Systematic review and meta-analysis of experimental multiple sclerosis studies

Background: Multiple sclerosis (MS) is the most common cause of disability in young people and yet there are no interventions available which reliably alter disease progression. This is despite several decades of research using the most common animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). There is now emerging evidence across the neurosciences to suggest that limited internal validity (measures to reduce bias) and external validity (e.g. using a clinically relevant animal model) may influence the translational success. Aim and objectives: To provide an unbiased summary of the scope of the literature on candidate drugs for MS tested in EAE to identify potential reasons for the failures to translate efficacy to clinical trials. My objectives were, across all of the identified publications, to: (1) describe the reporting of measures to reduce bias and to assess their impact on measures of drug efficacy; (2) assess the relationship between treatment related effects measured using different outcome measures; (3) assess the prevalence and impact of any publication bias; (4) compare findings from the above with another disease with limited translational success (Parkinson’s disease; PD). Methods: I used systematic searches of three online databases to identify relevant publications. Estimates of efficacy were extracted for neurobehavioural scores, inflammation, demyelination and axon loss. For PD experiments, we searched for dopamine agonists tested in animal models of PD with outcome assessed as change in neurobehavioural scores. I calculated normalised mean difference or standardised mean difference effect sizes and combined these in a meta-analysis using a random effects model. I used stratified meta-analysis or meta-regression to assess the extent to which different study design characteristics explained differences in reported efficacies. These characteristics included: measures to reduce bias (random allocation to group and blinded assessment of outcome), the animal species, sex, time of drug administration, route of drug administration and the number of animals per group. Publication bias was assessed using funnel plotting, Egger regression and “trim and fill”. Results: I identified 1464 publications reporting drugs tested in EAE. Reported study quality was poor: 11% reported random allocation to group, 17% reported blinded assessment of neurobehavioural outcomes, 28% reported blinded assessment of histological outcomes, and <1% reported a sample size calculation. Estimates of efficacy measured as the reduction in inflammation were substantially higher in unblinded studies (47.1% reduction (95% CI 41.8-52.4)) versus blinded studies (33.1% (25.8-40.4). Moreover, the same finding was identified for 121 publications on dopamine agonists tested in experimental PD models where efficacy was measured as change in neurobehavioural outcomes. For EAE studies we were unable to include data from 631 publications describing original research. Usually this was because the publication did not include basic details such as the number of animals in each group (115 publications), the observed variance (592) or suitable control data (49). For each category of outcome I found evidence of a substantial publication bias. Interventions were most commonly administered on or before the induction of EAE with shorter times to treatment associated with higher estimates of efficacy for the reduction in mean severity scores (a neurobehavioural outcome). Treatment related effects were found to vary across different outcome measures with the largest effect being for the reduction in axon loss. Where neurobehavioural scores and axon loss were measured in the same cohort of animals, the concordance between efficacies in these increased with later times to treatment. Conclusions: In this, the largest systematic review and meta-analysis of animal studies in any domain, I have found that a large number of publications present incomplete data. In addition, measures to reduce bias are seldom reported, the lack of which is associated with overstatements of efficacy for both a measure of drug efficacy in EAE and experimental PD studies. Translational success may have also been affected by the majority of studies administering drugs on or before EAE induction which is of limited relevance in the clinical setting where patients do not present at that stage of disease. Moreover, my analysis of the relationship between outcome measures provides empirical evidence from systematically identified studies to suggest that targeting axon loss as later time points is most strongly associated with improvements in neurobehavioural scores. Therefore drugs which are successfully able to target axon loss at these time points may offer substantial hope for clinical success. Overall, improvements in the conduct and reporting of preclinical studies are likely to improve their utility, and the prospects for translational success. While my findings relate predominately to the animal modelling of MS and PD it is likely that they also hold for other animal research

Systematic survey of the design, statistical analysis, and reporting of studies published in the 2008 volume of the Journal of Cerebral Blood Flow and Metabolism

Translating experimental findings into clinically effective therapies is one of the major bottlenecks of modern medicine. As this has been particularly true for cerebrovascular research, attention has turned to the quality and validity of experimental cerebrovascular studies. We set out to assess the study design, statistical analyses, and reporting of cerebrovascular research. We assessed all original articles published in the Journal of Cerebral Blood Flow and Metabolism during the year 2008 against a checklist designed to capture the key attributes relating to study design, statistical analyses, and reporting. A total of 156 original publications were included (animal, in vitro, human). Few studies reported a primary research hypothesis, statement of purpose, or measures to safeguard internal validity (such as randomization, blinding, exclusion or inclusion criteria). Many studies lacked sufficient information regarding methods and results to form a reasonable judgment about their validity. In nearly 20% of studies, statistical tests were either not appropriate or information to allow assessment of appropriateness was lacking. This study identifies a number of factors that should be addressed if the quality of research in basic and translational biomedicine is to be improved. We support the widespread implementation of the ARRIVE (Animal Research Reporting In Vivo Experiments) statement for the reporting of experimental studies in biomedicine, for improving training in proper study design and analysis, and that reviewers and editors adopt a more constructively critical approach in the assessment of manuscripts for publication

Correlation of Somatostatin Receptor 1–5 Expression, [68Ga]Ga-DOTANOC, [18F]F-FDG PET/CT and Clinical Outcome in a Prospective Cohort of Pancreatic Neuroendocrine Neoplasms

Purpose: The aim of this study was to correlate immunohistochemical (IHC) tissue levels of SSTR1-5 with the receptor density generated from [68Ga]Ga-DOTANOC uptake in a prospective series of NF-PNENs. Methods: Twenty-one patients with a total of thirty-five NF-PNEN-lesions and twenty-one histologically confirmed lymph node metastases (LN+) were included in this prospective study. Twenty patients were operated on, and one underwent endoscopic ultrasonography and core-needle biopsy. PET/CT with both [68Ga]Ga-DOTANOC and [18F]F-FDG was performed on all patients. All histological samples were re-classified and IHC-stained with monoclonal SSTR1-5 antibodies and Ki-67 and correlated with [68Ga]Ga-DOTANOC and [18F]F-FDG PET/CT. Results: Expression of SSTR1-5 was detected in 74%, 91%, 80%, 14%, and 77% of NF-PNENs. There was a concordance of SSTR2 IHC with positive/negative [68Ga]Ga-DOTANOC finding (Spearman’s rho 0.382, p = 0.043). All [68Ga]Ga-DOTANOC-avid tumors expressed SSTR2 or SSTR3 or SSTR5. Expression of SSTR5 was higher in tumors with a low Ki-67 proliferation index (PI) (−0.353, 95% CI −0.654–0.039, p = 0.038). The mean Ki-67 PI for SSTR5 positive tumors was 2.44 (SD 2.56, CI 1.0–3.0) and 6.38 (SD 7.25, CI 2.25–8.75) for negative tumors. Conclusion: SSTR2 was the only SSTR subtype to correlate with [68Ga]Ga-DOTANOC PET/CT. Our prospective study confirms SSTR2 to be of the highest impact for SST PET/CT signal

Correlation of Somatostatin Receptor 1–5 Expression, [68Ga]Ga-DOTANOC, [18F]F-FDG PET/CT and Clinical Outcome in a Prospective Cohort of Pancreatic Neuroendocrine Neoplasms

Purpose: The aim of this study was to correlate immunohistochemical (IHC) tissue levels of SSTR1-5 with the receptor density generated from [68Ga]Ga-DOTANOC uptake in a prospective series of NF-PNENs. Methods: Twenty-one patients with a total of thirty-five NF-PNEN-lesions and twenty-one histologically confirmed lymph node metastases (LN+) were included in this prospective study. Twenty patients were operated on, and one underwent endoscopic ultrasonography and core-needle biopsy. PET/CT with both [68Ga]Ga-DOTANOC and [18F]F-FDG was performed on all patients. All histological samples were re-classified and IHC-stained with monoclonal SSTR1-5 antibodies and Ki-67 and correlated with [68Ga]Ga-DOTANOC and [18F]F-FDG PET/CT. Results: Expression of SSTR1-5 was detected in 74%, 91%, 80%, 14%, and 77% of NF-PNENs. There was a concordance of SSTR2 IHC with positive/negative [68Ga]Ga-DOTANOC finding (Spearman’s rho 0.382, p = 0.043). All [68Ga]Ga-DOTANOC-avid tumors expressed SSTR2 or SSTR3 or SSTR5. Expression of SSTR5 was higher in tumors with a low Ki-67 proliferation index (PI) (−0.353, 95% CI −0.654–0.039, p = 0.038). The mean Ki-67 PI for SSTR5 positive tumors was 2.44 (SD 2.56, CI 1.0–3.0) and 6.38 (SD 7.25, CI 2.25–8.75) for negative tumors. Conclusion: SSTR2 was the only SSTR subtype to correlate with [68Ga]Ga-DOTANOC PET/CT. Our prospective study confirms SSTR2 to be of the highest impact for SST PET/CT signal

Prediction of the aggressiveness of non-functional pancreatic neuroendocrine tumors based on the dual-tracer PET/CT

Abstract Background Predicting the aggressive behavior of non-functional pancreatic neuroendocrine tumors (NF-PNET) remains controversial. We wanted to explore, in a prospective setting, whether the diagnostic accuracy can be improved by dual-tracer functional imaging 68Ga-DOTANOC and 18F-FDG-PET/CT in patients with NF-PNETs. Methods Thirty-one patients with NF-PNET (90% asymptomatic) underwent PET-imaging with 18F-FDG and 68Ga-DOTANOC, followed by surgery (n = 20), an endoscopic ultrasonography and fine-needle biopsy (n = 2) or follow-up (n = 9). A focal activity on PET/CT greater than the background that could not be identified as physiological activity was considered to indicate tumor tissue. The imaging results were compared to histopathology. The mean follow-up time was 31.3 months. Results Thirty-one patients presented a total of 53 lesions (40 histologically confirmed) on PET/CT. Thirty patients had a 68Ga-DOTANOC-positive tumor (sensitivity 97%) and 10 patients had an 18F-FDG-positive tumor. In addition, one 68Ga-DOTANOC-negative patient was 18F-FDG-positive. 18F-FDG-PET/CT was positive in 19% (3/16) of the G1 tumors, 63% (5/8) of the G2 tumors and 1/1 of the well-differentiated G3 tumor. 68Ga-DOTANOC-PET/CT was positive in 94% of the G1 tumors, 100% of the G2 tumors and 1/1 of the well-differentiated G3 tumor. Two out of six (33%) of the patients with lymph node metastases (LN+) were 18F-FDG-positive. The 18F-FDG-PET/CT correlated with tumor Ki-67 (P = 0.021). Further, the Krenning score correlated with tumor Ki-67 (P = 0.013). 18F-FDG-positive tumors were significantly larger than the 18F-FDG-negative tumors (P = 0.012). 18F-FDG-PET/CT showed a positive predictive value of 78% in the detection of potentially aggressive tumors (G2, G3, or LN + PNETs); the negative predictive value was 69%. Conclusions 18F-FDG-PET/CT is useful to predict tumor grade but not the LN+ of NF-PNETs. Patients with 18F-FDG-avid NF-PNETs should be referred for surgery. The 68Ga-DOTANOC-PET/CT also has prognostic value since the Krenning score predicts the histopathological tumor grade. Trial registration The study has been registered at ClinicalTrials.gov; Non-functional Pancreatic NET and PET imaging, NCT02621541

Prediction of the aggressiveness of non-functional pancreatic neuroendocrine tumors based on the dual-tracer PET/CT

Peer reviewe

ADHD ja päihteet - näin lääkitsen

Nykyisen tutkimusnäytön valossa päihde¬häiriöisen henkilön ADHD:n tutkiminen ja ¬hoitaminen on suositeltavaa. Yksilöllisesti ¬suunnitellusta lääkehoidosta on tutkimusten perusteella enemmän hyötyä kuin haittaa

ADHD ja päihteet - näin lääkitsen

Nykyisen tutkimusnäytön valossa päihde­häiriöisen henkilön ADHD:n tutkiminen ja ­hoitaminen on suositeltavaa. Yksilöllisesti ­suunnitellusta lääkehoidosta on tutkimusten perusteella enemmän hyötyä kuin haittaa

Prediction of the aggressiveness of non-functional pancreatic neuroendocrine tumors based on the dual-tracer PET/CT

Background: Predicting aggressive behavior of nonfunctional pancreatic neuroendocrine tumors (NF-PNET) remains controversial. We wanted to explore, in a prospective setting, whether the diagnostic accuracy can be improved by dual-tracer functional imaging 68Ga-DOTANOC and 18F-FDG-PET/CT in patients with NF-PNETs. Methods: Thirty-one patients with NF-PNET (90% asymptomatic) underwent PET-imaging with 18F-FDG and 68Ga-DOTANOC, followed by surgery (n=20), an endoscopic ultrasonography and fine-needle biopsy (n=2) or follow-up (n=9). A focal activity on PET/CT greater than the background that could not be identified as physiological activity was considered to indicate tumor tissue. The imaging results were compared to the histopathology. The mean follow-up time was 31.3 months. Results: Thirty-one patients presented a total of 53 lesions (40 histologically confirmed) on PET/CT. Thirty patients had a 68Ga-DOTANOC-positive tumor (sensitivity 97%) and ten patients had an 18F-FDG-positive tumor. In addition, one 68Ga-DOTANOC-negative patient was 18F-FDG-positive. 18F-FDG-PET/CT was positive in 19% (3/16) of the G1 tumors, 63% (5/8) of the G2 tumors and 1/1 of the well-differentiated G3 tumor. 68Ga-DOTANOC-PET/CT was positive in 94% of the G1 tumors, 100% of the G2 tumors and 1/1 of the well-differentiated G3 tumor. Two out of six (33%) of the patients with lymph node metastases (LN+) were 18F-FDG-positive. The 18F-FDG-PET/CT correlated with tumor Ki-67 (P=0.021). Further, the Krenning score correlated with tumor Ki-67 (P=0.013). 18F-FDG-positive tumors were significantly larger than the 18F-FDG-negative tumors (P=0.012). 18F-FDG-PET/CT showed a positive predictive value of 78% in the detection of potentially aggressive tumors (G2, G3 or LN + PNETs); the negative predictive value was 69%.Conclusions: 18F-FDG-PET/CT is useful to predict tumor grade but not the LN+ of NF-PNETs. Patients with 18F-FDG-avid NF-PNETs should be referred for surgery. The 68Ga-DOTANOC-PET/CT also has prognostic value since the Krenning score predicts the histopathological tumor grade. </p