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Nonresponders
Terms modified by Nonresponders Selected AbstractsInduction or expansion of T-cell responses by a hepatitis B DNA vaccine administered to chronic HBV carriersHEPATOLOGY, Issue 4 2004Maryline Mancini-Bourgine Despite the availability of effective hepatitis B vaccines for many years, over 370 million people remain persistently infected with hepatitis B virus (HBV). Viral persistence is thought to be related to poor HBV-specific T-cell responses. A phase I clinical trial was performed in chronic HBV carriers to investigate whether HBV DNA vaccination could restore T-cell responsiveness. Ten patients with chronic active hepatitis B nonresponder to approved treatments for HBV infection were given 4 intramuscular injections of 1 mg of a DNA vaccine encoding HBV envelope proteins. HBV-specific T-cell responses were assessed by proliferation, ELISpot assays, and tetramer staining. Secondary end points included safety and the monitoring of HBV viraemia and serological markers. Proliferative responses to hepatitis B surface antigen were detected in two patients after DNA injections. Few HBV-specific interferon ,,secreting T cells were detectable before immunization, but the frequency of such responses was significantly increased by 3 DNA injections. Immunization was well tolerated. Serum HBV DNA levels decreased in 5 patients after 3 vaccine injections, and complete clearance was observed in 1 patient. In conclusion, this study provides evidence that HBV DNA vaccination is safe and immunologically effective. We demonstrate that DNA vaccination can specifically but transiently activate T-cell responses in some chronic HBV carriers who do not respond to current antiviral therapies. Supplementary material for this article can be found on the HEPATOLOGYwebsite (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2004;40:874,882.) [source] Refined analysis of genetic variability parameters in hepatitis C virus and the ability to predict antiviral treatment responseJOURNAL OF VIRAL HEPATITIS, Issue 8 2008J. M. Cuevas Summary., Hepatitis C virus (HCV) infects approximately 3% of the world population. The chronicity of hepatitis C seems to depend on the level of genetic variability. We have recently (Torres-Puente et al., J Viral Hepat, 2008; 15: 188) reported genetic variability estimates from a large-scale sequence analysis of 67 patients infected with HCV subtypes 1a (23 patients) and 1b (44 patients) and related them to response, or lack of, to alpha-interferon plus ribavirin treatment.. Two HCV genome regions were analysed in samples prior to antiviral therapy, one compressing the three hypervariable regions of the E2 glycoprotein and another one including the interferon sensitive determining region and the V3 domain of the NS5A protein. Haplotype and nucleotide diversity measures showed a clear tendency to higher genetic variability levels in nonresponder than in responder patients. Here, we have refined the analysis of genetic variability (haplotype and nucleotide diversity, number of haplotypes and mutations) by considering their distribution in each of the biologically meaningful subregions mentioned above, as well as in their surrounding and intervening regions. Variability levels are very heterogeneous among the different subregions, being higher for nonresponder patients. Interestingly, significant differences were detected in the biologically relevant regions, but also in the surrounding regions, suggesting that the level of variability of the whole HCV genome, rather than exclusively that from the hypervariable regions, is the main indicator of the treatment response. Finally, the number of haplotypes and mutations seem to be better discriminators than haplotype and nucleotide diversity, especially in the NS5A region. [source] Brain Natriuretic Peptide Levels and Response to Cardiac Resynchronization Therapy in Heart Failure PatientsCONGESTIVE HEART FAILURE, Issue 5 2006Reynolds M. Delgado MD The authors used brain natriuretic peptide (BNP) as a reliable marker to identify nonresponders to cardiac resynchronization therapy (CRT) in patients with advanced heart failure. The study included 70 patients with left ventricular dysfunction (mean ejection fraction, 21±4%) and left bundle branch block (QRS duration, 164±25 milliseconds) treated with CRT. The authors reviewed data on New York Heart Association functional class, baseline ejection fraction, sodium, creatinine, QRS duration, and BNP levels 3 months before and after CRT therapy. The authors compared results of 42 patients who survived (973+192 days) after CRT implantation (responders) to those of 28 patients (nonresponders) who either expired (n=21) or underwent heart transplantation (n=5) or left ventricular assist device implantation (n=2) after an average of 371+220 days. Mean BNP levels after 3 months of CRT decreased in responders from 758±611 pg/mLto 479±451 pg/mL (P=.044), while in nonresponders there was increase in BNP levels from 1191 ±466 pg/mL to 1611 ±1583; P=.046. A rise in BNP levels was associated with poor response (death or need for transplantation or left ventricular assist device and impaired long-term outcome), which makes it a good predictor to identify such patients. [source] Contractile Reserve Assessed Using Dobutamine Echocardiography Predicts Left Ventricular Reverse Remodeling after Cardiac Resynchronization Therapy: Prospective Validation in Patients with Left Ventricular DyssynchronyECHOCARDIOGRAPHY, Issue 6 2010F.R.C.P.C., Mario Sénéchal M.D. Background: The presence of viable myocardium may predict response to cardiac resynchronization therapy (CRT). The aim of this study is to evaluate in patients with left ventricular (LV) dyssynchrony whether response to CRT is related to myocardial viability in the region of the pacing lead. Methods: Forty-nine consecutive patients with advanced heart failure, LV ejection fraction < 35%, QRS duration > 120 ms and intraventricular asynchronism , 50 ms were included. Dobutamine stress echocardiography was performed within the week before CRT implantation. Resting echocardiography was performed 6 months after CRT implantation. Viability in the region of LV pacing lead was defined as the presence of viability in two contiguous segments. Response to CRT was defined by evidence of reverse LV remodeling (,15% reduction in LV end-systolic volume). Results: Thirty-one patients (63%) were identified as responders at follow-up. The average of viable segments was 5.9 ± 2 in responders and 3.2 ± 3 in nonresponders (P = 0.0003). Viability in the region of the pacing lead had a sensitivity of 94%, a specificity of 67%, a positive predictive value of 83%, and a negative predictive value of 86% for the prediction of response to CRT. Conclusions: In patients with LV dyssynchrony, reverse remodeling after CRT requires viability in the region of the pacing lead. This simple method using echocardiography dobutamine for the evaluation of local viability (i.e., viability in two contiguous segments) may be useful to the clinician in choosing the best LV lead positioning. (Echocardiography 2010;27:668-676) [source] Usefulness and Limitation of Dobutamine Stress Echocardiography to Predict Acute Response to Cardiac Resynchronization TherapyECHOCARDIOGRAPHY, Issue 1 2010F.R.C.P.C., Mario Sénéchal M.D. Background: It has been hypothesized that a long-term response to cardiac resynchronization therapy (CRT) could correlate with myocardial viability in patients with left ventricular (LV) dysfunction. Contractile reserve and viability in the region of the pacing lead have not been investigated in regard to acute response after CRT. Methods: Fifty-one consecutive patients with advanced heart failure, LV ejection fraction , 35%, QRS duration > 120 ms, and intraventricular asynchronism , 50 ms were prospectively included. The week before CRT implantation, the presence of viability was evaluated using dobutamine stress echocardiography. Acute responders were defined as a ,15% increase in LV stroke volume. Results: The average of viable segments was 5.8 ± 1.9 in responders and 3.9 ± 3 in nonresponders (P = 0.03). Viability in the region of the pacing lead had an excellent sensitivity (96%), but a low specificity (56%) to predict acute response to CRT. Mitral regurgitation (MR) was reduced in 21 patients (84%) with acute response. The presence of MR was a poor predictor of response (sensibility 93% and specificity 17%). However, combining the presence of MR and viability in the region of the pacing lead yields a sensibility (89%) and a specificity (70%) to predict acute response to CRT. Conclusion: Myocardial viability is an important factor influencing acute hemodynamic response to CRT. In acute responders, significant MR reduction is frequent. The combined presence of MR and viability in the region of the pacing lead predicts acute response to CRT with the best accuracy. (Echocardiography 2010;27:50-57) [source] Worsening of Left Ventricular End-Systolic Volume and Mitral Regurgitation without Increase in Left Ventricular Dyssynchrony on Acute Interruption of Cardiac Resynchronization TherapyECHOCARDIOGRAPHY, Issue 7 2009Suman S. Kuppahally M.D. Background: Responders to cardiac resynchronization therapy (CRT) have greater left ventricular (LV) dyssynchrony than nonresponders prior to CRT. Aim: We conducted this study to see whether the long term responders have more worsening of LV dyssynchrony and LV function on acute interruption of CRT. Materials and Methods: We identified 22 responders and 13 nonresponders who received CRT as per standard criteria for 23.73 ± 7.9 months (median 24.5 months). We assessed the acute change in LV function, mitral regurgitation (MR) and compared LV dyssynchrony in CRT on and off modes. Results: On turning off CRT, there was no significant worsening of LV dyssynchrony in both responders and nonresponders. The dyssynchrony measurements by SPWMD, TDI and 3D echocardiography did not correlate significantly. LVESV increased (p = 0.02) and MR (p = 0.01) worsened in CRT-off mode in responders only without significant change in LVEF or LV dimensions. Discussion and Conclusion: In long-term responders to CRT, there is alteration in the function of remodeled LV with acute interruption of CRT, without significant worsening of LV dyssynchrony. The role of different echocardiographic parameters in the assessment of LV dyssynchrony remains controversial. Even after long-term CRT reversely remodels the LV, the therapy needs to be continued uninterrupted for sustained benefits. [source] High seizure frequency prior to antiepileptic treatment is a predictor of pharmacoresistant epilepsy in a rat model of temporal lobe epilepsyEPILEPSIA, Issue 1 2010Wolfgang Löscher Summary Purpose:, Progress in the management of patients with medically intractable epilepsy is impeded because we do not fully understand why pharmacoresistance happens and how it can be predicted. The presence of multiple seizures prior to medical treatment has been suggested as a potential predictor of poor outcome. In the present study, we used an animal model of temporal lobe epilepsy to investigate whether pharmacoresistant rats differ in seizure frequency from pharmacoresponsive animals. Methods:, Epilepsy with spontaneous recurrent seizures (SRS) was induced by status epilepticus. Frequency of SRS was determined by video/EEG (electroencephalography) monitoring in a total of 33 epileptic rats before onset of treatment with phenobarbital (PB). Results:, Thirteen (39%) rats did not respond to treatment with PB. Before treatment with PB, average seizure frequency in PB nonresponders was significantly higher than seizure frequency in responders, which, however, was due to six nonresponders that exhibited > 3 seizures per day. Such high seizure frequency was not observed in responders, demonstrating that high seizure frequency predicts pharmacoresistance in this model, but does not occur in all nonresponders. Discussion:, The data from this study are in line with clinical experience that the frequency of seizures in the early phase of epilepsy is a dominant risk factor that predicts refractoriness. However, resistance to treatment also occurred in rats that did not differ in seizure frequency from responders, indicating that disease severity alone is not sufficient to explain antiepileptic drug (AED) resistance. These data provide further evidence that epilepsy models are useful in the search for predictors and mechanisms of pharmacoresistance. [source] Predictors of pharmacoresistant epilepsy: Pharmacoresistant rats differ from pharmacoresponsive rats in behavioral and cognitive abnormalities associated with experimentally induced epilepsyEPILEPSIA, Issue 10 2008Alexandra M. Gastens Summary Purpose:, Patients with intractable temporal lobe epilepsy (TLE) exhibit an increased risk of psychiatric comorbidity, including depression, anxiety, psychosis, and learning disorders. Furthermore, a history of psychiatric comorbidity has been suggested as a predictor of lack of response to therapy with antiepileptic drugs (AEDs) in patients with epilepsy. However, clinical studies on predictors of pharmacoresistant epilepsy are affected by several confounding variables, which may complicate conclusions. In the present study, we evaluated whether behavioral alterations in epileptic rats are different in AED nonresponders versus responders. Methods:, For this purpose, we used an animal model of TLE in which AED responders and nonresponders can be selected by prolonged treatment of epileptic rats with phenobarbital (PB). Behavioral and cognitive abnormalities were compared between responders and nonresponders as well as between epileptic rats and nonepileptic controls in a battery of tests. Results:, Fifteen epileptic rats with spontaneous recurrent seizures (SRS) either responding (11 rats) or not responding (4 rats) to PB were used for this study. The nonresponders differed markedly in behavioral and cognitive abnormalities from responders and nonepileptic controls in tests of anxiety (open field, elevated-plus maze test), behavioral hyperexcitability (approach-response, touch-response, pick-up tests), and learning and memory (Morris water maze). Discussion:, Our hypothesis that AED-resistant rats will show more severe behavioral and cognitive changes than AED-responsive rats was confirmed by the present experiments. The data substantiate that rodent models of TLE are useful to delineate predictors of pharmacoresistant epilepsy. [source] Anticonvulsant Efficacy of Topiramate in Phenytoin-Resistant Kindled RatsEPILEPSIA, Issue 4 2000Elke Reissmüller Summary: Purpose: We evaluated the anticonvulsant efficacy of topiramate (TPM), a structurally novel antiepileptic drug (AED), in amygdala kindled rats that had been preselected with respect to their response to phenytoin (PHT). Methods: Anticonvulsant response was tested by determining the afterdischarge threshold (ADT;i.e., a sensitive measure for drug effects on focal seizure activity). By repeated testing with the PHT prodrug fosphenytoin (FOS) three groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (PHT responders), rats that showed no anticonvulsant response (PHT nonresponders), and rats with variable responses (variable PHT responders). The latter, largest group was used to evaluate at which doses and pretreatment times TPM exerted significant anticonvulsant effects on ADT. For this purpose, TPM was tested at four doses (20, 40, 80, 160 mg/kg i.p.) and two pretreatment times (1 and 4 h). The most effective treatment protocol was then used for TPM testing in PHT responders and nonresponders. Results: TPM proved to be an effective AED in the kindling model. At 40 mg/kg, significant ADT increases were obtained after both 1 and 4 h after administration. In addition to the effect on focal seizure threshold, seizure severity and duration recorded at ADT were decreased by TPM, indicating that this drug acts on both seizure threshold and seizure spread. In PHT nonresponders, TPM significantly increased ADT, which is in line with its proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, TPM was more efficacious in increasing ADT in PHT responders than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. Repeated testing of kindled rats with TPM indicated that, similar to PHT, there are individual kindled rats without anticonvulsant response to TPM (i.e., TPM nonresponders). Conclusions: The data of this study substantiate that PHT nonresponders are a unique model for the search of new AEDs with improved efficacy in refractory partial epilepsy. [source] Eradication of Helicobacter pylori increases platelet count in patients with idiopathic thrombocytopenic purpura in JapanEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2005T. Inaba Abstract Background, The effect of Helicobacter pylori eradication on the platelet count in patients with thrombocytopenic purpura is controversial. In this multicentre study, we prospectively assessed the effect of H. pylori eradication therapy in idiopathic thrombocytopenic purpura patients. Materials and methods, Thirty-five consecutive patients with chronic idiopathic thrombocytopenic purpura (11 males and 24 females, a median age of 57) were assessed for H. pylori infection by use of a urea breath test. All patients received 1-week triple therapy (amoxicillin, clarithromycin, and lansoprazole) to eradicate H. pylori. At 6 months, idiopathic thrombocytopenic purpura patients with a platelet count recovery of greater than 100 × 109 L,1 were defined as idiopathic thrombocytopenic purpura responders. Results,Helicobacter pylori infection was observed in 25 (71%) of the 35 patients. All infected patients were cured. Eleven patients were identified as idiopathic thrombocytopenic purpura responders; 24 were considered nonresponders. Platelet counts improved by more than 100 × 109 L,1 in 11 (44%) of the 25 patients cured of H. pylori infection, while none of the 10 patients H. pylori -negative patients experienced the same improvement (P = 0·015). Univariate analysis showed that H. pylori infection and its eradication were significant factors associated with platelet recovery (P = 0·015). Conclusions,Helicobacter pylori infection played a role in the pathogenesis of idiopathic thrombocytopenic purpura in approximately 30% of all patients assessed and 45% of the patients with H. pylori infection. Eradication of H. pylori in idiopathic thrombocytopenic purpura patients led to improved disease activity. [source] BDNF variability in opioid addicts and response to methadone treatment: preliminary findingsGENES, BRAIN AND BEHAVIOR, Issue 5 2008R. De Cid Brain-derived neurotrophic factor (BDNF) signaling pathways have been shown to be essential for opioid-induced plasticity. We conducted an exploratory study to evaluate BDNF variability in opioid addict responders and nonresponders to methadone maintenance treatment (MMT). We analyzed 21 single nucleotide polymorphisms (SNPs) across the BDNF genomic region. Responders and nonresponders were classified by means of illicit opioid consumption detected in random urinalysis. Patients were assessed by a structured interview (Psychiatric Research Interview for Substance and Mental Disorders (PRISM)-DSM-IV) and personality was evaluated by the Cloninger's Temperament and Character Inventory. No clinical, environmental and treatment characteristics were different between the groups, except for the Cooperativeness dimension (P < 0.001). Haplotype block analysis showed a low-frequency (2.7%) haplotype (13 SNPs) in block 1, which was more frequent in the nonresponder group than in the responder group (4/42 vs. 1/135; Pcorrected = 0.023). Fine mapping in block 1 allows us to identify a haplotype subset formed by only six SNPs (rs7127507, rs1967554, rs11030118, rs988748, rs2030324 and rs11030119) associated with differential response to MMT (global P sim = 0.011). Carriers of the CCGCCG haplotype had an increased risk of poorer response, even after adjusting for Cooperativeness score (OR = 20.25 95% CI 1.46,280.50, P = 0.025). These preliminary results might suggest the involvement of BDNF as a factor to be taken into account in the response to MMT independently of personality traits, environmental cues, methadone dosage and psychiatric comorbidity. [source] A Community-Based Study of Helicobacter pylori Therapy Using the Strategy of Test, Treat, Retest, and Re-treat Initial Treatment FailuresHELICOBACTER, Issue 5 2006Yi-Chia Lee Abstract Background:, Although eradication of Helicobacter pylori infection can decrease the risk of gastric cancer, the optimal regimen for treating the general population remains unclear. We report the eradication rate (intention-to-treat and per protocol) of a community-based H. pylori therapy using the strategy of test, treat, retest, and re-treat initial treatment failures. Materials and methods:, In 2004, a total of 2658 residents were recruited for 13C-urea breath testing. Participants with positive results for infection received a standard 7-day triple therapy (esomeprazole 40 mg once daily, amoxicillin 1 g twice daily, and clarithromycin 500 mg twice daily), and a 10-day re-treatment (esomeprazole 40 mg once daily, amoxicillin 1 g twice daily, and levofloxacin 500 mg once daily) if the follow-up tests remained positive. Both H. pylori status and side-effects were assessed 6 weeks after treatment. Results:, Among 886 valid reporters, eradication rates with initial therapy were 86.9% (95% confidence interval [CI]: 84.7,89.1%) and 88.7% (95%CI: 86.5,90.9%) by intention-to-treat and per protocol analysis, respectively. Re-treatment eradicated infection in 91.4% (95%CI: 86,96.8%) of 105 nonresponders. Adequate compliance was achieved in 798 (90.1%) of 886 subjects receiving the initial treatment and in all 105 re-treated subjects. Mild side-effects occurred in 24% of subjects. Overall intention-to-treat and per protocol eradication rates were 97.7% (95%CI: 96.7,98.7%) and 98.8% (95%CI: 98.5,99.3%), respectively, which were only affected by poor compliance (odds ratio, 3.3; 95%CI, 1.99,5.48; p < .0001). Conclusions:, A comprehensive plan using drugs in which the resistance rate is low in a population combined with the strategy of test, treat, retest, and re-treat of needed can result in virtual eradication of H. pylori from a population. This provides a model for planning country- or region-wide eradication programs. [source] Early on-treatment prediction of response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels,HEPATOLOGY, Issue 2 2010Vincent Rijckborst Peginterferon alfa-2a results in a sustained response (SR) in a minority of patients with hepatitis B e antigen (HBeAg),negative chronic hepatitis B (CHB). This study investigated the role of early on-treatment serum hepatitis B surface antigen (HBsAg) levels in the prediction of SR in HBeAg-negative patients receiving peginterferon alfa-2a. HBsAg (Architect from Abbott) was quantified at the baseline and during treatment (weeks 4, 8, 12, 24, 36, and 48) and follow-up (weeks 60 and 72) in the sera from 107 patients who participated in an international multicenter trial (peginterferon alfa-2a, n = 53, versus peginterferon alfa-2a and ribavirin, n = 54). Overall, 24 patients (22%) achieved SR [serum hepatitis B virus (HBV) DNA level < 10,000 copies/mL and normal alanine aminotransferase levels at week 72]. Baseline characteristics were comparable between sustained responders and nonresponders. From week 8 onward, serum HBsAg levels markedly decreased in sustained responders, whereas only a modest decline was observed in nonresponders. However, HBsAg declines alone were of limited value in the prediction of SR [area under the receiver operating characteristic curve (AUC) at weeks 4, 8, and 12 = 0.59, 0.56, and 0.69, respectively]. Combining the declines in HBsAg and HBV DNA allowed the best prediction of SR (AUC at week 12 = 0.74). None of the 20 patients (20% of the study population) in whom a decrease in serum HBsAg levels was absent and whose HBV DNA levels declined less than 2 log copies/mL exhibited an SR (negative predictive value = 100%). Conclusion: At week 12 of peginterferon alfa-2a treatment for HBeAg-negative CHB, a solid stopping rule was established with a combination of declines in serum HBV DNA and HBsAg levels from the baseline. Quantitative serum HBsAg in combination with HBV DNA enables on-treatment adjustments of peginterferon therapy for HBeAg-negative CHB. (HEPATOLOGY 2010) [source] Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders,,HEPATOLOGY, Issue 6 2009Vinod K. Rustgi Merimepodib (MMPD) is an orally administered, inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C (CHC) when combined with pegylated interferon alfa 2a (Peg-IFN-alfa-2a) and ribavirin (RBV). We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. Conclusion: The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR. (HEPATOLOGY 2009.) [source] Hepatitis C virus infection and its clearance alter circulating lipids: Implications for long-term follow-up,HEPATOLOGY, Issue 4 2009Kathleen E. Corey Hepatitis C associated hypolipidemia has been demonstrated in studies from Europe and Africa. In two linked studies, we evaluated the relationship between hepatitis C infection and treatment with lipid levels in an American cohort and determined the frequency of clinically significant posttreatment hyperlipidemia. First, a case-control analysis of patients with and without hepatitis C was performed. The HCV Group consisted of 179 infected patients. The Uninfected Control Group consisted of 180 age-matched controls. Fasting cholesterol, low density lipoprotein (LDL), high density lipoprotein and triglycerides were compared. Next was a retrospective cohort study (Treated Hepatitis C Group) of 87 treated hepatitis C patients with lipid data before and after therapy was performed. In the case-control analysis, the HCV Group had significantly lower LDL and cholesterol than the Uninfected Control Group. In the retrospective cohort, patients in the Treated Hepatitis C Group who achieved viral clearance had increased LDL and cholesterol from baseline compared to patients without viral clearance. These results persisted when adjusted for age, sex, and genotype. 13% of patients with viral clearance had increased LDL and 33% experienced increases in cholesterol to levels warranting lipid lowering therapy. Conclusion: Hepatitis C is associated with decreased cholesterol and LDL levels. This hypolipidemia resolves with successful hepatitis C treatment but persists in nonresponders. A significant portion of successfully treated patients experience LDL and cholesterol rebound to levels associated with increased coronary disease risk. Lipids should be carefully monitored in persons receiving antiviral therapy. (HEPATOLOGY 2009;50:1030,1037.) [source] Hepatitis C nonresponders: Re-treat or retreat?,HEPATOLOGY, Issue 4 2009Michael Leise No abstract is available for this article. [source] Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C,HEPATOLOGY, Issue 3 2008Robert J. Fontana This study determined the utility of a panel of serum fibrosis markers along with routine laboratory tests in estimating the likelihood of histological cirrhosis in a cohort of prior nonresponders with chronic hepatitis C. The relationship between serum markers and quantitative hepatic collagen content was also determined. Liver biopsy samples from 513 subjects enrolled in the HALT-C trial were assigned Ishak fibrosis scores. The collagen content of 386 sirius-red stained, nonfragmented biopsy samples was quantified using computerized morphometry. Serum tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), amino-terminal peptide of type III procollagen (PIIINP), hyaluronic acid (HA), and YKL-40 levels were determined using commercially available assays. Sixty-two percent of patients had noncirrhotic fibrosis (Ishak stage 2-4) whereas 38% had cirrhosis (Ishak stage 5,6). Multivariate analysis identified a 3-variable model (HA, TIMP-1, and platelet count) that had an area under the receiver operating curve (AUROC) of 0.81 for estimating the presence of cirrhosis. This model was significantly better than that derived from the cirrhosis discriminant score (AUROC 0.70), the AST-to-platelet ratio (AUROC 0.73), and a prior model developed in HALT-C patients (AUROC 0.79). Multivariate analysis demonstrated that the serum fibrosis markers correlated substantially better with Ishak fibrosis scores than with the log hepatic collagen content (AUROC 0.84 versus 0.72). Conclusion: A 3-variable model consisting of serum HA, TIMP-1, and platelet count was better than other published models in identifying cirrhosis in HALT-C Trial subjects. The stronger correlation of the serum markers with Ishak scores suggests that serum fibrosis markers reflect the pattern of fibrosis more closely than the quantity of hepatic collagen. (HEPATOLOGY 2008.) [source] Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta,,HEPATOLOGY, Issue 3 2006Grazia Anna Niro Therapy of chronic hepatitis delta with standard interferon therapy has met with limited efficacy. This study was designed to examine the efficacy and safety of peginterferon with or without ribavirin. Thirty-eight serum hepatitis B surface antigen- and HDV RNA-positive patients with alanine aminotransferase (ALT) more than 1.5 times the upper normal limit received peginterferon alpha-2b (1.5 ,g/kg) alone as monotherapy (n = 16) or in combination with ribavirin (n = 22), for 48 weeks. Thereafter, all the patients were maintained on peginterferon for 24 weeks and followed for 24 weeks off therapy. The primary end point studied was the virological and biochemical response at the end of follow-up. HDV RNA was determined by single or nested polymerase chain reaction assays. Twenty-seven patients (71%), 11 receiving monotherapy and 16 receiving the combination treatment, completed the follow-up. At the end of treatment, a virological response was observed in 3 of the patients treated with peginterferon (19%) and in 2 of the patients treated with combination therapy (9%), and a biochemical response was observed in 6 (37.5%) and 9 patients (41%), respectively. In nonresponders, ALT diminished from a mean of 174 ± 53 to 86 ± 41 IU/L. At the end of follow-up, serum HDV RNA was negative in 8 patients (21%), and a biochemical response was detected in 10 patients (26%). Treatment was discontinued in 25% of the patients, and dosing was modified in 58%. In conclusion, a prolonged course of peginterferon alpha-2b resulted in clearance of serum HDV RNA and ALT normalization in a fifth of patients with chronic hepatitis D, while ribavirin had no effect on the viral clearance rate. Overall tolerance of therapy was poor. (HEPATOLOGY 2006;44:713,720.) [source] Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisoloneHEPATOLOGY, Issue 6 2003Philippe Mathurin M.D. Early identification of patients with severe (discriminant function ,32) biopsy-proven alcoholic hepatitis (AH) who are not responding to corticosteroids would be clinically relevant. Our goal was to develop simple criteria that will help physicians to promptly identify nonresponders to corticosteroids. A total of 238 patients were included. We used 6 months survival as an end point because of the rule requiring 6 months for listing alcoholic patients for transplantation. Overall survival at 1 and 6 months was 85% ± 2.3% and 64.3% ± 3.3%, respectively. An early change in bilirubin levels (ECBL) at 7 days (defined as bilirubin level at 7 days lower than bilirubin level on the first day of treatment) was observed in 73% of patients. At 7 days, in patients with ECBL, bilirubin decreased (84 ± 75 ,mol/L [4.94 ± 4.40 mg/dL]), whereas it increased in patients without ECBL (76.5 ± 77 ,mol/L [4.50 ± 4.54 mg/dL], P < .0001). Ninety-five percent of patients with ECBL continued to have improved liver function during treatment. At 6 months, survival of patients with ECBL was significantly higher than that of patients without ECBL, 82.8% ± 3.3% versus 23% ± 5.8%, P < .0001. On multivariate analysis, ECBL, discriminant function and creatinine were independent prognostic variables, and ECBL had the most important prognostic value. In conclusion, ECBL is a very simple predictive factor for identifying nonresponders. A recommendation to discontinue corticosteroids after 7 days in patients without ECBL, suggested by our results, awaits additional confirmation. [source] A pilot study of interferon alfa and ribavirin combination in liver transplant recipients with recurrent hepatitis CHEPATOLOGY, Issue 5 2002A. Obaid Shakil Although interferon alfa (IFN-,) and ribavirin are widely used in the treatment of hepatitis C, their role in the transplant recipient is unclear. We conducted a pilot study to determine the efficacy and safety of this therapy in transplant recipients with recurrent hepatitis C. Patients at least 6 months posttransplantation were treated with IFN-, 3 million units 3 times a week subcutaneously and ribavirin 800 mg daily by mouth for 48 weeks followed by ribavirin monotherapy for 24 weeks. The primary end point was sustained virologic response, and secondary end points included biochemical, virologic, and histologic responses at the end of combination treatment. Thirty-eight patients initiated therapy but 16 withdrew due to adverse effects, including 2 with myocardial infarction. Median age was 50 years; 74% were men, and 91% had genotype 1. The median interval between transplantation and enrollment was 23 months. On an intention-to-treat basis, 7 patients (18%) had a biochemical and 5 (13%) had a virologic response at the end of combination treatment. Inflammatory activity did not change, but fibrosis worsened in virologic nonresponders. Ribavirin maintenance caused a further decrease in serum alanine aminotransferase levels, but hepatitis C virus (HCV) RNA levels increased. Only 2 of the 38 patients (5%) had a sustained virologic response. Several patients required treatment with erythropoietin for anemia. In conclusion, IFN-, and ribavirin are effective in a small proportion of liver allograft recipients with recurrent hepatitis C. Adverse effects occur commonly, requiring dose reductions and treatment withdrawal. [source] A randomized 4-arm multicenter study of interferon alfa,2b plus ribavirin in the treatment of patients with chronic hepatitis C not responding to interferon aloneHEPATOLOGY, Issue 1 2001Giorgio Saracco To determine whether a higher dosage of interferon (IFN) associated with ribavirin and/or prolonged time of administration may improve therapeutic efficacy, we conducted a 4-arm randomized trial on patients with chronic hepatitis C not responding to one or more previous treatment courses with IFN monotherapy. Group 1 (n = 139) received 3 million units (MU) IFN-,2b 3 times a week (t.i.w.) plus ribavirin 1,000 mg/d for 12 months; group 2 (n = 162) received 5 MU t.i.w. plus ribavirin for 12 months; group 3 (n = 142) received 3 MU t.i.w. plus ribavirin for 6 months; and group 4 (n = 151) received 5 MU t.i.w. plus ribavirin for 6 months. The primary end point was hepatitis C virus (HCV)-RNA clearance at the end of 6-month follow-up. HCV-RNA was negative in 15% of group 1, 23% of group 2, 11% of group 3, 16% of group 4 (group 2 vs. group 3, P = .04). Among patients with genotypes 1 and 4, sustained response was significantly higher in group 2 vs. group 3 (18% vs. 7%, P = .03; group 1 = 9%, group 4 = 12%, P = not significant [NS]). In patients with genotypes 2 and 3, sustained virologic response was not affected by the different regimens (group 1 = 32%, group 2 = 30%, group 3 = 30%, group 4 = 35%, P = NS). In conclusion, about 23% of nonresponders to IFN monotherapy may achieve a sustained response if re-treated by 5 MU t.i.w. IFN plus ribavirin 1,000 mg/d for 1 year. Patients with genotype 1 should receive a high dosage of IFN plus ribavirin for 12 months, whereas therapy for patients with genotype 2 or 3 should be less aggressive. [source] Antibodies Against Hepatitis C Virus,Like Particles and Viral Clearance in Acute and Chronic Hepatitis CHEPATOLOGY, Issue 3 2000Thomas F. Baumert M.D. We recently described the efficient assembly of hepatitis C virus (HCV) structural proteins into HCV-like particles (HCV-LPs) in insect cells. These noninfectious HCV-LPs have similar morphologic and biophysical properties as putative virions isolated from HCV-infected humans and can induce a broadly directed immune response in animal models. The HCV envelope proteins of HCV-LPs are presumably presented in a native, virion-like conformation and may therefore interact with antienvelope antibodies directed against conformational epitopes. In this study, HCV-LPs were used as capture antigens in an enzyme-linked immunosorbent assay (ELISA) to detect and quantify antibodies against HCV structural proteins in patients with acute and chronic hepatitis C. High titers of anti,HCV-LP antibodies were detected in patients chronically infected with HCV genotypes 1 to 6. In contrast to individuals with chronic hepatitis C, patients with acute self-limited hepatitis C displayed only a transient and weak seroreactivity against HCV-LPs. Patients with chronic HCV infection successfully treated with interferon demonstrated a gradual decline of anti,HCV-LP titers during or subsequent to viral clearance. Sustained interferon responders were characterized by significantly higher pretreatment levels of anti,HCV-LP antibodies as compared with nonresponders (P = .0001). In conclusion, HCV infection is associated with limited humoral immunity against the envelope proteins present on the HCV-LPs. An HCV-LP,based ELISA may be a useful diagnostic tool to distinguish acute hepatitis C from chronic HCV infection with exacerbation, and to predict viral clearance in response to interferon. [source] Hospitalization risk following initiation of highly active antiretroviral therapyHIV MEDICINE, Issue 5 2010SA Berry Objectives While highly active antiretroviral therapy (HAART) decreases long-term morbidity and mortality, its short-term effect on hospitalization rates is unknown. The primary objective of this study was to determine hospitalization rates over time in the year after HAART initiation for virological responders and nonresponders. Methods Hospitalizations among 1327 HAART-naïve subjects in an urban HIV clinic in 1997,2007 were examined before and after HAART initiation. Hospitalization rates were stratified by virological responders (,1 log10 decrease in HIV-1 RNA within 6 months after HAART initiation) and nonresponders. Causes were determined through International Classification of Diseases, 9th Revision (ICD-9) codes and chart review. Multivariate negative binomial regression was used to assess factors associated with hospitalization. Results During the first 45 days after HAART initiation, the hospitalization rate of responders was similar to their pre-HAART baseline rate [75.1 vs. 78.8/100 person-years (PY)] and to the hospitalization rate of nonresponders during the first 45 days (79.4/100 PY). The hospitalization rate of responders fell significantly between 45 and 90 days after HAART initiation and reached a plateau at approximately 45/100 PY from 91 to 365 days after HAART initiation. Significant decreases were seen in hospitalizations for opportunistic and nonopportunistic infections. Conclusions The first substantial clinical benefit from HAART may be realized by 90 days after HAART initiation; providers should keep close vigilance at least until this time. [source] An open study of risperidone liquid in the acute phase of schizophreniaHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 4 2005Reiji Yoshimura Abstract An open-label study was performed to investigate the clinical efficacy and mechanisms of risperidone liquid in ameliorating positive symptoms in the acute phase of schizophrenia. Eighty-eight patients (M/F: 50/38; age: 18,74 years;, mean±SD =32±16 years) meeting DSM-IV criteria for schizophrenia and treated with risperidone liquid (14 patients also used lorazepam) were evaluated with regard to their clinical improvement and extrapyramidal side effects using the positive and negative syndrome scale (PANSS) and the Simpson and Angus scale (SAS), while plasma concentrations of HVA and MHPG were analysed by HPLC-ECD before and 4 weeks after risperidone liquid administration. Patients showing a 50% or greater improvement in PANSS scores were defined as responders. An improvement in the PANSS scores related to excitement, hostility and poor impulse control was seen within 7 days after administration of risperidone liquid, and an improvement with regard to hallucinatory behaviour and uncooperativeness was seen within 14 days after its administration. Finally, 68% of patients were classified as responders 4 weeks after risperidone liquid administration. The scores of SAS were not changed after risperidone liquid administration. Pretreatment plasma homovanillic acid (HVA) levels in the responders (8.1±2.9,ng/ml) were higher than those in nonresponders (5.9±1.9,ng/ml). In addition, a negative correlation was seen between the changes in plasma HVA levels and the percentage of improvement in PANSS scores. On the other hand, there were no differences between pretreatment plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and those of nonresponders. These results suggest that risperidone liquid is effective and well tolerated for the treatment of acute phase schizophrenic patients, and that efficacy is related to its affects on dopaminergic activity, not noradrenergic activity. Copyright © 2005 John Wiley & Sons, Ltd. [source] Milnacipran plasma levels and antidepressant response in Japanese major depressive patientsHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 4 2003Hisashi Higuchi Abstract The relationship between antidepressant effects and plasma levels of milnacipran was studied in 49 cases of major depression without psychotic features during 6 weeks of milnacipran treatment. The daily dose of milnacipran was 50,mg/day for the first week, and up to 100,mg/day thereafter. Depressive symptoms were evaluated by the Montgomery and Åsberg depression rating scale (MADRS) before treatment and at 1, 2, 4 and 6 weeks after the beginning of this study. Thirty-four patients (69.4%) were responders (defined as a 50% or greater decrease in the baseline MADRS score). Significant differences of MADRS scores were seen from 1 week after the beginning of this study (p,=,0.004, unpaired t -test) between responders and nonresponders. The mean plasma milnacipran level of responders, 82.0,±,29.4,ng/ml, was similar to that of non-responders, 78.6,±,23.1,ng/ml; there was no significant difference between responders and nonresponders. Neither a significant linear nor a curvilinear relationship was obtained between the final MADRS score and the plasma levels of milnacipran. Although there was no significant relationship between the plasma levels of milnacipran and the antidepressant response, milnacipran should be considered an efficacious agent in the treatment of major depressive patients. Copyright © 2003 John Wiley & Sons, Ltd. [source] Human neutrophil peptides 1,3 are useful biomarkers in patients with active ulcerative colitisINFLAMMATORY BOWEL DISEASES, Issue 6 2009Shuji Kanmura MD Abstract Background: A specific useful biomarker for diagnosing ulcerative colitis (UC) has not yet been described. This study employed proteomics to identify serum protein biomarkers for UC. Methods: Ninety-four blood samples were isolated from patients and controls (including 48 UC, 22 Crohn's disease [CD], 5 colorectal cancer, and 6 infectious colitis patients and 13 healthy subjects). Serum samples were analyzed using the SELDI-TOF/MS ProteinChip system. After applying the samples to ProteinChip arrays, we assessed differences in the proteomes using Ciphergen ProteinChip software and identified candidate proteins, which were then characterized in immunoassays. Results: Preliminary analysis using the ProteinChip system revealed significant peak-intensity differences for 27 serum proteins between 11 patients with UC and 7 healthy subjects. Among these proteins, 3 proteins (with mass/charge ratios of approximately 3400) were identified as human neutrophil peptides 1,3 (HNP 1,3). The presence of HNP 1,3 in the patient sera was confirmed using immunoassays. Enzyme-linked immunosorbent assays demonstrated that the mean plasma concentration of HNP 1,3 was significantly higher in patients with active UC (n = 28) than in patients whose UC was in remission (n = 20) or patients with CD (n = 22), infectious colitis, or healthy subjects, and tended to be higher than in patients with colon cancer. In addition, the plasma concentration of HNP 1,3 in patients that responded to corticosteroids-based therapy decreased after treatment, whereas it was not changed in nonresponders. Conclusions: HNP 1,3 is a novel biomarker that may be useful for diagnosing patients with active UC and predicting treatment outcomes. (Inflamm Bowel Dis 2008) [source] MDR1 polymorphisms and response to azathioprine therapy in patients with Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 5 2007Juan L. Mendoza MD Abstract Background: To investigate the contribution of multidrug resistance 1 (MDR1) gene pharmacogenetics (G2677T/A and C3435T) to the efficacy of azathioprine in inducing remission in patients with Crohn's disease (CD). Methods: A cohort of 327 unrelated Spanish patients with CD recruited from a single center was studied. All patients were rigorously followed up for at least 2 years (mean time, 11.5 years). A case-control analysis of MDR1 G2677T/A and C3435T SNPs and 2 loci haplotypes in 112 steroid-dependent CD patients treated with azathioprine was performed. Patients were classified on the basis of response to azathioprine. Results: A total 76 patients treated with azathioprine for longer than 3 months were included. Remission was achieved in 42 CD patients (55.3%). A higher frequency of the 2677TT genotype was found in nonresponders than in responders (17.65% versus 7.14%; OR = 2.8; 95% CI; 0.6,12.1; P = 0.11). Nonresponders to azathioprine were found to have a higher frequency of the 3435TT genotype than did CD patients who had achieved clinical remission (17.64% versus 4.76%; OR = 4.3; 95% CI, 0.8,22.8; P = 0.06). The 2677T/3435T haplotype was also more abundant in nonresponders (29.4% versus 20.2%), whereas the 2677G/3435C haplotype was more frequent in responders (58.3% versus 47.1%). Lack of response to azathioprine therapy in CD patients was 1.8-fold greater in carriers of the 2677T/3435T haplotype than in carriers of the 2677G/3435C haplotype (OR = 1.8; 95% CI, 0.82,3.9; P = 0.14). Conclusions: The results of our study indicate higher frequencies of the 2677TT and 3435TT genotypes and the 2677T/3435T haplotype in CD patients who did not respond to azathioprine. Additional replications in independent populations would confirm the real impact of these polymorphisms in response to azathioprine therapy. (Inflamm Bowel Dis 2007) [source] Predictors of early response to infliximab in patients with ulcerative colitisINFLAMMATORY BOWEL DISEASES, Issue 2 2007Marc Ferrante MD Abstract Background: Our objective is to report the outcome of infliximab (IFX) in ulcerative colitis (UC) patients from a single center and to identify predictors of early clinical response. Methods: The first 100 UC patients (45 female; median age, 37.9 years) who received IFX at a single center were included. Eighty-four patients received 5 mg/kg IFX, and 37 patients received a 3-dose IFX induction at weeks 0, 2, and 6. The Mayo endoscopic subscore, assessed by sigmoidoscopy before inclusion, was 1, 2, and 3 in 5%, 52%, and 43% of patients, respectively. Sixty percent had pancolitis, 63% were on concomitant immunosuppressive therapy, 9% were active smokers, 64% had C-reactive protein ,5 mg/dL, and 44% were pANCA+/ASCA,. Five patients received IFX because of severe acute colitis refractory to intravenous corticosteroids. Results: Early complete and partial clinical responses were observed in 41% and 24% of patients. Patients with early clinical response were significantly younger than nonresponders (median age, 35.7 versus 41.6 years, P = 0.041). Patients who were pANCA+/ASCA, had a significantly lower early clinical response (55% versus 76%; odds ratio [OR] = 0.40 (0.16,0.99), P = 0.049). Concomitant immunosuppressive therapy and the use of an IFX induction scheme did not influence early clinical response. Only 1 of 5 patients who received IFX for acute steroid-refractory colitis required colectomy within 2 months. Conclusions: IFX is an efficient therapy in UC, as shown by 65% early clinical response. A pANCA+/ASCA, serotype and an older age at first IFX infusion are associated with a suboptimal early clinical response. (Inflamm Bowel Dis 2006) [source] Infliximab efficacy in pediatric ulcerative colitis,INFLAMMATORY BOWEL DISEASES, Issue 3 2005Alexandra P Eidelwein MD Abstract Background: The effects of infliximab, a tumor necrosis factor-alpha (TNF-,) antibody, have been well established in adult patients with inflammatory and fistulizing Crohn's disease. This study evaluates short- and long-term efficacy of infliximab in children with ulcerative colitis. Methods: All pediatric patients with ulcerative colitis who received infliximab between July 2001 and November 2003 at the Johns Hopkins Children's Center were identified. Short- and long-term outcomes and adverse reactions were evaluated. Results: Twelve pediatric patients with ulcerative colitis received infliximab for treatment of fulminant colitis (3 patients), acute exacerbation of colitis (3), steroid-dependent colitis (5), and steroid-refractory colitis (1). Nine patients had a complete short-term response, and 3 had partial improvement. The mean per patient dose of corticosteroid after the first infliximab infusion decreased from 45 mg/day at the first infusion to 22.2 mg/day at 4 weeks (P = 0.02) and 7.8 mg/day at 8 weeks (P = 0.008). Eight patients were classified as long-term responders with a median follow-up time of 10.4 months. Of the 4 long-term nonresponders, 3 underwent colectomy, and the fourth has ongoing chronic symptoms. Three of 4 long-term nonresponders were steroid-refractory compared with 1 of 8 long-term responders. Patients receiving 6-mercaptopurine had a better response to infliximab. Conclusion: Infliximab should be considered in the treatment of children with symptoms of acute moderate to severe ulcerative colitis. [source] Molecular determinants of irinotecan efficacyINTERNATIONAL JOURNAL OF CANCER, Issue 10 2006Daniel Vallböhmer Abstract Molecular markers predicting the efficacy of CPT-11 based chemotherapies in patients with colorectal cancer (CRC) are unknown. Therefore, we investigated whether mRNA levels of drug targets (Topoisomerase I, TS), enzymes involved in 5-FU metabolism (DPD), in angiogenesis (EGFR, IL-8, VEGF) and in DNA-repair/drug detoxification (ERCC1, GST-P1) are associated with the clinical outcome of patients with CRC treated with first-line CPT-11 based chemotherapy. Thirty three patients with metastatic CRC were included in the study. Intratumoral gene expression levels were assessed from paraffin-embedded tissue samples, using laser capture microdissection and quantitative Real-Time PCR. Complete response was observed in 1 patient, partial response in 12 patients, stable disease in 13 patients and progressive disease in 6 patients. Response was inevaluable for 1 patient. Patients with complete response or partial response were classified as responders, while patients with stable disease or progressive disease were classified as nonresponders. High intratumoral mRNA levels of EGFR, ERCC1 and GSPT-P1 were each significantly associated with response to CPT-11 based chemotherapy. Recursive partitioning analysis showed that mRNA levels of EGFR and ERCC1 are primarily responsible for delineating responders from nonresponders. Also, the combination of high intratumoral gene expression levels of both EGFR and ERCC1 was significantly associated with progression-free survival. The mRNA levels of EGFR had a significant correlation with expression levels of ERCC1, GST-P1 and VEGF. This small retrospective study suggests that gene expression levels of EGFR, ERCC1 and GST-P1 may be useful in predicting the clinical outcome of patients with metastatic CRC treated with first-line CPT-11 based chemotherapy. © 2006 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||||||||