Clinical Research Group Research Articles

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology.

The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular, and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an "omics"-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical, and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer's disease. The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group "Alzheimer Precision Medicine" (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development toward breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND.

Treatment Design and Rationale for a Randomized Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for SCLC: PREMER Trial on Behalf of the Oncologic Group for the Study of Lung Cancer/Spanish Radiation Oncology Group-Radiation Oncology Clinical Research Group

BackgroundProphylactic cranial irradiation (PCI) is part of the usual treatment in most patients with small-cell lung cancer (SCLC) and response after treatment of the primary tumor. Clinical evidence suggests that radiation dose received by the hippocampus during whole brain radiotherapy might play a role in radiation-induced neurocognitive decline. Patients and MethodsThis study is a multicenter phase III trial (NCT02397733) randomizing SCLC patients after informed consent, to receive standard PCI treatment or PCI with hippocampus avoidance (PCI-HA) by using intensity modulated radiation therapy or volumetric modulated arc therapy. The primary objective is assessment of hippocampus-dependent memory functioning and safety after PCI with or without hippocampus sparing by the Free and Cued Selective Reminding Test. Secondary objectives are assessment of other neurotoxicity/quality of life, radiological brain abnormalities on magnetic resonance images, and evaluation of the incidence and location of brain metastases after PCI-HA compared with standard PCI. The originally planned sample size (n = 150) has been calculated to detect a 50% difference in the 3-month delayed recall score between the 2 treatment arms, with a statistical power of 80% (β = 20%) and a significance level of 5% (α = 5%), with a maximum loss to follow-up of 10%. ConclusionThis study is an important step in introducing a new therapeutic approach to patients with SCLC candidates for PCI.

Progress and Challenges in Frontotemporal Dementia Research: A 20-Year Review.

The landscape of frontotemporal dementia (FTD) has evolved remarkably in recent years and is barely recognizable from two decades ago. Knowledge of the clinical phenomenology, cognition, neuroimaging, genetics, pathology of the different subtypes of FTD, and their relations to other neurodegenerative conditions, has increased rapidly, due in part, to the growing interests into these neurodegenerative brain conditions. This article reviews the major advances in the field of FTD over the past 20 years, focusing primarily on the work of Frontier, the frontotemporal dementia clinical research group, based in Sydney, Australia. Topics covered include clinical presentations (cognition, behavior, neuroimaging), pathology, genetics, and disease progression, as well as interventions and carer directed research. This review demonstrates the improvement in diagnostic accuracy and capacity to provide advice on genetic risks, prognosis, and outcome. The next major challenge will be to capitalize on these research findings to develop effective disease modifying drugs, which are currently lacking.

Documenting Clinical Microbiology Impact: Basic Concepts for Designing Clinical Studies and Outcome Research Using Principles of Biostatistics

While most clinical laboratorians do not consider themselves part of a formal clinical research group, many quality improvement projects and method verification studies are, or should be, performed with the rigor of scientific research, even if the project intent is not research. When describing pilot results for business plans and for documenting laboratory impact for interdisciplinary committees, planning for scientific rigor will prove to be very valuable. Clinical, operational, and quality improvement studies in laboratory medicine and clinical microbiology are becoming more data driven, outcome oriented, and evidence based. This trend is expected to continue and to broaden in scope and complexity. As such, laboratory directors, managers, and staff will need to acquire advanced background in experimental study design and in biostatistical methods so they can play an active role in documenting the impact of the clinical microbiology laboratory on the larger health care system. This review translates the design concepts of patient-oriented and clinical research into practical guidelines that can be adapted and relevant to clinical microbiologists. This review focuses on types of experimental designs that may be useful for clinical microbiologists to ensure a successful project and to generate laboratory impact data.

Late normal tissue response in the rat spinal cord after carbon ion irradiation

BackgroundThe present work summarizes the research activities on radiation-induced late effects in the rat spinal cord carried out within the “clinical research group ion beam therapy” funded by the German Research Foundation (DFG, KFO 214).Methods and materialsDose–response curves for the endpoint radiation-induced myelopathy were determined at 6 different positions (LET 16–99 keV/μm) within a 6 cm spread-out Bragg peak using either 1, 2 or 6 fractions of carbon ions. Based on the tolerance dose TD50 of carbon ions and photons, the relative biological effectiveness (RBE) was determined and compared with predictions of the local effect model (LEM I and IV). Within a longitudinal magnetic resonance imaging (MRI)-based study the temporal development of radiation-induced changes in the spinal cord was characterized. To test the protective potential of the ACE (angiotensin converting enzyme)-inhibitor ramipril™, an additional dose–response experiment was performed.ResultsThe RBE-values increased with LET and the increase was found to be larger for smaller fractional doses. Benchmarking the RBE-values as predicted by LEM I and LEM IV with the measured data revealed that LEM IV is more accurate in the high-LET, while LEM I is more accurate in the low-LET region. Characterization of the temporal development of radiation-induced changes with MRI demonstrated a shorter latency time for carbon ions, reflected on the histological level by an increased vessel perforation after carbon ion as compared to photon irradiations. For the ACE-inhibitor ramipril™, a mitigative rather than protective effect was found.ConclusionsThis comprehensive study established a large and consistent RBE data base for late effects in the rat spinal cord after carbon ion irradiation which will be further extended in ongoing studies. Using MRI, an extensive characterization of the temporal development of radiation-induced alterations was obtained. The reduced latency time for carbon ions is expected to originate from a dynamic interaction of various complex pathological processes. A dominant observation after carbon ion irradiation was an increase in vessel perforation preferentially in the white matter. To enable a targeted pharmacological intervention more details of the molecular pathways, responsible for the development of radiation-induced myelopathy are required.

Efforts aimed at the qualitative improvements of pharmacists in emergency medicine and intensive care at clinical emergency medical pharmacy research group

Efforts aimed at the qualitative improvements of pharmacists in emergency medicine and intensive care at clinical emergency medical pharmacy research group

How are we managing fistulating perianal Crohn’s disease? Results of a national survey of consultant gastroenterologists

ObjectiveFistulating perianal Crohn’s disease represents a significant challenge to both clinicians and patients. This survey set out to describe current practice and variation in the medical management of this condition.DesignA...

Three-Dimensional Cross-Sectional Light-Sheet Microscopy Imaging of the Inflamed Mouse Gut

Three-Dimensional Cross-Sectional Light-Sheet Microscopy Imaging of the Inflamed Mouse Gut

ICORG 10-14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study (Neo-AEGIS)

BackgroundNeoadjuvant therapy is increasingly the standard of care in the management of locally advanced adenocarcinoma of the oesophagus and junction (AEG). In randomised controlled trials (RCTs), the MAGIC regimen of pre- and postoperative chemotherapy, and the CROSS regimen of preoperative chemotherapy combined with radiation, were superior to surgery only in RCTs that included AEG but were not powered on this cohort. No completed RCT has directly compared neoadjuvant or perioperative chemotherapy and neoadjuvant chemoradiation. The Neo-AEGIS trial, uniquely powered on AEG, and including comprehensive modern staging, compares both these regimens.MethodsThis open label, multicentre, phase III RCT randomises patients (cT2-3, N0-3, M0) in a 1:1 fashion to receive CROSS protocol (Carboplatin and Paclitaxel with concurrent radiotherapy, 41.4Gy/23Fr, over 5 weeks). The power calculation is a 10% difference in favour of CROSS, powered at 80%, two-sided alpha level of 0.05, requiring 540 patients to be evaluable, 594 to be recruited if a 10% dropout is included (297 in each group). The primary endpoint is overall survival, with a minimum 3-year follow up. Secondary endpoints include: disease free survival, recurrence rates, clinical and pathological response rates, toxicities of induction regimens, post-operative pathology and tumour regression grade, operative in-hospital complications, and health-related quality of life. The trial also affords opportunities for establishing a bio-resource of pre-treatment and resected tumour, and translational research.DiscussionThis RCT directly compares two established treatment regimens, and addresses whether radiation therapy positively impacts on overall survival compared with a standard perioperative chemotherapy regimen Sponsor: Irish Clinical Research Group (ICORG).Trial registrationNCT01726452. Protocol 10-14. Date of registration 06/11/2012.

Évaluation des pratiques dans la prise en charge de la gale chez les enfants

Scabies has been on the rise in France in recent years and has posed therapeutic problems, mainly due to the withdrawal of benzyl benzoate. The objective of this study was to describe prescribing practices for scabies in children. A national survey was conducted by means of a standardized questionnaire covering various clinical situations of scabies and the drugs used preferentially according to age, which was sent out between December 2014 and March 2015 to members of the clinical research group of the French Society of Paediatric Dermatology. Of the 38 experts contacted, 20 replied. For a typical case of scabies, 55% of the experts initially prescribed oral ivermectin for children aged 6 years, 15% prescribed ivermectin in children aged 2 years, and 5% in infants aged 3 months. Ivermectin was more widely prescribed after failure of prior treatment or recurrence of scabies, on skin lesions or impetigo, if precarious, especially for profuse hyperkeratotic scabies. A total of 35% of the experts reported no prescribing restrictions with regard to patient age or weight. Discrepancies were observed concerning the mode of administration and the time between consecutive doses. Esdepallethrin remained the preferred local treatment among the experts (38% of all topical prescriptions) except in asthmatic children, while permethrin was the least-prescribed topical agent. This study confirms the heterogeneity of our practices. Formal expert recommendations are awaited, particularly concerning the use of ivermectin in infants.

M59 - POLYGENIC BURDEN ANALYSIS OF LONGITUDINAL CLUSTERS OF QUALITY OF LIFE AND FUNCTIONING IN PATIENTS WITH SEVERE MENTAL ILLNESS

Background Psychiatric illnesses such as bipolar disorder, schizophrenia and schizoaffective disorder are severe, disabling disorders associated with decreased quality of life (QOL) and functioning (Bobes, Garcia-Portilla, Bascaran, Saiz, & Bousono, 2007; Latalova, Prasko, Diveky, Kamaradova, & Velartova, 2010; Merikangas et al., 2012). Stigmatization, co-morbidities, adverse effects of medications, care models with deficits in personal and social recovery needs and chronic symptoms due to treatment resistance are factors that can lead to severe reductions in quality of life and functioning (Kahn et al., 2015; Sum, Ho, & Sim, 2015). In this study we aim to characterize patients with good and poor outcomes according to QOL and functioning scores. Using cluster analysis, we sought to identify longitudinal trajectories and investigate whether levels of QOL and functioning are associated with polygenic risk scores. Determining clusters of patients at higher risk of poorer outcomes is critical to provide early and effective interventions. Methods Longitudinal data was used from the Clinical Research Group 241 and PsyCourse studies in Germany. Participants were phenotyped using a comprehensive battery which included data on socio-demographics, history of illness, symptomatology, QOL and functioning. Data was collected at four equidistant time points over an 18-month period. The Infinium Psycharray from Illumina was used to genotype patients. Relevant questionnaire items (i.e. QOL, functioning scores, and socio-demographic data) were pre-selected and factor analysis for mixed data was applied to identify trends in the data. This allowed for the computation of abstract data dimensions which were used for calculation of longitudinal trajectories. These trajectories can be seen as a representation of the overall status of patients and both the overall level as well as the longitudinal change of this status were used as inputs for a k-mean clustering for longitudinal data (Genolini et al., 2013). This, in turn, resulted in the identification of three distinct subpopulations of patients. In a linear regression model we used clusters as predictive variables for polygenic risk scores at 11 thresholds. Results The dimension which explained the most variance was used for cluster analysis. This dimension was mainly driven by scores for self-satisfaction, life enjoyment, ability to cope with daily tasks, energy, and quality of life. In a sample of 198 patients, three clusters were observed; cluster A (39,4%) consisted of participants with the highest average scores for functioning and QOL, cluster B (33,8%) including participants with the lowest average scores for functioning and QOL, and cluster C (26,8%) consisting of participants who had great improvement in functioning and QOL scores over the course of the longitudinal study. Male patients were substantially overrepresented in cluster A and the inverse effect was observed in cluster B. No significant differences were seen for age of onset, age at interview, or duration of illness within the clusters. Polygenic risk scores at certain thresholds can be predicted by the clusters. In cluster B there was a trend for higher polygenic risk scores. Discussion Phenotypic data provide insight to target sufferers of severe mental illness with worse outcomes. Levels of functioning and QOL seem to be associated with polygenic risk scores. Further investigations are needed.

Clinical trial network for the promotion of clinical research for rare diseases in Japan: muscular dystrophy clinical trial network.

BackgroundDuchenne muscular dystrophy (DMD) is the most commonly inherited neuromuscular disease. Therapeutic agents for the treatment of rare disease, namely “orphan drugs”, have recently drawn the attention of researchers and pharmaceutical companies. To ensure the successful conduction of clinical trials to evaluate novel treatments for patients with rare diseases, an appropriate infrastructure is needed. One of the effective solutions for the lack of infrastructure is to establish a network of rare diseases.MethodsTo accomplish the conduction of clinical trials in Japan, the Muscular dystrophy clinical trial network (MDCTN) was established by the clinical research group for muscular dystrophy, including the National Center of Neurology and Psychiatry, as well as national and university hospitals, all which have a long-standing history of research cooperation.ResultsThirty-one medical institutions (17 national hospital organizations, 10 university hospitals, 1 national center, 2 public hospitals, and 1 private hospital) belong to this network and collaborate to facilitate clinical trials. The Care and Treatment Site Registry (CTSR) calculates and reports the proportion of patients with neuromuscular diseases in the cooperating sites. In total, there are 5,589 patients with neuromuscular diseases in Japan and the proportion of patients with each disease is as follows: DMD, 29 %; myotonic dystrophy type 1, 23 %; limb girdle muscular dystrophy, 11 %; Becker muscular dystrophy, 10 %. We work jointly to share updated health care information and standardized evaluations of clinical outcomes as well. The collaboration with the patient registry (CTSR), allows the MDCTN to recruit DMD participants with specific mutations and conditions, in a remarkably short period of time.ConclusionCounting with a network that operates at a national level is important to address the corresponding national issues. Thus, our network will be able to contribute with international research activity, which can lead to an improvement of neuromuscular disease treatment in Japan.

Editorial introductions

Editorial introductions

163 Historical trends in high-risk prostate cancer patients characteristics: A 27 years old observational study from the European multicenter prostate cancer clinical and translational research group (EMPaCT) data base

163 Historical trends in high-risk prostate cancer patients characteristics: A 27 years old observational study from the European multicenter prostate cancer clinical and translational research group (EMPaCT) data base

Identification and treatment of tobacco dependence among young people in residential homes during the statutory annual health assessment: a retrospective case-note review

BackgroundRates of tobacco smoking are substantially higher among young people accommodated in residential homes than in the general youth population. Public health guidance from the National Institute for Health and Care Excellence (NICE) recommends that all smokers should be identified, advised to quit, and offered treatment for tobacco dependence during health-care consultations. Opportunities to address tobacco dependence are available for young people in residential care through the annual statutory health review assessment (HRA). However, little is known about the extent to which HRA is used to address tobacco dependence among this population. We aimed to assess smoking-related recording and clinical practice during the HRA. MethodsA retrospective review of the statutory health assessment forms of all young people accommodated in residential homes by an English local authority in the East Midlands between June 1, 2013, and May 31, 2014, was conducted. Practice was assessed with standards developed from statutory and NICE guidance relating the recording of smoking-related information during annual health assessments. Descriptive statistics were used to summarise the characteristics of the young people and the level of smoking-related recording. Associations between categorical variables were analysed with χ2 tests, and one-way ANOVA was used to assess continuous data. Ethics approval was provided by the Families, Young People & Children Clinical Audit, Standards, Effectiveness and Research Group of Leicestershire Partnership NHS Foundation Trust, and data were accessed under Section 251 of the NHS Act. Findings31 young people were included in the review, of whom 30 (97%) had completed a statutory HRA. Inquiries about smoking were made in 23 (77%) instances. 12 (52%) of those who had participated in the HRA and who were asked about smoking were identified as smokers. Nine (75%) of these smokers engaged in discussions about their smoking and were offered treatment for tobacco dependence: two (22%) accepted a referral for treatment. The reasons for declining support for smoking cessation were documented in two (17%) cases. InterpretationOpportunities to address tobacco dependence among young people in residential homes are being missed during the HRA. Further research should explore clinician practice and attitudes to addressing tobacco dependence during the HRA and the perceptions of these young people in relation to receiving smoking cessation advice and the treatment offered. FundingThis study was funded by a UK Centre for Tobacco and Alcohol Studies PhD studentship.

Venomous snake bites: clinical diagnosis and treatment.

Snake bites are life-threatening injuries that can require intensive care. The diagnosis and treatment of venomous snake bites is sometimes difficult for clinicians because sufficient information has not been provided in clinical practice. Here we review the literature to present the proper management of bites by mamushi, habu, and yamakagashi snakes, which widely inhabit Japan and other Asian countries. No definite diagnostic markers or kits are available for clinical practice; therefore, definitive diagnosis of snake-venom poisoning requires positive identification of the snake and observation of the clinical manifestations of envenomation. Mamushi (Gloydius blomhoffii) bites cause swelling and pain that spreads gradually from the bite site. The platelet count gradually decreases due to the platelet aggregation activity of the venom and can decrease to <100,000/mm3. If the venom gets directly injected into the blood vessel, the platelet count rapidly decreases to <10,000/mm3 within 1 h after the bite. Habu (Protobothrops flavoviridis) bites result in swelling within 30 min. Severe cases manifest not only local signs but also general symptoms such as vomiting, cyanosis, loss of consciousness, and hypotension. Yamakagashi (Rhabdophis tigrinus) bites induce life-threatening hemorrhagic symptoms and severe disseminated intravascular coagulation with a fibrinolytic phenotype, resulting in hypofibrinogenemia and increased levels of fibrinogen degradation products. Previously recommended first-aid measures such as tourniquets, incision, and suction are strongly discouraged. Once airway, breathing, and circulation have been established, a rapid, detailed history should be obtained. If a snake bite is suspected, hospital admission should be considered for further follow-up. All venomous snake bites can be effectively treated with antivenom. Side effects of antivenom should be prevented by sufficient preparation. Approved antivenoms for mamushi and habu are available. Yamakagashi antivenom is used as an off-label drug in Japan, requiring clinicians to join a clinical research group for its use in clinical practice.

Barriers and opportunities for enhancing patient recruitment and retention in clinical research: findings from an interview study in an NHS academic health science centre.

BackgroundIn the UK, the recruitment of patients into clinical research is a national health research and development policy priority. There has been limited investigation of how national level factors operate as barriers or facilitators to recruitment work, particularly from the perspective of staff undertaking patient recruitment work. The aim of this study is to identify and examine staff views of the key organisational barriers and facilitators to patient recruitment work in one clinical research group located in an NHS Academic Health Science Centre.MethodsA qualitative study utilizing in-depth, one-to-one semi-structured interviews with 11 purposively selected staff with particular responsibilities to recruit and retain patients as clinical research subjects. Thematic analysis classified interview data by recurring themes, concepts, and emergent categories for the purposes of establishing explanatory accounts.ResultsThe findings highlight four key factors that staff perceived to be most significant for the successful recruitment and retention of patients in research and identify how staff located these factors within patients, studies, the research centre, the trust, and beyond the trust. Firstly, competition for research participants at an organisational and national level was perceived to undermine recruitment success. Secondly, the tension between clinical and clinical research workloads was seen to interrupt patient recruitment into studies, despite national funding arrangements to manage excess treatment costs. Thirdly, staff perceived an imbalance between personal patient burden and benefit. Ethical committee regulation, designed to protect patients, was perceived by some staff to detract from clarification and systematisation of incentivisation strategies. Finally, the structure and relationships within clinical research teams, in particular the low tacit status of recruitment skills, was seen as influential.ConclusionsThe results of this case-study, conducted in an exemplary NHS academic research centre, highlight current systematic challenges to patient recruitment and retention in clinical studies more generally as seen from the perspective of staff at the 'sharp end’ of recruiting. Staff experience is that, beyond individual clinical research design and protocol factors, wider organisational and extra-organisational norms, structures, and processes operate as significant facilitators or hindrances in the recruitment of patients as research subjects.

Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr.

Four individuals stand out as pioneers of the early work that led to levodopa becoming a revolutionary new treatment for Parkinson's disease: Arvid Carlsson, Oleh Hornykiewicz, George C. Cotzias, and Melvin D. Yahr. All four were MDs. The first three had extra training in pharmacology, and in fact did their research in pharmacology. The fourth was a clinical neurologist, the only one in this group with those credentials. The story starts with Carlsson, who became interested in studying the mechanism of reserpine's sedative effect, now recognized as a drug-induced parkinsonian state. A key experiment in 1957 showed that levodopa (l-dopa) could alleviate the immobility induced by reserpine in animals. Carlsson then showed that reserpine depleted brain dopamine, and that l-dopa restored it. Carlsson developed a sensitive fluorescent technique to measure dopamine levels, and his laboratory also showed the distribution of dopamine in animal brain to be highest in the striatum. Within a year, Carlsson postulated that dopamine appears to play a role in motor function. His proposal that dopamine serves as a neurotransmitter in brain was met with much skepticism, but he persisted and continued to study brain dopamine, eventually leading to being awarded the Nobel Prize in Medicine in 2000. Hornykiewicz also went into pharmacology research after graduating from medical school. Fortuitously, his assigned first project was on the blood pressure effects of dopamine, recognized as a precursor of norepinephrine. When he completed his postdoctoral studies, Carlsson's work on the reserpinized animal and on the regional distribution of brain dopamine was published. This inspired Hornykiewicz to determine dopamine levels in patients with Parkinson's disease. He obtained postmortem material, and his 1960 paper showed a marked depletion of dopamine in the striatum in this disorder. He went on in subsequent papers to correlate severity of parkinsonian features with the amount of striatal dopamine depletion. In the meantime, after his discovery of low dopamine in brains of patients with Parkinson's disease, Hornykiewicz persuaded Walther Birkmayer to inject l-dopa into patients. They reported success and continued this treatment, usually combining it with the use of a monoamine oxidase inhibitor. However, the response was limited in duration, and subsequent trials by others were not achieving similar success, and many failed to find any benefit. The fulfilment of the l-dopa story stemmed from the hypothesis held by Cotzias that Parkinson's disease was caused by loss of brain neuromelanin in the substantia nigra. Although Cotzias's research had been in pharmacology, he also headed a clinical pharmacology research group at a federal laboratory on Long Island, New York, USA. He decided to try to restore this pigment in patients, not animals, and one of the three drugs he tried was d,l-dopa. As reported in his 1967 article, d,l-dopa proved to be dramatically successful in reversing the symptoms, but at extremely high dosages and with considerable hematologic adverse effects. Cotzias immediately tested l-dopa and found the same benefit with half the dosage and without the hematologic problems. Yahr was a clinical neurologist who had been treating patients with PD with available therapy and also headed a federally financed research group investigating the disorder. Always on the lookout for potential new treatments, he was initially skeptical about l-dopa when studies with low doses were being reported. Seeing videos of patients presented by Cotzias, however, he realized that the results needed confirmation through a double-blind controlled clinical trial. He proceeded to develop and execute such a trial with l-dopa, duplicating Cotzias's success. Both Cotzias and Yahr had encountered motor fluctuations and dyskinesias, but the amelioration of bradykinesia, rigidity, and tremor was so pronounced that these adverse effects did not prevent regulatory approval of l-dopa, and almost 50 years later l-dopa remains the most effective pharmacologic agent for treating Parkinson's disease. This article relates the personal stories of these four pioneers and how they achieved their success.

Clinical trials in lung cancer surgery and research cooperation.

With China having an increasingly huge burden of lung cancers, the number of Chinese studies was the second largest all over the world. We used the advanced search option available on the ClinicalTrials.gov to review clinical trials regarding surgical issues. In the drop down menus, we chose "all studies" for recruitment status and "interventional" for study type and all trials reported until Aug, 2013 on the website were included. Clinical trials on lung cancer surgeries (658 records) mainly aim at surgical procedures and (neo)adjuvant clinical studies, among which phase III trials account for 15.5%. Only 34.9% (230 records) trials were completed, and 43 studies presented their results on ClinicalTrials.gov. The median time to completion (MTC) of phase III surgical procedure trials is 9.4 years. The MTCs of phase III neo-adjuvant and adjuvant trials have not been reached, but definitely are longer than 10 years. In comparison, the MTC of phase III trials in the first-line treatment are only 4.3 years. We summarized the characteristics of these trials using real-world case examples. Our analyses reveal that it is critically needed for regulatory authorities, clinical trial sponsors, collaborative research groups, and academic institutions to work together to build up the infrastructure and research cooperation for clinical trials with a surgical component. In 2007, a national collaborative clinical research group, Chinese Thoracic Oncology Group (CTONG), was established. CTONG is a network of researchers, physicians and health-care professionals in public institutions throughout China and currently has a growing membership of 25 hospitals. A CTONG-sponsored trial (CTONG1104) is discussed to illustrate our experience in surgical clinical trials. In summary, it is imperative for investigators to collaborate in cooperative clinical trials in order to expedite applications of therapies from clinical researches to cancer treatment. Since cancer treatment is multidisciplinary, current surgical trials should have multiple treatment combinations while retaining a surgical focus, and be carried out systematically with the cooperation of extensive monitoring and coordinating systems.

Persistent post-surgical pain (PPP) reduced by high-quality management of acute pain extended to sub-acute pain at home

The high risk of long-lasting new pain after surgery – persistent ost-surgical pain (PPP) [1] can be reduced by extending highuality acute pain management to the early days and weeks at ome followingdischarge fromhospital [2]. In this issueof the Scaninavian Journal of Pain Elina Tiippana and her co-workers in Eija also’s eminent clinical pain research group in Helsinki, confirm his important observation [3].