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The Cochrane Database of Systematic... Mar 2017Between 40% and 70% of people with treatment-resistant schizophrenia do not respond to clozapine, despite adequate blood levels. For these people, a number of treatment... (Review)
Review
BACKGROUND
Between 40% and 70% of people with treatment-resistant schizophrenia do not respond to clozapine, despite adequate blood levels. For these people, a number of treatment strategies have emerged, including the prescription of a second anti-psychotic drug in combination with clozapine.
OBJECTIVES
To determine the clinical effects of various clozapine combination strategies with antipsychotic drugs in people with treatment-resistant schizophrenia both in terms of efficacy and tolerability.
SEARCH METHODS
We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (to 28 August 2015) and MEDLINE (November 2008). We checked the reference lists of all identified randomised controlled trials (RCT). For the first version of the review, we also contacted pharmaceutical companies to identify further trials.
SELECTION CRITERIA
We included only RCTs recruiting people of both sexes, aged 18 years or more, with a diagnosis of treatment-resistant schizophrenia (or related disorders) and comparing clozapine plus another antipsychotic drug with clozapine plus a different antipsychotic drug.
DATA COLLECTION AND ANALYSIS
We extracted data independently. For dichotomous data, we calculated risk ratios (RRs) and 95% confidence intervals (CI) on an intention-to-treat basis using a random-effects meta-analysis. For continuous data, we calculated mean differences (MD) and 95% CIs. We used GRADE to create 'Summary of findings' tables and assessed risk of bias for included studies.
MAIN RESULTS
We identified two further studies with 169 participants that met our inclusion criteria. This review now includes five studies with 309 participants. The quality of evidence was low, and, due to the high degree of heterogeneity between studies, we were unable to undertake a formal meta-analysis to increase the statistical power.For this update, we specified seven main outcomes of interest: clinical response in mental state (clinically significant response, mean score/change in mental state), clinical response in global state (mean score/change in global state), weight gain, leaving the study early (acceptability of treatment), service utilisation outcomes (hospital days or admissions to hospital) and quality of life.We found some significant differences between clozapine combination strategies for global and mental state (clinically significant response and change), and there were data for leaving the study early and weight gain. We found no data for service utilisation and quality of life. Clozapine plus aripiprazole versus clozapine plus haloperidolThere was no long-term significant difference between aripiprazole and haloperidol combination strategies in change of mental state (1 RCT, n = 105, MD 0.90, 95% CI -4.38 to 6.18, low quality evidence). There were no adverse effect data for weight gain but there was a benefit of aripiprazole for adverse effects measured by the LUNSERS at 12 weeks (1 RCT, n = 105, MD -4.90, 95% CI -8.48 to -1.32) and 24 weeks (1 RCT, n = 105, MD -4.90, 95% CI -8.25 to -1.55), but not 52 weeks (1 RCT, n = 105, MD -4.80, 95% CI -9.79 to 0.19). Similar numbers of participants from each group left the study early (1 RCT, n = 106, RR 1.27, 95% CI 0.72 to 2.22, very low quality evidence). Clozapine plus amisulpride versus clozapine plus quetiapine One study showed a significant benefit of amisulpride over quetiapine in the short term, for both change in global state (Clinical Global Impression (CGI): 1 RCT, n = 50, MD -0.90, 95% CI -1.38 to -0.42, very low quality evidence) and mental state (Brief Psychiatric Rating Scale (BPRS): 1 RCT, n = 50, MD -4.00, 95% CI -5.86 to -2.14, low quality evidence). Similar numbers of participants from each group left the study early (1 RCT, n = 56, RR 0.20, 95% CI 0.02 to 1.60, very low quality evidence) Clozapine plus risperidone versus clozapine plus sulpirideThere was no difference between risperidone and sulpiride for clinically significant response, defined by the study as 20% to 50% reduction in Positive and Negative Syndrome Scale (PANSS) (1 RCT, n = 60, RR 0.82, 95% CI 0.40 to 1.68, very low quality evidence). There were similar equivocal results for weight gain (1 RCT, n = 60, RR 0.40, 95% CI 0.08 to 1.90, very low quality evidence) and mental state (PANSS total: 1 RCT, n = 60, MD -2.28, 95% CI -7.41 to 2.85, very low quality evidence). No-one left the study early. Clozapine plus risperidone versus clozapine plus ziprasidoneThere was no difference between risperidone and ziprasidone for clinically significant response (1 RCT, n = 24, RR 0.80, 95% CI 0.28 to 2.27, very low quality evidence), change in global state CGI-II score (1 RCT, n = 22, MD -0.30, 95% CI -0.82 to 0.22, very low quality evidence), change in PANSS total score (1 RCT, n = 16, MD 1.00, 95% CI -7.91 to 9.91, very low quality evidence) or leaving the study early (1 RCT, n = 24, RR 1.60, 95% CI 0.73 to 3.49, very low quality evidence). Clozapine plus ziprasidone versus clozapine plus quetiapineOne study found, in the medium term, a superior effect for ziprasidone combination compared with quetiapine combination for clinically significant response in mental state (> 50% reduction PANSS: 1 RCT, n = 63, RR 0.54, 95% CI 0.35 to 0.81, low quality evidence), global state (CGI - Severity score: 1 RCT, n = 60, MD -0.70, 95% CI -1.18 to -0.22, low quality evidence) and mental state (PANSS total score: 1 RCT, n = 60, MD -12.30, 95% CI -22.43 to -2.17, low quality evidence). There was no effect for leaving the study early (1 RCT, n = 63, RR 0.52, CI 0.05 to 5.41, very low quality evidence).
AUTHORS' CONCLUSIONS
The reliability of results from this review is limited, evidence is of low or very low quality. Furthermore, due to the limited number of included studies, we were unable to undertake formal meta-analyses. As a consequence, any conclusions drawn from these findings are based on single, small-sized RCTs with high risk of type II error. Properly conducted and adequately powered RCTs are required. Future trialists should seek to measure patient-important outcomes such as quality of life, as well as clinical response and adverse effects.
Topics: Adult; Amisulpride; Antipsychotic Agents; Aripiprazole; Clozapine; Dibenzothiazepines; Drug Resistance; Drug Therapy, Combination; Female; Haloperidol; Humans; Male; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Sulpiride; Thiazoles; Weight Gain
PubMed: 28333365
DOI: 10.1002/14651858.CD006324.pub3 -
The Cochrane Database of Systematic... Mar 2017Infection with hepatitis B virus (HBV) can be symptomatic or asymptomatic. Apart from chronic HBV infection, the complications related to acute HBV infection are severe... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Infection with hepatitis B virus (HBV) can be symptomatic or asymptomatic. Apart from chronic HBV infection, the complications related to acute HBV infection are severe acute viral hepatitis and fulminant hepatitis characterised by liver failure. The optimal pharmacological treatment of acute HBV infection remains controversial.
OBJECTIVES
To assess the benefits and harms of pharmacological interventions in the treatment of acute HBV infection through a network meta-analysis and to generate rankings of the available treatments according to their safety and efficacy. As it was not possible to assess whether the potential effect modifiers were similar across different comparisons, we did not perform the network meta-analysis, and instead, assessed the benefits and harms of different interventions using standard Cochrane methodological procedures.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, WHO International Clinical Trials Registry Platform, and randomised clinical trials (RCTs) registers to August 2016 to identify RCTs on pharmacological interventions for acute HBV infection.
SELECTION CRITERIA
RCTs, irrespective of language, blinding, or publication status in participants with acute HBV infection. We excluded trials if participants had previously undergone liver transplantation and had other coexisting viral diseases such as hepatitis C virus and HIV. We considered any of the various pharmacological interventions compared with each other or with placebo, or no intervention.
DATA COLLECTION AND ANALYSIS
We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed risk of bias, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE.
MAIN RESULTS
Seven trials (597 participants) met our review inclusion criteria. All trials provided information for one or more outcomes; however, five participants were excluded from analysis by study authors. All the trials were at high risk of bias. Overall, all the evidence was low or very low quality evidence because of risk of bias (downgraded one level for risk of bias), small sample size (downgraded one level for imprecision), and wide CIs (downgraded one more level for imprecision in some comparisons). Of the seven trials, six were two-armed trials, while one trial was a three-armed trial. The comparisons included hepatitis B immunoglobulin (HBIG) versus placebo (one trial; 55 participants); interferon versus placebo (two trials; 200 participants); lamivudine versus placebo or no intervention (four trials; 316 participants); lamivudine versus entecavir (one trial; 90 participants); and entecavir versus no intervention (one trial; 131 participants). One trial included only people with acute HBV with hepatic encephalopathy (i.e. people with fulminant liver failure); one trial included only people with severe acute HBV, but it did not state whether any of the people also had fulminant HBV infection; three trials excluded fulminant HBV infection; and two trials did not report the severity of acute HBV infection. The mean or median follow-up period in the trials ranged from three to 12 months in the trials that provided this information.There was no evidence of any differences in short-term mortality (less than one year) in any of the comparisons: HBIG versus placebo (OR 1.13, 95% CI 0.36 to 3.54; participants = 55; 1 trial), lamivudine versus placebo or no intervention (OR 1.29, 95% CI 0.33 to 4.99; participants = 250; 2 trials); lamivudine versus entecavir (OR 1.23, 95% CI 0.13 to 11.65; participants = 90; 1 trial), or entecavir versus no intervention (OR 1.05, 95% CI 0.12 to 9.47; participants = 131; 1 trial). The proportion of people who progressed to chronic HBV infection was higher in the lamivudine group than the placebo or no intervention group (OR 1.99, 95% CI 1.05 to 3.77; participants = 285; 3 trials) and in the lamivudine group versus entecavir group (OR 3.64, 95% CI 1.31 to 10.13; participants = 90; 1 trial). There was no evidence of a difference in the proportion of people who progressed to chronic HBV infection between the entecavir and the no intervention groups (OR 0.58, 95% CI 0.23 to 1.49; participants = 131; 1 trial). None of the trials reported progression to fulminant HBV infection. Three trials with 371 participants reported serious adverse events. There were no serious adverse events in any of the groups (no intervention: 0/183 (0%), interferon: 0/67 (0%), lamivudine: 0/100 (0%), and entecavir: 0/21 (0%)). The proportion of people with adverse events was higher in the interferon group than the placebo group (OR 348.16, 95% CI 45.39 to 2670.26; participants = 200; 2 trials). There was no evidence of a difference in the proportion of people with adverse events between the lamivudine group and the placebo or no intervention group (OR 1.42, 95% CI 0.34 to 5.94; participants = 35; 1 trial) or number of adverse events between the lamivudine group and the placebo or no intervention group (rate ratio 1.72, 95% CI 1.01 to 2.91; participants = 35; 1 trial). One trial with 100 participants reported quality of life at one week. The scale used to report the health-related quality of life was not stated and lacked information on whether higher score meant better or worse, making it difficult to interpret the results. None of the trials reported quality of life beyond one week or other clinical outcomes such as mortality beyond one year, liver transplantation, cirrhosis, decompensated cirrhosis, or hepatocellular carcinoma.Two trials received funding from pharmaceutical companies; three trials were funded by parties without any vested interest in the results or did not receive any special funding; the source of funding was not available in the remaining two trials.
AUTHORS' CONCLUSIONS
Low or very low quality evidence suggests that progression to chronic HBV infection was higher in people receiving lamivudine compared with placebo, no intervention, or entecavir. Low quality evidence suggests that interferon may increase the adverse events after treatment for acute HBV infection. Based on a very low quality evidence, there is currently no evidence of benefit of any intervention in acute HBV infection. There is significant uncertainty in the results and further RCTs are required.
Topics: Acute Disease; Antiviral Agents; Disease Progression; Guanine; Hepatic Encephalopathy; Hepatitis B; Hepatitis C, Chronic; Humans; Immunization, Passive; Interferons; Lamivudine; Network Meta-Analysis; Odds Ratio; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors
PubMed: 28321877
DOI: 10.1002/14651858.CD011645.pub2 -
Cancer Treatment Reviews Mar 2017It is assumed that DNA methylation plays a key role in both tumour development and therapy resistance. Demethylating agents have been shown to be effective in the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
It is assumed that DNA methylation plays a key role in both tumour development and therapy resistance. Demethylating agents have been shown to be effective in the treatment of haematological malignancies. Based on encouraging preclinical results, demethylating agents may also be effective in solid tumours. This systematic review summarizes the evidence of the effect of demethylating agents on clinical response, methylation and the immune system in solid tumours.
METHODS
We conducted a systematic literature search from 1949 to December 2016, according to the PRISMA guidelines. Studies which evaluated treatment with azacitidine, decitabine, guadecitabine, hydralazine, procaine, MG98 and/or zebularine in patients with solid tumours were included. Data on clinical response, effects on methylation and immune response were extracted.
RESULTS
Fifty-eight studies were included: in 13 studies complete responses (CR) were observed, 35 studies showed partial responses (PR), 47 studies stable disease (SD) and all studies except two showed progressive disease (PD). Effects on global methylation were observed in 11/15 studies and demethylation/re-expression of tumour specific genes was seen in 15/17 studies. No clear correlation between (de)methylation and clinical response was observed. In 14 studies immune-related responses were reported, such as re-expression of cancer-testis antigens and upregulation of interferon genes.
CONCLUSION
Demethylating agents are able to improve clinical outcome and alter methylation status in patients with solid tumours. Although beneficial effect has been shown in individual patients, overall response is limited. Further research on biomarker predicting therapy efficacy is indicated, particularly in earlier stage and highly methylated tumours.
Topics: Antimetabolites, Antineoplastic; Azacitidine; Cytidine; DNA Methylation; Decitabine; Humans; Hydralazine; Immune System; Methylation; Neoplasms; Procaine; Treatment Outcome
PubMed: 28189913
DOI: 10.1016/j.ctrv.2017.01.004 -
The Cochrane Database of Systematic... Jan 2017The therapeutic management of people with metastatic colorectal cancer (CRC) who did not respond to first-line treatment represents a formidable challenge. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The therapeutic management of people with metastatic colorectal cancer (CRC) who did not respond to first-line treatment represents a formidable challenge.
OBJECTIVES
To determine the efficacy and toxicity of second-line systemic therapy in people with metastatic CRC.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 4), Ovid MEDLINE (1950 to May 2016), Ovid MEDLINE In-process & Other Non-Indexed Citations (1946 to May 2016) and Ovid Embase (1974 to May 2016). There were no language or date of publication restrictions.
SELECTION CRITERIA
Randomized controlled trials (RCTs) assessing the efficacy (survival, tumour response) and toxicity (incidence of severe adverse effects (SAEs)) of second-line systemic therapy (single or combined treatment with any anticancer drug, at any dose and number of cycles) in people with metastatic CRC that progressed, recurred or did not respond to first-line systemic therapy.
DATA COLLECTION AND ANALYSIS
Authors performed a descriptive analysis of each included RCT in terms of primary (survival) and secondary (tumour response, toxicity) endpoints. In the light of the variety of drug regimens tested in the included trials, we could carry out meta-analysis considering classes of (rather than single) anticancer regimens; to this aim, we applied the random-effects model to pool the data. We used hazard ratios (HRs) and risk ratios (RRs) to describe the strength of the association for survival (overall (OS) and progression-free survival (PFS)) and dichotomous (overall response rate (ORR) and SAE rate) data, respectively, with 95% confidence intervals (CI).
MAIN RESULTS
Thirty-four RCTs (enrolling 13,787 participants) fulfilled the eligibility criteria. Available evidence enabled us to address multiple clinical issues regarding the survival effects of second-line systemic therapy of people with metastatic CRC.1. Chemotherapy (irinotecan) was more effective than best supportive care (HR for OS: 0.58, 95% CI 0.43 to 0.80; 1 RCT; moderate-quality evidence); 2. modern chemotherapy (FOLFOX (5-fluorouracil plus leucovorin plus oxaliplatin), irinotecan) is more effective than outdated chemotherapy (5-fluorouracil) (HR for PFS: 0.59, 95% CI 0.49 to 0.73; 2 RCTs; high-quality evidence) (HR for OS: 0.69, 95% CI 0.51 to 0.94; 1 RCT; moderate-quality evidence); 3. irinotecan-based combinations were more effective than irinotecan alone (HR for PFS: 0.68, 95% CI 0.60 to 0.76; 6 RCTs; moderate-quality evidence); 4. targeted agents improved the efficacy of conventional chemotherapy both when considered together (HR for OS: 0.84, 95% CI 0.77 to 0.91; 6 RCTs; high-quality evidence) and when bevacizumab was used alone (HR for PFS: 0.67, 95% CI 0.60 to 0.75; 4 RCTs; high-quality evidence).With regard to secondary endpoints, tumour response rates generally paralleled the survival results; moreover, higher anticancer efficacy was generally associated with worse treatment-related toxicity, with the important exception of bevacizumab-containing regimens, where the addition of the targeted agent to chemotherapy did not result in a significant increase in the rate of SAE. Finally, we found that oral (instead of intravenous) fluoropyrimidines significantly reduced the incidence of adverse effects (without compromising efficacy) in people treated with oxaliplatin-based regimens.We could not draw any conclusions on other debated aspects in this field of oncology, such as ranking of treatments (not all possible comparisons have been tested and many comparisons were based on single trials enrolling a small number of participants) and quality of life (virtually no data available).
AUTHORS' CONCLUSIONS
Systemic therapy offers a survival benefit to people with metastatic CRC who did not respond to first-line treatment, especially when targeted agents are combined with conventional chemotherapeutic drugs. Further research is needed to define the optimal regimen and to identify people who most benefit from each treatment.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Randomized Controlled Trials as Topic; Survival Rate
PubMed: 28128439
DOI: 10.1002/14651858.CD006875.pub3 -
PloS One 2017HBeAg seroconversion is an important intermediate outcome in HBeAg-positive chronic hepatitis B (CHB) patients. This study aimed to compare the effect of nucleos(t)ide... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
HBeAg seroconversion is an important intermediate outcome in HBeAg-positive chronic hepatitis B (CHB) patients. This study aimed to compare the effect of nucleos(t)ide analogs (NAs) on HBeAg seroconversion in treating CHB with lamivudine, adefovir, telbivudine, entecavir, and tenofovir.
METHODS
Network meta-analysis of NA treatment-induced HBeAg seroconversion after 1-2 years of treatment was performed. In addition, NA treatment-induced HBeAg seroconversion after 3-5 years of treatment was systematically evaluated.
RESULTS
A total of 31 articles were included in this study. Nine and five studies respectively reporting on 1- and 2-year treatment were included in our network meta-analysis. In addition, 6, 5, and 5 studies, respectively reporting on 3-, 4-, and 5-year treatment were included in our systematic evaluation. Telbivudine showed a significantly higher HBeAg seroconversion rate after a 1 year treatment period compared to the other NAs (odds ratio (OR) = 3.99, 95% CI 0.68-23.6). This was followed by tenofovir (OR = 3.36, 95% CI 0.70-16.75). Telbivudine also showed a higher seroconversion rate compared to the other NAs after a 2 year treatment period, (OR = 1.38, 95% CI 0.92-2.22). This was followed by entecavir (OR = 1.14, 95% CI 0.72-1.72). No significant difference was observed between spontaneous induction and long-term telbivudine treatment-induced HBeAg seroconversion. However, entecavir and tenofovir treatment-induced HBeAg seroconversions were significantly lower than spontaneous seroconversion.
CONCLUSION
Long-term treatment with potent anti-HBV drugs, especially tenofovir and entecavir, may reduce HBeAg seroconversion compared with spontaneous HBeAg seroconversion rate. Telbivudine treatment, whether short term or long term, is associated with higher HBeAg seroconversion compared with the other NAs. However, the high rates of drug resistance likely limit the application of telbivudine.
Topics: Antiviral Agents; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Telbivudine; Thymidine
PubMed: 28107377
DOI: 10.1371/journal.pone.0169444 -
Journal of B.U.ON. : Official Journal... 2016To assess the efficacy and safety of S-1 plus sorafenib for the treatment of advanced hepatocellular carcinoma (HCC). (Review)
Review
PURPOSE
To assess the efficacy and safety of S-1 plus sorafenib for the treatment of advanced hepatocellular carcinoma (HCC).
METHODS
PubMed, the Cochrane Library, EMBASE, and ClinicalTrials.gov were searched using the terms "Hepatocellular Carcinoma" or "HCC" or "Hepatoma" or "Liver cancer" and "S-1" and "Sorafenib" or "Nexavar". Outcomes of main interest included overall survival (OS) and toxicities.
RESULTS
We identified 2 studies of S"1 plus sorafenib from 77 references that included a total of 65 patients. The percentage of male patients ranged from 70.0 to 89.5%. Median age was 59.2 years and ranged from 48.0 to 65.5 years. The percentage of hepatitis B virus ranged from 23.1 to 90.0%. The recommended dose of S-1 and sorafenib was 80 or 64 mg/m/day and 800 mg/day, respectively and treatment was administered orally on days 1-14 and days 1-21, respectively. Median OS were 10.4 and 10.5 months, respectively. The incidence of all-grade toxicities of more than 30% were hand"foot syndrome (HFS) and rash. The incidence of grade 3/4 toxicities more than 5% were thrombocytopenia, elevated AST/ALT and hyperbilirubinemia.
CONCLUSION
This systematic review suggests that S-1 plus sorafenib showed modest clinical efficacy and tolerable toxicity profile in patients with advanced HCC. The recommended dose of S-1 and sorafenib was 80 or 64 mg/m/day and 800 mg/day, respectively.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Disease Progression; Disease-Free Survival; Drug Combinations; Female; Humans; Liver Neoplasms; Male; Middle Aged; Niacinamide; Oxonic Acid; Phenylurea Compounds; Protein Kinase Inhibitors; Sorafenib; Tegafur; Time Factors; Treatment Outcome
PubMed: 28039697
DOI: No ID Found -
Annals of the Rheumatic Diseases Aug 2017The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new...
The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.
Topics: Angiotensin-Converting Enzyme Inhibitors; Delphi Technique; Endothelin Receptor Antagonists; Europe; Fingers; Fluoxetine; Gastrointestinal Diseases; Glucocorticoids; Hematopoietic Stem Cell Transplantation; Humans; Hypertension, Pulmonary; Kidney Diseases; Lung Diseases; Phosphodiesterase 5 Inhibitors; Prostaglandins I; Pyrazoles; Pyrimidines; Raynaud Disease; Rheumatology; Scleroderma, Systemic; Selective Serotonin Reuptake Inhibitors; Ulcer
PubMed: 27941129
DOI: 10.1136/annrheumdis-2016-209909 -
Oncotarget Jan 2017Ten-eleven translocation (TET) enzymes catalyze the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and then to 5-formylcytosine (5-fC) and... (Meta-Analysis)
Meta-Analysis Review
Ten-eleven translocation (TET) enzymes catalyze the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and then to 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC), resulting in genomic DNA demethylation. Decreased 5-hmC levels have been reported in a variety of cancers, and loss of 5-hmC might be considered an epigenetic hallmark of cancer. However, the prognostic value of decreased 5-hmC in cancers remain controversial. Here, a systematic review was performed by conducting an electronic search of PubMed, EMBASE, Web of Science and the Cochrane Library. Finally, ten studies with a total of 1736 patients with cancer were included in the present study. Negative/low 5-hmC levels were significantly associated with lymph node metastasis [OR=2.20, 95% CI=1.23-3.96, P=0.008] and advanced TNM stage [OR=2.89, 95% CI=1.21-6.92, P=0.017]. More importantly, negative/low 5-hmC levels were significantly associated with poor prognosis of cancer patients [overall survival: HR=1.76, 95% CI=1.41-2.11, P < 0.001; disease free survival: HR=1.28, 95% CI=0.60-1.96, P < 0.001]. The results of this meta-analysis indicate that decreased 5-hmC levels are an indicator of poor survival of cancer patients. Given variability related to ethnicity, cancer types and detection methods, additional well-designed studies with larger sample sizes are required to further confirm our findings.
Topics: 5-Methylcytosine; Cytosine; DNA Methylation; Humans; Lymphatic Metastasis; Neoplasms; Prognosis
PubMed: 27911867
DOI: 10.18632/oncotarget.13719 -
Advances in Therapy Jan 2017Regulatory requirements mandate that new drugs for treatment of patients with type 2 diabetes mellitus (T2DM), such as dipeptidyl peptidase-4 (DPP-4) inhibitors and... (Review)
Review
INTRODUCTION
Regulatory requirements mandate that new drugs for treatment of patients with type 2 diabetes mellitus (T2DM), such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, are evaluated to show that they do not increase cardiovascular (CV) risk.
METHODS
A systematic review was undertaken to evaluate the association between DPP-4 inhibitor and GLP-1 receptor agonist use and major adverse cardiac events (MACE). The National Institutes of Health Medline database was searched for pooled analyses, meta-analyses, and randomized controlled trials (RCTs) of DPP-4 inhibitors and GLP-1 receptor agonists that included CV endpoints.
RESULTS
Thirty-six articles met the inclusion criteria encompassing 11 pooled analyses, 17 meta-analyses, and eight RCTs (including secondary analyses). Over the short term (up to 4 years), patients with T2DM exposed to a DPP-4 inhibitor or GLP-1 receptor agonist were not at increased risk for MACE (or its component endpoints) compared with those who received comparator agents. Two meta-analyses showed a significant reduction in the incidence of MACE associated with DPP-4 inhibitor therapy as a drug class, but this beneficial effect was not observed in other meta-analyses that included large RCT CV outcome studies. In four RCTs that evaluated alogliptin, saxagliptin, sitagliptin, or lixisenatide, there was no overall increased risk for MACE relative to placebo in T2DM patients at high risk for CV events or with established CV disease, although there was an increased rate of hospitalization for heart failure associated with saxagliptin. A fifth RCT showed that liraglutide reduced MACE risk by 13% versus placebo.
CONCLUSION
Overall, incretin therapy does not appear to increase risk for MACE in the short term.
Topics: Adamantane; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Meta-Analysis as Topic; Peptides; Piperidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Uracil
PubMed: 27844335
DOI: 10.1007/s12325-016-0432-4 -
The Cochrane Database of Systematic... Nov 2016Any type of seizure can be observed in Alzheimer's disease (AD). Antiepileptic drugs seem to prevent the recurrence of epileptic seizures in most people with AD. There... (Review)
Review
BACKGROUND
Any type of seizure can be observed in Alzheimer's disease (AD). Antiepileptic drugs seem to prevent the recurrence of epileptic seizures in most people with AD. There are pharmacological and non-pharmacological treatments for epilepsy in people with AD. There are no current systematic reviews to evaluate the efficacy and tolerability of the treatment. This review aims to review those different modalities.
OBJECTIVES
To assess the efficacy and tolerability of the treatment of epilepsy for people with Alzheimer's disease (AD) (including sporadic AD and dominantly inherited AD).
SEARCH METHODS
We searched the Cochrane Epilepsy Group Specialized Register (1 February 2016), the Cochrane Central Register of Controlled Trials (1 February 2016), MEDLINE (Ovid, 1 February 2016) and ClinicalTrials.gov (1 February 2016). In an effort to identify further published, unpublished and ongoing trials, we searched ongoing trials' registers, reference lists and relevant conference proceedings, and contacted authors and pharmaceutical companies.
SELECTION CRITERIA
We included randomised and quasi-randomised controlled trials investigating treatment for epilepsy in people with AD, with the outcomes of proportion of seizure freedom or experiencing adverse events.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. We performed no meta-analyses due to the limited available data.
MAIN RESULTS
We included one randomised controlled trial with 95 participants. Concerning the proportion of participants with seizure freedom, no significant differences were found in levetiracetam (LEV) versus lamotrigine (LTG) (risk ratio (RR) 1.20, 95% confidence interval (CI) 0.53 to 2.71), in levetiracetam versus phenobarbital (PB) (RR 1.01, 95% CI 0.47 to 2.19), or in LTG versus PB (RR 0.84, 95% CI 0.35 to 2.02). It seemed that LEV could improve cognition and LTG could relieve depression; while PB and LTG could worsen cognition, and LEV and PB could worsen mood. We judged the quality of the evidence to be very low.
AUTHORS' CONCLUSIONS
This review does not provide sufficient evidence to support LEV, PB and LTG for the treatment of epilepsy in people with AD. Regarding the efficacy and tolerability, no significant differences were found between LEV, PB and LTG. In the future, large randomised, double-blind, controlled, parallel-group clinical trials are required to determine the efficacy and tolerability of treatment for epilepsy in people with AD.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Anticonvulsants; Cognition; Depression; Epilepsy; Female; Humans; Lamotrigine; Levetiracetam; Male; Phenobarbital; Piracetam; Randomized Controlled Trials as Topic; Triazines
PubMed: 27805721
DOI: 10.1002/14651858.CD011922.pub2