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The Liver Meeting— 54th Annual Meeting of The American Association for the Study of Liver Diseases, October 24 - 28, Boston, MA—Day 3
Alan Franciscus
Editor-in-Chief, HCV Advocate
Poster 106: INTERNATIONAL, MULTICENTER, RANDOMIZED, CONTROLLED STUDY FOR THE TREATMENT OF PATIENTS WITH CHRONIC HEPATITIS C AND PERSISTENTLY NORMAL ALT LEVELS WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS®) AND RIBAVIRIN (COPEGUS®)
Stefan Zeuzem, Saarland University Hospital, Homburg/Saar, Germany; Moisés Diago, Hospital General de, Valencia, Spain; Edward Gane, Middlemore Hospital, Auckland, New Zealand; Rajender Reddy, University of Pennsylvania, Philadelphia, PA; Paul Pockros, The Scripps Clinic, La Jolla, CA; Patrizia Farci, Universita di Cagliari, Cagliari, Italy; Norman Gitlin, Emory University, Atlanta, GA; François Lamour, Pilar Lardelli, Roche, Basel, Switzerland; Mitchell Shiffman, VCU Health System, Richmond, VA.
The combination of pegylated interferon alfa and ribavirin is the currently recommended treatment for patients with chronic hepatitis C (CHC) and elevated alanine aminotransferase (ALT) levels. Recent data with peginterferon alfa-2a (40 KD) 180 µg/week and ribavirin have established that the treatment duration for CHC patients with elevated ALT should be based on the HCV genotype: 48 weeks for genotype 1 and 24 weeks for genotype 2/3 patients.
However, many patients with chronic hepatitis C (CHC) have persistently normal serum ALT levels. The effectiveness of interferon alfa (IFN-a) therapy in these patients is controversial. The US and EU consensus conferences on hepatitis C recommend not to treat normal ALT CHC patients until data from controlled clinical studies become available.
An international, multicenter, randomized, controlled study has been performed to determine the efficacy and safety of peginterferon alfa-2a (40KD) (PEG-IFN alfa-2a) in combination with ribavirin administered during 2 different treatment durations in CHC patients with normal ALT.
491 patients were randomized (ratio 3:3:1) into three arms: 212 were treated with PEG-IFN alfa-2a 180 µg/week plus ribavirin 800 mg/day for 24 weeks, 210 received the same combination for 48 wks and 69 patients received no treatment and were monitored for 72 weeks. All patients were required to have CHC infection documented by positive anti-HCV antibody test and detection of HCV RNA by PCR. Persistently normal ALT activity was defined by at least 3 ALT determinations < the upper limit of normal (ULN), a minimum of 4 weeks apart, with 1 value within the 42-day screening time and 1 value 6 to 18 months before the study onset. Patients with ALT levels > ULN during the 18 months preceding baseline were excluded from the study. Liver disease consistent with CHC was confirmed by biopsy within 36 months before the study. Cirrhotic patients and patients with other chronic liver disease or co-infected with human immunodeficiency virus were excluded from the trial. Sustained virological response (SVR) was defined as HCV RNA negativity by PCR (<50 IU/mL COBAS AMPLICOR® HCV Test v. 2.0) at the end of 24 weeks of untreated follow-up.
Demographic and baseline virologic features were similar in all three groups. Male gender: 42%, 39%, 38%; median age: 44, 44, 41 years, and median weight, 74 kg, 73 kg, 70 kg, respectively. Genotype 1: 68%, 67%, 66 %; and mean viral load: 1.2, 1.1 and 1.3 x 106 IU/mL, respectively. Overall SVR was 30% and 52% for the 24 and 48 wk treatment groups, respectively, versus 0% for the untreated control group (p <0.0001). For genotype 1, SVR was 13% in the 24 wk treatment group vs 40% in the 48 wk treatment group (p<0.001). For genotypes 2 and 3, 24 weeks treatment had a SVR of 72% vs 78% in patients treated for 48 weeks (p = ns). The safety profile was typical of IFN treatment but the incidence of the commonest IFN-related adverse events was lower than in previous studies on abnormal ALT CHC patients. ALT values remained normal or near normal in the vast majority of patients from both treatment and control groups. Median ALT levels decreased from baseline in treatment responders. Mild, transient ALT elevations were observed after end of treatment in relapsers from treatment groups. Only 2 patients, one treated for 24 weeks, and one from the control group, developed ALT flares (>10x ULN).
The efficacy results are comparable to those obtained in previous trials in CHC patients with elevated ALT (Hadziyannis et al. J Hepatol 2002; 36(S1) pp.3A) and a duration of treatment according to genotype can be recommended following established algorithms.
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Poster 136: ANTIVIRAL EFFECT OF BILN 2061, A NOVEL HCV SERINE PROTEASE INHIBITOR, AFTER ORAL TREATMENT OVER 2 DAYS IN PATIENTS WITH CHRONIC HEPATITIS C, NON-GENOTYPE 1
Markus Reiser, Medizinische Universitätsklinik Bochum, Bochum, Germany; Holger Hinrichsen, I Medizinische Universitätsklinik Kiel, Kiel, Germany; Yves Benhamou, Goup Hospitalier Pitie-Salpetriere Paris, Paris, France; Roel Sentjens, Academisch Medisch Centrum Amsterdam, Amsterdam, Netherlands; Heiner Wedemeyer, Medizinische Hochschule Hannover, Hannover, Germany; Luis Calleja, Clinica Puerta de Hierro Madrid, Madrid, South Africa; Xavier Forns, Hospital Clinico Barcelona, Barcelona, Spain; Jens Croenlein, Boehringer Ingelheim, Biberach, Germany; Chan Yong, Boehringer Ingelheim, Ridgefield, CT; Gerhard Nehmiz, Gerhard Steinmann, Boehringer Ingelheim, Biberach, Germany.
BILN 2061 is a potent and specific inhibitor of the HCV serine protease in-vitro and in patients infected with genotype 1 (GT 1) as recently reported. In a first exploratory trial, the effect of a 2-day oral treatment with BILN 2061 was investigated in GT 2 and GT 3 patients with minimal liver fibrosis.
In a randomized, double-blind group comparison, 10 male patients with HCV other than GT 1 (InnoLiPA) and no or minimal liver fibrosis (Ishak 0-2) were administered 500 mg BILN 2061 or placebo in an oral solution (randomized 8:2) b.i.d. over 2 days. Virus load (VL) was measured as HCV RNA by Cobas Amplicor HCV Monitor v2.0.
Mean age of all 10 patients was 37 +/-7 years. HCV genotypes were GT 2 (3 patients) and GT 3 (7 patients). 9/10 patients were naive for anti-HCV therapy. All patients completed the study and were followed up for 12 +/-2 days. VL decreased by >1 LOG10 unit in 4/8 patients treated with 500mg BILN 2061 b.i.d., without detectable difference between GTs 2 and 3. A weak response was observed in 1 BILN 2061-treated patient, whereas 3/8 BILN 2061-treated patients and 2/2 patients given placebo experienced no response. The largest VL decrease was observed in the one patient with GT 2 HCV that had been previously treated with anti-HCV therapy. However HCV-RNA was still detectable. After end of treatment, VL returned to baseline levels within 1-7 days. No adverse events were reported. Liver function tests did not change during treatment. Vital signs, routine laboratory and ECG did not show relevant drug-induced changes. Tolerability was rated "good" by the investigators in 9 patients and "satisfactory" in 1 BILN 2061-treated patient.
BILN 2061, given p.o. over 2 days at 500 mg b.i.d., demonstrated antiviral activity in 5/8 non-GT-1 in patients. In contrast to our previous results in GT-1 patients, the antiviral activity was not uniform and less pronounced. No safety issues were identified among the 8 patients exposed to BILN 2061.
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Poster 145: ANALYSIS OF UNOS DATA SHOWS THAT THE OUTCOME OF LIVER TRANSPLANTATION IN PATIENTS WITH HEPATITIS C HAS REMAINED UNCHANGED BETWEEN 1991-2001 IN THE USA
Hwan Y. Yoo, Indiana University School of Medicine, Indianapolis, IN; Paul J. Thuluvath, The Johns Hopkins University School of Medicine, Baltimore, MD.
It has been suggested that, for hitherto unexplained reasons, the survival of patients with HCV has declined among those who were transplanted more recently.
To compare the outcome of liver transplantation (LT) in patients with HCV at different time intervals between 1991-2001. We selected 1991 since the data on HCV status was unavailable prior to that period.
UNOS (United Network for Organ Sharing) data from 1991 to 2001 was used after excluding pediatric patients, patients with multiple transplantation and those with incomplete survival data. Based on the time of transplantation, patients were arbitrarily divided into 3 groups: 1991-1993 (Period 1), 1994-1997 (Period II) and 1998-2001 (Period III). Patients with HCV were compared to those without HCV ('Case -Controls') to adjust for improvement in overall outcome during the same period.
There were 7,455 patients with HCV (Period 1-1,173, Period II-2, 679, Period III- 3,603) and 20,734 patients in control group (Period 1-4,806, Period II- 8,419, Period III-7, 509). Survival of patient was analyzed after adjusting for age, sex, race, ABO blood type matching status, cold ischemia time, UNOS listing status, serum creatinine, body mass index and age of the donor. As expected, 3-year patient survival was lower in HCV compared to that of controls (78.5% vs. 81.4%, HR 1.12, 95% CI 1.04-1.20, p=0.003). However, there was no difference in patient survival among HCV patients who were transplanted between 1991-1993, 1994-1997 and 1998-2001 (77.4%, 79.6% and 78.5% respectively). The graft survival also showed similar results (72.8%, 71.0% and 69.8% respectively). The patient and graft survival for control patients showed significant improvement in period 2 and 3 compared to period 1.
The analysis of UNOS data shows that patient and graft survival in HCV patients has remained unchanged between 1991-2001.
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Poster 146: A MORE SEVERE HEPATITIS C RECURRENCE (HCVR) POST LIVER TRANSPLANTATION (OLT) OBSERVED IN RECENT YEARS MAY BE EXPLAINED BY THE USE OF LOWER-DOSE CORTICOSTEROID (CS) MAINTENANCE PROTOCOLS
Carlos G. Fasola, George J. Netto, Nicholas Onaca, Mark Thomas, Edmund Q. Sanchez, Shrina Chinnakotla, Robert M. Goldstein, Marlon F. Levy, Gary L. Davis, Goran B. Klintmalm, Baylor University Medical Center, Dallas, TX.
To assess the effect of steroids in HCVR post OLT at two years post OLT in recent years.
Hep C 1994 -1999 OLT (n=133) outcome, at years 1 (Y1) and 2 (Y2), was analyzed in 3 groups of patients according to the steroid maintenance dose received from their immunosuppression (IS) standpoint and according to the era studied ('94-95; '96-97 and '98-99). IS was based on calcineurin-inhibitors (CNI:CSA [80%] or FK [20%] ) + Prednisolone (P). Patients were categorized according to total amount of Prednisolone maintained in Y1 (range: 2,958-10,113 mg) and Y2 (range: 2,958-13,763 mg) as: low (Y1: less than 5,162 mg; Y2: less than 6,500 mg), medium (Y1:5,162-6,315; Y2:6,500-8500) or high dose (Y1: more than 6,315; Y2: more than 8,500). Selection criteria was based on percentiles 33 and 66 range distribution. Laboratory data and liver histology were evaluated by protocol, in all patients, at 1 and 2 years post OLT and respectively compared. HCV recurrence was assessed by the degree of fibrosis (stages (S) 0 to 4), as defined in the past (A.J.S. Pathology 19(12):1409, 1995). Patient and graft survivals were compared among groups. Demographics, UNOS status, ICU and Hospital stay, incidences of ACR, bacterial and CMV infections were assessed. Fisher's exact and Chi-Square tests* were used for table analyses. Kaplan-Meier for actuarial survivals. A p value < 0.05 = significant.
No statistical differences were found regarding age, gender, race, UNOS status, hospital and ICU stay, infections and blood tests. The tables show the era impact in graft histology done at 2-year of follow up and in the amount of steroids used. It also show the effect of maintenance steroids in HCVR at 2 years. Graft survivals at 2 years for eras I, II and III were respectively: 92%, 96% and 97% (p=0.51) and for steroid doses: 96% (low), 91% (medium) and 100% (high, p=0.40). Patient survival was better for all groups, but statistically no different.
More severe HCV recurrence post OLT has been reported recently. Our data support those publications. Rather than a pure era effect, our findings of more aggressive HCV recurrence can be explained by the shorter and lesser amount of steroids used in recent years. Corticosteroids may be an important component of IS in HCV-OLT and minimize severe HCVR. The current practice of early CS withdrawal should be reconsidered and examined in prospective studies.
Hepatitis C Recurrence at 2 Years of Follow Up
Corticosteroid Maintenance Doses
Hepatitis C Recurrence at 2 Years Post OLT According to Steroid Maintenance Doses
Poster 147: SHOULD WE DISCARD OLD DONORS FOR HEPATITIS C CANDIDATES ? THE IMPORTANCE OF DONOR STEATOSIS
Marta Ponce, Marina Berenguer, Martín Prieto, Victoria Aguilera, Domingo Carrasco, Miguel Rayón, Francisco Orbis, Joaquín Berenguer, La Fe Hospital, Valencia, Spain.
Recurrent Hepatitis C following liver transplantation is a major concern in transplant units. Recent data have shown that the age of the donor is significantly associated with the outcome, with a worse histological progression in those receiving older donors. Unfortunately, the increasing imbalance between donors and potential candidates makes it impossible to discard these "so-called" marginal donors.
(1) to analyze the outcome of HCV-infected patients receiving organs from donors older than 50 years;
(2) in these patients, to determine pre and/or early post-transplant factors associated with a worse histological outcome.
91/145 HCV-infected patients transplanted between 1999 and 2001, with at least one year of follow-up, were included. Protocol biopsies were performed at yearly intervals (median/patient:1, range:1-3). An aggressive course was defined by the progression to fibrosis 3 or 4 in the first 3 years post-transplantation. Potential predictors of outcome included demographics, donor-related variables (steatosis, sex, age, anti-HBc positivity), host variables (history of alcohol consumption, Child-Pugh / HCC / nutritional status at transplantation, interferon therapy pretransplantation, HBV markers), early post-transplant variables (immunosuppression, biochemical tests, early surgical complications- vascular thrombosis and/or biliary complications-, development of recurrent histological acute hepatitis.
32/ 91 patients progressed to F3-4 in the first 3 years post-transplantation. Variables predicting the negative outcome were: age of the donor (p=0.07), degree of steatosis in the organ-donor (p=0.02); AST and ALT levels at 1 and 2 months post-transplantation (p=0.05; 0.04; and 0.006; 0.009; respectively), GGT at 2 months (p=0.03); and development of acute hepatitis (p=0.02). Of the 48 (53%) patients receiving an organ from a donor older than 50, 21 (44%) developed F3-4 within 2-3 years of transplantation. In contrast, of 43 patients receiving organs from younger donors, only 11 (25%) progressed to F3-4 (p=0.07). The median donor age in those progressing to F3-4 was higher than in those with benign outcome (54 vs 48 years, p=0.07). Variables associated with an aggressive course in those receiving organs from old donors were: development of recurrent acute hepatitis (p=0.05), and AST-ALT levels at 2 months post-transplantation (p=0.04 and 0.006, respectively). In those receiving grafts from younger donors, variables associated with a negative outcome were: significant steatosis in the organ donor (p=0.01) and development of early surgical complications (p=0.03).
The use of organs from old donors is associated with a high risk of developing aggressive recurrent hepatitis C. If these organs are used, the development of acute hepatitis and/or significant increases in the transaminase levels in the early post-transplant period may help in predicting a negative outcome. In contrast, when using young donors, the degree of liver steatosis is probably the single most important factor in influencing clinical outcome. These findings may help implementing early antiviral therapy and/or directing some of these organs to non-C candidates.
Poster 148: IMPACT OF PEGYLATED INTERFERON alfa-2b AND RIBAVIRIN ON LIVER FIBROSIS FOR RECURRENT HEPATITIS C IN LIVER TRANSPLANATION-A SINGLE CENTER EXPERIENCE
Sandeep Mukherjee, Richard K Gilroy, Joyce Rogge, Lynne Weaver, Timothy M McCashland, Daniel F Schafer, University of Nebraska Medical Center, Omaha, NE
Recurrent hepatitis C (HCV) is universal after orthotopic liver transplantation(OLT). Patients are often treated with interferon-based therapy to eradicate the virus and prevent cirrhosis requiring retransplantation. We describe our experience with pegylated-interferon and ribavirin combination therapy on 39 patients with recurrent HCV from a single liver transplant program.
Between November 2001 and September 2002, consecutive patients with recurrent HCV were screened to determine if they were eligible for treatment. Recurrent HCV was defined as the presence of HCVRNA viremia with a liver biopsy demonstrating recurrent hepatitis, steatosis or non-specific changes in patients transplanted for HCV. This cohort was followed prospectively after starting a treatment protocol of pegylated interferon alfa-2b 1.5 µg/kg qweekly and ribavirin 800mg qd (Schering-Plough, Kenilworth, NJ, USA) with folic acid 1 mg qd. Patients with genotypes 1 and 4 were treated for 12 months, other genotypes for 6 months and doses adjusted per treatment protocol. Steroids were discontinued prior to treatment. Complete blood counts were performed weekly for the first month and monthly thereafter with liver function tests. HCVRNA was repeated at 3 months, end of treatment (EOT) and 6 months after EOT for patients HCVRNA negative at EOT. Liver biopsies were repeated at EOT and biopsies scored according to the methodology described by Batts and Ludwig.
45 patients were screened and 39 eligible for treatment. There were 33 males and 6 females with a median age of 50.4 years. 31 patients were genotype 1, 2 were genotype 2 and 3 each were genotype 3 and 4. Median pre-treatment viral load was 1.7 million iu/ml and median interval between OLT and treatment initiation was 20 months. 18 patients have completed treatment, 4 remain on treatment and 17 were intolerant. Of the 18 patients who completed treatment, 17 were HCVRNA negative at 3 months and 15HCVRNA negative at EOT (this included 1 patient who was HCVRNA positive at 3 months). 6 months after EOT, 12 patients remain HCVRNA negative ( HCVRNA pending in 3). Improved fibrosis scores, defined as a downstaging of the EOT biopsy by at least 1 stage, were present in 6 patients, unchanged in 10 and worse in 2. Interestingly, of the 3 non-responders to treatment, one patient each had an improved score or unchanged score at EOT.
Side effects are an important limiting factor in the treatment. of recurrent HCV with only 46.1% of patients completing treatment. Sustained HCV eradication occurred in at least 66.7% of patients who completed treatment but in an intention-to-treat analysis, sustained eradication occurred in 30.8% of patients. However, improved fibrosis scores were demonstrated in responders and non-responders to treatment. This suggests that failure to eradicate the virus should not necessarily lead to treatment discontinuation as a subgroup of patients may benefit from maintenance therapy if serial liver biopsies demonstrate improved fibrosis.
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Poster 189: TREATMENT OF CHRONIC HEPATITIS C WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS®) AND RIBAVIRIN (COPEGUS®): PATIENT AGE HAS A MARKED INFLUENCE ON THE INDIVIDUAL ESTIMATED PROBABILITY OF ACHIEVING A SUSTAINED VIROLOGICAL RESPONSE
Graham R Foster, Digestive Disease Research Centre, Barts and The London, London, United Kingdom; Michael W Fried, University of North Carolina, Chapel Hill, NC; Stephanos J Hadziyannis, Henry Dunant Hospital, Athens, Greece; Monique Chaneac, Roche, Basel, Switzerland.
Overall sustained virological response (SVR) rates to peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin (COPEGUS®) ranged from 56 to 61% in pivotal trials in patients with chronic hepatitis C (CHC). The probability of achieving an SVR varied with HCV genotype, viral load, histological status and other patient factors. In patients infected with HCV genotype 1, only pretreatment viral load had a greater influence than age on the probability of achieving an SVR.
In this analysis we investigated the influence of age and adherence on the probability of achieving an SVR with peginterferon alfa-2a (40KD) and ribavirin in an individual patient infected with HCV genotype 1.
Data from 2 international, randomized trials in which patients received peginterferon alfa-2a (40KD) 180 µg/wk plus ribavirin were combined. In 1 study (Fried et al. N Engl J Med. 2002;347:975-982), patients were treated for 48 wk with a standard dose of ribavirin (1000 or 1200 mg/day). In the second study (Hadziyannis et al. J Hepatol. 2002; 36 [suppl 1]: 3A), patients were randomized to 1 of 4 groups: all patients received peginterferon alfa-2a (40KD) combined with either a low dose (800 mg/day) or the standard dose of ribavirin, and were treated for 24 or 48 wk. SVR was defined as absence of HCV RNA in serum by qualitative PCR (<50 IU/mL, COBAS AMPLICOR® HCV Test, v2.0) on or after wk 60.
All 1737 patients who received peginterferon alfa-2a (40KD)/ribavirin were aged >18 yr, had HCV RNA levels >2000 copies/mL, elevated ALT levels, and a liver biopsy consistent with a diagnosis of CHC. Data included in this analysis were restricted to patients infected with HCV genotype 1 (n = 736) as described below.
Logistic regression models were constructed based on HCV genotype 1, baseline time point and adherence (>80% and <80%). An adherent patient was defined as one who received the assigned dosages of peginterferon alfa-2a (40KD)/ribavirin for >80% of the planned duration of treatment. Because of the low number of non-Caucasian patients, the model was restricted to Caucasian patients. The analysis was limited to patients aged <60 yr and with a BMI of <30 kg/m2. Patients with very extreme values were also excluded from the analysis.
Parameters used in the model include the following: pretreatment viral load (100,000 to 24 x 106 copies/mL); age (20 to 60 yr); duration of treatment (24 or 48 wk); pretreatment ALT quotient range (1-7); BMI (18-30); histological status (cirrhosis or noncirrhosis); and Caucasian race.
Of 736 patients with HCV genotype 1 infection used to build the model, 336 (45.6%) had an SVR. In addition, 597 of 736 patients (81.1%) were adherent.
When the model was programmed for a noncirrhotic, Caucasian patient with a baseline ALT quotient of 3, HCV RNA level of 3.269 x 106 copies/ml and a BMI of 25, the probability of a 20-year-old patient achieving an SVR was 74.4% (95% confidence interval [95% CI]: 66.1 - 81.7%). In contrast, the probability of achieving an SVR in a 60-year-old with the same baseline characteristics was 44.2% (95% CI: 35.2 - 53.5%). When the model parameters include, in addition to those mentioned above, an assumption that the patient would be adherent (as defined above), the probability of achieving an SVR increased to 85.4% (95% CI: 78.0 - 90.7%) in the 20-year-old and 52.9% (95% CI: 42.6 - 63.0%) in the 60-year-old.
In conclusion, patient age has a profound influence on the probability of achieving an SVR with peginterferon alfa-2a (40KD) and ribavirin therapy. Clinicians and their patients should consider the influence of patient age on the timing of the decision to start treatment. With our model, it is possible to predict the probability of achieving an SVR in an individual patient, and to demonstrate the impact of adherence on treatment outcome. This tool will be useful in motivating patients to adhere to treatment.
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Poster 192: EARLY VIRAL KINETICS PREDICTION OF SUSTAINED VIROLOGICAL RESPONSE AFTER 1 OR 4 WEEKS OF PEG-INTERFERON-ALFA-2A AND RIBAVIRIN THERAPY (DITTO-HCV PROJECT)
Avidan U Neumann, Esther Hagai, Bar-Ilan University, Ramat-Gan, Israel; Solko W Schalm, University Hospital Rotterdam Dijkzigt, Rotterdam, Netherlands; Michael von Wagner, Saarland University Hospital, Homburg/Saar, Germany; Georgios Germanidis, Aristotle University of Thessaloniki, Thessaloniki, Greece; Yoav Lurie, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel; Gabriele Missale, Azienda Ospedaliera di Parma, Parma, Italy; Maria Martell, Hospital General Vall d'Hebron, Barcelona, Spain; Jan-Maarten Vrolijk, University Hospital Rotterdam Dijkzigt, Rotterdam, Netherlands; Cristophe Hezode, Hopital Henri Mondor - Universite Paris XII, Creteil, France; Gunnar Norkrans, University of Goeteborg, Goetoborg, Sweden; Francesco Negro, Hospital University of Geneve, Geneve, Switzerland; Alexandre Soulier, Hopital Henri Mondor - Universite Paris XII, Creteil, France; Elke Verheij-Hart, University Hospital Rotterdam Dijkzigt, Rotterdam, Netherlands; Giuseppe Colucci, Tegimenta AG, Rotkreuz, Switzerland; Carlo Ferrari, Azienda Ospedaliera di Parma, Parma, Italy; Stefan Zeuzem, Saarland University Hospital, Homburg/Saar, Germany; Jean-Michel Pawlotsky, Hopital Henri Mondor - Universite Paris XII, Creteil, France; for the DITTO-HCV group.
Early Hepatitis C viral (HCV) kinetics was previously shown to predict sustained virological response (SVR). The current consensus stopping rule is defined at 12 weeks of treatment with peginterferon-alfa and ribavirin. Earlier prediction is needed in order to improve the cost/effect ratio. However, the predictive value of earlier viral kinetics for the current standard of care has not yet been established.
The DITTO-HCV European funded project is for now the largest study of frequent early viral kinetics during therapy with peginterferon-alfa and ribavirin. We aim to optimize viral kinetics prediction criteria in order to enable stopping or tailoring treatment as early as possible. Our objectives: 1) negative predictive value (NPV) as close as possible to 100% (thus minimalizing stopped patients with missed SVR), 2) high specificity (thus increasing the fraction of patients that can be safely stopped). 3) a high positive predictive value (PPV) using the same criteria.
134 chronically HCV infected naïve patients received peginterferon-alfa-2a (40KD) (Pegasys ®) (180 µg qw) plus ribavirin (Copegus ®) (1000-1200 mg qd) for 48 weeks. Of those, 67%, 28%, 4% and 1% had HCV genotype 1, 2-3, 4 or 5 respectively. Viral kinetics were measured according to centralized serum HCV RNA quantifications on days 0, 1, 4, 7, 8, 15, 22 and 29 (Cobas Amplicor® HCV Monitor v2, Roche). SVR was defined as undetectable serum HCV RNA (<50 IU/ml) after 24 weeks of follow-up post treatment. The early viral response prediction criteria (EVR) and thresholds tested here (see Table) were prospectively defined.
The overall SVR rate was 64%. The EVR studied, together with their NPV, PPV, specificity (SP), statistical significance and number of HCV-RNA quantifications needed (NSMP), are given in the Table.
The EVR-w12 criteria has good NPV (100%) but its specificity is low (21%), thus relatively few non-responders can be stopped. None of the simple 2nd-slope or Week-1 criteria shows NPV higher than 90%, thus not adequate for a stopping rule. A new composite criteria (DITTO-2nd-slp) gives NPV=100% and specificity=34% already after 4 weeks of treatment. Furthermore, another new composite criteria (DITTO-1st-week) also gives NPV=100% with specificity=28% already after 1 week. Although composite, these new criteria are simple to calculate and necessitate only 1 or 2 more viral quantifications compared to the current Week-12 criteria. Thus allowing to lower the mean cost by 2410 USD per patient. Note that SVR (56% for gen 1 and 87% for gen 2-3) is predicted independently of genotype. Moreover, by selecting more strict thresholds for the DITTO-1st-week (e.g. 4.5 log at day 4 and 2 log decline at day 7) and DITTO-2nd-slope (e.g, 0.6 log/week) criteria one can obtain higher PPV up to 90%.
Sustained viral response to treatment with peginterferon-alfa-2a (40KD) and ribavirin can be predicted, independent of genotype, as early as 1 or 4 weeks of treatment by new composite, but still simple and practical, criteria of viral kinetics. Similar NPV and PPV and better specificity was obtained here by the DITTO-1st-week or DITTO-2nd-slope prediction criteria, giving rise to significantly lower cost/effect as compared to the current stopping rule at 12 weeks. These results warrant future prospective testing in larger trials, since they can give rise to considerable saving in cost and quality of life related to over-treatment or alternatively allow early tailoring of treatment.
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Poster 971: LONG TERM FOLLOW UP OF SUSTAINED RESPONDERS TO INTERFERON ALPHA IN CHRONIC HEPATITIS C: A META-ANALYSIS ASSESSING TRUE CLINICAL ENDPOINTS
Bart J Veldt, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Giorgio Saracco, Ospedale Molinette, Torino, Italy; Bettina E. Hansen, Solko W Schalm, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; For the Eurohep* study group.
Sustained virological response at six months after treatment is the key outcome for treatment efficacy in hepatitis C. However, reports about the incidence of clinical events during long term follow up of European patients with a sustained response to interferon treatment are scarce.
To determine the virological relapse rate and to assess clinical endpoints during long term follow-up in European sustained responders to interferon treatment.
Meta-analysis of individual patient data of 8 European protocolled follow-up studies.
286 sustained responders were followed up for 59 months (range 12-120). Fifteen sustained responders had cirrhosis before treatment. HCV-RNA was detected in 25 (8.7%) of 286 sustained responders; the late relapse rate at five years of follow up was 10.5% (95%CI 6.5%-14.5%). The only factor predictive of late virological relapse was the total dose of interferon, acccording to multivariate analysis (Hazard Ratio=0.650; 95%CI 0.426-0.991, p=0.045); doses = 216 MU being associated with the highest late relapse rate. Two patients originally not classified as having cirrhosis, developed decompensation at 30 and 60 months of follow up (rate of decompensation at 5 year follow up: 1.0% (95 %CI 0.0-2.3), the latter died of this decompensated cirrhosis. No HCCs were detected. The outcome in cirrhotic patients did not differ from other patients with sustained response to interferon.
The late virological relapse rate at five years of follow up was 10.5% (95%CI 6.5%-14.5%) in sustained responders to interferon treatment. Treatment with a high total dose of interferon reduces the risk of late virological relapse. The five year occurrence of clinical events was 1.0 % (95%CI 0.0-2.3) among 286 sustained responders.
*Eurohep study group participants are U Hopf, Berlin; N Boyer, Clichy; O Weiland, Huddinge; F Nevens, Leuven; I Castillo, Madrid; A Bellobuono, Milan; C Cammà and A Craxi, Palermo; P Marcellin, Paris; S W Schalm and J T Brouwer, Rotterdam and G Saracco, Torino
Poster 972: VX-950: THE DISCOVERY OF AN INHIBITOR OF THE HEPATITIS C NS3•4A PROTEASE AND A POTENTIAL HEPTITIS C VIRUS THERAPEUTIC
Robert B Perni, Gurudatt Chandorkar, Pravin R Chaturvedi, Lawrence F Courtney, Caroline J Decker, Cynthia A Gates, Scott L Harbeson, Ann D Kwong, Chao Lin, Yu-Ping Luong, William Markland, Govinda Rao, Roger D Tung, John A Thomson, Vertex Pharmaceuticals Inc., Cambridge, MA
The deficiencies of current anti-HCV therapy are well known. The poor tolerability of the interferon-alpha (IFN-alpha)-ribavirin combination therapy limits its value, particularly versus Genotype 1 where even the pegylated IFN-alpha/ribavirin combinations are generally less than 50% effective in achieving sustained viral responses. The need for a direct anti-viral therapy for hepatitis C is clear. The NS3•4A protease of the hepatitis C virus represents an attractive target that should be amenable to modern drug design techniques. Designing small molecules that have high affinity for the shallow, largely hydrophobic active site of this serine protease has been a significant challenge and only recently the first HCV protease inhibitor to show anti-viral activity in humans was reported (Lamarre et al, 2002, Hepatology, 36, Pt2, 301A). Nature has designed this protein with a natural substrate recognition sequence of a lengthy 10 amino acids. Consequently, numerous hydrophobic interactions and hydrogen bonds are required to effectively bind any potential inhibitor. In addition, either a charged terminus or a covalent attachment of the inhibitor to the catalytic serine is needed to anchor the assembly. To maximize binding while simultaneously maintaining an acceptable biological profile, we have chosen to base our inhibitor scaffolds on a reversible covalent warhead motif in order to eliminate charged groups and facilitate cellular penetration. We now report the discovery of VX-950, a small molecule inhibitor of the hepatitis C NS3•4A protease. This molecule was derived through structure-based drug design methodology, evolving from the natural NS5A-NS5B substrate. VX-950 has a measured Ki of 44 nM versus the NS3•4A enzyme. Inhibition of the polyprotein processing in hepatocytes as measured by the HCV replicon assay has been demonstrated. VX-950 is orally bioavailable in several species with a favorable pharmacokinetic profile. The uptake of the drug is characterized by first pass hepatic extraction resulting in high concentrations of drug in the liver, which should be advantageous for treatment of chronic HCV. On the basis of these attributes VX-950 has been selected for clinical evaluation in humans.
The authors wish to gratefully acknowledge the significant contributions to this research by our collaborators at Eli Lilly and Co
Poster 974: IFN-A 2B INHIBITS INTERNAL RIBOSOME ENTRY SITE MEDIATED TRANSLATION OF GREEN FLUORESCENCE PROTEIN FROM SIX DIFFERENT HCV GENOTYPES
Alfredo Panebra, Krishna Shah, Ramesh Prabhu, Frank Bastian, Robert F Garry, Virendara Joshi, Salima Haque, Fredric G Regenstein, Tulane University Health Sciences Center, New Orleans, LA; Richard Elliott, University of Glasgow, Glasgow, United Kingdom; Srikanta Dash, Tulane University Health Sciences Center, New Orleans, LA
Interferon alpha is the standard therapy for chronic hepatitis C, but the mechanism(s) by which this cytokine inhibits HCV replication is not understood. We reported previously that different forms of interferon inhibit replication of hepatitis C virus by directly blocking at the level of viral RNA translation.
This study was conducted to examine the regulation of internal ribosome entry site mediated translation (IRES) of different HCV genotypes by IFN-a 2b and other cytokines in Huh-7 cells.
Chimeric clones consisting of the 5'UTR-IRES sequences of different HCV genotypes (HCV1a, HCV1b, HCV2a, HCV2b, HCV 3, HCV4, HCV5 and HCV6) and the green fluorescence protein (GFP) gene were constructed. High-level expression of GFP was achieved using a replication defective adenovirus that expresses T7 RNA polymerase. Direct effects of IFN-a 2b as well as other cytokines (for example TNF-a, interleukins) on translation of GFP were determined by fluorescence microscopy and Western blot analysis.
IFN-a 2b specifically inhibits translation of GFP mediated by IRES sequences from six major HCV genotypes in a concentration dependent manner. This inhibition is not due to intracellular degradation of GFP mRNA, but rather due to a block at the level of GFP mRNA translation. Other cytokines such as TNF-alpha or interleukins did not inhibit IRES mediated translation of GFP mRNA.
Interferon alpha directly inhibits IRES mediated translation of RNA from different HCV genotypes. This inhibition is specific to IFN-a 2b since other cytokines have no effect on IRES mediated translation of GFP.
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Poster 976: TOTAL HCV CORE ANTIGEN CORRELATES WITH HCV RNA, AND PREDICTS RESPONSE TO PEGINTERFERON ALFA 2-A (PEG-IFN) AND RIBAVIRIN (RIB) THERAPY IN CHRONIC HEPATITIS C
Eduardo Padilla, Ramon Planas, Vicky González, Hospital Germans Trias i Pujol, Badalona, Spain; Celia Perez, Hospital General de Valencia, Badalona, Spain; Dolors Gimenez, Hospital del Mar, Barcelona, Spain; Lourdes Matas, Rosa Maria Morillas, Eduard Cabre, Hospital Germans Trias i Pujol, Badalona, Spain; Ricard Sola, Hospital del Mar, Barcelona, Spain; Moises Diago, Hospital General de Valencia, Valencia, Spain; Vicens Ausina, Hospital Germans Trias i Pujol, Badalona, Spain
Assessment of early virological response (EVR) may predict outcome in chronic hepatitis C patients treated with PEG-IFN and Rib. A decrease in HCV RNA to undetectable levels or by at least 2 log10 units after 12 weeks is considered the optimal definition of EVR. The core Ag of HCV may constitute an alternative direct marker for assessing the levels of viremia in chronic hepatitis C patients.
To determine the correlation between total HCV core Ag and HCV RNA levels, as well as to assess whether total HCV core Ag quantification at baseline, 1 month, and 3 months after treatment could predict sustained virological response (SVR) to PEG-IFN and Rib combination therapy, in comparison to HCV RNA.
HCV viremia was determined using the total HCV core Ag test (trak-C, Ortho-Clinical Diagnostics, Raritan, NJ), and qualitative/quantitative HCV RNA assays (Amplicor, and Amplicor Monitor COBAS V.2.0, Roche Diagnostics, CA) in 62 patients with chronic hepatitis C infected with genotype 1 in 46 (74.2%), and genotype non-1 in 16 (25.8%) (genotype 3: 10, 4: 4, and 2:2) cases, respectively.
SVR was achieved in 34 (54.8%) patients (20/46: 43.5% in genotype 1, and 14/16: 87.6% in genotype non-1). SVR was significantly associated with baseline HCV RNA (p=0.04) and total HCV core Ag (p=0.01) levels, and infecting genotype (p=0.002). There was a good correlation between total HCV core Ag and HCV RNA concentrations considering 115 samples out of 134 that tested positive for both markers (r=0.91; p<0.001), as well as at baseline (r=0.89), 1 month (r=0.83) and 3 months after therapy (r=0.76). We estimated that 1 pg/mL of total HCV core Ag is equivalent to approximately 10,000 HCV-RNA IU/mL. Viral replication was not detected by total HCV core Ag in 28 out of 38 (73.6%) samples with an HCV RNA below 23.000 IU/ml. SVR was predicted at baseline in 67.9% of cases using total HCV core Ag levels<80 pg/mL, and in 65.2% of cases using HCV RNA quantification (<800.000 UI/mL). At 1 month after therapy, the positive predictive value (PPV) of response to therapy - defined as the proportion of SVR patients among patients with HCV core Ag levels ≤2.5 pg/mL - was 65.9%, and 68.4% considering the HCV RNA drop ≥ 2 log criteria. Corresponding figures at 3 months after therapy were 56.1% and 56.4%, respectively. For HCV core Ag, the negative predictive value (NPV) at 1 and 3 months after therapy were 76.5% and 100% respectively, whereas for HCV RNA the NPV were 69.6% and 80% respectively.
Total HCV core Ag is a quick, reproducible, and easy to perform alternative to HCV RNA methods. Moreover, the prediction of response to PEG-IFN and Rib combination therapy based on HCV core Ag levels before therapy, or at 3 months, was similar to that observed with HCV RNA.
Poster 982: PEGYLATED INTERFERON ALFA-2B IN COMBINATION WITH RIBAVIRIN FOR THE TREATMENT OF CHRONIC HEPATITISC GENOTYPE 4
Fuad Hasan, Haifa Asker, Jamila Al-Khaldi, Iqbal Siddique, Salim F Owaid, Misfer Al-Ajmi, Basil Al-Nakib, Kuwait University, Kuwait, Kuwait
The hepatitis C virus (HCV) genotype is an important predictive parameter for the success of pegylated interferon plus ribavirin therapy. To date, most published therapeutic trials had enrolled patients infected mainly with HCV genotypes 1, 2 and 3. Data regarding the responsiveness of genotype 4, the predominant type of HCV in the Middle East, are very limited.
To assess the efficacy of pegylated interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis caused by HCV genotype 4.
Patients and Methods
44 treatment naive patients infected with HCV genotype 4 were enrolled in this open label, prospective study. Cohort characteristics included the following: 30 M/14F, mean age 44.4 + 8.9 yrs, mean weight 73.3 + 7 kg. All patients had raised ALT and were compensated. The median pre-treatment HCV-RNA level was 2.35 x 106 copies /ml (0.47 x 106 iu/ml), range 0.3 x 106 - 30 x 106 copies/ml. 13 patients (30%) exhibited cirrhosis and 2 (4%) had bridging fibrosis on pretreatment liver biopsy specimens. All patients were to receive pegylated interferon alfa-2b 1.5 mcg/kg/wk plus ribavirin 1000-1200 mg/day for 48 weeks. Patients were followed up for 24 weeks after completing therapy. End of treatment viral response (ETR) and sustained viral response (SVR) were defined as absence of HCV-RNA from serum (<100 copies/ml) at 48 weeks of treatment and at the end of follow-up, respectively. Data were analyzed on an intention - to- treat basis.
ETR and SVR were 68% and 61% respectively. Among patients with pre-treatment HCV-RNA > 2 x 106, SVR was 50% compared with SVR of 81% among patients with HCV-RNA < 2 x 106 (P=0.05). Patients with cirrhosis or severe fibrosis had significantly lower SVR rate compared to those with mild or no fibrosis (33% vs 76%; P<0.05).
Two patients (4.5%) discontinued therapy because of severe flu-like symptoms. One patient developed hypothyroidism. Dose reduction of ribavirin and pegylated interferon alfa-2b were necessary in 27% and 2% of patients respectively.
Pegylated interferon alfa-2b in combination with ribavirin is effective in the treatment of HCV genotype 4. Treatment was well tolerated by most patients.
COMBINATION THERAPY OF PEGINTERFERON ALFA-2a (40KD) (PEGASYS®) AND RIBAVIRIN (COPEGUS®) SIGNIFICANTLY ENHANCE SUSTAINED VIROLOGICAL AND BIOCHEMICAL RESPONSE RATE IN CHRONIC HEPATITIS C GENOTYPE 4 PATIENTS IN SAUDI ARABIA
O A Shobokshi, F E Serebour, L Skakni, N Al-Jasser, A O Tantawi, A Sabah, T Dinish, M Al-Quaiz, K Qahtani, A Sandokji, A Al-Blowi, M Al-Karawi, B Al-Kayyal, S Al-Momen, H Akbar, A Ayoola, M El-Hazmi, A Humaida, I El-Hazmi, H Eissa, F Khawajah, M Al-Khalifa.
Hepatitis C genotype 4 accounts for 60 to 90% of HCV chronic infections in the Eastern Mediterranean region but this is rare in other parts of the world. Earlier studies have reported poor treatment response rates for conventional interferons with HCV genotype 4. The advent of pegylated IFN and its success with other genotypes was our motivation for this study.
To determine and compare the efficacy and safety of peginterferon alfa-2a plus ribavirin with peginterferon alfa-2a monotherapy and IFN alfa-2a (Roferon® A) plus ribavirin combination therapy in the treatment of chronic hepatitis C genotype 4 patients in Saudi Arabia.
Open label multicenter clinical trial in which 180 patients infected with chronic hepatitis C genotype 4 were randomized into treatment groups (1:1:1) as follows:
GROUP A: Peginterferon alfa-2a (40KD) 180µg qw plus ribavirin (400mg) bid.
GROUP B: Peginterferon alfa-2a (40KD) 180µg qw.
GROUP C: IFN alfa-2a (Roferon® A)(4.5MIU) tiw plus ribavirin (400mg) bid.
Treatment duration was for 48 weeks and follow up period of 24 weeks was observed.
Early virological response (>2-log drop or HCV-RNA clearance) at week 12 was 77%, 60% and 43% in groups A, B and C, respectively. End of treatment response (week 48) for the groups were 67%, 59% and 37%. Sustained virological responses (week 72) were 50%, 28% and 30% respectively. Among week 12 early responders the sustained virological responses were 65.2% and 47.2% in the two pegylated IFN groups and the sustained biochemical response was 69.6% and 69.4%.
Twelve patients (6.7%) dropped out of the study as follows: group A, 7 patients (11.7%), group B, 4 (6.7%) and group C, 1 (1.7%). These were various adverse events ranging from alopecia, thyroiditis, oesophageal varices, tonic convulsion, encephalopathy and depression. Interestingly 5 of the 12 patients had early virological response.
a) A 100% negative predictive value among non-responders was observed for all treatment groups at early virological response at week 12.
b) Despite the use of a low dose ribavirin of 400mg bid, an enhanced sustained virological response of 50% (65% in early responders) was determined for the combination of peginterferon alfa-2a plus ribavirin.
c) A comparatively low relapse rate was observed in patients treated with peginterferon alfa-2a plus ribavirin.
d) Patients infected with HCV genotype 4 can be safely and effectively treated with peginterferon alfa-2a (PEGASYS®) plus ribavirin (COPEGUS®).
Poster1013: A DYNAMIC MODEL TO PREDICT SUSTAINED VIROLOGICAL RESPONSE TO COMBINATION PEGINTERFERON ALFA-2a (40KD) (PEGASYS®) AND RIBAVIRIN (COPEGUS®) THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C
Peter Ferenci, University of Vienna, Vienna, Austria; Michael W. Fried, University of North Carolina, Chapel Hill, NC; Monique Chaneac, Roche, Basel, Switzerland.
Overall, 56% of patients achieved sustained virological responses (SVR) after 48 weeks of treatment with the combination of peginterferon alfa-2a (40KD) (PEGASYS®) 180 µg/week and ribavirin (COPEGUS®) 1000 or 1200 mg/day in a large international, randomized, phase 3 trial.(Fried et al. N Engl J Med. 2002;347:975-982). In this study, 97% of patients without an early virological response (EVR), defined as either a ≥2-log10 drop in viral load or complete disappearance of HCV RNA in serum by 12 weeks of therapy, failed to achieve an SVR. This information is useful because it allows for the early termination of treatment in those unlikely to respond to a full course of treatment.
To refine the ability to predict the likelihood of achieving a sustained virological response after treatment with peginterferon alfa-2a (40KD) and ribavirin, based on virological response data obtained at week 4 and week 12 of therapy
The dynamic model is based on data from patients treated with peginterferon alfa-2a (40KD) 180 µg/week and ribavirin 1000 or 1200 mg/day for 48 weeks in a large, international, randomized trial (Fried et al. N Engl J Med. 2002;347:975-982). For the purpose of this analysis, an early virological response (EVR) was defined as undetectable HCV RNA by qualitative polymerase chain reaction (PCR) assay (<50 IU/mL; COBAS AMPLICOR® HCV Test, v2.0; Roche Diagnostics) or a decrease of ≥2-log10 in HCV RNA levels as determined by quantitative PCR (COBAS AMPLICOR HCV MONITOR® Test, v2.0; Roche Diagnostics) after 12 weeks of treatment. For this analysis SVR was defined as a single undetectable HCV RNA level by qualitative PCR on or after week 60. Treatment was to be stopped in patients with detectable HCV RNA after 24 weeks.
A total of 453 patients were randomized to treatment with peginterferon alfa-2a (40KD) and ribavirin and received study medication. The disposition of patients who were HCV RNA negative after 24 weeks of treatment is shown in the Table and grouped according to their HCV RNA status at week 4, 12 and 24. Patients with missing data at any of these time points were not included in the analysis. Patients with ≥2-log10 drop in HCV RNA levels at a given time point, and who were negative at the previous and following time point, were grouped with patients assessed as HCV RNA negative at that time point (n = 8). The probability of achieving an SVR increased in inverse proportion to the time taken to achieve undetectable HCV RNA levels. Thus, the highest SVR rate (89%) and, correspondingly, the lowest relapse rate during follow-up (8%), was obtained in patients who were consistently HCV RNA negative at weeks 4, 12 and 24.
The outcome of combination therapy with peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin (COPEGUS®) is highly dependent on the rapidity of the virological response. Patients who become HCV RNA negative after 4 weeks have the best chance for achieving an SVR. It may be hypothesized that to decrease the frequency of relapse in the remaining patients, treatment longer than 48 weeks may be required. This approach should be tested in a prospective trial.
HCV RNA Status
End of treatment response (EOT) = HCV RNA negative at week 48
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Ommegang Gift Set
"This gift set comes with a 750ml bottle of Hennepin Saison, Three Philosophers Quadrupel, and Chocolate Indulgence Stout. An oversized Chalice is included in the set."
Reviewed by: Kyle Fornek
Winter Seasonal - Check All Stores »
Select Store for Price3 Pack of 750ml Bottles
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Prerequisites: Junior or senior standing, PSCI 203 and permission of the department. (Either semester/1 credit)
A junior or senior major may serve as teaching assistant in introductory courses. The assistant would attend classes, tutor students, show films and participate in periodic conferences with the instructor and other teaching assistants. Other duties would include assisting the instructor in other class-related projects, such as organizing field trips, speakers and discussion sessions. May be taken only once. Grading is on a satisfactory/unsatisfactory basis.
Hood College prepares students to excel in meeting the personal, professional and global challenges of the future. Hood is committed to the integration of the liberal arts, the professions and technology, to the exploration of values, a sense of community and to the preparation of students for lives of responsibility, leadership and service.
401 Rosemont Ave.
Frederick, MD 21701


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These socks won't put a squeeze on your leg... or your wallet! Ring-spun, combed cotton socks with a touch of spandex for elastic S-T-R-E-T-C-H that won't constrict or leave marks on your legs! Ideal for people with Diabetes or poor circulation because they keep blood flowing through legs and feet all day long! As comfy and toasty as they are practical! Available in 6 rich colors in 2 different styles — crew and ankle! Machine wash and dry. There are 2 pairs per pack. Hurry up!
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(BPT) - Despite the beauty of snowcapped mountains, multicolored gardens and the glamour of old cities, little is more indelibly alluring or relaxing than the idea of a beach - soft waves lapping the shore and sunshine warming your skin. If the mere thought of white sand and turquoise waters doesn't stir you into planning your next vacation, DreamPlanGo gives 10 more reasons to inspire in the form of the world's most insanely gorgeous beaches.
Verdant green hills, white pebbled beaches and brilliant blue waters make Myrtos Beach one of the world's tropical treasures. For a more peaceful visit, travel in the spring and early summer to avoid the throngs of high-summer visitors.
More than a thousand miles of coastline and crystal waters make this Mediterranean Island a healthy dose of paradise. If all that sun and open sky is too much, explore the stunning caves found in the heart of the island.
An archipelago off the coast of East Africa, the beaches of Zanzibar are legendary for their exotic appeal and pristine shores. Pwani Mchangani, in the north of the island, is particularly private and is the ultimate backdrop for relaxation.
The largest and arguably most beautiful of the Whitsunday Islands, Whitehaven Beach is a marvel to behold. For the best view of its changing blue waters, hike to Tongue Point at low tide.
A cluster of 104 islands off the coast of northwestern Malaysia in the Adaman Sea, Langkawi is the ideal option for the traveler seeking both adventure and leisure. Sail through the islands, meander through the rural villages on a bicycle or experience a guided tour of Langkawi's 'magical' rainforest.
Most accessible by boat from Puerto Vallarta, Yelapa Beach is a charming seaside village that feels worlds away from most Mexican hotspots. Cool off by snorkeling through the refreshing waters or toss inhibition aside and take in the views via parasailing.
The year-round sunshine and mild weather make Algarve the perfect escape for any season. Praia do Amado is the ideal beach for surfers and body boarders while the nearby towns of Portimao and Albufeira offer a variety of Portuguese markets and restaurants.
A local beach away from the bustling tour areas, Playa Nacascolo is undoubtedly among Costa Rica's prettiest beaches. The water is so clear that snorkeling gear isn't even necessary to enjoy the vibrant sea-life below.
On the coast of Oahu, you will find Lanikai, appropriately called 'heavenly sea' in Hawaiian. Kayak, surf or swim in the turquoise waters and bring your camera to take pictures of the famous Mokulua Islands, located only a mile from shore.
The small Caribbean islands of Turks and Caicos are a mosaic of amusement. Explore the historic capital of Gran Turk, tour one of the 32 uninhabited islands or enjoy the fabulous snorkeling and diving of Grace Bay.


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Sacks for Sandy Spreads Holiday Cheer to Kids
Michele Catalano of East Meadow and Leah Reich of California joined efforts from across the country to children affected by the storm.
Posted by Jaime Sumersille ,
Catalano and Reich created their website, Sacks for Sandy, and in just one week have collected more than 700 toys for children affected by Sandy. There has also been a social media movement surrounding the effort.
Inspired by the Occupy Sandy Registry, the two started their mission by creating a wish list of on Amazon.com and then spread the word on their personal Facebook and Twitter accounts. It probably helped their cause that Catalano has nearly 1 million Twitter followers.
For more stories like this or to upload information about a similar effort, follow our Giving and Volunteering groups.
"We put it up and then people started responding, sharing our statuses and donating," Catalano said.
The gifts will be donated to firehouses in Lindenhurst, Massapequa, Lido Beach, Island Park and East Rockaway for distribution. The two women hope to collect 1,000 gifts by Friday when the collection drive ends.
Reich said that watching the coverage of a storm that affected her close friend made her want to give back.
"You just feel helpless," she told Patch via Skype. "People lost basic things, but the kids still love the holidays. They should still have Christmas and Hanukkah after all the devastation."
Catalano, who was without electricity for 13 days herself, agreed that normalcy is important for those who remain displaced or are in the rebuilding process.
Catalano said that she came to the realization that people do care about one another and that the Internet is in fact a powerful tool.
"If we don't collect 1,000 gifts, we still got an overwhelming amount from strangers over the Internet," she said. "And it proves that social media can be used to do good because you are able to reach so many people. I have met some of my closest friends online."
But in the end, it is all about the children.
"They went through a devastating thing and have been traumatized," Catalano said. "We just want to bring smiles to these kids faces." Want to help? Donate a gift to Sacks for Sandy here.
Story by Danielle De Souza
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Mike recently composed the score and soundtrack for the movie "The Raid: Redemption." Has anyone seen it? If so, what are your thoughts on the score and the movie?
Get the score & soundtrack at TheRaidSoundtrack.com, and see when The Raid is coming to a theater near you HERE.
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I'm so proud I lived in Indonesia, so I can see The Raid movie :D because The Raid movie is from Indonesia :)) It's so damn awesome movie I've ever seen that come from INDONESIA!!!!!
hmmm... so THE RAID hah???
mike is really awesome.................his music made the movie even better
woooow how great it is! it's movie from indonesia. big thanks to mike, i love your encoring music so much
I like it a lot :)
i havent watched it but i know if mike is in this work it is great
Yeah I saw the movie! The music was aweomse just like the movie! Easily the most action packed movie I have ever seen and perfect music to go with. We saw the trailer and new straight away that it was Mike! The Best as they say!
I saw it!!!! :D super awesome action scenes! if you are a die hard action fan, you will be amazed if you see the movie! o yea and the music was amazing too :)
Its not coming to my neck of the woods but I have been finding some of the music and score of the film on Youtube. I like it. Hopefully I will be able to get it later on if it come out on dvd or downloads.
It is an awesome movie and the soundtrack is good too. You people should listen to Razors Out after the movie ends. It is very good song
i saw the german trailer....the film comes at the 12.7.12 in germany in the cinemas...the tailer was great...


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Ardis I. WardMarch 02,2013
Ardis I. WardArdis I. Ward
WINOOSKI Ardis Irene Ward of Winooski died in Fletcher Allen Health Care after suffering a heart attack on Monday, Feb. 25, 2013.
Born in Hartland on Jan. 22, 1925, to Watson D. Davis and Grace E. Colby, she attended Woodstock High School, Class of 43. Shortly after school, she married John F. Bowley Sr., a union which lasted 23 years and produced five children, John F., Thomas G., Susan D., Sheila I. and Shelly J. Bowley.
During her time in Hartland, she taught at 4H, co-founded the Hartland Riding Club with Connie Tessier and was its first president, sang in the North Hartland Methodist Church Choir, tended a large flower garden, and decorated her and others homes with her oil paintings. Though she could be described as a homemaker, her real calling was to inspire others with her joy for living and indomitable spirit in the face of a persistent struggle with multiple sclerosis.
Her second marriage to James A. Ward in 1971 gave her five stepchildren, Greg, Rodney, Gigi, Roger and James II, whom she loved as her own. After her children had grown, life brought her to Franklin, N.H., White River Junction, Vt., Somerville, Fla., and finally to Winooski.
She is survived by her loving husband of 42 years; 10 children; 27 grandchildren; 12 great-grandchildren; and a wide community of friends and relatives, whom she touched during her 88-year-long dance with life.
A memorial service will be held on March 16, 2013, at 1 p.m. at the LaVigne Funeral Home, 132 Main St. in Winooski. She will be memorialized in the Taftsville Cemetery, at rest with her parents and other family members.MORE IN Obituaries0729 RH Obits Polcaro brief no photo no flag Full Story0729 RH Obits Jones rites no photo no flag Full Story0729 RH Obits Busier paid photo no flag Full Story
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Paradise Bay - Beach
Boracay Island, Tulubhan, Manok-Manok, Boracay Island, Philippines
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The Paradise Bay Beach Resort Boracay is located direct on the beach of a picturesque, romantic, and quiet bay on the northeastern side of Boracay Island, Philippines, where an unforgettable experience awaits you. The scenery is breathtaking and the sea breeze is truly refreshing.
Paradise Bay offers a choice of luxurious rooms with approximately 35, 45, and 65 sq. m. floor area, SEA VIEW, Swimmingpool with POOL-BAR plus all the conveniences you can expect from a high standard Hotel.
Paradise Bay offers a choice of luxurious rooms with approximately 35, 45, and 65 sq. m. floor area, SEA VIEW, Swimmingpool with POOL-BAR plus all the conveniences you can expect from a high standard Hotel.
Latest Review
I think this hotel is only suitable for older singles / couples. My partner and I were looking for a quieter hotel on the other side of Boracay Island, which the hotel delivers (and with a stunning view), however everything else did not suit a those on a budget. Food was only available until 8pm and had to be 'pre ordered'; and the 'free shuttle' into town was never available/around, and so we walked the 2+km back and forth into town most days/nights. A bit inconvenient for a couple.Read More
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- Anonymous, Canada, Couple, 25-30
- 24 Hour Reception
- 24 Hour Security
- Adaptors
- Air Conditioning
- Airport Transfers
- Bar
- Book Exchange
- Breakfast Not Included
- Business centre
- Cable TV
- Café
- Ceiling Fan
- Currency Exchange
- Fax Service
- Free Parking
- Hairdryers
- Housekeeping
- Internet Access
- Key Card Access
- Laundry Facilities
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BRADENTON -- The Manatee County Commission on Thursday unanimously approved a general plan for commercial and housing development that may include an assisted living facility.
Trees Direct LLC proposed to build a mixed-use development on 85.5 acres that front Interstate 75, north of Mendoza Road near Ellenton.
While the neighboring community, Covered Bridge Estates, has reached a signed agreement with the developer to review the plans as they are developed, a smaller, adjacent community was opposed to the vagueness of the details in the proposal.
Charles Gregory, speaking for the Oak Creek Homeowners Association, said his community's concerns are with an increase in crime, insufficient roads to handle the additional traffic, lack of a buffer from highway noise and possible flooding issues.
The entrance to the proposed development would be off Mendoza Road, as an
extension of 60th Avenue East, following a drainage creek that borders the Oak Creek community.
Gregory said one con-cern was that the trees along the creek buffering 10homes in Oak Creek from the noise of I-75 would be removed.
Bill Merrill, the attorney for Trees Direct, explained the trees along the creek would probably remain in that area because the easement between the proposed entrance and the creek is not wide enough to allow for development.
But Gregory also said he was concerned with the increase in housing density and the added traffic to the narrow Mendoza Road and 60th Avenue East, which feeds traffic to the Ellenton Prime Outlet mall.
He said there are more than 1,500 housing unitsin the area now and theproposed developmentwould add as many as 500 more.
Misty Servia, the lead planner with King Engineering, which is developing the plans, said county codes require a traffic study be performed before final approval of the plans,
Several commissioners said they understood the concerns of the Oak Creek residents, but thought the plan was basically good for the area.
Commissioner Carol Whitmore said she would hope the developer would extend the same consideration to those residents it has agreed to with the homeowners of Covered Bridge Estates.
Servia also told commissioners the developer was requesting a smaller buffer zone along the interstate than what the county planners have suggested.
She said the developer would like to use construction methods and materials such as double-pane windows to mitigate the noise of the freeway.
Although commissioners got an overview of the general plans for the development, approval of the final details are left to the county planning department.


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The New York State constitution charges the District Attorney's Office with the responsibility of prosecuting all crimes in Onondaga County, however, I believe in doing far more.
Not only must we punish the guilty, but we must protect the innocent; not only must we convict an abusing spouse, but make sure all citizens can live in a safe environment; and not only must we put violent predators behind bars, but make sure our children are prepared to live productive and crime free lives.
If you have any questions or comments, please contact my office at 315.435.2470, or e-mail us at firstname.lastname@example.com .
"The office of the District Attorney is responsible for all criminal prosecutions in Onondaga County and works in conjunction with all the law enforcement organizations in the boundaries of the County to investigate any criminal felonies or misdemeanors."


text: Our new unique Sleep Sheep is a must have toy for your little one! Measuring 10" the sleep sheep will keep your baby company during naptime or playtime. Made and stuffed with 100% GOTS certified organic Egyptian cotton. Washing instructions: Machine wash only. Tumble dry until toy is completely dry. Do not immerse in water and leave out to dry. Tip* Place a bath towel in the dryer with the toy to dry faster.


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Description: Darice Funnel is great for all your crafting needs. Whether its putting embossing powder back in its jar, beads into their tube, or glitter into its container, this little tool will be a great help. Mini 1.5" Clear 2pc- 1 1/2" wide by 1 7/8" long.
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text: Welcome to the Museum of the Great PlainsWe invite you to Explore, Discover, Experience & Learn. There are always new things to do and see at the Museum of the Great Plains. Discover Lawton's history through numerous exhibits and explore the settlement of the Great Plains. Check out our fun and interactive exhibits. And, be sure to check this page frequently to stay up-to-date on all of our fun-filled events, tours, workshops, school programs and family-friendly activities. All close to home!


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(FILES) This file picture taken by North Korea's official Korean Central News Agency (KCNA) on December 12, 2012 shows North Korean rocket Unha-3, carrying the satellite Kwangmyongsong-3, lifting off from the launching pad in Cholsan county, North Pyongan province in North Korea. North Korea said on January 24, 2013 it planned to carry out a third nuclear test and more rocket launches aimed at its "arch-enemy" the United States in response to tightened UN sanctions, but offered no timeframe. AFP PHOTO / KCNA vis KNS / FILES
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Home > Professional Resources > Publications > Trial > March 2011 > Update - March 2011
Stand out from the crowd! Advertise in Trial to reach a national audience of major decision-makers who are looking for products and services to improve their legal practices.
Ruling 8-0, the justices held that the federal Motor Vehicle Safety Act does not block state law tort suits over defective seat belts. In an amicus brief, AAJ "argued that state tort remedies complement, rather than conflict with, federal safety regulation and urged the Court to rein in the overly expansive use of 'obstacle' preemption to deny tort victims their day in court," said AAJ President Gibson Vance.


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How-To Geek
The Legend of Digital Zelda [Video]
This clever animation project combines a real-world set, a great soundtrack, and a novel approach to showcasing the adventure Link goes through to rescue Zelda.
Got Feedback? Join the discussion at discuss.howtogeek.com
Comments (4)
a̶p̶p̶l̶e̶ Zelda the c̶o̶m̶m̶e̶r̶c̶i̶a̶l̶ animation!
That was great!
@san looks more like yet another school that doesn't know how to spend the tax dollars they get efficiently and blows it on over priced items
@Cody But if students don't have the latest and greatest Apple products, how can they possibly be expected to learn anything? I can rest easy knowing that my tax dollars are being wisely invested, in large amounts, in the indoctrination (I mean education) of our youth.


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"When people talk about awful trades, the conversation always turns to A.J. Pierzynski for Francisco Liriano/Joe Nathan, or Bartolo Colon for Grady Sizemore/Cliff Lee/Brandon Phillips. But Cabrera was acquired from the Mariners for the last 43 games of Eduardo Perez's career. When the Mariners gave Cabrera up, they were 41-40 -- only two games out of first place, but hardly a juggernaut. Perez came over to DH, but the Mariners felt like he needed a platoon partner. So they did what most of us would have done, which was give up Shin-Soo Choo for Ben Broussard. Once Mariners fans take enough prescription drugs, they can convince themselves that the Indians really are the 2011 Mariners, and then they don't mind so much"
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And he is 6 feet under. Seriously, if the bet is to "drink a quart of female antelope urine" OR view "Screw My Wife Please #14", opt for the antelope urine. Only Mrs. Jacob is kind of, sort of, somewhat attractive. And even she looks 40+. The Old Man Narrator gets "horn jobbed" by about every girl in the movie which takes away from the realism of this staged series. Also, the acting is sub-par compared with other movies in the series. In fact the actors barely make an effort to sell you on them being a real couple. Rent #41 or #49 in the series if you want more realism with some prettier girls. Many scenes are shot outdoors in #14 and at times it washes out the actors. I was unable to use this film to "pet the penguin" -- enough said.
Plenty of hammering goes on but nothing all that spectacular. The 2nd scene is much better than the 1st. The 1st is loaded with a bunch of nasty asses. Most of the girls had too much of a road whore/stripper look, more testosterone than the men and weren't even good looking. It just didn't fire me up. Lena Julliett has a tight ass and looks great riding tool. She even takes it in the corn while riding. Scene one opens with a lezbo orgy that lasts for ten plus minutes. One Asian girl (looks Filipino) has a few extra pounds but at least comes off a little more natural in the sex and lets the actor do the work. She takes it up the ass but visually it isn't great since her skin is all stretched out and far from aesthetically pleasing to the eye. She looked nice blowing horn. Jazmin is a pretty girl and looks hot doing doggie. A white girl with a nice ass does a MMF doggie sequence that is pretty hot. Eventually I tuned out on scene one though because there were simply too many loose unattractive labia flapping in the wind. Scene 2 had a cheerleader theme and three winners: Destiny, Asia and Kammy. This scene had much more MMF and FFM out of the gate. Asia acts like a Hood Rat which didn't sell but at least she had energy. Unfortunately, she was a broken record with her nasty talk. She looked terrific taking a Clydesdale penis and sucking on it. quite a contrast given her tiny frame. At one point she shows her contortionist abilities. They should've utilized this more in a variety of positions. I dated a Chinese contortionist briefly and it brought back some excellent memories. Destiny (Indian) is neglected for the most part and no doggie included. Lucia is a thick Brazilian girl but too thick for my tastes. Kammy is the winning performer participating in some serious "butt fondue" in a MMMF segment. You should have no problem doing the "Tool Tango" to this DVD even though it is nothing to write home about.
There are some pretty girls and I was excited to see a Korean in one of these interracial films. Typically we see happa (half Asian), Filipino or Thai girls. Unfortunately, Karen's body appeared to contain a few Krispy Kreme's too many for my taste. The creamy white skin was nice but I couldn't get past the thunder thighs and flat butt. I'll admit the camera work didn't provide her with much of an assist. Keelani has a great ass (minus the distracting low back tat) and looked hot getting her corn buttered by Mr. Marcus. He really hammers away which she seems to be fairly into. I do wish her noise making were a little more genuine during vaginal sex…but at least the "backdoor bingo" brought out the authenticity in her vocal stylings. Carla was the hottest girl with great close-up doggie action of her sweet posterior. Her pretty face looked nice as it was being decorated but you could clearly tell she was "not a fan". The Nautica/Katsumi (both girls look happa) sausage tag-team was just "ok". The spray-down was unleashed on Katsumi's toes and Nautica lapped it up like a kitten would milk (ok, not that much enthusiasm was involved). Lisa looked good getting whaled on while wearing her tall whore boots. They skip doggie which was disappointing since her ass looked nice during cowgirl. More positions here would've increased the heat. Gissle (I guess we know what she likes about sex) looks Thai (possibly Vietnamese) and is barely affected by the sex with a large weapon. Her name is semi-confirmed as her handiwork during oral is impressive. She had too many skin blemishes on her body for me so I moved on. All in all, several good looking girls but this just isn't all that special with moderate heat at best.
The director has some great ideas and there are some great camera angles but most aren't held for more than 15 seconds. I'm not sure why directors forget that this is a "peeling the onion" movie. SARINA – as usual, face not as pretty as it looks on the box cover. Weird paper clip looking clip-on piercing is on her clit (it was placed on in the "bonus scene"). Lots of puss licking, corn licking and dildo/vibrator/bullet play. The vibrator in the foxhole while smoking horn was a nice concept but not executed that well…barely fired her up. Nice horn-blow cam angles; great side 45 degree angle shots with her on her knees; too much underneath doggie-style shots. MARI – excessive oral/dildo play; nice subjective view doggie-style shot; ass is a touch flat but overall it is nice. YUKA – orange hair color is not hot; skinny body with medium-sized ass; condom on but it is pink so you nearly forget about it; twenty seconds of dragon position…what were you thinking?; lots of nice doggie-style at the end…if only she didn't have ass bruises this would've been really good. The best thing about this is most Japanese girls only shag Japanese guys on film. This one features whitey actors.
The premise of this movie is ri-coc-u-lous in that the girls cluck like chickens upon command. CHANEL CHAVEZ – She has looked better and the braids weren't as hot as I'd anticipated. A hung black actor corns her with spit as lube. This would be as good as it gets. The camera angles mostly blew doors. There was some brief "wheel barrel" action, lying on side and doggie-style (with way too much underneath camera work). There were no high angle shots, subjective view or panning shots around that nice body. ASIA – When this girl opens her mouth it sniffs like a $2.00 road whore with an elementary school education. What a turn-off! Her body is decent excluding the Papermate project illustrated on her backside. This MMMF scene concludes with the actors painting her eyes, face and hair. Her eyes were pelted with enough saltwater surprise to drown a cat. She was clearly not a fan and the crew and actors made it worse by taking their time in getting her what she requested. Finally one guy pours bottled water over her face which only slightly improved her disposition. RANDI WRIGHT – This girl has some hideous ink and isn't very attractive but her body looks pretty splendid when they bend her over the couch in a doggie-style horn-blow segment. There is a hot high-angle shot and even the medium shot is nice. DILLAN – This girl is fairly attractive but the sex just didn't fire me up. The oral was standard and the positions and camera work were mediocre. Unfortunately, this overall effort is simply typical blasé porn.
JASMINE – Sweet pea looks a lot prettier on the box cover than she is on screen. I know, typical. Regardless, her body is pudgy and she has an unappealing skin complexion on the bod. The best thing about her is the face. She has stretch marks on the ass as well. The sex is decent but there are way too many close-ups and poorly selected camera angles. She sounds Indian (dots not feathers) as best I can tell or recall. ASIA – "same ol, same ol" for this girl. HEATHER HUNT – Her face is pretty and the body is even better. I didn't like her rack of lamb or fur patch tat but those legs, skin and ass are outstanding. This girl is seriously "long". The doggie-style could've been way better had there been panning side shots, high-angle or dragon position (flat on stomach). She seemed to have to fake enthusiasm given the average-sized "lumber" she was provided. Regardless of the tool size it looks like a snug fit in her foxhole. That is a refreshing thing in porn. Again, the shape of this girl's ass is something that won't soon be forgotten. A small low back tat is only a mild distraction given the camera angles. I wasn't sure whether I should be disgusted or turned on by all the drawn out cornhole creampies. One girl had a nasty looking corn and I thought my dinner might soon be "painting the wall by number".
The directing style is very nice and the POV camera angles are excellent. The only girl worth two squirts is Heidi Ho. Her face isn't going to win any beauty pageants but the body sure will. She is long and thin with a tight little butt. Watching Mr. Marcus go the "corn-route" on her was hot. She wasn't a big fan initially and they ended up having the smaller actors go there first. She makes some pretty nice noise (seemingly authentic) and the sex scenes are good and long. I concur that there is no way this little girl was climbing stairs for a few days. Rent it for Heidi, pocket-veto the others.
There may be one small foxhole but it never takes a cock so who really knows or cares. Several of the girls either self-masturbate or blow horn only. This is total "weak sauce"…literally and figuratively. JADE – this is an overly tan Jade Marcela with tats now added; yuck, she has looked better. RAINY – thin body; light brown hair; fair skin (common throughout movie); self-masturbation only…boring. NIKKI – thick body; looks Filpo; fair skin; no thank you; of course she takes a pole. KARIZMA – face decent; nice thin body with decent ass; horn-blow facial decent but no penetration = lame; self-masturbation; nice real C- titty size; no tats (mostly common in this movie); best looking girl in the movie. CHAINA – terrible actress; over-acting to the point of annoyance; face not cute; body mediocre and thick; 69 sex; actor so hairy with hairy corn exposed couldn't hang; extreme close-up of her spraying a river into the toilet…nasty ass. This is some weak ass bullshard with no big dongs or hot tail. NEXT!
CORA – I normally prefer the exotic look but this girl is too pretty to ignore. She has a long thin body with white blonde hair. It was one of the few times I could "almost" forget about a tramp stamp. The "horn fest" with the five guys is pretty good. It gets a lot better when she has all holes filled in the cowgirl position. That ass is well shaped and looks great getting corned. She is a pretty good multi-tasker but she is often distracted from "smoking the pony". You don't often find girls this pretty in porn so enjoy my friends. ASIA – This girl doesn't work for me but I managed to fast forward through some of the scene. The best part is her "horn jobbing" some meaty tools. She is too professional during the sex for it to get me going. MARTINA – Nawe kid! Next!
There are some hilarious ginormous lameo tats on the "brawn shot crew" actors. It was amazing to see a xxx movie with more tats on the dudes than the ladies. The actors dished out some large tool on these ladies but they handled it like pros…unfortunately. There were some flattering doggie style shots (medium shots and high-angle shots). ANN – her body is okay her face is cute. DAISY – this was shot in 2003 and I never recall her having so many tats even in newer movies. ANDER – bad teeth; nice ass; has too much of a white-t look to fire me up. BOO – cute face; really nice body and a good ass. Had this not been full of pros and a tat convention of male actors it might have been better. Next!


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Updated Thursday, October 23rd, 2008
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Total Time: 30
Yield: 2 cups
Giblets are the turkey's neck, heart, gizzard, and liver, which are usually found tucked, like a prize, inside the cavity. Be sure to remove before brining and certainly before roasting. Giblets make a terrific gravy, but I don't include the liver, as it adds a bitter flavor, so save it in the freezer for another use.
In a medium saucepan, combine giblets, stock, and vegetables. Bring to a boil, then lower to a simmer and cook until reduced by half. Strain and discard solids. In a small bowl, whisk together flour and 4 tablespoons hot broth. Then slowly whisk mixture back into the main portion of hot broth and cook about 5 minutes. Season to taste with salt and pepper.
In this issue: Summer Off the Beaten Path
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Girls' Names
A Public Board frequented by parents searching for the perfect girl's name and by posters with naming expertise, interests and strong opinions that want to help. Sometimes these groups overlap. If you want honest opinions on names, naming, trends and long-lost monikers, this is the place for you. We are diverse in naming styles, favorite names, and naming pet peeves, but we're usually a fiery bunch, so if you can't stand the heat, as the saying goes . . . please keep comments about names and recognize that opinions on names do not extend to opinions on children who answer to them less
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Attention future Black Ops 2 players...firefighter03 Nov 8, 2012 10:19 AM
I dont usually post on here. However, I've finally got to the point that enough is enough and it's time to call some of you out. If this post offends a lot of you then YOU are probably "That Guy"!
With the new score system of Black Ops 2, in objective based games (Domination, S&D, etc..), you will no longer benefit from sitting back and playing for yourself. That's right you selfish, greedy players! You will actually have to do something in order to be rewarded! In MW3, more times than not, I outscore the entire lobby during a match and most of the time come close to doubling the score of the second place guy on my team and yet we still end up losing the match. Isn't that AMAZING? It's really the way of the democrat. You lazy people want someone else to do do all the work for you while you sit back and do nothing but try to reap the rewards. Well, here is a news flash: I will no longer be your "flag" *****. You greedy little people are going to have to pull your own weight because I will no longer do it for you. I am so glad that the COD series has finally evolved into rewarding the real players. Now I would assume that most of you know how to play Domination but apparently some of you need a refresher. It's really simple...wait for it...: Your team has to control 2 of 3 flags for the majority of the time alloted! That's it! No really, that's it! It's not rocket science. Well for some of you idiots, it may be. Anyway, here are some tips for winning and scoring high in Domination.
1: At the beginning, only 1 guy should be capping the A or C flag. It doesn't take the whole group! Every other guy should be running towards the B flag. Remember boys and girls, that's how you win the match. An orangutan could easily understand this concept but somehow most of you still don't get it.
2: Here is another bright concept: If you lose one of the flags, then the next thing you should be trying to do is go recap it. Time and time again I see my team lose a flag and then, strangely, I am the only one trying to recap it. All the while, 2 other of my so called idiot teammates are sitting back in a corner shooting the tires on a truck. You get a ton of experience for that...not.
Now I know that most of you are wondering why there aren't more tips but if you understand the concept of Domination then you really don't need anymore than that. If you are confused, then start back at the top and read again. If you want to sit back and play for yourself, then go play Team Deathmatch or Free-For-All. Stay out of objective based lobbies unless you are going to play the objective. If you are playing in an objective based lobby, then grow a set and help out your team. Thanks!


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Next For Texas: Texas Tech
Connor Lammert could benefit the most from Jonathan Holmes having to miss three to six weeks with a broken hand.
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It's officially official.
Palestine interim City Manager Wendy Ellis accepted the official position after a lengthy executive session held during the second monthly city council meeting on Monday.
Ellis has been acting city manager since June, when former City Manager Mike Ohrt resigned to take a similar position with another city.
"I greatly appreciate the opportunity," Ellis said Tuesday. "I want to continue doing what we've been doing -- making good things happen for Palestine. I want to continue working with the city council, all the city departments, Main Street, the EDC and everyone else to keep us moving forward, in a positive direction."
Ellis was the Palestine Economic Development Corporation director before accepting the city manager's position. City officials said the search for a new PEDC director will begin soon.
"I think Wendy will make an excellent city manager," PEDC Assistant Director Greg Laudadio said Tuesday. "I've worked with her for the last three years. She's got excellent leadership skills and I think she'll be great for the city."
In other business, the Palestine City Council approved purchasing a used artificial ice skating rink from IceRinks2Go.
"It should be here just in time for Christmas," City Secretary Terese Herrera said. "We'll have it open through the month of December."
Also on Monday, the council:
• APPROVED a bid for HVAC equipment for the mall; and
• APPROVED renaming PC 6078 to Sanderson Farms Parkway.


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Honister Slate Mine boss Jan vows to fight zip wire snub
Last updated at 14:35, Friday, 11 January 2013
Honister Slate Mine is set to appeal after controversially being denied permission to build a zip wire at the site.
The Lake District National Park Authority's planning board on Wednesday went against the advice of planning experts and voted seven to four against the development.
The decision followed a three-hour discussion - the longest in the committee's history - and came despite nearly 400 letters of support.
Among the speakers at the meeting was a representative of the Friends of the Lake District, which opposed the plans.
But the group's vice president, Caldbeck mountaineer Sir Chris Bonington, spoke in favour.
He later resigned from the group because of its handling of the plans.
After the decision, Jan Wilkinson, owner of the slate mine, said: "There are two options - to appeal or to shut the doors. There are 26 people who need their wages every Friday. I'm not going to do that to them."
Jan, who has run the mine since the death of her partner Mark Weir nearly two years ago, said last month that the zip wire was needed to keep the tourist attraction fresh and give people a reason to keep visiting.
Slate mining is expensive and she said tourism was needed to support it.
The zip wire would have been used by people who had completed the mine's Via Ferrata climbing attraction.
It would have taken them from Honister Crags to the car park.
In September 2011 the authority rejected the slate mine's initial plan for a zip wire.
Following that decision, the company worked with planners to amend the plans.
The start point was moved from the horizon, the length reduced and the proposed zip wire made quieter.
Under the fresh plans, the mine wanted to put up the zip wire for a temporary period of 18 months.
During that time an independent study would have been done by the University of Cumbria to assess its impact on visitors to the area.
After that, a decision would have been taken by the national park authority to extend the permission or order its removal.
But the planning board threw out the plans, concerned about the effect the development would have on the landscape.
Jack Ellerby, policy officer for Friends of the Lake District, said there was no justification for eroding the wild and tranquil area of Borrowdale.
He added: "The Alps cannot compete with what the Lake District has to offer, so let's keep it that way."
Sir Chris said after the meeting that the Friends of the Lake District did some good work "but they've got this one terribly wrong".
Ms Wilkinson said she planned to lodge an appeal as soon as she received the decision paperwork.
She added that, if the appeal was won, the mine would have to install the zip wire in time for the start of the 2014 tourist season, a year later than planned.
The zip wire must be up for two summers to be viable as a temporary venture.
She said: "We were totally willing after 18 months to say if it wasn't working we'd walk away.
"We haven't been given that option and it's incredulous in my opinion.
"It beggars belief that they'd go against the officers who have recommended it for approval.
"There's nothing more that I can do than work with the authorities.
"All I have got now is hope.
"People have said 'is it just Mark's dream, is that what pushes you on?' There is an element of that but it's because I have seen people come up here in all weathers to the Via Ferrata. It makes them question what they're capabilities are. I see that positive effect on people."
First published at 14:34, Friday, 11 January 2013
Published by http://www.timesandstar.co.uk
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The Zip Wire would have been a fitting memorial to Neil who put so much into the Old Slate Mine, and yes in order to keep it going it needs Finance and the prifit from the proposed wire would have brought that in, but I think Dave and the so caleed Friends of the Lakes should remember the national Park belongs to us all, so next time do the right thing and get this passed, then let the Mine move on. posted by Alex Craig 17 th. January.
Yet again our beloved planning committee fail to see the true potential that such an initiative will deliver - boost for tourism and jobs for locals. I accept we need to protect the great environment in which we live, but this will cause far less harm than the thousands of walkers, the thousands of sheep and all the others who we let enjoy this great place. Wake up LDNP committee, and have the guts to make a balanced decision to allow this application. For the team at Honnister Mine do not lose faith and battle on - good will win in the end I hope.
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Located on the southside of the Tramontana Mountains only 30 min. away from Palma, the CCA Andratx is dedicated to the creation and exhibition of contemporary art. To the general public it offers a unique cultural experience, whereas the studio program is open to national and international artists.
The CCA Andratx was founded in 2001 by Jacob and Patricia Asbaek. The 4.000 m2 building with a minimal but traditional style is perfectly integrated in the breathtaking natural scenery of its surroundings and is one of the largest centres of contemporary art in the Balearic Islands as well as in the rest of Europe.
Visitors, collectors and artists are invited to spend a day exploring art and nature and enjoying the many facilities of the CCA Andratx.