A novel framework to assess haematology and oncology registration trials: The THEOREMM project.

BACKGROUND: Methodological limitations affect a significant number of oncology and haematology trials, raising concerns about the applicability of their results. For example, a suboptimal control arm or limited access to best care upon progression may skew the trial results toward a benefit in the experimental arm. Beyond the fact that such limitations do not prevent drugs reaching the market, other assessment tools, such as those developed by professional societies-ESMO-MCBS and ASCO Value Framework-do not integrate these important shortcomings. METHODS: We propose creating a novel framework with the scope of assessing registration cancer clinical trials in haematology and oncology (randomized or single arm)-that is trials leading to a marketing authorization. The main steps of the methods are (1) assembling a scientific board; (2) defining the scope, goal and methods through pre-specified, pre-registered and protocolized methodology; (3) preregistration of the protocol; (4) conducting a scoping review of limitations and biases affecting oncology trials and assessing existing scores or methods; (5) developing a list of features to be included and assessed within the framework; (6) assessing each feature through a questionnaire sent to highly cited haematologists and oncologists involved in clinical trials; and (7) finalizing the first version of framework. RESULTS: Not applicable. CONCLUSIONS: Our proposal emerged in response to the lack of consideration for key limitations in current trial assessments. The goal is to create a framework specifically designed to assess single trials leading to marketing authorization in the field of oncology and haematogy.

A multiverse analysis of meta-analyses assessing acupuncture efficacy for smoking cessation evidenced vibration of effects.

OBJECTIVE: To explore the impact of methodological choices on the results of meta-analyses (MAs), with acupuncture for smoking cessation as a case study. STUDY DESIGN AND SETTING: After performing an umbrella review (using MEDLINE, the COCHRANE Library, the Wan Fang database, and the Chinese Journal Full-text Database/March 2018) of MAs exploring the use of acupuncture for smoking cessation, we extracted all randomized controlled trials. Numerous MAs were performed as per every possible combination of various methodological choices (e.g., characteristics of the intervention and control procedures, outcome, publication status, language) to assess their vibration of effects or more precisely the existence of a Janus effect, that is, whether the 10th and 90th percentiles in the distribution of effect sizes were in opposite directions. RESULTS: After including 7 MAs and 39 randomized controlled trials, we performed 496,528 MAs. The effect size was negative at the 10th percentile (-0.1, favoring controls) and positive at the 90th percentile (1.17, favoring acupuncture). In all, 104,491 MAs showed a statistically significant difference in favor of acupuncture, whereas 392,037 failed to demonstrate the efficacy of acupuncture (including 96 that showed a statistically significant difference in favor of the control). CONCLUSION: The methodological choices made in performing pairwise MAs can result in substantial vibration of effects, occasionally leading to opposite results.

Tivozanib in renal cell carcinoma: a systematic review of the evidence and its dissemination in the scientific literature.

BACKGROUND: Tivozanib (Fotivda) is an anti-angiogenic tyrosine kinase inhibitor that was denied access to the US market by the Food and Drug Administration (FDA). In contrast, it was granted approval by the European Medicines Agency (EMA) for the treatment of Renal Cell Carcinoma in adults. Given the conflicting decisions from these regulatory agencies, the objectives of the following study are (i) to critically review the evidence supporting the approval of tivozanib; (ii) to analyse the dissemination of this evidence in the literature by way of a citation analysis. METHODS: Pivotal trials were searched by two independent reviewers using Medline, Cochrane Library, ClinicalTrials.gov and the European Public Assessment Report. The risk of bias for each trial was then inductively assessed. Articles citing any of these trials were identified using Web of Sciences. Finally, the quality of the citations was evaluated by two independent reviewers according to standard data extraction methods. RESULTS: The search for primary evidence identified two pivotal studies: TIVO-1 upon which the FDA and the EMA decisions were based, and TIVO-3 which was conducted after the agencies' decisions had been issued. The TIVO-1 trial presented several limitations that compromised causal inference, in relation to (i) design (absence of blinding, inappropriate comparator, and one-way crossover), (ii) poor internal consistency in the results for the primary endpoint, (iii) a discrepancy between a benefit observed for progression-free survival (HR: 0.80, 95% CI [0.64-0.99]) and the absence of difference for overall survival (HR: 1.25, 95% CI [0.95 - 1.62]). Our citation search protocol identified 229 articles that cited TIVO-1 in the 7 years following its publication, among which 151 (65.9%) citing articles discussing efficacy. Presence of spin was identified in 64 (42.4%) of these 151 citing articles, and 39 (25.8%) additional articles citing results without providing enough elements to interpret the TIVO-1 results. CONCLUSION: EMA's approval was based on a single pivotal trial presenting critical limitations, rendering the results from the trial potentially inconclusive. The broad dissemination of TIVO-1 results in the scientific literature may have been affected by spin or results were presented in an inadequate critical manner.

Clinical Trial Evidence Supporting US Food and Drug Administration Approval of Novel Cancer Therapies Between 2000 and 2016.

Importance: Clinical trial evidence used to support drug approval is typically the only information on benefits and harms that patients and clinicians can use for decision-making when novel cancer therapies become available. Various evaluations have raised concern about the uncertainty surrounding these data, and a systematic investigation of the available information on treatment outcomes for cancer drugs approved by the US Food and Drug Administration (FDA) is warranted. Objective: To describe the clinical trial data available on treatment outcomes at the time of FDA approval of all novel cancer drugs approved for the first time between 2000 and 2016. Design, Setting, and Participants: This comparative effectiveness study analyzed randomized clinical trials and single-arm clinical trials of novel drugs approved for the first time to treat any type of cancer. Approval packages were obtained from drugs@FDA, a publicly available database containing information on drug and biologic products approved for human use in the US. Data from January 2000 to December 2016 were included in this study. Main Outcomes and Measures: Regulatory and clinical trial characteristics were described. For randomized clinical trials, summary treatment outcomes for overall survival, progression-free survival, and tumor response across all therapies were calculated, and median absolute survival increases were estimated. Tumor types and regulatory characteristics were assessed separately. Results: Between 2000 and 2016, 92 novel cancer drugs were approved by the FDA for 100 indications based on data from 127 clinical trials. The 127 clinical trials included a median of 191 participants (interquartile range [IQR], 106-448 participants). Overall, 65 clinical trials (51.2%) were randomized, and 95 clinical trials (74.8%) were open label. Of 100 indications, 44 indications underwent accelerated approval, 42 indications were for hematological cancers, and 58 indications were for solid tumors. Novel drugs had mean hazard ratios of 0.77 (95% CI, 0.73-0.81; I2 = 46%) for overall survival and 0.52 (95% CI, 0.47-0.57; I2 = 88%) for progression-free survival. The median tumor response, expressed as relative risk, was 2.37 (95% CI, 2.00-2.80; I2 = 91%). The median absolute survival benefit was 2.40 months (IQR, 1.25-3.89 months). Conclusions and Relevance: In this study, data available at the time of FDA drug approval indicated that novel cancer therapies were associated with substantial tumor responses but with prolonging median overall survival by only 2.40 months. Approval data from 17 years of clinical trials suggested that patients and clinicians typically had limited information available regarding the benefits of novel cancer treatments at market entry.

[Data sharing policies of clinical trials funders in France]. / Les politiques de partage de données des financeurs d'essais cliniques en France.

AIMS: The aims of this survey were to evaluate the percentage of French clinical trial funders with a data sharing policy, to describe their data sharing policies and, more generally, the transparency of the research they fund. METHODS: The different funders of clinical trials in France have been identified from 3 lists of tenders for clinical research projects: the internal list of the University Hospital Center (CHU) of Rennes, the list of the Interregional Group for Clinical Research and Innovation (GIRCI EST), the list of the portal for calls for projects in health research. Funders were contacted, first by email and then by phone (at least two email and/or phone reminders) to respond to an online survey via Google form. The questionnaire aimed to assess the existence of a sharing policy or not, as well as the way in which it was set up. RESULTS: Out of 190 funders contacted, 94 did not respond. Sixty-five of the respondents were excluded because they did not fund clinical trials. Of the 31 funders included (including Direction générale de l'offre de soins [DGOS], Institut national contre le cancer [INCa], Groupement Interrégional de Recherche Clinique et d'Innovation [GIRCIs]), only 9 (29%) had implemented a data sharing policy. Among these nine funders, only one had a mandatory sharing policy and eight a policy supporting but not enforcing data sharing. Five allowed the use of budget lines dedicated to data sharing. Three reported granting data sharing incentives. Three had dedicated guidelines indicating a specific mode of sharing data (sharing on request and/or on a specialized platform) and specifying the type of data (individual patient data and/or protocol and amendments). For all three, there were restrictions on sharing data to researchers only. Data sharing policies concerned 19% of the total financial volume (850,032,000 euros) of the 26 funders who reported this information. CONCLUSION: Despite international interest in clinical trial data sharing practices, clinical trials funders with a strong data-sharing policy remain an exception in France.

Clinical application of mesenchymal stem cells in periodontal regeneration: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the potential efficacy of mesenchymal stem cells (MSCs) in periodontal regeneration in humans on the following main outcomes: clinical attachment level (CAL), probing depth (PD), and gingival recession (GR). BACKGROUND: The clinical application of stem cells in periodontal regeneration has begun in recent years, but clinical practices are not yet standardized and no recommendations are available at this time. METHODS: Electronic database searches and hand searches were conducted. All types of studies, case series, and case reports were qualitatively described. Double-blind randomized controlled trials (RCTs) evaluating MSCs in periodontal regeneration were included in a meta-analysis if they compared administration of MSCs vs application of stem cell-free therapy in the control group, in healthy patients with periodontal defects, with a minimum of three mo of follow-up. RESULTS: Fifteen reports were included in qualitative analysis, involving 123 patients and 158 periodontal defects. Only two small RCTs at high risk of bias, with a total of 59 patients and 70 periodontal defects, were included in the meta-analysis. A small but significant difference between test and control groups was found for CAL at three mo (-0.90 mm, 95% CI [-1.51; -0.29]), but not for PD and GR. CONCLUSION: Low-quality evidence suggests that MSC-based therapy may have a small impact on periodontal regeneration. However, due to the monocentric character, the small sample size, and potential heterogeneity across the two included RCTs, these results must not be considered as definitive. High-quality RCTs are needed before any clinical use of MSCs in periodontal regeneration.

Association between gifts from pharmaceutical companies to French general practitioners and their drug prescribing patterns in 2016: retrospective study using the French Transparency in Healthcare and National Health Data System databases.

OBJECTIVE: To evaluate the association between gifts from pharmaceutical companies to French general practitioners (GPs) and their drug prescribing patterns. DESIGN: Retrospective study using data from two French databases (National Health Data System, managed by the French National Health Insurance system, and Transparency in Healthcare). SETTING: Primary care, France. PARTICIPANTS: 41 257 GPs who in 2016 worked exclusively in the private sector and had at least five registered patients. The GPs were divided into six groups according to the monetary value of the received gifts reported by pharmaceutical, medical device, and other health related companies in the Transparency in Healthcare database. MAIN OUTCOME MEASURES: The main outcome measures were the amount reimbursed by the French National Health Insurance for drug prescriptions per visit (to the practice or at home) and 11 drug prescription efficiency indicators used by the National Health Insurance to calculate the performance related financial incentives of the doctors. Doctor and patient characteristics were used as adjustment variables. The significance threshold was 0.001 for statistical analyses. RESULTS: The amount reimbursed by the National Health Insurance for drug prescriptions per visit was lower in the GP group with no gifts reported in the Transparency in Healthcare database in 2016 and since its launch in 2013 (no gift group) compared with the GP groups with at least one gift in 2016 (-€5.33 (99.9% confidence interval -€6.99 to -€3.66) compared with the GP group with gifts valued at €1000 or more reported in 2016) (P<0.001). The no gift group also more frequently prescribed generic antibiotics (2.17%, 1.47% to 2.88% compared with the ≥€1000 group), antihypertensives (4.24%, 3.72% to 4.77% compared with the ≥€1000 group), and statins (12.14%, 11.03% to 13.26% compared with the ≥€1000 group) than GPs with at least one gift between 2013 and 2016 (P<0.001). The no gift group also prescribed fewer benzodiazepines for more than 12 weeks (-0.68%, -1.13% to -0.23% compared with the €240-€999 group) and vasodilators (-0.15%, -0.28% to -0.03% compared with the ≥€1000 group) than GPs with gifts valued at €240 or more reported in 2016, and more angiotensin converting enzyme (ACE) inhibitors compared with all ACE and sartan prescriptions (1.67%, 0.62% to 2.71%) compared with GPs with gifts valued at €1000 or more reported in 2016 (P<0.001). Differences were not significant for the prescription of aspirin and generic antidepressants and generic proton pump inhibitors. CONCLUSION: The findings suggest that French GPs who do not receive gifts from pharmaceutical companies have better drug prescription efficiency indicators and less costly drug prescriptions than GPs who receive gifts. This observational study is susceptible to residual confounding and therefore no causal relation can be concluded. TRIAL REGISTRATION: OSF register OSF.IO/8M3QR.

The Comparative Effectiveness of Innovative Treatments for Cancer (CEIT-Cancer) project: Rationale and design of the database and the collection of evidence available at approval of novel drugs.

BACKGROUND: The available evidence on the benefits and harms of novel drugs and therapeutic biologics at the time of approval is reported in publicly available documents provided by the US Food and Drug Administration (FDA). We aimed to create a comprehensive database providing the relevant information required to systematically analyze and assess this early evidence in meta-epidemiological research. METHODS: We designed a modular and flexible database of systematically collected data. We identified all novel cancer drugs and therapeutic biologics approved by the FDA between 2000 and 2016, recorded regulatory characteristics, acquired the corresponding FDA approval documents, identified all clinical trials reported therein, and extracted trial design characteristics and treatment effects. Herein, we describe the rationale and design of the data collection process, particularly the organization of the data capture, the identification and eligibility assessment of clinical trials, and the data extraction activities. DISCUSSION: We established a comprehensive database on the comparative effects of drugs and therapeutic biologics approved by the FDA over a time period of 17 years for the treatment of cancer (solid tumors and hematological malignancies). The database provides information on the clinical trial evidence available at the time of approval of novel cancer treatments. The modular nature and structure of the database and the data collection processes allow updates, expansions, and adaption for a continuous meta-epidemiological analysis of novel drugs. The database allows us to systematically evaluate benefits and harms of novel drugs and therapeutic biologics. It provides a useful basis for meta-epidemiological research on the comparative effects of innovative cancer treatments and continuous evaluations of regulatory developments.

Is electroconvulsive therapy an evidence-based treatment for catatonia? A systematic review and meta-analysis.

We aimed to review and discuss the evidence-based arguments for the efficacy of electroconvulsive therapy (ECT) in the treatment of catatonia. Randomized controlled trials (RCTs) and observational studies focusing on the response to ECT in catatonia were selected in PubMed, the Cochrane Library, Embase, ClinicalTrials.gov and Current Controlled Trials through October 2016 and qualitatively described. Trials assessing pre-post differences using a catatonia or clinical improvement rating scale were pooled together using a random effect model. Secondary outcomes were adverse effects of anesthesia and seizure. 564 patients from 28 studies were included. RCTs were of low quality and were heterogeneous; therefore, it was not possible to combine their efficacy results. An improvement of catatonic symptoms after ECT treatment was evidenced in ten studies (SMD = -3.14, 95% CI [-3.95; -2.34]). The adverse effects that were reported in seven studies included mental confusion, memory loss, headache, or adverse effects associated with anesthesia. ECT protocols were heterogeneous. The literature consistently describes improvement in catatonic symptoms after ECT. However, the published studies fail to demonstrate efficacy and effectiveness. It is now crucial to design and perform a quality RCT to robustly validate the use of ECT in catatonia.Prospero registration information: PROSPERO 2016: CRD42016041660.

Pallidal stimulation in Parkinson's patients with contraindications to subthalamic target: A 3 years follow-up.

INTRODUCTION: Over a 3-year period, we monitored the efficacy and safety of deep-brain stimulation of the globus pallidus pars interna in patients with advanced Parkinson's disease whose cognitive, psychiatric impairment and/or dopa-resistant axial motor signs made them ineligible for surgery targeting the subthalamic nucleus. METHODS: A total of 25 patients were assessed before surgery, 1 year and 3 years after surgery, on the UPDRS and a neuropsychological battery. RESULTS: We noted a significant improvement of 65.9% in the Clinical global self-perceived Improvement by Visual Analog Scale and an improvement of 20.6% in the total UPDRS-III motor score at 3 years in the off-dopa condition compared to before surgery. There was an improvement in the treatment's motor complications, as measured by the UPDRS-IV, with a particularly marked reduction of 50% in the Dyskinesia subscore. Cognitive performances remained stable at 1 year but had fallen by the third year. We interpreted this deterioration as due to disease progression. CONCLUSION: Bilateral pallidal stimulation in patients with contraindications to subthalamic surgery therefore seems to be effective over the long term in treating motor symptoms, especially dyskinesias, with good neuropsychological safety.

Are There Factors Predictive of Postoperative Complications in Circumferential Contouring of the Lower Trunk? A Meta-Analysis.

BACKGROUND: The massive weight loss patient may require a circumferential contouring of the lower trunk. OBJECTIVES: To summarize the complication rates and explore the possibility of predictive risk factors for complications. METHODS: We performed a systematic review using the PubMed and Cochrane databases to identify published articles on the topic. Random effects meta-analyses and meta-regression were conducted to synthesize the data gathered. RESULTS: The analysis included 28 studies and 1380 patients. All but one were retrospective cohorts or case studies. Circumferential contouring of the lower trunk resulted in 37% [95%-CI 30%; 44%] overall complications; 17% [95%-CI 12%; 24%] wound dehiscences; 4% [95%-CI 3%; 5%] skin necrosis; 5% [95%-CI 3%; 9%] infections; 3% [95%-CI 2%; 4%] hematomas; 13% [95%-CI 9%; 18%] seromas; 12% [95%-CI 7%; 21%] scar irregularities; 3% [95%-CI 2%; 5%] thromboembolism; and 5% [95%-CI 3%; 8%] revisions for complications. Lower body lift-related techniques were associated with a higher rate of overall complications than belt lipectomy-related techniques (P = .002). No difference in complication rate was shown when performing a gluteal augmentation with flap. Due to insufficient data reported in the studies, risk factors for postoperative complications could not be assessed. CONCLUSIONS: The whole literature provides very low reliable information. Confusion factors could not be ruled out to explain the increased complications rate for the lower body lift compared to the belt lipectomy. This finding needs to be confirmed in randomized trials. Collaborative efforts must be made to improve the evidence level of our practices and to serve patients in an optimal way. LEVEL OF EVIDENCE: 3 Therapeutic.

Mortality, cardiovascular risk, and androgen deprivation therapy for prostate cancer: A systematic review with direct and network meta-analyses of randomized controlled trials and observational studies.

UNLABELLED: Androgen deprivation therapy (ADT) is a cornerstone therapy for advanced prostate cancer (PCa). We hypothesized that cardiovascular (CV) risk is different across the various ADT modalities to compare their effects on CV morbidity and mortality, and all-cause mortality in patients with PCa. To investigate more in depth potential CV risk heterogeneity focusing on coronary (main outcome) and cerebrovascular risk, CV, and overall mortality. We performed a Medline and Embase query, without language restriction, since 1950 up to July 2014. We included randomized controlled trials (RCTs) and observational studies providing that they compared at least 1 ADT modality to another one or to placebo and they gave data on CV event or all-cause mortality. Sixty-eight studies out of 3419 met our eligibility criteria. Eleven observational studies were analyzed. Direct meta-analyses showed that antiandrogen was associated with a 30% decrease risk for myocardial infarction (MI) compared to GnRH agonists (RR, 0.70 [0.54-0.91]); combined androgen blockade (CAB) was associated with a 10% increase risk for stroke when compared to antiandrogen (RR, 1.10 [1.02-1.19]). With regard to RCTs, 57 were included: direct meta-analyses suggested that CAB was associated with a 10% decrease of all-cause mortality when compared to GnRH agonist (RR, 0.90 [0.82-1.00]). Network analysis could only be performed for all-cause mortality and it remains difficult to disentangle benefit (positive impact on cancer survival) and risk (including CV risk). The impact of the ADT modalities on CV morbidity remains difficult to quantify and more detailed prospective collection is required. REGISTRATION: PROSPERO, CRD42014010598.

Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network.

BACKGROUND: Treatment of relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) is poorly defined, because randomized trials and large studies are lacking. The aim of this study was to analyze the characteristics, management, and outcome of R/R PCNSL patients after first-line therapy in a nationwide cohort. METHODS: We analyzed R/R PCNSL patients following first-line treatment who had been prospectively registered in the database of the French network for oculocerebral lymphoma (LOC) between 2011 and 2014. RESULTS: Among 563 PCNSL patients treated with first-line therapy, we identified 256 with relapsed (n = 93, 16.5%) or refractory (n = 163, 29.0%) disease. Patients who were asymptomatic at relapse/progression (25.5%), mostly diagnosed on routine follow-up neuroimaging, tended to have a better outcome. Patients who received salvage therapy followed by consolidation (mostly intensive chemotherapy plus autologous hematopoietic stem cell transplantation [ICT + AHSCT]) experienced prolonged survival compared with those who did not receive salvage or consolidation therapy. Independent prognostic factors at first relapse/progression were: KPS ≥ 70 vs KPS < 70), sensitivity to first-line therapy (relapsed vs refractory disease), duration of first remission (progression-free survival [PFS] ≥1 y vs <1 y), and management at relapse/progression (palliative care vs salvage therapy). Patients who relapsed early after first-line therapy (ie, PFS < 1 y) had a poor outcome, comparable to that of refractory patients. Conversely, patients experiencing late relapses (PFS ≥ 1 y) and/or undergoing consolidation with ICT + AHSCT experienced prolonged survival. CONCLUSIONS: About a third of PCNSL patients are primary refractory to first line treatment. We identified several independent prognostic factors that can guide the management of R/R PCNSL patients.

Controlled Attenuation Parameter and Liver Stiffness Measurements for Steatosis Assessment in the Liver Transplant of Brain Dead Donors.

BACKGROUND: One of the main selection criteria of the quality of a liver graft is the degree of steatosis, which will determine the success of the transplantation. The aim of this study was to evaluate the ability of FibroScan and its related methods Controlled Attenuation Parameter and Liver Stiffness to assess objectively steatosis and fibrosis in livers from brain-dead donors to be potentially used for transplantation. METHODS: Over a period of 10 months, 23 consecutive brain dead donors screened for liver procurement underwent a FibroScan and a liver biopsy. RESULTS: The different predictive models of liver retrievability using liver biopsy as the gold standard have led to the following area under receiver operating characteristic curve: 76.6% (95% confidence intervals [95% CIs], 48.2%-100%) when based solely on controlled attenuation parameter, 75.0% (95% CIs, 34.3%-100%) when based solely on liver stiffness, and 96.7% (95% CIs, 88.7%-100%) when based on combined indices. CONCLUSIONS: Our study suggests that a preoperative selection of brain-dead donors based on a combination of both Controlled Attenuation Parameter and Liver Stiffness obtained with FibroScan could result in a good preoperative prediction of the histological status and degree of steatosis of a potential liver graft.

Preoperative brain metabolism and quality of life after subthalamic nucleus stimulation in Parkinson's disease.

Subthalamic nucleus deep brain stimulation (STN-DBS) has been proven to improve health-related quality of life (HRQoL) in patients with Parkinson's disease (PD) presenting medically refractory motor complications and dyskinesia. However, some patients fail to benefit from STN-DBS despite rigorous preoperative selection. We postulated that they have a particular, clinically ineloquent, brain metabolism before surgery. We divided 40 stimulated PD patients into two groups (responders vs. nonresponders) depending on whether they reported or not a clinically significant improvement in their quality of life 1 year after surgery. We retrospectively compared their preoperative brain metabolism on the basis of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) scans. We also analyzed their neuropsychological and psychiatric profiles before and after surgery. All 40 patients met the STN-DBS selection criteria, but only 50% of them had significantly improved 1 year after surgery. Preoperative PET scans showed that metabolism was higher in the left insula, both inferior frontal gyri and left precentral gyrus in nonresponders than in responders. Clinically, postoperative motor scores were similar in both groups, but a worsening of the depression score was observed among nonresponders. PET imaging revealed that nonresponders were characterized by distinctive brain functioning pre-surgery, in regions involved in associative and limbic circuits, as a result of PD-related degeneration. STN-DBS may have interfered with this already abnormal circuitry, leading to the occurrence of complex nonmotor symptoms reducing quality of life. Preoperative brain metabolism could be a useful biomarker for anticipating STN-DBS efficacy in terms of HRQoL in the context of advanced PD.

Limbic versus cognitive target for deep brain stimulation in treatment-resistant depression: accumbens more promising than caudate.

High-frequency deep brain stimulation (DBS) represents a major stake for treatment for treatment-resistant depression (TRD). We describe a preliminary trial of DBS of two potential brain targets in chronic TRD: the nucleus accumbens (Acb) and, in the event of failure, the caudate nucleus. Patients were followed for 6 months before surgery (M0). From M1 to M5, they underwent stimulation of the Acb target. PET scans allowed us to track metabolic modifications resulting from this stimulation. The caudate target of nonresponders was stimulated between M5 and M9. Patients then entered an extension phase, in which it was possible to adapt stimulation parameters and treatments. Six patients were included and four were operated on. At M5, none of the patients were either responders or remitters, but we did observe a decrease in Hamilton Depression Rating Scale (HDRS) scores. Three patients were switched to caudate stimulation, but no improvement was observed. During the extension phase, the Acb target was stimulated for all patients, three of whom exhibited a significant response. A decrease in glucose metabolism was observed after Acb stimulation, in the posterior cingulate gyrus, left frontal lobe, superior and medial gyrus, and bilateral cerebellum. An increase in metabolism was observed in the bilateral frontal lobe (superior gyrus), left frontal lobe (medial gyrus), and right limbic lobe (anterior cingulate gyrus). The results of this trial suggest that Acb is a more promising target than the caudate. NCT01569711.