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BACKGROUND Meningiomas are common intracranial neoplasms with female predominance and sharply rising incidence in the perimenopausal years. As they often express estrogen receptors, hormone replacement therapy (HRT) poses a theoretical risk inducing accelerated growth. Although HRT has been linked to slightly increased incidence, its actual effect on meningioma growth-rate had not been studied in a clinical population. AIM: We aimed to retrospectively compare tumor characteristics and grow-rates of incidental meningiomas of those with a ≥6-month history of estrogen-based HRT (e-HRT) before or during surveillance compared to those without (no-HRT). METHODS Forty females with e-HRT and 80 age-matched HRT-naïve females were identified from the NorthShore Incidental Meningioma Database. Tumor characteristics and diameters were analyzed on initial and all follow-up MRIs. Progression-free survival (PFS) was assessed. RESULTS Twenty-one patients completed e-HRT before, 10 started before and continued during, and 9 started e-HRT during surveillance. Patient and radiographic characteristics were similar between the groups (mean age 62y in both, parity; tumor calcification, T2W-intensity), whereas those with e-HRT had significantly lower body weight (68±16kg vs. 77±21kg; p=0.01) and tended to have longer follow-up (6.7±3.9yrs vs. 5.3±3.9yrs; p=0.07). Those with e-HRT had significantly smaller meningiomas (13±6mm vs. 16±9mm at diagnosis and 15±7mm vs. 19±11mm at end of follow-up; p=0.03 for both), and slower absolute grow-rates (0.5±0.8 vs 1.0±2.1mm/year; p=0.05) than those of no-HRT. Proportional growth-rate differences were not significant (3.3%/year vs. 5.4%/year p >0.05). Subgroup analyses showed no difference between vaginal vs. oral/subcutaneous/transdermal route e-HRT vs. no-HRT. PFS defined by RECIST1.1, RANO and clinical (new symptoms or treatment) criteria were 11.1, 6.6 and 14.7years in e-HRT versus 10.5, 5.4 and 11.4years in no-HRT. None of the differences were significant (log-rank p >0.1). CONCLUSIONS In this preliminary analysis, those with e-HRT had smaller tumors that grew slower, suggesting that e-HRT may be safe in incidental meningioma.

While recent years have witnessed a steady rise in the number of studies exploring transcranial direct current stimulation (tDCS) as a potential therapy for disorders of the central nervous system, there are to date no FDA approved clinical indications for this form of noninvasive neuromodulation. Successful development of tDCS as an approved therapy in the US and elsewhere will require the implementation of well designed, appropriately powered clinical trials, which, in turn, requires careful consideration of a variety of methodological factors. The choice of study design (e.g. between-subjects, within-subjects) is one the most fundamental decisions in designing a clinical trial. This choice is often influenced by the specific symptoms and natural histories of the disorders being investigated. Disease-related symptoms and disability may influence the design and execution of tDCS trials in other ways, for instance interfering with the ability of patients to participate in studies that involve frequent stimulation sessions in a research setting, or complicating the ability of patients to provide informed consent. Common medical co-morbidities may also influence the efficacy of tDCS as a therapy, either negatively by interfering with the effectiveness of brain stimulation, or positively by providing new treatment targets. The parameters being used to deliver tDCS including stimulation intensity, frequency, and duration, as well as electrode size, number, and location, also play a critical but only partially understood role in tDCS studies. Finally, the use of robust control conditions is an important concern in all clinical trials, including those involving tDCS. This chapter will review these issues as they pertain to the design of tDCS clinical trials, and will conclude with recommendations for the standardization of methods for tDCS clinical trial reporting.

Despite promising preliminary results in treating fibromyalgia (FM) pain, no neuromodulation technique has been adopted in clinical practice because of limited efficacy, low response rate, or poor tolerability. This phase II open-label trial aims to define a methodology for a clinically effective treatment of pain in FM by establishing treatment protocols and screening procedures to maximize efficacy and response rate. High-definition transcranial direct current stimulation (HD-tDCS) provides targeted subthreshold brain stimulation, combining tolerability with specificity. We aimed to establish the number of HD-tDCS sessions required to achieve a 50% FM pain reduction, and to characterize the biometrics of the response, including brain network activation pain scores of contact heat-evoked potentials. We report a clinically significant benefit of a 50% pain reduction in half (n = 7) of the patients (N = 14), with responders and nonresponders alike benefiting from a cumulative effect of treatment, reflected in significant pain reduction ( P = .035) as well as improved quality of life ( P = .001) over time. We also report an aggregate 6-week response rate of 50% of patients and estimate 15 as the median number of HD-tDCS sessions to reach clinically meaningful outcomes. The methodology for a pivotal FM neuromodulation clinical trial with individualized treatment is thus supported. Online Registration Registered in Clinicaltrials.gov under registry number NCT01842009. Perspective In this article, an optimized protocol for the treatment of fibromyalgia pain with targeted subthreshold brain stimulation using high-definition transcranial direct current stimulation is outlined.

This chapter provides an overview of safety assessment in clinical trials, including challenges for designing and reporting studies measuring safety. Adverse events are undesirable, unfavorable, harmful, and unexpected effects resulting from a normal dosage of drug, medication, therapy, or any other intervention such as surgery. Monitoring of adverse events is critical to the patient’s safety (i.e., human subject’s protection) and data integrity in clinical trials. Moreover, this chapter reviews the regulatory aspects related to adverse events in clinical trials. Finally it presents a case discussion in which an unexpected adverse effect is detected and investigators need to determine whether this event is or is not related to the intervention and define a plan of action.

Chapter 1 explores the history, ethical issues, and importance of regulations in clinical research. The history of clinical research is long and fascinating, starting from dietary therapy, such as legumes and lemons, and advancing to modern-day drugs and regulations. Advances in medical treatments today have been achieved because of the application of knowledge gained from experiments conducted hundreds of years ago. The rules and regulations were required to address unethical issues and the misuse of the clinical research. The chapter asserts that the development of clinical research regulations may still be under development in terms of optimizing safety and the use of future drugs and medical devices.

This chapter discusses the important aspect of changing trial aspects, including analyzing data, before formal completion of a trial. Interim analysis (or analyses before trial is finished) should be planned and described in the study protocol, before starting the trial, to ensure the potential penalties for doing such analyses do not invalidate trial results and/or satisfy ethical requirements. The chapter discusses reasons and methods to perform interim analysis. Based on the results from interim analysis, some adjustments in the trial should be required, including early termination. Although the main goal of adaptive design is to increase the success of clinical development, making the studies more efficient and more likely to demonstrate the effect of a treatment, the investigator needs to be careful when using these methods as they can also introduce other potential biases in the study.

Transcranial pulsed current stimulation (tPCS) is emerging as an option in the field of neuromodulation; however, little is known about its effects on cognition and behavior and its neurophysiological correlates as indexed by autonomic responses. Our aim was to identify the effects of tPCS on arithmetic processing and risk-taking behavior, and to further categorize physiological autonomic responses by heart rate variability (HRV) and electrodermal activity measurements before, during, and after exposure to task performance and stimulation. Thirty healthy volunteers were randomized to receive a single session of sham or active stimulation with a current intensity of 2 mA and a random frequency between 1 and 5 Hz. Our results showed that tPCS has a modest and specific effect on cognitive performance as indexed by the cognitive tasks chosen in this study. There was a modest effect of active tPCS only on performance facilitation on a complex-level mathematical task as compared to sham stimulation. On autonomic responses, we observed that HRV total power increased while LF/HF ratio decreased in the tPCS active group compared to sham. There were no group differences for adverse effects. Based on our results, we conclude that tPCS, in healthy subjects, has a modest and specific cognitive effect as shown by the facilitation of arithmetical processing on complex mathematical task. These effects are accompanied by modulation of the central autonomic network providing sympathetic-vagal balance during stressful conditions. Although behavioral results were modest, they contribute to the understanding of tPCS effects and cognitive enhancement., This research was supported in part by a grant from BrainGear Inc. LMQ appreciates the mentoring support offered by Dr. Lee Hadlington and Dr. Mark Scase from De Montfort University.

Fibromyalgia is a highly prevalent, debilitating disease, characterized by chronic widespread pain. The mechanisms underlying pain are not completely understood, but it is believed to be associated with important neuroplastic changes in pain-related neural circuits. Although the involvement of the pain matrix in fibromyalgia is well established, another area that has been found to play a role in the maintenance and treatment of chronic pain is the primary motor cortex (M1). Maladaptive plasticity of M1 is a common finding in patients with chronic pain and many studies in animal models and in human subjects have shown that modulation of the activity of this cortical area induces significant analgesic effects. Furthermore, studies in other chronic pain syndromes have found alterations in baseline characteristics of M1, including an increase in cortical excitability and an abnormally enhanced response to incoming sensory stimuli. Given these findings, we hypothesize that M1 is a major modulator of pain in fibromyalgia and therefore its baseline activity reflects this strong feedback between M1 and pain-related neural areas. However, the feedback loop between M1 and the pain matrix is not enough to decrease pain in fibromyalgia per se, thus increasing its modulatory effect by engaging this network through different behavioral and modulatory techniques is a potentially beneficial treatment for pain in fibromyalgia.

Solid organ transplantation has greatly improved survival in children with end-stage disease, becoming one of the main treatment options in this population. Nonetheless, there are significant challenges associated with validating and optimizing the effects of these interventions in clinical trials. Therefore, we reviewed the main issues related to conducting clinical transplantation research in children. We divided these challenges into three different categories: (i) challenges related to surgical techniques and anesthetic procedures, (ii) challenges related to post-transplant care and (iii) challenges specific to a particular population group and disease type. Some of the observed burdens for clinical research in this field are related to the limitations of conducting studies with a placebo or sham procedure, determining the standard of care for a control group, low prevalence of cases, ethical concerns related to use of a placebo control group and lack of generalizability from animal studies and clinical trials conducted in adult populations. To overcome some of these barriers, it is necessary to utilize alternative clinical trial designs, such as observational studies or non-inferiority trials, and to develop multicenter collaborations to increase the recruitment rate. In conclusion, the lack of robust data related to pediatric transplantation remains problematic, and further clinical trials are needed to develop more efficacious and safer treatments.