Non-response Patients Research Articles

Early cessation and non-response are important and possibly related problems in growth hormone therapy: An OZGROW analysis

ObjectiveTo investigate growth hormone (GH) treatment and treatment cessation with respect to efficacy and efficiency. To identify factors that best classify or predict cessation type: completed treatment (CT), early cessation (EC), or non-response (NR). DesignObservational study (1990–2013) of the Australian GH Program comparing CT, EC, and NR groups with respect to demographic, clinical, and response criteria. All patients treated for GH deficiency (GHD; 909), short stature and slow growth (SSSG; 2144), and Turner Syndrome (TS; 626) were included. Information was retrieved from the OZGROW database. Results51.9% of patients were EC, 40.7% CT and 7.4% NR.Median treatment durations for NR patients were often longer than patients who completed treatment. EC and NR groups were both associated with poor growth response with males overrepresented.Socioeconomic status differentiated NR (higher) and EC (lower) groups. ConclusionsEC was observed at very high rates and appears, generally, to be a little-recognised but frequent problem in GH therapy.EC and delayed recognition of NR may be interrelated being differentiated by the decision to cease or continue treatment following poor response.Poor treatment compliance is likely a major causal factor in EC.Strategies to address poor response and compliance have been developed, however, given the scale of these problems, it may be that long acting GH formulations or individualized treatment need consideration.

Neutralizing Antibody and Botulinum Toxin Therapy: A Systematic Review and Meta-analysis.

The formation of neutralizing antibodies (NAbs) directed specifically against the active neurotoxin part of the botulinum neurotoxin (BoNT) complex is often cited as a major cause of secondary non-responsiveness (SnR) to treatment. This systematic and meta-analytic review evaluates the frequency of NAbs among patients treated with BoNT therapy for any clinical indication. A comprehensive database search strategy was designed to retrieve relevant clinical data from the published literature up to April 2013. All English-language publications that analyzed NAbs prevalence in more than ten patients were included, regardless of BoNT formulation, assay method, and study design. For the meta-analysis, patients were divided into three categories: secondary nonresponse (SnR) patients, clinically responding patients and all patients, independently of BoNT responsiveness. The meta-analysis included 61 studies reporting data for 8525 patients; 4972 dystonic patients, 1170 patients with spasticity, 294 patients with urologic indications, 396 patient with hyperhidrosis, 1659 patients with glabellar line, and 34 patients with hypersalivation. Among the ‘‘all patients’’ group NAbs frequency was 20%for dystonia, 5.9%for spasticity, and 2.7% for urologic patients and 1.1% for other conditions. The prevalence of NAbs was lower (3.5%) among clinically responding patients and higher in 53.5%SnR patients. About a half of patients with SnR do not have NAbs. NAbs was high among patients treated with RIMA but it was not associated with clinical non-responsiveness. Meta-analysis of the frequency of NAbs and SnR are limited by the heterogeneity of study design and reported outcomes. Indeed the analysis of several factors that can influence the development of NAbs, i.e.,MHCof patients, frequency and site of injection, injection technique, cumulative dose, and toxin denaturation, was not specifically evaluated due to the paucity and heterogeneity of data. The identification of all these missing data should be taken into account in order to improve the methodology of future studies.

Clinical analysis of 123 cases of primary immune thrombocytopenia in adults

Objective To investigate the clinical characteristics of primary immune thrombocytopenia (ITP) in adults and to summarize the experience in order to improve the clinical diagnosis and treatment of ITP. Methods from February 2008 to June 2014, a total of 123 cases of adult patients with ITP in Taizhou People's Hospital affiliated to Yangzhou University were collected into this study, as the research object. The clinical data, clinical manifestation, laboratory examination, treatment and therapeutic effect of 123 cases of adult ITP were retrospectively analyzed. The study protocol was approved by the Ethical Review Board of Investigation in Human at Taizhou People's Hospital affiliated to Yangzhou University. Informed consent was obtained from all participants. All adult ITP patients peripheral blood and bone marrow like, immunological indexes were detected; and the adult ITP patients in different age patients with male and female incidence ratio were statistically analyzed. Results ①The ratio of male to female was 1∶9.5 in patients with ITP from 21to 40 years old, and the ratio of male to female was 1∶2.3 in patients with ITP from 41 to 60 years old There was significant difference between incidence rates of male and female in two age periods(χ2=4.474, P=0.034). ②19 out of 123 cases of adult ITP patients had a clear incentive, and incentives were all upper respiratory tract infection. Adult ITP patients's bleeding parts from high frequency to low were as follows: the skin and mucosa, menorrhagia, urinary tract and digestive tract and intracranial hemorrhage .The complications of adult ITP patients with pulmonary infection were 4 cases, and femoral head necrosis were 2 cases. The occurrence of steroid diabetes were 12 cases. Low potassium were 8 cases. Before treatment, the adult ITP platelet count in patients was (14.6±12.2)×109/L. The number of bone marrow megakaryocytes were increased in 75 cases (61%), and the rest 48 cases (39%) were normal. All the patients had megakaryocyte maturation disorder. ③The follow-up time was 3 months to 32 years, and the median time was 42 months. After first-line treatment of glucocorticoid treatment scheme, 69 cases of patients (56.1%) obtained complete response (CR), partial response (PR) were 29 cases (23.6%) and non-response (NR) were 25 cases (20.3%). After cessation of glucocorticoids, platelet count of 69 cases obtained CR maintained at a normal level, and platelet count of 29 cases obtained PR were more than 30×109/L, without obvious bleeding manifestations. 25 cases of NR patients were treated with second-line therapy. second-line therapy respectively were vincristine, cyclosporine A (CSA) and rituximab and splenectomy, and treatment efficiency were 44.4%. 50.0%, 80.0% and 85.7%, respectively. Conclusion Adult ITP treatment should pay attention to the principle of individual treatment, so that the blood platelet count increased to a safe level, and over treatment should be avoided as far as possible. Key words: Thrombocytopenia; Adult; Glucocorticoids

Secondary Enucleations for Uveal Melanoma: A 7-Year Retrospective Analysis

To describe the indications for secondary enucleations in uveal melanoma and analyze associations and outcomes. Retrospective interventional case series. Data of patients who underwent secondary enucleation for uveal melanoma in the London Ocular Oncology Service, between 2008 and 2014, were retrieved from medical records analyzed. Cox regression model was performed to analyze associations with secondary enucleation and metastases and Kaplan-Meier estimates to assess the probability of metastatic spread and death. During the study period 515 enucleations were performed for uveal melanoma, 99 (19%) of which were secondary enucleations. Tumors were located at the ciliary body in 21 eyes (21%), juxtapapillary in 31 (31%), and choroid elsewhere in 47 (48%). Primary treatment included Ru(106) plaque radiotherapy, proton beam radiotherapy, and transpupillary thermotherapy in 85, 11, and 3 eyes, respectively. Indications for secondary enucleation were tumor recurrence in 60 (61%), neovascular glaucoma in 21 (21%), and tumor nonresponse in 18 eyes (18%). Twenty patients (20%) were diagnosed with metastasis and 12 out of 20 died of metastatic spread. On multivariate analysis, juxtapapillary tumor location was found to associate with tumor nonresponse (P= .004) and nonresponding patients with metastatic spread (P= .04). Indications for secondary enucleations for uveal melanoma were tumor recurrence, neovascular glaucoma, and tumor nonresponse. This review identified a possible high-risk group (nonresponse), which proved radioresistant to treatment. These tumors were more frequently found in the juxtapapillary location and were associated with metastatic spread.

Mesenchymal Stem Cells Ameliorate Thymic Functions in aGVHD Patients after Allogenetic Haematopoietic Stem Cell Transplantation

Background Mesenchymal stem cells (MSCs) have been considered as a promising strategy for the prevention and treatment of graft-versus-host disease (aGVHD), but the mechanism of MSCs ameliorating GVHD is still not fully understood. In mice aGVHD model, some studies proposed that MSCs ameliorated GVHD via enhancements in proliferation and function of thymic epithelial cells, but it is not performed in patients.Methods Twenty-five refractory aGVHD patients were enrolled in this study, including 13 patients receiving MSCs treatment and 12 without MSCs treatment as the control group. MSCs derived from bone marrow (BM) of a third-party donor and given at a median dose of 1×106 cells/kg once weekly until aGVHD got complete response (CR) or MSCs were infused for a total of 8 doses. CD4+CD25+Foxp3+ regulatory T cells (Tregs) in peripheral blood were analyzed by flow cytometry and signal joint T-cell receptor excision circle (sjTREC) was monitored by real-time polymerase chain reaction (PCR) before and 4, 8, 12, 16, 24 and 36 weeks after treatments.Results In MSCs group,the overall response (OR) rate for aGVHD was 76.9%, including complete response (CR) in 53.8% and partial response (PR) in 23.1%, while the OR rate in non-MSCs group was 33.3%, including CR in 25% and PR in 8.3%. The OR rate in MSC group is significantly higher than those in the control group (P=0.028). No evident difference of CD4+CD25+Foxp3+Tregs and sjTREC were shown between the patients in MSCs and the control groups before the study treatment (P=0.762, P=0.870). In the evaluated patients, the level of sjTREC in MSCs group is significantly higher at 8, 16, 24 weeks than the control group after treatments (P=0.043, P=0.0301 and P=0.039, respectively.). The level of sjTREC significantly increased at 8 weeks after MSCs treatment, compared with pre-MSCs treatment (P=0.034), and sustained to 36 weeks after MSCs treatment. In the control group, sjTREC increased, but did not change significantly before and after treatments (P>0.05). The level of sjTREC in CR patients is significantly higher than non-response patients at 8, 12, 16, and 24 weeks after MSCs treatment, and sjTREC levels correlated with the response of MSCs treatment (r=0.782). With respect to CD4+CD25+Foxp3+Tregs, they were significantly higher in MSC group at 8, 12 weeks after treatment than the control group (P=0.026 and P=0.029). In MSCs group, the proportion of CD4+CD25+Foxp3+Tregs showed a significant increase at 8 weeks compared with pre-MSCs treatment (P=0.012), and sustained to 36 weeks after MSCs treatment. In the control group, CD4+CD25+Foxp3+Tregs did not significantly change before and after treatment.Conclusions MSCs derived from BM of a third-party donor are effective to refractory aGVHD. MSCs ameliorated aGVHD via repairing thymus, including the enhancements of thymic output function and inducing the generation of Tregs. DisclosuresWu:It was supported by National Natural Science Foundation of China (81270647, 81300445, 81200388); National High Technology Research and Development Program of China (863 Program) (2011AA020105): Research Funding; It was supported by the Technology Plan of Guangdong Province of China (2012B031800403); the project of the Zhujiang Science & Technology Star of Guangzhou city (2013027).: Research Funding. Liu:It was supported by National Natural Science Foundation of China (81270647, 81300445, 81200388); National High Technology Research and Development Program of China (863 Program) (2011AA020105); National Public Health Grand Research Foundation (201202017);: Research Funding; It was supported by Natural Science Foundation of Guangdong Province (S2012010009299); the project of health collaborative innovation of Guangzhou city (201400000003-4, 201400000003-1);: Research Funding; It was supported by the Technology Plan of Guangdong Province of China (2012B031800403); the project of the Zhujiang Science & Technology Star of Guangzhou city (2013027).: Research Funding.

The hENT1 and DCK genes underlie the decitabine response in patients with myelodysplastic syndrome

Decitabine is approved for the treatment of MDS, but resistance to this agent is common. To determine the mechanisms underlying decitabine resistance, we measured the mRNA expression of metabolism (hENT1, DCK, CDA) and apoptosis (BCL2L10) genes and found that the hENT1 mRNA level was significantly higher in response compared with non-response patients (P=0.004). Furthermore, the DCK level was significantly reduced for relapse (P=0.012) compared with those with continued marrow CR (P=0.222). These findings indicate that the decitabine metabolic pathway affects its therapeutic effects, lower hENT1 expression may induce primary resistance and down-regulated DCK expression may be related to secondary resistance.

Association between low molecular polypeptide 7 single nucleotide polymorphism and response to therapy in hepatitis C virus infection

To investigate the relationship between low molecular polypeptide-7 (LMP-7) gene polymorphism and response to interferon (IFN) therapy in chronic hepatitis C virus (HCV) patients. LMP-7 polymorphism at codon 49 with nucleotide substitution from A to C was amplified in 104 chronic HCV patients of genotype 4. The amplicons were digested with restriction endonuclease BsmI and the produced restriction fragment length polymorphism was analyzed. Patients received IFN + regional blood volume therapy for 48 wk and the frequency of this single nucleotide polymorphism (SNP) was statistically correlated with treatment response. The exclusion criteria for these patients were stated by the national health program for treating viral hepatitis. Main exclusion criteria included co-infection with hepatitis B virus or schistosomiasis, thyroid dysfunction, uncontrolled diabetes mellitus, history of long term drug or alcohol intake and autoimmune hepatitis. Multivariate analyses were done to correlate LMP-7 SNP plus several factors such as age, gender, weight, serum alpha-fetoprotein (AFP) and alanine aminotransferase levels, liver activity, fibrosis score and viral load with response to therapy. The data presented in this study clearly demonstrated statistically significant differences between sustained virological response (SVR) (defined as the absence of HCV RNA levels in the patient's sera at least 6 mo after discontinuation of treatment) and non-response (NR) (where HCV RNA levels in the patient's sera never become undetectable for 6 mo during or after treatment). Variables were described as odds ratio with 95%CI. The data were considered significant if P values were ≤ 0.05; highly significant if P < 0.01 and very highly significant if P < 0.001. Current data showed that 91.7% of patients carrying LMP-7 C/C allele were associated with SVR, while the other two genotypes C/A and A/A were associated with NR patients, 83.3% and 64.3% respectively, showing that genotype CC was strongly associated with response to interferon (95%CI: 12.0719-134.6572, P = 0.0001). The majority of parameters recorded in SVR and NR patients included higher values of mean age (P = 0.004), alanine aminotransferase (P = 0.001), AFP (P = 0.001), body weight (P = 0.025), viral load (P = 0.025), higher fibrosis and histological activity index indices among NR vs SVR patients. Also, the multivariate statistical analysis of the different factors of fibrosis score, liver activity grade, genotypes and alleles of LMP-7 gene polymorphism in responders and NRs of HCV patients in this study showed that HCV patients with A allele had a very highly significant association with the NRs, high fibrosis and higher liver activity, while the C allele had a very highly significant association with the responders, low fibrosis and lower liver activity (95%CI: 3.5800-13.2519, P = 0.0001). LMP-7 SNP is a candidate gene that should be considered when designing a mathematical model for predicting response to therapy and disease progression in HCV patients.

Incidence of hepatocellular carcinoma in HCV-infected patients with normal alanine aminotransferase levels categorized by Japanese treatment guidelines

This study was conducted to evaluate Japanese treatment guidelines for patients with chronic hepatitis C virus (HCV) infection and normal alanine aminotransferase (N-ALT) levels from the viewpoint of the incidence of hepatocellular carcinoma (HCC). Four groups of patients with chronic HCV infection treated with pegylated interferon (Peg-IFN) plus ribavirin, and classified according to the N-ALT guidelines, were examined for HCC incidence: group A (n=353), ALT ≤30IU/L and platelet (PLT) ≥15×10(4)/mm(3); group B (n=123), ALT ≤30IU/L and PLT <15×10(4)/mm(3); group C (n=233), 30<ALT≤40IU/L and PLT ≥15×10(4)/mm(3); and group D (n=100), 30<ALT≤40IU/L and PLT <15×10(4)/mm(3). The mean observation period was 36.2±16.5months In groups A and C, the HCC incidence was low even in patients with non-response (NR) (cumulative rates at 3years, 0.0 and 2.9%, respectively). In groups B and D, 14.5 and 5.3% of NR patients had developed HCC at 3years, but none of the patients with sustained virologic response (SVR) or relapse had developed HCC. In group B, no patients with mild fibrosis developed HCC irrespective of the antiviral effect of the treatment. Among patients with PLT <15×10(4)/mm(3) (group B plus group D), the HCC incidence was significantly lower in patients with SVR and relapse than in NR patients (p<0.001, p=0.021, respectively). These results suggest that N-ALT patients with PLT <15×10(4)/mm(3) could be candidates for early antiviral therapy.

Goal-directed nursing model based on multivariate regression analysis for increasing response rates of patients with portal hypertension

Objective To analyze factors influencing β-blocker response rates of patients with portal hypertension and to explore the effect of nursing interference for increasing response rates with goal-directed nursing model. Methods 83 cases of portal hypertension were enrolled.Questionnaire about medical visiting behaviors and medication compliance were compared and analyzed after routine medication for 3 months.Bivariate and multivariate regression analysis were performed and related factors were used to establish a goal-directed nursing model for nursing interference guidance.52 non-response patients were randomly divided into the study group(27 cases)and the control group(25 cases).In the study group,compensation system and supportive-education according to Orem model were given,while the control group was given routine nursirng.Response rates and related factors were compared after 3 months of nursing intervention. Results Awareness of self-care responsibility,knowledge about the medication target,risk of sudden drug withdrawal,related medical knowledge,ability for pulse rate measurement and dose adjustment according to pulse rate changes were related to the response rates.Multivariate regression analysis showed that awareness of self-care responsibility,sudden drug withdrawal,utilization of social support and regular return visit were the independent factors.In the study group,ability for pulse rate measurement and dose adjustment acconding to pulse rate changes improved,phenomenon of sudden drug withdrawal declined and response rate increased,comparing with the control grpup. Conclusins For patients fail to respond to β-blockers,compliance behavior and medication compliance should be analyzed,and much attention should be paid to the education of the related medical knowledge,risk of sudden drug withdrawal and drag using targets.Goal-directed medel could be a guidance for nursing intervention to increase the response rates. Key words: Portalhypertension; β-blocker; Responzerate; Multivariate factors; Goal-directed nursing model

Long-term results for pentostatin and cladribine treatment of hairy cell leukemia

Over the past 25 years we have collected data at our institution from 242 patients with hairy cell leukemia (HCL), treated with pentostatin (n = 188) or cladribine (n = 54), with a median follow-up of 16 years. From this we have been able to conclude that there is no significant difference in outcome between the two agents either at first or subsequent lines of therapy. Overall, the complete response (CR) rate is 81% and the median disease-free survival (DFS) is 16 years. After relapse or non-response patients can be successfully retreated with pentostatin or cladribine achieving a lower rate of CRs with each line of therapy, although these remain equally durable. Complete response and pretreatment counts of hemoglobin >10 g/dL together with platelets >100 × 109/L are associated with the longest DFS. Importantly, for patients achieving a CR the DFS is five times as long as for those achieving a partial response (PR). Patients still in CR at 5 years have only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease have improved with the addition of rituximab to either purine analog. Overall, only eight patients have died of HCL-related causes. Patients with HCL who achieve a CR can expect a normal lifespan.

影响门脉高压β受体阻滞剂应答率的多因素回归研究

：Objective To analyzefactors influencing β -blockerresponds rates on patients with portal hypertension and to investigate the independentfactors on basis of multivariate analysis in an aim to offer objective guideline fornursing intervention. Methods 60 cases of portal hypertension having indication of takinginderal were analyzed after 3 months routine inderal taking. Social support rating scaleand self-designed questionale were collected and analyzed. Multivariate regressionanalysis was performed to establish the independent influencing factors. Results comparingto those with non-response patients,total sc ore of social support was higher in thosewith response patients, among which objective support and utilization degree scores werehigher with statistics significance. Multifactorial analysis showed utilization degreescores and knowledge about the disease and related medicine acquired by patient'srelatives are the independent factors influencing the response rates. Conclusion muchattention should be drawn to the utilization degree from social support and the knowledgeof the disease and related medicine acquired by the patient's relatives in dealing withportal hypertension patients taking β -blocker. Key words: Portal hypertension;

Characterization of elevated alanine aminotransferase levels during pegylated‐interferon α‐2b plus ribavirin treatment for chronic hepatitis C

Elevation of alanine aminotransferase (ALT) levels during pegylated-interferon (peg-IFN) plus ribavirin therapy in patients with chronic hepatitis C [CHC] is a problem that cannot be disregarded. The aim of this study is to assess the frequency and to characterize clinical parameters of this phenomenon. Two hundred and thirty-five (235) CHC patients with genotype 1b receiving peg-IFN α-2b plus ribavirin therapy were analyzed. Clinical parameters that may be associated with abnormal ALT values during treatment and therapy outcomes were evaluated statistically. One hundred and sixteen (116) patients treated with peg-IFN α-2a plus ribavirin were also included for partial analysis. Abnormal ALT values during treatment were observed in 23.0% of patients. It was observed in 14.5% of those with sustained virological response (SVR) and 17.8% of those with relapse, in whom viral clearance was observed during therapy. Multivariate logistic regression analysis revealed that pretreatment ALT values, therapy outcome, and body mass index (BMI) were significant factors related to abnormal ALT values during treatment. Abnormal ALT values during treatment became normal in SVR patients at 6 months after the completion of treatment, but not in NR (non-response) patients. Mean ALT values were significantly higher at some time points during treatment in patients treated with α-2a when compared to those treated with α-2b. Abnormal ALT values during peg-IFN plus ribavirin treatment are observed relatively frequently, even in patients without detectable HCV RNA. Direct or indirect involvement of drugs is considered as one possible cause.

Viral sequence evolution in Chinese genotype 1b chronic hepatitis C patients experiencing unsuccessful interferon treatment

The efficiencies of IFN-α based therapy in chronic genotype 1b HCV patients are still unsatisfied to date. The mechanisms underlining treatment failure remain unclear and controversial. To investigate HCV sequence evolution in unsuccessfully treated genotype 1b patients before, during and after the therapy, full-length open-reading-frame of HCV genomes at week 0, week 48 and year 5 in one breakthrough and one nonresponse patients were amplified by reverse transcription (RT)-nested-PCR and sequenced. Mutations were scored and analyzed according to their locations in the HCV genome. HCV sequences in the breakthrough patient displayed significantly more mutations during the one-year therapy than that in the nonresponse patient, with p7 and NS2 encoding regions having the highest mutation rates. Most of the mutations selected during the therapy phase in the breakthrough patient were maintained and few new mutations arose in the four-year post-therapy phase, suggesting these mutations might not compromise viral fitness. Altogether our data suggest that mutations occurred during the therapy phase in the breakthrough patient are likely driven by the action of interferon and ribavirin, and these mutations may have important effects on the responses to interferon based therapy in genotype 1b HCV patients.

Outcome of children and adolescents with relapsed acute lymphoblastic leukaemia and non-response to salvage protocol therapy: A retrospective analysis of the ALL-REZ BFM Study Group

Aim of the study Non-response (NR) to treatment of childhood relapsed acute lymphoblastic leukaemia (ALL) is an end-point of protocol therapy. Subsequent management has not yet been standardised. This study analyses different approaches after NR to aid optimising future strategies. Patients and methods Ninety-three children with NR to treatment according to ALL relapse-protocols of the Berlin/Frankfurt/Muenster (BFM) Study Group (03/1990–2006/1999) were retrospectively assigned to a curative (C: intensive polychemotherapies, stem cell transplantation (SCT); n = 51), palliative (P: 1–2 antineoplastic agents; n = 23) or supportive (S: no antineoplastic therapy; n = 19) treatment approach. Results Median survival after diagnosis of NR were 121 (C), 89 (P) and 42 (S) days, respectively ( p < 0.001). In cohort C, a complete remission (2ndCR) was obtained in 16/51 patients, among these 13 only after SCT, and nine children achieved partial remission. Ten of the 51 patients died from treatment-related complications, 39/51 from disease progression. Today, two patients are still in continuous CR after SCT. Adverse prognostic factors were overrepresented in the non-curative cohorts. Time-point of relapse and treatment after NR were independent predictors of survival duration. Most patients without antineoplastic treatment died at home, the majority of the others in the hospital. Conclusions Treatment after NR has been heterogeneous and customised. Therapies with curative intent are capable of inducing 2ndCR but associated with high treatment-related morbidity, -mortality and minimal survival. NR patients may, therefore, be ideal candidates for controlled phase I/II trials, thus offering them a chance to benefit from new drugs and promoting drug development for cohorts with better prognosis.

Successful antiviral therapy determines a significant decrease in squamous cell carcinoma antigen‐associated (SCCA) variants’ serum levels in anti‐HCV positive cirrhotic patients*

Aberrant squamous cell carcinoma antigen (SCCA) expression is an early event in hepatocarcinogenesis, and increasing serum levels of SCCA variants IgM immune complexes (SCCA-IgM IC) have been found in cirrhotic patients developing hepatocellular carcinoma (HCC). We longitudinally evaluated a cohort of cirrhotic patients with hepatitis C virus infection (HCV) who underwent pegylated interferon (PEG-IFN) and ribavirin treatment. SCCA-IgM IC levels were assessed in the sera of 33 cirrhotic patients with HCV (21 males, median age 57 years) before, at the end and at 6-month and 1-year follow-up after treatment with PEG-IFN and ribavirin. SCCA-IgM IC serum levels (arbitrary units/mL, AU/mL) were evaluated according to treatment outcome: sustained virological response (SVR) vs nonresponse (NR). Overall, 15 patients obtained a SVR to antiviral therapy (45%). There was no significant difference in baseline SCCA-IgM IC serum levels between SVR and NR patients. When compared to baseline (451.2 AU/mL), SVR patients showed a significant decrease in median SCCA-IgM IC serum levels at the end of treatment (186.8 AU/mL, P = 0.013) and at both 6-month (96.8 AU/mL, P < 0.001) and 1-year follow-up (52.4 AU/mL, P < 0.001), while no significant modification was observed in NR patients. In patients with HCV-related liver cirrhosis, successful antiviral therapy is associated with a dramatic and significant decrease in SCCA-IC serum levels. Because of the pathophysiological correlation between SCCA and liver carcinogenesis, it is hypothesized that in patients with liver cirrhosis, SVR may be accompanied by a decreased proliferative stimulation.

Evidence of a Significant Role for Fas-Mediated Apoptosis in HCV Clearance during Pegylated Interferon plus Ribavirin Combination Therapy

The role of apoptosis in treatment-induced HCV clearance is controversial. We sought to assess the kinetics of serum apoptosis-related cytokines during pegylated interferon-α2a or -α2b plus weight-based ribavirin therapy for genotype 1 chronic HCV infection. Serum levels of soluble Fas (sFas), soluble Fas ligand (sFasL) and soluble tumour necrosis factor receptor I (sTNF-RI) were measured at baseline, week 12 and 24 weeks after the end of therapy. Sustained virological response (SVR) was achieved in 46% of the 164 included patients, 29% had a non-response (NR) and 25% had relapse (RR). NR patients presented with higher levels of sFasL at baseline and lower levels of sTNF-RI at week 12 as compared to RR and SVR patients. Lower concentrations of sFas were observed in SVR patients 24 weeks after treatment as compared to RR and NR patients. An increase in sFas at week 12 followed by a significant drop 24 weeks after therapy was observed among SVR patients. An increase in sFasL during and after treatment was observed in RR and SVR patients. NR patients exhibited an earlier drop in sTNF-RI levels as compared to RR and SVR patients. Virological response during HCV therapy was associated with an increase of sFas and sFasL, and maintenance of increased concentrations of sTNF-RI.

Genotypic resistance to entecavir in chronic hepatitis B patients

The prevalence and clinical characteristics of entecavir (ETV) resistance is not well known. The aim of this study was to determine the frequency of genotypic resistance in nonresponders and virologic breakthrough (VBT) patients. The medical records of 76 chronic hepatitis B patients treated for a least 6 months from October 2006 to October 2008 were reviewed retrospectively. We divided patients into two groups: nucleoside analogue (NA)-naive patients (n=38) and LAM experienced patients (n=38). NA-naive and LAM experienced patients received ETV at 0.5 and 1.0 mg/day, respectively. The virologic response and VBT were investigated in both groups. We used the multiplex restriction fragment mass polymorphism (RFMP) method to test genotypic resistance at the rtI169, rtT184, rtS202, rtM204, and rtM250 sites. Age, gender, serum ALT, and HBV DNA level before treatment did not differ between the groups. Neither VBT nor nonresponse was observed in the NA-naive group, whereas VBT and nonresponse were observed in three patients each in the lamivudine (LAM)-experienced group; all six patients had YMDD mutation at study enrollment, all three patients with VBT had genotypic resistance to ETV, but the three nonresponse patients did not have genotypic resistance to ETV. We suspect that VBT is mostly associated with genotypic resistance to ETV. However, nonresponse might be associated with the continuance or reselection of the YMDD mutant in LAM-experienced patients.

Efficacy of the Addition of Prokinetics for Proton Pump Inhibitor (PPI) Resistant Non-erosive Reflux Disease (NERD) Patients: Significance of Frequency Scale for the Symptom of GERD (FSSG) on Decision of Treatment Strategy

Non-erosive reflux disease (NERD) is a more difficult to treat than reflux esophagitis (RE) due to the high prevalence of PPI resistance. Consequently, the treatment strategy for NERD is yet to be established. Subjects were 467 GERD patients (NERD 349, RE 118, 47.4 +/- 16.7 years) with reflux symptoms such as heartburn. PPI was administered for 2 weeks, and total score (TS) of symptoms, seven items of reflux symptoms e.g. heartburn (reflux score: RS), and five items of dyspeptic symptoms e.g. heavy stomach (dyspeptic score: DS) were assessed using the frequency scale for the symptoms of GERD (FSSG), a GERD-specific questionnaire developed in Japan. Improvement <50% in TS was defined as non-responder. Patients' background, and pretreatment TS, RS, DS, and 12 items of FSSG were assessed. Furthermore, the effect of additional prokinetics (4 weeks) for 117 PPI non-response NERD patients was also examined. Younger age, constipation, higher TS, DS, F2 (bloated stomach), 3 (heavy stomach), 5 (sick feeling after meal), 8 (satiety during meal) in FSSG were factors to be PPI non-responders in NERD. Significant improvement in TS were observed (pretreatment: 17.4 +/- 7.7 vs. 2 weeks 14.6 +/- 6.0 vs. 6 weeks 7.7 +/- 5.2, p<0.0001) after the addition of prokinetics in PPI non-response NERD. Younger age, constipation, dysmotility were factors of PPI non-response in NERD. As high DS is correlated with PPI non-response, it is indicated that patients with strong dysmotility and functional dyspepsia complication might be PPI resistant. The efficacy of additional prokinetics for PPI non-response NERD was observed.

Application of SENP-1, HIF-1α and VEGF Gene Expressions in Prognostic Prediction for Normal Karyotypic Acute Leukemia Patients with NPM1 + and FLT3-ITD-.

Abstract 4723In our study, 26 BM species from 23 normal karyotypic acute leukemia patients (non-APL) with NPM+ and FLT3-ITD- gene mutation were collected in our department. Compared to healthy controls, SENP1, HIF-1alpha and VEGF mRNA expression in ALL and AML patients were elevated to 10.0, 13.2, 16.6 and 43.1, 97.75, 240.0 folds, respectively, by RT-real time PCR. The levels of SENP1, HIF-1αand VEGF mRNA in AML patients were greatly higher than those in ALL (p<0.05). SENP1 and HIF-1alpha expression levels were positively and significantly correlated (linear regression analysis, r = 0.88, p<0.05) both in ALL and AML. The correlation between HIF-1alpha and VEGF mRNA level was statistically significant (linear regression analysis, r = 0.34, p<0.05). Among AML patients, SENP1, HIF-1alpha and VEGF gene expressive level in non-response (NR) patients (n=7) were higher than patients with CR (n=9), p<0.01. For ALL patients, the expressive level (‘X±S) of SENP1, HIF-1alpha, VEGF gene in NR(n=3)were slightly higher than those in CR (n=4): 10.5±2.7, 6.8±3.4; 13.2±16.6, 3.9±3.0; 13.1±10.1,11.1±12.1. Elevated gene expression of SENP1, HIF-1alpha and VEGF indicate shorter survival time of patients, p<0.01.The levels of SENP1, HIF-1alpha and VEGF gene decreased after treatment in 3 AML patients. Thus, higher SENP1, HIF-1alpha and VEGF gene levels might be associated with shortened survival and worse clinical process. Therefore, although higher expression of SENP1, HIF-1alpha and VEGF gene might throw an impact on the prognostic prediction in acute leukemia patients, confirmation of this hypothesis need to be done in more large population. Disclosures:No relevant conflicts of interest to declare.

Increased Plasma Brain-Derived Neurotropic Factor, Not Nerve Growth Factor-Beta, in Schizophrenia Patients with Better Response to Risperidone Treatment

Background: Some neurotropins, including brain-derived neurotropic factor (BDNF) or nerve growth factor-β (β-NGF), play important roles in neurodevelopment and neuroprotection. We examined the plasma levels of these 2 factors in schizophrenia patients at the time of admission and after 6 weeks of treatment with risperidone. Methods: Plasma BDNF and β-NGF levels were measured in 36 schizophrenia patients and 36 healthy controls. All the patients underwent 6 weeks of treatment with risperidone. The severity of schizophrenia and response to treatment were assessed with the positive and negative syndrome scale (PANSS). We compared plasma BDNF and β-NGF levels among much-improved (n = 13, 36.1%, ≥50% PANSS score reduction), minimal-improved (n = 15, 41.7%, ≥25% and <50% PANSS score reduction) and nonresponse patients (n = 8, 22.2%, <25% PANSS score reduction). Results: At baseline, plasma BDNF had no significant difference between schizophrenia patients and controls, but β-NGF levels were significantly lower in schizophrenia patients than controls (p = 0.037). Plasma BDNF and β-NGF in all schizophrenia patients had no significant changes between pre- and posttreatment. Baseline BDNF levels were significantly lower in nonresponse patients than others (p = 0.038). After treatment, much-improved patients had significantly higher plasma BDNF than nonresponse patients (p = 0.023). However, β-NGF levels had no significant differences between them. Conclusions: Our data suggest that higher plasma BDNF levels might be associated with better response to risperidone treatment, while plasma β-NGF levels might have no effect on the clinical response in schizophrenia patients.