-day mean annual air temperature (MAT)-delta(18)OH(2)O relation a MAT of 19.3 +/- 1.5 degrees C can be reconstructed for Sandelzhausen. A Gomphotherium subtapiroideum tusk serially sampled for delta(18)O values does not record a clear pattern of seasonality. Thus most taxa were C(3) browsers in a forested and humid floodplain environment in the Molasse Basin, which experienced a warm-temperate to subtropical climate and possibly low seasonality.

Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients.

BACKGROUND & AIMS: Genetic variation in the interleukin 28B (IL28B) gene has been associated with the response to interferon-alfa/ribavirin therapy in hepatitis C virus (HCV) genotype 1-infected patients. The importance of three IL28B single nucleotide polymorphisms (rs8099917, rs12980275 and rs12979860) for HCV genotype 2/3-infected patients is unknown. METHODS: In patients with chronic hepatitis C genotype 2/3 (n=267), IL28B host genotypes (rs8099917, rs12980275 and rs12979860) were analyzed for associations with sustained virologic response (SVR) to antiviral therapy with (pegylated) interferon-alfa and ribavirin and with respect to epidemiological, biochemical, and virological parameters. For comparison, hepatitis C genotype 1 patients (n=378) and healthy controls (n=200) were included. RESULTS: The rs12979860 CC genotype, lower age, and genotype 2 were significantly associated with SVR in HCV genotype 2/3-infected patients (p=0.01, p=0.03 and p=0.03, respectively). No association was observed for rs8099917 and rs12980275. In addition, an SVR in patients with rapid virologic response (RVR) was associated with the rs12979860 CC genotype (p=0.05), while for non-RVR no association was found. Furthermore, a significant association with a higher baseline viral load was observed for all three IL28B genotypes in genotype 1/2/3-infected patients. Finally, increasing frequencies of the rs12979860 CC genotypes were observed in genotype 1- (33.9%), genotype 3- (38.9%), and genotype 2-infected (51.9%) patients in comparison with healthy controls (49.0%) (p<0.01). CONCLUSIONS: In genotype 2/3-infected patients, rs12979860 was significantly associated with SVR. The frequency of the rs12979860 CC genotype is lower in HCV genotype 1 vs. genotype 2/3 patients. All major IL28B genotypes are associated with HCV-RNA concentration.

Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial.

BACKGROUND: Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1. METHODS: Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400200;×200;10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with ClinicalTrials.gov, number NCT00659789. FINDINGS: 174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23200;100 copies per mL Vacc-4x vs 71200;800 copies per mL placebo; p=0·025) and week 52 (median 19200;550 copies per mL vs 51200;000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations. INTERPRETATION: The proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies. FUNDING: Norwegian Research Council GLOBVAC Program and Bionor Pharma ASA.

Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients. METHODS: We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid β (Aβ)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759). FINDINGS: 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aβ(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group. INTERPRETATION: Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease.

Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial.

BACKGROUND: Postoperative hemithoracic radiotherapy has been used to treat malignant pleural mesothelioma, but it has not been assessed in a randomised trial. We assessed high-dose hemithoracic radiotherapy after neoadjuvant chemotherapy and extrapleural pneumonectomy in patients with malignant pleural mesothelioma. METHODS: We did this phase 2 trial in two parts at 14 hospitals in Switzerland, Belgium, and Germany. We enrolled patients with pathologically confirmed malignant pleural mesothelioma; resectable TNM stages T1-3 N0-2, M0; WHO performance status 0-1; age 18-70 years. In part 1, patients were given three cycles of neoadjuvant chemotherapy (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 given every 3 weeks) and extrapleural pneumonectomy; the primary endpoint was complete macroscopic resection (R0-1). In part 2, participants with complete macroscopic resection were randomly assigned (1:1) to receive high-dose radiotherapy or not. The target volume for radiotherapy encompassed the entire hemithorax, the thoracotomy channel, and mediastinal nodal stations if affected by the disease or violated surgically. A boost was given to areas at high risk for locoregional relapse. The allocation was stratified by centre, histology (sarcomatoid vs epithelioid or mixed), mediastinal lymph node involvement (N0-1 vs N2), and T stage (T1-2 vs T3). The primary endpoint of part 1 was the proportion of patients achieving complete macroscopic resection (R0 and R1). The primary endpoint in part 2 was locoregional relapse-free survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00334594. FINDINGS: We enrolled patients between Dec 7, 2005, and Oct 17, 2012. Overall, we analysed 151 patients receiving neoadjuvant chemotherapy, of whom 113 (75%) had extrapleural pneumonectomy. Median follow-up was 54·2 months (IQR 32-66). 52 (34%) of 151 patients achieved an objective response. The most common grade 3 or 4 toxic effects were neutropenia (21 [14%] of 151 patients), anaemia (11 [7%]), and nausea or vomiting (eight [5%]). 113 patients had extrapleural pneumonectomy, with complete macroscopic resection achieved in 96 (64%) of 151 patients. We enrolled 54 patients in part 2; 27 in each group. The main reasons for exclusion were patient refusal (n=20) and ineligibility (n=10). 25 of 27 patients completed radiotherapy. Median total radiotherapy dose was 55·9 Gy (IQR 46·8-56·0). Median locoregional relapse-free survival from surgery, was 7·6 months (95% CI 4·5-10·7) in the no radiotherapy group and 9·4 months (6·5-11·9) in the radiotherapy group. The most common grade 3 or higher toxic effects related to radiotherapy were nausea or vomiting (three [11%] of 27 patients), oesophagitis (two [7%]), and pneumonitis (two [7%]). One patient died of pneumonitis. We recorded no toxic effects data for the control group. INTERPRETATION: Our findings do not support the routine use of hemithoracic radiotherapy for malignant pleural mesothelioma after neoadjuvant chemotherapy and extrapleural pneumonectomy. FUNDING: Swiss Group for Clinical Cancer Research, Swiss State Secretariat for Education, Research and Innovation, Eli Lilly.