Study Protocol for a Randomised Controlled Trial on Pulmonary Metastasectomy vs. Standard of Care in Colorectal Cancer Patients With ≥ 3 Lung Metastases (PUCC-Trial)

This is a multicentre prospective randomised controlled trial for patients with 3 or more resectable pulmonary metastases from colorectal carcinoma. The study investigates the effects of pulmonary metastasectomy in addition to standard medical treatment in comparison to standard medical treatment plus possible local ablative measures such as SBRT. This trial is intended to demonstrate an overall survival difference in the group undergoing pulmonary metastasectomy. Further secondary and exploratory endpoints include quality of life (EORTC QLQ-C30, QLQ-CR29 and QLQ-LC29 questionnaires), progression-free survival and impact of mutational status. Due to the heterogeneity and complexity of the disease and treatment trajectories in metastasised colorectal cancer, well powered trials have been very challenging to design and execute. The goal of this study is to create a setting which allows treatment as close to the real life conditions as possible but under well standardised conditions. Based on previous trials, in which patient recruitment in the given setting hindered successful study completion, we decided to (1) restrict inclusion to patients with 3 or more metastases (since in case of lesser, surgery will probably be the preferred option) and (2) allow for real world standard of care (SOC) treatment options before and after randomisation including watchful waiting (as opposed to a predefined treatment protocol) and (3) possibility that patient can receive SOC externally (to reduce patient burden). Moreover, we chose to stipulate 12 weeks of systemic treatment prior to possible resection to further standardize treatment response and disease course over a certain period of time. Hence, included patients will be in the disease state of oligopersistence rather than primary oligometastatic. The trial was registered in the German Clinical Trials Register (DRKS-No.: DRKS00024727)

ESCAlate – Adaptive treatment approach for adolescents and adults with ADHD: study protocol for a randomized controlled trial

Background: Over the last decade, a wide range of attention-deficit/hyperactivity disorder (ADHD) treatment approaches for adults, including both pharmacological interventions and psychosocial treatments, have been proposed and observed to be efficient. In practice, individual treatment concepts are based on results of clinical studies as well as international guidelines (NICE Guidelines) that recommend a step-by-step treatment approach. Since the evidence supporting this approach is limited, the aim of the present study is to determine an optimal intervention regarding severity levels of ADHD symptomatology conducting a randomized controlled trial. Method: We aim to include 279 ADHD subjects aged between 16 and 45 years. First, participants are randomized to either a face-to-face psychoeducation, telephone assisted self-help (TASH), or a waiting control group (Step 1). All participants assigned to the control group are treated using TASH after a 3-month waiting period. Participants are then allocated to one of three groups, based on their remaining severity level of ADHD symptoms, as (1) full responder, (2) partial responder, or (3) non-responder (Step 2). Full responders receive counseling, partial responders receive either counseling only or counseling and neurofeedback (NF), and non-responders receive either pharmacological treatment only or pharmacological treatment and NF, followed by a 3 month period without intervention. Discussion: The naturalistic sample is one of the study’s advantages, avoiding highly selective inclusion or exclusion criteria. The efficacy of an evidence-based stepped care intervention is explored by primary (reduction of severity of ADHD symptoms) and secondary outcomes (functional outcomes, e.g., quality of life, anger management, enhancement of psychosocial well-being). Predictors of therapeutic response and non-response are being investigated at each step of intervention. Further, sex differences are also being explored. Trial registration: This study is registered by the German Trial Register (reference number: DRKS00008975 ), 23 October 2015

Modular-Based Psychotherapy (MoBa) versus Cognitive Behavioural Therapy (CBT) for patients with comorbid depression and a history of childhood maltreatment: Study protocol for a randomised controlled feasibility trial

Introduction: In depression treatment, most patients do not reach response or remission with current psychotherapeutic approaches. Major reasons for individual non-response are interindividual heterogeneity of etiological mechanisms and pathological forms, and a high rate of comorbid disorders. Personalised treatments targeting comorbidities as well as underlying transdiagnostic mechanisms and factors like early childhood maltreatment may lead to better outcomes. A Modular-Based Psychotherapy (MoBa) approach provides a treatment model of independent and flexible therapy elements within a systematic treatment algorithm to combine and integrate existing evidence-based approaches. By optimally tailoring module selection and application to the specific needs of each patient, MoBa has great potential to improve the currently unsatisfying results of psychotherapy as a bridge between disorder-specific and personalised approaches. Methods and analysis: In a randomized controlled feasibility trial (RCT), N=70 outpatients with episodic or persistent major depression, comorbidity and childhood maltreatment are treated in 20 individual sessions with MoBa or standard Cognitive Behavioural Therapy (CBT) for depression. The three modules of MoBa focus on deficits associated with early childhood maltreatment: the systems of negative valence, social processes, and arousal. According to a specific questionnaire-based treatment algorithm, elements from Cognitive Behavioral Analysis System of Psychotherapy (CBASP), Mentalization-Based Psychotherapy (MBT) and/or Mindfulness (MBCT) are integrated for a personalised modular procedure. As a proof of concept, this trial will provide evidence for the feasibility and efficacy (post-treatment and six month follow-up) of a modular add-on approach for patients with depression, comorbidities and a history of childhood maltreatment. Crucial feasibility aspects include targeted psychopathological mechanisms, selection (treatment algorithm), sequence and application of modules, as well as training and supervision of the study therapists. Ethics and dissemination: This study obtained approval from independent Ethics Committees. All findings will be disseminated broadly via peer-reviewed articles in scientific journals and contributions to national and international conferences. Trial registration: German Clinical Trials Register (www.drks.de): DRKS00022093

The dentato-rubro-thalamic tract as the potential common deep brain stimulation target for tremor of various origin: an observational case series

Introduction!#!Deep brain stimulation alleviates tremor of various origins. The dentato-rubro-thalamic tract (DRT) has been suspected as a common tremor-reducing structure. Statistical evidence has not been obtained. We here report the results of an uncontrolled case series of patients with refractory tremor who underwent deep brain stimulation under tractographic assistance.!##!Methods!#!A total of 36 patients were enrolled (essential tremor (17), Parkinson's tremor (8), multiple sclerosis (7), dystonic head tremor (3), tardive dystonia (1)) and received 62 DBS electrodes (26 bilateral; 10 unilateral). Preoperatively, diffusion tensor magnetic resonance imaging sequences were acquired together with high-resolution anatomical T1W and T2W sequences. The DRT was individually tracked and used as a direct thalamic or subthalamic target. Intraoperative tremor reduction was graded on a 4-point scale (0 = no tremor reduction to 3 = full tremor control) and recorded together with the current amplitude, respectively. Stimulation point coordinates were recorded and compared to DRT. The relation of the current amplitude needed to reduce tremor was expressed as TiCR (tremor improvement per current ratio).!##!Results!#!Stimulation points of 241 were available for analysis. A total of 68 trajectories were tested (62 dB leads, 1.1 trajectories tested per implanted lead). Tremor improvement was significantly decreasing (p < 0.01) if the distance to both the border and the center of the DRT was increasing. On the initial trajectory, 56 leads (90.3%) were finally placed. Long-term outcomes were not part of this analysis.!##!Discussion!#!Tremor of various origins was acutely alleviated at different points along the DRT fiber tract (above and below the MCP plane) despite different tremor diseases. DRT is potentially a common tremor-reducing structure. Individual targeting helps to reduce brain penetrating tracts. TiCR characterizes stimulation efficacy and might help to identify an optimal stimulation point

Tractography-assisted deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB DBS) in major depression

Background: Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (slMFB) emerges as a - yet experimental - treatment for major depressive disorder (MDD) and other treatment refractory psychiatric diseases. First experiences have been reported from two open label pilot trials in major depression (MDD) and long-term effectiveness for MDD (50 months) has been reported. Objective: To give a detailed description of the surgical technique for DBS of the superolateral branch of the medial forebrain bundle (slMFB) in MDD. Methods: Surgical experience from bilateral implantation procedures in n = 24 patients with MDD is reported. The detailed procedure of tractography-assisted targeting together with detailed electrophysiology in 144 trajectories in the target region (recording and stimulation) is described. Achieved electrode positions were evaluated based on postoperative helical CT and fused to preoperative high resolution anatomical magnetic resonance imaging (MRI; Philips Medical Systems, Best, Netherlands), including the pre-operative diffusion tensor imaging (DTI) tractographic information (StealthViz DTI, Medtronic, USA; Framelink 5.0, Medtronic, USA). Midcommissural point (MCP) coordinates of effective contact (EC) location, together with angles of entry into the target region were evaluated. To investigate incidental stimulation of surrounding nuclei (subthalamic nucleus, STN; substantia nigra, SNr; and red nucleus, RN) as a possible mechanism, a therapeutic triangle (TT) was defined, located between these structures (based on MRI criteria in T2) and evaluated with respect to EC locations. Results: Bilateral slMFB DBS was performed in all patients. We identified an electrophysiological environment (defined by autonomic reaction, passive microelectrode recording, acute effects and oculomotor effects) that helps to identify the proper target site on the operation table. Postoperative MCP-evaluation of effective contacts (EC) shows a significant variability with respect to localization. Evaluation of the TT shows that responders will typically have their active contacts inside the triangle and that surrounding nuclei (STN, SNr, RN) are not directly hit by EC, indicating a predominant white matter stimulation. The individual EC position within the triangle cannot be predicted and is based on individual slMFB (tractography) geometry. There was one intracranial bleeding (FORESEE I study) during a first implantation attempt in a patient who later received full bilateral implantation. Typical oculomotor side effects are idiosyncratic for the target region and at inferior contacts. Conclusion: The detailed surgical procedure of slMFB DBS implantation has not been described before. The slMFB emerges as an interesting region for the treatment of major depression (and other psychiatric diseases) with DBS. So far it has only been successfully researched in open label clinical case series and in 15 patients published. Stimulation probably achieves its effect through direct white-matter modulation of slMFB fibers. The surgical implantation comprises a standardized protocol combining tractographic imaging based on DTI, targeting and electrophysiological evaluation of the target region. To this end, slMFB DBS surgery is in technical aspects comparable to typical movement disorder surgery. In our view, slMFB DBS should only be performed under tractographic assistance. Keywords: Deep brain stimulation, Depression, Diffusion tensor imaging, Fiber tracking, Medial forebrain bundle, OCD, slMFB, Stereotactic surgery, Tractograph

Individualised stepwise adaptive treatment for 3-6-year-old preschool children impaired by attention-deficit/hyperactivity disorder (ESCApreschool): study protocol of an adaptive intervention study including two randomised controlled trials within the consortium ESCAlife

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a psychosocially impairing and cost-intensive mental disorder, with first symptoms occurring in early childhood. It can usually be diagnosed reliably at preschool age. Early detection of children with ADHD symptoms and an early, age-appropriate treatment are needed in order to reduce symptoms, prevent secondary problems and enable a better school start. Despite existing ADHD treatment research and guideline recommendations for the treatment of ADHD in preschool children, there is still a need to optimise individualised treatment strategies in order to improve outcomes. Therefore, the ESCApreschool study (Evidence-Based, Stepped Care of ADHD in Preschool Children aged 3 years and 0 months to 6 years and 11 months of age (3;0 to 6;11 years) addresses the treatment of 3-6-year-old preschool children with elevated ADHD symptoms within a large multicentre trial. The study aims to investigate the efficacy of an individualised stepwise-intensifying treatment programme. METHODS: The target sample size of ESCApreschool is 200 children (boys and girls) aged 3;0 to 6;11 years with an ADHD diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or a diagnosis of oppositional defiant disorder (ODD) plus additional substantial ADHD symptoms. The first step of the adaptive, stepped care design used in ESCApreschool consists of a telephone-assisted self-help (TASH) intervention for parents. Participants are randomised to either the TASH group or a waiting control group. The treatment in step 2 depends on the outcome of step 1: TASH responders without significant residual ADHD/ODD symptoms receive booster sessions of TASH. Partial or non-responders of step 1 are randomised again to either parent management and preschool teacher training or treatment as usual. DISCUSSION: The ESCApreschool trial aims to improve knowledge about individualised treatment strategies for preschool children with ADHD following an adaptive stepped care approach, and to provide a scientific basis for individualised medicine for preschool children with ADHD in routine clinical care. TRIAL REGISTRATION: The trial was registered at the German Clinical Trials Register (DRKS) as a Current Controlled Trial under DRKS00008971 on 1 October 2015. This manuscript is based on protocol version 3 (14 October 2016)

Experimental Research on Heterogeneous N2O Decomposition with Ash and Biomass Gasification Gas

In this paper, the promoting effects of ash and biomass gas reburning on N2O decomposition were investigated based on a fluidized bed reactor, with the assessment of the influence of O2 on N2O decomposition with circulating ashes. Experimental results show that different metal oxides contained in ash play distinct roles in the process of N2O decomposition with biomass gas reburning. Compared with other components in ash, CaO is proven to be very active and has the greatest promoting impact on N2O decomposition. It is also found that O2, even in small amounts, can weaken the promoting effect of ash on N2O decomposition by using biomass gas reburning

ESCAschool study: trial protocol of an adaptive treatment approach for school-age children with ADHD including two randomised trials

Abstract Background The ESCAschool study addresses the treatment of school-age children with attention-deficit/hyperactivity disorder (ADHD) in a large multicentre trial. It aims to investigate three interrelated topics: (i) Clinical guidelines often recommend a stepped care approach, including different treatment strategies for children with mild to moderate and severe ADHD symptoms, respectively. However, this approach has not yet been empirically validated. (ii) Behavioural interventions and neurofeedback have been shown to be effective, but the superiority of combined treatment approaches such as medication plus behaviour therapy or medication plus neurofeedback compared to medication alone remains questionable. (iii) Growing evidence indicates that telephone-assisted self-help interventions are effective in the treatment of ADHD. However, larger randomised controlled trials (RCTs) are lacking. This report presents the ESCAschool trial protocol. In an adaptive treatment design, two RCTs and additional observational treatment arms are considered. Methods The target sample size of ESCAschool is 521 children with ADHD. Based on their baseline ADHD symptom severity, the children will be assigned to one of two groups (mild to moderate symptom group and severe symptom group). The adaptive design includes two treatment phases (Step 1 and Step 2). According to clinical guidelines, different treatment protocols will be followed for the two severity groups. In the moderate group, the efficacy of telephone-assisted self-help for parents and teachers will be tested against waitlist control in Step 1 (RCT I). The severe group will receive pharmacotherapy combined with psychoeducation in Step 1. For both groups, treatment response will be determined after Step 1 treatment (no, partial or full response). In severe group children demonstrating partial response to medication, in Step 2, the efficacy of (1) counselling, (2) behaviour therapy and (3) neurofeedback will be tested (RCT II). All other treatment arms in Step 2 (severe group: no or full response; moderate group: no, partial or full response) are observational. Discussion The ESCAschool trial will provide evidence-based answers to several important questions for clinical practice following a stepped care approach. The adaptive study design will also provide new insights into the effects of additional treatments in children with partial response. Trial registration German Clinical Trials Register (DRKS) DRKS00008973 . Registered 18 December 2015

Stereotactic cisternal lavage in patients with aneurysmal subarachnoid hemorrhage with urokinase and nimodipine for the prevention of secondary brain injury (SPLASH): study protocol for a randomized controlled trial

Background!#!Delayed cerebral infarction (DCI) is a major cause of death and poor neurological outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). Direct intrathecal therapies with fibrinolytic and spasmolytic drugs have appeared promising in clinical trials. However, access to the subarachnoid space for intrathecal drug administration is an unsolved problem so far, especially in patients with endovascular aneurysm securing. We investigate a therapy protocol based on stereotactic catheter ventriculocisternostomy (STX-VCS), a new approach to overcome this problem. The primary objective of this study is to assess whether cisternal lavage with urokinase, nimodipine, and Ringer's solution administered via a stereotactically implanted catheter into the basal cisterns (= investigational treatment (IT)) is safe and improves neurological outcome in patients with aSAH.!##!Methods!#!This is a randomized, controlled, parallel-group, open-label phase II trial. Fifty-four patients with severe aSAH (WFNS grade ≥ 3) will be enrolled at one academic tertiary care center in Southern Germany. Patients will be randomized at a ratio of 1:1 to receive either standard of care only or standard of care plus the IT. The primary endpoint is the proportion of subjects with a favorable outcome on the Modified Rankin Scale (defined as mRS 0-3) at 6 months after aSAH. Further clinical and surrogate outcome parameters are defined as secondary endpoints.!##!Discussion!#!New approaches for the prevention and therapy of secondary brain injury in patients with aSAH are urgently needed. We propose this RCT to assess the clinical safety and efficacy of a novel therapy protocol for intrathecal administration of urokinase, nimodipine, and Ringer's solution.!##!Trial registration!#!Deutsches Register Klinischer Studien (German Clinical Trials Register), DRKS00015645 . Registered on 8 May 2019