Mucinous cystic neoplasms of the mesentery: a case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Mucinous cystic neoplasms arise in the ovary and various extra-ovarian sites. While their pathogenesis remains conjectural, their similarities suggest a common pathway of development. There have been rare reports involving the mesentery as a primary tumour site.</p> <p>Case presentation</p> <p>A cystic mass of uncertain origin was demonstrated radiologically in a 22 year old female with chronic abdominal pain. At laparotomy, the mass was fixed within the colonic mesentery. Histology demonstrated a benign mucinous cystadenoma.</p> <p>Methods and results</p> <p>We review the literature on mucinous cystic neoplasms of the mesentery and report on the pathogenesis, biologic behavior, diagnosis and treatment of similar extra-ovarian tumors. We propose an updated classification of mesenteric cysts and cystic tumors.</p> <p>Conclusion</p> <p>Mucinous cystic neoplasms of the mesentery present almost exclusively in women and must be considered in the differential diagnosis of mesenteric tumors. Only full histological examination of a mucinous cystic neoplasm can exclude a borderline or malignant component. An updated classification of mesenteric cysts and cystic tumors is proposed.</p

Disconnection of drug-response and placebo-response in acute-phase antipsychotic drug trials on schizophrenia? Meta-regression analysis

Differences in efficacy between antipsychotics and placebo in schizophrenia trials have decreased over the past decades. Previous studies have tried to identify potential explanatory factors focusing on response to placebo; however, it is still not clear which factors, if any, specifically moderate drug-response, as they may be different from those moderating placebo-response. Therefore, in this meta-regression analysis we explore whether there is an interaction between drug-response and placebo-response in terms of effect size. We systematically searched multiple electronic databases, ClinicalTrials.gov, and the US Food and Drug Administration website for randomized, placebo-controlled trials investigating the efficacy of antipsychotics in patients with acute schizophrenia (last update: October 2016). The main outcome was the change on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale score from baseline to endpoint after at least 3 weeks of treatment. Multiple patient-, design-, and drug-related potential predictors of response were analyzed by meta-regressions, as predefined in the study protocol. Overall, 167 trials with 28,102 participants were included. Publication year, the number of participants and sites, mean dose, minimum severity threshold as an inclusion criterion, chronicity, industry sponsorship, type of rating scale, diagnostic criteria, and number of medications had a different impact on drug and placebo response. By contrast, baseline severity, duration of wash-out, study duration, and study region affected drug and placebo response in a similar way without a net effect on effect sizes. No other factors had a significant effect on either drug-response or placebo-response. In conclusion, as individual moderators may have different impact on placebo-response and drug-response, it is important to consider also the specific factors influencing drug-response in order to fully understand the difference between antipsychotics and placebo. These results shed further light on the phenomenon of decreasing effect size of antipsychotics for schizophrenia over time and should help design future randomized controlled trials in the field (Prospero registration number CRD42013003342)

Disconnection of drug-response and placebo-response in acute-phase antipsychotic drug trials on schizophrenia? Meta-regression analysis

Differences in efficacy between antipsychotics and placebo in schizophrenia trials have decreased over the past decades. Previous studies have tried to identify potential explanatory factors focusing on response to placebo; however, it is still not clear which factors, if any, specifically moderate drug-response, as they may be different from those moderating placebo-response. Therefore, in this meta-regression analysis we explore whether there is an interaction between drug-response and placebo-response in terms of effect size. We systematically searched multiple electronic databases, ClinicalTrials.gov, and the US Food and Drug Administration website for randomized, placebo-controlled trials investigating the efficacy of antipsychotics in patients with acute schizophrenia (last update: October 2016). The main outcome was the change on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale score from baseline to endpoint after at least 3 weeks of treatment. Multiple patient-, design-, and drug-related potential predictors of response were analyzed by meta-regressions, as predefined in the study protocol. Overall, 167 trials with 28,102 participants were included. Publication year, the number of participants and sites, mean dose, minimum severity threshold as an inclusion criterion, chronicity, industry sponsorship, type of rating scale, diagnostic criteria, and number of medications had a different impact on drug and placebo response. By contrast, baseline severity, duration of wash-out, study duration, and study region affected drug and placebo response in a similar way without a net effect on effect sizes. No other factors had a significant effect on either drug-response or placebo-response. In conclusion, as individual moderators may have different impact on placebo-response and drug-response, it is important to consider also the specific factors influencing drug-response in order to fully understand the difference between antipsychotics and placebo. These results shed further light on the phenomenon of decreasing effect size of antipsychotics for schizophrenia over time and should help design future randomized controlled trials in the field (Prospero registration number CRD42013003342)

60 years of placebo-controlled antipsychotic drug trials in acute schizophrenia: Meta-regression of predictors of placebo response

Objective: A recent meta-regression had shown that the degree of placebo response, which has increased over the decades, is the major predictor of drug-placebo differences in antipsychotic drug trials in acutely ill patients with schizophrenia. Drug response, however, had remained stable. In the current meta-regression we explored the factors that are associated with placebo-response. Method: We searched multiple electronic databases, ClinicalTrials.gov and the FDA website for randomized, placebo-controlled, antipsychotic drug trials in patients with acute exacerbations of schizophrenia. The outcome was the degree of placebo response measured by the BPRS or PANSS change from baseline to endpoint. 26 patient-, design-, and drug-related potential predictors of placebo response were analyzed by univariable and multivariable meta-regressions. Results: 167 double-blind randomized controlled trials with 28,102 participants were included. The mean PANSS change from baseline was 6.25 (95% CI 4.64,7.85). More recent publication year, larger study sample size, more study sites, use of the PANSS rather than the BPRS scale to measure response, shorter wash-out phases, shorter study duration, lower mean age and shorter duration of illness were associated with larger placebo response in univariable analyses. In a multivariable analysis only the number of study participants and mean participant age had an impact on placebo response. Conclusions: The degree of placebo response is moderated by a number of design and patient-related factors. These explanatory variables of placebo response are only in part identical with those that moderated drug-placebo differences

Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors

Objective: Antipsychotic drug efficacy may have decreased over the decades. We, therefore, present a comprehensive meta-analysis of all placebo-controlled trials in acute schizophrenia, we investigate which trial characteristics have changed over the years and which ones are moderators of drug-placebo efficacy differences. Method: We searched multiple electronic databases, ClinicalTrials.gov and the FDA website. The outcomes were overall efficacy (primary outcome), responder rates, drop-out rates, positive, negative and depressive symptoms, quality of life, functioning, and major side-effects. Multiple potential moderators of overall efficacy were analyzed by meta-regression. Results: 167 double-blind randomized controlled trials with 28102 participants were included. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% CrI 0.42,0.51), but accounting for small trial effects/publication bias reduced the SMD to 0.38. 51% in the antipsychotic group versus 30% in placebo had at least a ‘minimal’ response, and 23% versus 14% had a ‘good’ response. Positive symptoms improved more than negative symptoms and depression. There were also small-to medium sized improvements in quality of life and functioning (SMDs 0.35 and 0.34). In the analysis of response predictors, 17 of 26 trial characteristics analyzed changed over the decades. But in a multivariable meta-regression, only industry-sponsorship and increasing placebo response were significant moderators of effect sizes. Importantly, drug response remained stable over time. Conclusions: Approximately two times more patients improved under antipsychotics compared to placebo, but only a minority experienced a good response. Industry sponsorship reduced, rather than increased effect sizes. The decrease of effect sizes over the years was caused by increasing placebo response, not by decreasing drug response. Meta-analyses need to take this confounder into account. In drug development, somewhat smaller sample sizes but better selected patients may overcome a possible vicious circle of increasing sample sizes, more variability and smaller effect sizes

Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis

Background: The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs. Methods: We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation. Findings: We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0.88, 0.73-1.03; amisulpride 0.66, 0.53-0.78; olanzapine 0.59, 0.53-0.65; risperidone 0.56, 0.50-0.63; paliperidone 0.50, 0.39-0.60; zotepine 0.49, 0.31-0.66; haloperidol 0.45, 0.39-0.51; quetiapine 0.44, 0.35-0.52; aripiprazole 0.43, 0.34-0.52; sertindole 0.39, 0.26-0.52; ziprasidone 0.39, 0.30-0.49; chlorpromazine 0.38, 0.23-0.54; asenapine 0.38, 0.25-0.51; lurasidone 0.33, 0.21-0.45; and iloperidone 0.33, 0.22-0.43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0.43 for the best drug (amisulpride) to 0.80 for the worst drug (haloperidol); for extrapyramidal side-effects 0.30 (clozapine) to 4.76 (haloperidol); and for sedation 1.42 (amisulpride) to 8.82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from -0.09 for the best drug (haloperidol) to -0.74 for the worst drug (olanzapine), for prolactin increase 0.22 (aripiprazole) to -1.30 (paliperidone), and for QTc prolongation 0.10 (lurasidone) to -0.90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses. Interpretation: Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines